HK40087938A - Heterocyclic modulators of lipid synthesis - Google Patents

Description

Heterocyclic regulators of lipid synthesis

This application is a divisional application of the invention application filed on November 13, 2017, with Chinese application number 201780083446.7 and invention title "Heterocyclic Regulator of Lipid Synthesis".

Related applications

This application claims priority and interest in the following cases: U.S. Provisional Application No. 62/574,497, filed October 19, 2017; and U.S. Application No. 15/349,960, filed November 11, 2016, which is a partial continuation of U.S. Application No. 14/874,961, filed October 5, 2015; which is a continuation of U.S. Application No. 14/315,133, filed June 25, 2014, which has been abandoned; and which is a continuation of U.S. Application No. 14/315,133, filed March 8, 2012. The application filed on [date] is a continuation of U.S. Application No. 13/415,660, now U.S. Patent No. 8,871,790. U.S. Application No. 13/415,660 and now U.S. Patent No. 8,871,790 claim the interests of previously filed Provisional Applications No. 61/450,561 (filed March 8, 2011), No. 61/508,611 (filed July 16, 2011), and No. 61/585,642 (filed January 11, 2012), and is a partial continuation of U.S. Application No. 15/201,824 (filed July 5, 2016). US Patent Application No. 15/201,824 is a divisional of U.S. Application No. 14/587,908, now U.S. Patent No. 9,428,502, filed on December 31, 2014. U.S. Application No. 14/587,908, now U.S. Patent No. 9,428,502, is a continuation of PCT/US2013/048950, filed on July 1, 2013. PCT/US2013/048950 requests the earlier filed U.S. Provisional Application No. 61/667,894, filed on July 3, 2012, and U.S. Provisional Application No. 61/698,511, filed on September 7, 2012. The rights to U.S. Provisional Application 61/699,819, filed September 11, 2012, and U.S. Provisional Application 61/785,933, filed March 14, 2013, and a partial continuation of U.S. Application 15/110,154, filed July 7, 2016. U.S. Application 15/110,154 is a U.S. national phase application filed under Section 371 of the United States Code, PCT/US2015/010459, filed January 7, 2015, which claims the rights to the earlier filed U.S. Provisional Application 61/924,520, filed January 7, 2014.

The entire contents of each of these applications are incorporated hereby by reference for all purposes.

Technical Field

This disclosure generally relates to heterocyclic regulators of lipid synthesis and methods of using them. The heterocyclic regulators of lipid synthesis disclosed herein can be used to treat conditions in subjects characterized by fatty acid synthase dysfunction by modulating the fatty acid synthase pathway and/or fatty acid synthase function.

Background Technology

Viral diseases pose a significant health threat to a large portion of the population. Some characteristics associated with viral infections that are of concern to healthcare professionals include their high transmissibility (e.g., HIV, SARS) and high mutability. Some viruses are also carcinogenic (such as HPV, EBV, and HBV). Although viruses are among the simplest organisms in structure, they are considered the most difficult to control and present a significant challenge to the development of antiviral drugs.

To date, only a few antiviral drugs have been widely used in patients, such as amantadine and oseltamivir for influenza; acyclovir for HSV-related infections; ganciclovir for CMV infections; and various agents for the treatment of AIDS, including co-blended drugs (efavirenz, emtricitabine, and tonfovir disoproxilfumarate). These drugs have a variety of adverse neurological, metabolic, and immunological side effects. Therefore, the development of new antiviral therapies has become a major focus of medical and pharmaceutical research and development.

Hepatitis C virus (HCV) infection is a serious health problem. It is estimated that 170 million people worldwide are chronically infected with HCV. HCV infection can lead to chronic hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. Chronic HCV infection is therefore a leading cause of premature liver-related death worldwide.

Current standard of care for HCV infection involves a combination therapy of interferon-alpha and ribavirin, often with the addition of a direct-acting protease inhibitor (terapivvir or boprevir). Treatment is cumbersome and sometimes has debilitating and severe side effects. Consequently, many patients do not receive treatment in the early stages of the disease. Furthermore, some patient groups do not respond to treatment sustainably. There is an urgent need for novel and effective treatments for HCV infection.

Current main treatments for cancer include surgical removal of the primary tumor, tumor irradiation, and non-enteric administration of anti-mitotic cytotoxic agents. Unfortunately, only a relatively small percentage of cancer patients have tumors that are "addicted" to specific pathways and are therefore available for treatment with newer targeted agents. Survival rates for the majority of cancer patients have not improved, reflecting the continued dominance of these long-established therapies. In addition to limited clinical success rates, traditional therapies are accompanied by devastating side effects. Both radiation-based and cytotoxic therapies damage rapidly dividing hematopoietic cells and intestinal epithelial cells, leading to impaired immune function, anemia, and reduced nutrient absorption. Surgical interventions often result in the release of tumor cells into the circulation or lymphatic system, from which metastatic tumors can subsequently form. Improved cancer treatments are needed.

Nonalcoholic liver disease (NAFLD) is a condition in which the liver contains more than 5% fat by weight and is not caused by alcohol consumption. It currently affects approximately 20-30% of the total population in the United States and the Western world, and is associated with a significantly increased risk of developing cardiovascular disease (i.e., carotid atherosclerotic plaques and endothelial dysfunction), chronic kidney disease, and malignant diseases. Obesity and metabolic syndrome are two key risk factors for NAFLD, characterized by an imbalance between energy utilization and storage. This imbalance leads to metabolic pathway dysregulation and inflammatory responses, resulting in other changes that cause liver damage and comorbidities. As metabolic syndrome progresses, NAFLD leads to more advanced liver disease, starting with nonalcoholic steatohepatitis (NASH) and then progressing to severe liver diseases, including cirrhosis and hepatocellular carcinoma.

In subjects with metabolic syndrome and NAFLD, fatty acid synthesis in the liver (a pathway known as de novo lipogenesis (DNL)) was increased (Donnelly, K.L. et al., “Sources of Fatty Acids Stored in Liver and Secreted via Lipoproteins in Patients with Nonalcoholic Fatty Liver Disease,” J. Clin. Invest. 115(5). 2005, 1343-51; Lambert, J.E. et al., “Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals with Nonalcoholic Fatty Liver Disease,” Ygast 146(3). 2014, 726-35). The DNL pathway not only produces fatty acids that increase triglyceride liver reserves, but also produces saturated fatty acids, mainly palmitic acid, which contributes to signaling events that enhance liver inflammation (Wei, Y., “Saturated Fatty Acids Induce Endoplasmic Reticulum Stress and Apoptosis Independently of Ceramide in Liver Cells,” Am. J. Physio. Endocrinol. Metab. 291(2): 2006, E275-81; Kakazu, E. et al., “Hepatocytes Release Ceramide-rich Proinflammatory Extracellular Vesicles in an IRE 1alpha-dependent manner,” Abstract 58. AASLD-The Liver Meeting, San Francisco, CA, USA, 13-17, November 2015). One of the key enzymes in the DNL pathway is fatty acid synthase (FASN), which is solely responsible for synthesizing palmitic acid. Therefore, DNL is an important therapeutic intervention pathway that can reduce the consequences associated with metabolic syndrome and NAFLD.

Inhibiting FASNs has the potential to be a treatment for a variety of diseases, including cancer, viral diseases, metabolic diseases, NAFLD, NASH, and inflammatory diseases (i.e., rheumatoid arthritis, gout, pulmonary fibrosis, COPD, IBD, and graft rejection). Additionally, FASN inhibition may offer therapeutic benefits in cardiovascular diseases, type 2 diabetes, and metabolic syndrome. Successful treatment of these diseases remains a pressing need. While treatments exist for diabetes and cardiovascular diseases, there are currently no approved drugs for treating metabolic syndrome, NAFLD, or NASH. Therefore, novel and effective small-molecule FASN inhibitors are needed to treat these diseases.

Summary of the Invention

This disclosure addresses the shortcomings of antiviral and anticancer therapies by providing novel heterocyclic regulators of lipid synthesis with improved antiviral and anticancer activities.

In several respects, this disclosure provides compounds of structure (I) or pharmaceutically acceptable salts thereof:

in:

X, Y and Z are each independently CR or NR′, where R is hydrogen or _C1-6 alkyl and R′ is hydrogen, _C1-6 alkyl or absent;

A is CH or N;

R1 can be hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _{2R20 , R4} and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl or alkylamino;

_R17 and _R18 are each independently hydrogen or alkyl, or may optionally be bonded together to form a bond;

n is 1 or 2; and

m is 0 or 1.

In several respects, this disclosure provides compounds of structure (II) or pharmaceutically acceptable salts thereof:

in:

X, Y, and Z are each independently CR or NR′, where R is hydrogen or _C1-6 alkyl and R′ is hydrogen, _C1-6 alkyl, or absent;

L and D are each independently C or N;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _{2R20 , R4} and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl or alkylamino;

_R17 and _R18 are each independently hydrogen or alkyl, or may optionally be bonded together to form a bond;

n is 1 or 2; and

m is 0 or 1.

In several respects, this disclosure provides compounds of structure (III) or pharmaceutically acceptable salts thereof:

in:

X, Y and Z are each independently CR or NR′, where R is hydrogen or _C1-6 alkyl and R1 is hydrogen, _C1-6 alkyl or absent;

Q is either C or N;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or if Q is N, then _R3 does not exist;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _{2R20 , R4} and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl or alkylamino;

_R17 and _R18 are each independently hydrogen or alkyl, or may optionally be bonded together to form a bond;

R ₁₉ is aryl, heteroaryl, cycloalkyl, or heterocyclic;

n is 0, 1, or 2; and

m is 0 or 1.

In several respects, this disclosure provides compounds of the (IV-A), (IV-B), or (IV-C) structure or pharmaceutically acceptable salts thereof:

in:

_L1 , _L2 , _L3 , _L4 and A are each independently CH or N;

R1 can be hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(O) _{2R20 ;}

_R23 is hydrogen, -N( _R13 )( _R14 ), _C1-6 alkyl, _C1-6 alkoxy. If _L1 is N, then _R23 is absent, or _R23 and _R24 together with the atoms they are attached to are bonded together to form a heterocyclic group, heteroaryl group or cycloalkyl group.

R ₂₄ is hydrogen, -N(R ₁₃ )(R ₁₄ ), C _1-6 alkyl, C _1-6 alkoxy, -(C _1-6 alkoxy)(heterocyclic), heterocyclic, or R ₂₃ and R ₂₄ together with the atoms they are attached to form a heterocyclic, heteroaryl, or cycloalkyl group.

R ₂₆ is hydrogen, heteroaryl, heterocyclic, -N(R ₁₃ )(R ₁₄ ) or -S(＝O) _{2R 20} ;

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

R ₂₅ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy; and

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

In several respects, this disclosure provides compounds of structure (V) or pharmaceutically acceptable salts thereof:

in:

_L7 is either N or O, where if _L7 is O, then _R30 does not exist;

A is CH or N;

R1 can be hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is a halogen, a _C1-6 alkyl group, or a _C1-6 alkoxy group;

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₂₉ and R ₃₀ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxyalkyl, heteroaryl, heterocyclic, -N(R ₁₅ R ₁₆ ), -C(=O)R ₄₆ , -R _48C (=O)R ₄₇ , or R ₂₉ and R ₃₀ together with the atoms they are attached to form a heteroaryl or heterocyclic group, wherein if L ₇ is O, then R ₃₀ is not present;

R ₄₆ and R ₄₇ are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, -N (R ₁₅ R ₁₆ ) or -S (=O) ₂ R ₂₀ ;

R ₄₈ is an alkyl group or is absent;

R ₃₁ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy;

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino; and

v is 0 or 1.

In several respects, this disclosure provides compounds of structure (VI-A) or (VI-B) or pharmaceutically acceptable salts thereof:

in:

_L13 , _L14 , _L15 and A are each independently CH or N;

R1 can be hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is a halogen, a _C1-6 alkyl group, or a _C1-6 alkoxy group;

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₃₄ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, cycloalkyl, hydroxyl, hydroxyalkyl, aryl, heterocyclic, heteroaryl, alkylamino, CF ₃ , -OCF ₃ , -S(=O) _{2R 20} or -N (R ₁₅ R ₁₆ );

R ₃₅ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy;

R ₃₆ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, -N (R ₁₅ R ₁₆ ), heterocyclic or heteroaryl;

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ; and

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

In several respects, this disclosure provides compounds of structure (VI-J) or pharmaceutically acceptable salts thereof:

in:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azircyclobutane-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group.

In some aspects of the structure (VI-J), ^R3 is H or a halogen.

In some aspects of the structure (VI-J), ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some aspects of the structure (VI-J), ^R22 is a _C1 - _C2 alkyl group.

In some aspects of the structure (VI-J), ^R21 is cyclobutyl and ^R22 is _C1 - _C2 alkyl.

In some aspects of the structure (VI-J), R ²¹ is cyclobutyl.

In some aspects of the structure (VI-J), R ³ is H or F.

In some aspects of the structure (VI-J), ^R1 is -CN.

In some aspects of the structure (VI-J), ^R1 is _-CF3 .

In some aspects of the structure (VI-J), R ²² is H, methyl, or ethyl.

In some aspects of the structure (VI-J), R ²² is H.

In some aspects of the structure (VI-J), R ²² is methyl.

In some aspects of the structure (VI-J), R ³⁵ is -C(O)-NHR ³⁵¹ .

In some aspects of the structure (VI-J), R ³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of the structure (VI-J), R ³⁵¹ is (R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

In some aspects of the structure (VI-J), ^R1 is -CN, each of ^R2 is hydrogen, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is H, and ^R35 is -C(O)-NHR ³⁵¹ , wherein ^R351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of the structure (VI-J), R ³⁵ is -C(O)-OR ³⁵¹ .

In some aspects of the structure (VI-J), R ³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of the structure (VI-J), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is H, and ^R35 is -C(O)-OR ³⁵¹ , wherein ^R351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of the structure (VI-J), R ³⁵¹ is (R)-3-tetrahydrofuranyl or (S)-3-tetrahydrofuranyl.

In some aspects of the structure (VI-J), the compound has a structure selected from the following:

In several respects, this disclosure provides compounds of structure (VII-A) or (VII-B) or pharmaceutically acceptable salts thereof:

in:

_L16 is C or N, where if _L16 is N, then _R41 does not exist;

_L17 , _L18 and A are each independently CH or N;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₄₀ , R ₄₂ and R ₄₃ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, -S(=O) _{2R 20} , -C(=O)R, hydroxyalkyl, hydroxyl, -N (R ₁₃ R ₁₄ ), or R ₄₁ and R ₄₂ together with the atoms they are attached to form a heteroaryl or heterocyclic group;

R ₄₁ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, -S(=O) _{2R 20} , -C(=O)R, hydroxyalkyl, hydroxyl, -N (R ₁₃ R ₁₄ ). If L ₁₆ is N, then R ₄₁ is absent, or R ₄₁ and R ₄₂ together with the atoms they are attached to form a heteroaryl or heterocyclic group.

R is hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

R ₃₉ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy;

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ; and

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

In several respects, this disclosure provides compounds of structure (VIII-A), (VIII-B) or (VIII-C) or pharmaceutically acceptable salts thereof:

in:

L ₁₉ and A are each independently CH or N;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₃₉ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy;

R ₄₄ and R ₄₅ are each independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, cycloalkyl, hydroxyalkyl, aryl, heterocyclic, heteroaryl, alkylamino, -S(=O) _2R20 , -C(=O)R, or _-N ( _R13R14 ); _and

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ; and

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

In several respects, compounds of structure (IX) or pharmaceutically acceptable salts thereof are provided:

in:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot ( _C3 - _C5 cycloalkyl), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group.

In some aspects of the structure (IX), R ²⁴ is a _C1 - _C4 straight-chain or branched alkyl or -( _C1 - _C4 alkyl) _tO- ( _C1 - _C4 straight-chain or branched alkyl), where t is 0 or 1.

In some aspects of the structure (IX), R ²¹ is a halogen; _C1 - _C4 straight-chain or branched alkyl; _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; -S(O) _u- ( _C1 - _C4 straight-chain or branched alkyl), wherein u is 0 or 2; or -S(O) _u- ( _C3 - _C5 cycloalkyl), wherein u is 0 or 2.

In some aspects of the structure (IX), ^R3 is H or a halogen.

In some aspects of the structure (IX), ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some aspects of the structure (IX), both ^L1 and ^L2 are N.

In some aspects of the structure (IX), R ²¹ is a _C1 - _C2 alkyl or a _C3 - _C5 cycloalkyl and R ²² is a _C1 - _C2 alkyl.

In some aspects of the structure (IX), R ²¹ is a _C3 - _C5 cycloalkyl and R ²² is a _C1 - _C2 alkyl.

In some aspects of the structure (IX), R ²⁴ is -(C ₁ -C ₂ alkyl) _t -O-(C ₁ -C ₂ alkyl), where t is 0 or 1.

In some aspects of the structure (IX), R ²¹ is a _C3 - _C5 cycloalkyl, R ²² is a _C1 - _C2 alkyl and R ²⁴ is a _C1 - _C2 alkyl.

In some aspects of the structure (IX), R ²¹ is cyclobutyl, R ²² is _C1 - _C2 alkyl and R ²⁴ is _C1 - _C2 alkyl.

In some aspects of the structure (IX), R ²¹ is cyclobutyl.

In some aspects of the structure (IX), ^R3 is H or F.

In some aspects of the structure (IX), ^R1 is -CN.

In some aspects of the structure (IX), ^R1 is _-CF3 .

In some aspects of the structure (IX), R ²² is H, methyl, or ethyl.

In some aspects of the structure (IX), R ²² is H.

In some aspects of the structure (IX), R ²² is methyl.

In some aspects of the structure (IX), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 and ^L2 are N, and ^R24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of the structure (IX), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 and ^L2 are N, and ^R24 is methoxy or ethoxy.

In some aspects of the structure (IX), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 is CH, ^L2 is N, and ^R24 is methyl, ethyl, hydroxymethyl, methoxymethyl or 2-methoxyethyl.

In some aspects of the structure (IX), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 is N, ^L2 is CH, and ^R24 is methyl, ethyl, hydroxymethyl, methoxymethyl or 2-methoxyethyl.

In some aspects of structure (IX), the compound has a structure selected from the following:

In several respects, a compound of structure (X) or a pharmaceutically acceptable salt thereof is provided:

in:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1, and

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally including oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1, and

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1, and

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each R ⁶⁰¹ and R ⁵⁰¹ is independently an H or C ₁ -C ₄ straight-chain or branched alkyl group; and two of R ²⁶ , R ⁶⁰ , R ⁵⁰ , R ⁵⁰¹ and R ⁶⁰¹ are optionally joined to form a ring, wherein two of R ²⁶ , R ⁶⁰ , R ⁵⁰ , R ⁵⁰¹ and R ⁶⁰¹ may be two R ²⁶ , two R ⁶⁰ , two R ⁵⁰ , two R ⁵⁰¹ or two R ⁶⁰¹ .

In some aspects of the structure (X), R ²¹ is a halogen, a _C1 - _C4 straight-chain or branched alkyl group, or a _C3 - _C5 cycloalkyl group.

In some aspects of the structure (X), ^R3 is H or a halogen.

In some aspects of the structure (X), ^R1 is -CN or _C1 - _C2 haloalkyl.

In some aspects of the structure (X), ^R3 is H or F.

In some aspects of the structure (X), ^R1 is -CN.

In some aspects of the structure (X), ^R1 is _-CF3 .

In some aspects of the structure (X), n is 1.

In some aspects of the structure (X), n is 2.

In some aspects of the structure (X), m is 1.

In some aspects of the structure (X), m is 2.

In some aspects of structure (X), ^R21 is a _C1 - _C2 alkyl or a _C3 - _C5 cycloalkyl and ^R22 is a _C1 - _C2 alkyl.

In some respects of structure (X), ^R21 is a _C3 - _C5 cycloalkyl and ^R22 is a _C1 - _C2 alkyl.

In some aspects of the structure (X), n is 2, m is 1, and ^L3 is -NC(O)-O-( _C1 - _C2 alkyl).

In some aspects of the structure (X), ^L3 is ^NR50 ; ^R50 is _C1 - _C2 alkyl; ^R21 is cyclobutyl; ^R22 is H or methyl; ^R3 is H; ^R1 is -CN; m is 2 and n is 1 or 2.

In some aspects of the structure (X), n is 2, m is 1, ^L3 is 0 and s is 0.

In some aspects of the structure (X), ^R22 is H, methyl, or ethyl.

In some aspects of structure (X), R ²² is methyl.

In some aspects of structure (X), R ²² is H.

In some aspects of the structure (X), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, n is 2 and ^L3 is NR ⁵⁰ , wherein R ⁵⁰ is methyl or ethyl.

In some aspects of the structure (X), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, n is 2 and ^L3 is O.

In some aspects of structure (X), the compound has a structure selected from the following:

In several respects, compounds of structure (XI) or pharmaceutically acceptable salts thereof are provided:

in:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azircyclobutane-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In some aspects of the structure (XI), ^R3 is H or a halogen.

In some aspects of the structure (XI), ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some aspects of the structure (XI), R ²¹ is a _C3 - _C4 cycloalkyl and R ²² is a _C1 - _C2 alkyl.

In some aspects of the structure (XI), ^R21 is cyclobutyl and ^R22 is _C1 - _C2 alkyl.

In some aspects of the structure (XI), R ²¹ is cyclobutyl.

In some aspects of structure (XI), ^R3 is H or F.

In some aspects of the structure (XI), ^R1 is -CN.

In some aspects of the structure (XI), ^R1 is _-CF3 .

In some aspects of the structure (XI), R ²² is H, methyl, or ethyl.

In some aspects of structure (XI), R ²² is H.

In some aspects of the structure (XI), R ²² is methyl.

In some aspects of the structure (XI), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is cyclobutyl, ^R22 is methyl and ^R351 is methyl or ethyl.

In some aspects of structure (XI), the compound has a structure selected from the following:

In several aspects, this disclosure provides pharmaceutical compositions comprising any one of compounds of structure (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI) and a pharmaceutically acceptable carrier, excipient, or diluent.

In several aspects, this disclosure provides a method for treating a condition characterized by fatty acid synthase dysfunction in a subject, the method comprising administering to the subject requiring the treatment an effective amount of a compound of any one of structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI). In several aspects, the condition characterized by fatty acid synthase dysfunction is a viral infection or cancer. In several aspects, a viral infection is treated by combining a compound of any one of structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI) with one or more additional antiviral treatments. In several aspects, cancer is treated by combining a compound of any one of structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI) with one or more additional cancer treatments. In several aspects, the viral infection is hepatitis C.

In various respects, this disclosure relates to a method for treating fatty liver disease in a subject of need, the method comprising administering a fatty acid synthase inhibitor having the following formula to the subject of need:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L _x Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L _- Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L _- Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L _- Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for treating non-alcoholic steatohepatitis (NASH) in a subject of need, the method comprising administering a fatty acid synthase inhibitor having the following formula to the subject of need:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L _x Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L _- Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for treating non-alcoholic fatty liver disease (NAFLD) in a subject of need, the method comprising administering to the subject of need a fatty acid synthase inhibitor having the following formula:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for treating metabolic syndrome in a subject of need, the method comprising administering a fatty acid synthase inhibitor having the following formula to the subject of need:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L _- Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for treating cirrhosis in a subject in need, the method comprising administering a fatty acid synthase inhibitor having the following formula to the subject in need:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for treating liver fibrosis in a subject of need, the method comprising administering a fatty acid synthase inhibitor having the following formula to the subject of need:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ^5O is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for treating liver cancer in a subject of need, the method comprising administering a fatty acid synthase inhibitor having the following formula to the subject of need:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for treating a disease or condition in a subject of need with elevated interleukin 1β (IL1β) levels, the method comprising administering to the subject of need a fatty acid synthase inhibitor having the following formula:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for treating a disease or condition in which a subject in need has elevated levels of t-helper (Th) cells, the method comprising administering to the subject in need a fatty acid synthase inhibitor having the following formula:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for treating a disease or condition in which regulatory T cells (T _reg ) are reduced or suppressed in a subject of need, the method comprising administering to the subject of need a fatty acid synthase inhibitor having the following formula:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for reversing definitive nonalcoholic steatohepatitis (NASH), the method comprising administering a fatty acid synthase inhibitor having the following formula to a subject in need:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for reducing fibrosis gene expression, said method comprising administering a fatty acid synthase inhibitor having the following formula to a subject in need:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -(C1- _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, this disclosure relates to a method for treating skin fibrosis, the method comprising administering a fatty acid synthase inhibitor having the following formula to a subject in need:

(a) Equation (IX)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or

(b) Equation (X):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, a halogen, a _C1 - _C4 straight-chain or branched alkyl group, or a _C3 - _C5 cycloalkyl group, wherein the _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1; and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or

(c) Equation (VI-J)

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

(d) Formula (XII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and

R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or

(e) Equation (XIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1;

Each u is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(f) Equation (XIV):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein:

Each t is independently 0 or 1; and

Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or

(g) Equation (XV):

Or its pharmaceutically acceptable salt, wherein:

^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m can be 1 or 2, and the constraint is that n+m≥3;

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(h) formula (XVI):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or

(i) Equation (XVII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

The constraint is that when u is 1, t is 1; and

R ²⁴¹ is H or _C1 - _C2 alkyl; or

(j) Equation (XVIII):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar is a constraint condition that is, when L-Ar is true and Ar is not true.

^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or

(k) Equation (XIX):

Or its pharmaceutically acceptable salt, wherein:

Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-;

Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl);

Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring;

Ar for

Het is a 5- to 6-membered heteroaryl group;

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted by one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or

(l) Equation (XX):

Or its pharmaceutically acceptable salt, wherein:

L-Ar is

Ar for

^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 alkyl;

^R3 is H or F;

R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and

R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or

(m) Equation (XI):

Or its pharmaceutically acceptable salt, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In various respects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 may be used to manufacture agents for treating non-alcoholic steatohepatitis (NASH) or symptoms of NASH. In other respects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 may be used to treat non-alcoholic steatohepatitis (NASH) or symptoms of NASH.

In various aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to manufacture agents for the treatment of non-alcoholic fatty liver disease (NAFLD). In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to treat non-alcoholic fatty liver disease (NAFLD).

In various respects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 may be used to manufacture medicaments for the treatment of metabolic syndrome. In other respects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 may be used to treat metabolic syndrome.

In various aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to manufacture agents for the treatment of cirrhosis. In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to treat cirrhosis.

In various aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to manufacture agents for the treatment of liver fibrosis. In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to treat liver fibrosis.

In various aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to manufacture agents for treating liver cancer. In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to treat liver cancer.

In various aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to manufacture agents for the treatment of liver fibrosis. In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to treat liver fibrosis.

In all respects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 may be used to manufacture agents for treating diseases or conditions with elevated interleukin-1β (IL1β) levels.

In all respects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 may be used to manufacture agents for treating diseases or conditions with elevated t-helper ( _Th ) cell levels.

In all respects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 may be used to manufacture agents for treating diseases or conditions in which regulatory T cells ( _Tregs ) are reduced or suppressed.

In various respects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 may be used to manufacture agents for the treatment or reversal of definitive nonalcoholic steatohepatitis (NASH). In other respects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 may be used to treat or reverse definitive nonalcoholic steatohepatitis (NASH).

In various respects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1, may be used to manufacture agents for reducing the expression of fibrosis genes. In other respects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1, may be used to reduce the expression of fibrosis genes.

In various aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to manufacture agents for treating skin fibrosis. In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used to treat skin fibrosis.

Attached Figure Description

Figure 1 shows the correlation between FASN inhibition and HCV inhibition.

Figure 2 shows images of liver tissue samples taken from C57BL/6NCrSim mice treated with the medium or 10 mg/kg compound 364A, stained with Oil Red O or Masson's stain. The results show that treatment with the FASN inhibitor compound 364A inhibited the development of steatosis.

Figure 3 shows images of liver tissue samples taken from C57BL/6J mice treated with the medium for 28 days, 57 days, or 28 days followed by treatment with 10 mg/kg compound 364A for 29 days, stained with Oil Red O. The results show that treatment with the FASN inhibitor compound 364A inhibited the development of hepatic steatosis.

Figure 4 shows the IL-1β levels in untreated rats and rats treated with the medium, 60 mg/kg compound 6B, or 100 mg/kg compound 6B. The results showed that treatment with compound 6B reduced serum IL-1β levels in fasted rats.

Figure 5 shows the IL-1β levels in rats treated with the medium, 60 mg/kg compound 6B, or 100 mg/kg compound 6B. The results showed that treatment with compound 6B reduced serum IL-1β levels 22 hours after feeding to fasted rats.

Figure 6A shows the IL-1β levels in mice fed a high-fat diet for 14 days and then treated with a mediator, 3 mg/kg of compound 364A, or 10 mg/kg of compound 364A. Figure 6B shows the IL-1β levels in mice fed a high-fat diet for 37 days and then treated with a mediator, 3 mg/kg of compound 364A, or 10 mg/kg of compound 364A. Compared with mice receiving the mediator, mice treated with compound 364A had reduced IL-1β levels on both day 14 and day 37, both before and after reintroduction of food.

Figure 7A shows the levels of IL-1β secreted from human PBMCs after 24 hours of stimulation with lipopolysaccharide (LPS) or lipoteichoic acid (LTA) in the absence of stimulation, when treated with a mediated substance or with 10 μM compound 242A. Figure 7B shows the levels of IL-1β secreted from human monocytes after 24 hours of stimulation with lipopolysaccharide (LPS) or lipoteichoic acid (LTA) in the absence of stimulation, when treated with a mediated substance or with 10 μM compound 242A. For monocytes, treatment with compound 242A reduced IL-1β levels induced by LTA stimulation, while only a slight reduction was observed after LPS stimulation. For PBMCs, treatment with compound 242A reduced IL-1β levels induced by both LTA and LPS stimulation.

Figures 8A and 8B show the flow cytometry results of mouse T cells treated with the medium (DMSO) or 50 nM compound 364A. FASN inhibition of mouse CD4+ primordial T cells under 4-day Th ₁₇ differentiation conditions suppressed Th ₁₇ cell differentiation and stimulated T _reg differentiation.

Figures 9A and 9B show the flow cytometry analysis results of human T cells from donor 1 treated with either DMSO or 50 nM compound 364A. Figures 9C and 9D show the flow cytometry analysis results of human T cells from donor 2 treated with either DMSO or 50 nM compound 364A. Under 4-day Th ₁₇ differentiation conditions, FASN inhibition of human CD4+ primordial T cells from two different donors with compound 364A inhibited Th ₁₇ cell differentiation and stimulated T _reg differentiation.

Figures 10A and 10B show the flow cytometry results of human T cells from donor 1 treated with either DMSO or 50 nM compound 152. Figures 10C and 10D show the flow cytometry results of human T cells from donor 2 treated with either DMSO or 50 nM compound 152. Under 4-day Th ₁₇ differentiation conditions, FASN inhibition of human CD4+ primordial T cells from two different donors with compound 152 inhibited Th ₁₇ cell differentiation and stimulated T _reg differentiation.

Figure 11 is a schematic diagram of the study design and dosage group for compound 364A and pirfenidone in Example 10.

Figure 12A shows the changes in plasma alanine aminotransferase (ALT) with treatment with compound 364A and/or pirfenidone. Figure 12B shows the changes in plasma aspartate aminotransferase (AST) with treatment with compound 364A and/or pirfenidone. Figure 12C shows the changes in plasma total cholesterol (TC) with treatment with compound 364A and/or pirfenidone.

Figure 13A shows the changes in liver triglycerides after treatment with compound 364A and/or pirfenidone. Figure 13B shows the changes in liver cholesterol after treatment with compound 364A and/or pirfenidone.

Figure 14A shows the changes in hepatic steatosis after administration of the mediator (control). Figure 14B shows the changes in hepatic steatosis after administration of compound 364A. Figure 14C shows the changes in hepatic steatosis after administration of pirfenidone. Figure 14D shows the changes in hepatic steatosis after administration of both compound 364A and pirfenidone.

Figure 15A shows the changes in liver inflammation after administration of the mediator (control). Figure 15B shows the changes in liver inflammation after administration of compound 364A. Figure 15C shows the changes in liver inflammation after administration of pirfenidone. Figure 15D shows the changes in liver inflammation after administration of both compound 364A and pirfenidone.

Figure 16A shows the changes in liver ballooning after administration of the mediator (control). Figure 16B shows the changes in liver ballooning after administration of compound 364A. Figure 16C shows the changes in liver ballooning after administration of pirfenidone. Figure 16D shows the changes in liver ballooning after administration of both compound 364A and pirfenidone.

Figure 17A shows the changes in liver fibrosis after administration of the mediator (control). Figure 17B shows the changes in liver fibrosis after administration of compound 364A. Figure 17C shows the changes in liver fibrosis after administration of pirfenidone. Figure 17D shows the changes in liver fibrosis after administration of both compound 364A and pirfenidone.

Figure 18A shows the changes in liver NAFLD activity score (NAS) after administration of the mediator (control). Figure 18B shows the changes in liver NAFLD activity score (NAS) after administration of compound 364A. Figure 18C shows the changes in liver NAFLD activity score (NAS) after administration of pirfenidone. Figure 18D shows the changes in liver NAFLD activity score (NAS) after administration of both compound 364A and pirfenidone.

Figure 19 shows the changes in liver collagen gene expression after administration of the mediator (control), compound 364A, pirfenidone, or compounds 364A and pirfenidone.

Figure 20 is a 2-D diagram showing the changes in liver collagen gene expression obtained by gene analysis of liver biopsy sections after administration of the mediator (control), compound 364A, pirfenidone, or compound 364A and pirfenidone.

Figure 21 is a schematic diagram of the study design and dosage group in Example 11.

Figure 22 shows the change in collagen content in mouse skin with the dosage of compound 364A in Example 11.

Figure 23 shows the relative mRNA expression of fibrosis genes in immortalized human hepatic stellate cells (LX-2 cells) after treatment with compound 364A or sorafenib. Figure 23A shows the mRNA expression of Col 1a1. Figure 23B shows the mRNA expression of αSMA. Figure 23C shows the mRNA expression of βPDGFR. Figure 23D shows the mRNA expression of TGFbR1. Figure 23E shows the mRNA expression of TIMP1. Figure 23F shows the mRNA expression of TIMP2. Figure 23G shows the mRNA expression of MMP2.

Invention Details

This disclosure addresses the shortcomings in treating patients with conditions characterized by FASN dysfunction, such as viral infections, cancer, and metabolic disorders, by providing novel heterocyclic regulators of lipid synthesis.

In some aspects, this disclosure provides compositions and methods for treating viral infections. Generally, the compositions and methods for treating viral infections target the regulation of fatty acid synthesis pathways. Fatty acid synthesis pathways are involved in viral replication into host cells. This invention implements methods for treating viral infections such as hepatitis C infection, yellow fever infection, and human rhinovirus infection, or any virus targeting fatty acid synthesis pathways.

In some respects, this disclosure provides compositions and methods for treating cancer. Fatty acid synthase is responsible for converting malonyl-CoA into long-chain fatty acids, an early reaction in fatty acid biosynthesis. Fatty acid synthase is overexpressed in many cancer cells. Without being bound by any particular theory, it is assumed that selective inhibition of fatty acid synthase expression or activity inhibits cancer cell proliferation and induces cancer cell death with minimal toxicity to normal cells.

Furthermore, this disclosure provides compounds and methods for modulating host cell targets targeted by viruses. Such modulation of host cell targets may include activation or inhibition of the host cell targets. Therefore, compounds that modulate (e.g., inhibit) the activity of non-viral proteins (e.g., host cell proteins, such as components of fatty acid synthesis pathways) can be used as antiviral agents.

definition

As those skilled in the art will understand, chemical moieties referred to as monovalent chemical moieties (e.g., alkyl, aryl _, etc.) also encompass structurally permissible polyvalent moieties. For example, while the term "alkyl" generally refers to a monovalent group (e.g., _CH3CH2- ), in appropriate cases _, "alkyl" can also refer to a divalent group (e.g., _-CH2CH2- , which is equivalent to "alkylene"). Similarly, where a divalent moieties are required, those skilled in the art will understand that the term "aryl" refers to the corresponding divalent arylene.

All atoms should be understood to have their normal bonding valences (e.g., carbon 4, N 3, O 2, and S 2, 4, or 6, depending on the oxidation state of the atom). Sometimes, a part can be defined, for example, as (A) _a B, where a is 0 or 1. In this case, when a is 0, the part is B, and when a is 1, the part is AB.

If the number of substituents can vary in the same type of atoms or groups (e.g., alkyl groups can be _C1 , _C2 , _C3 , etc.), then the number of repeating atoms or groups can be expressed by a range (e.g., _C1 - _C6 alkyl), which includes each and every number in that range and any and all subranges. For example, _C1 - _C3 alkyl includes _C1 , _C2 , _C3 , _C1-2 , _C1-3 , and _C2-3 alkyl.

"Alkyl group" refers to a carbonyl group with a low-carbon alkyl group as a substituent.

"Alkylamino" refers to an amino group that is substituted with an alkyl group.

"Alkoxy" refers to an O atom substituted with an alkyl group as defined herein, such as methoxy [ _-OCH3 , _C1 alkoxy]. The term " _C1-6 alkoxy" encompasses _C1 alkoxy, _C2 alkoxy, _C3 alkoxy, _C4 alkoxy, _C5 alkoxy, _C6 alkoxy, and any of their subranges.

"Alkoxycarbonyl" refers to a carbonyl group that has an alkoxy group as a substituent.

"alkyl," "alkenyl," and "ynyl" refer to optionally substituted straight-chain and branched aliphatic groups having 1 to 30 carbon atoms, preferably 1 to 15 carbon atoms, or more preferably 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, vinyl, allyl, isobutylenyl, ethynyl, and propynyl. As used herein, the term "heteroalkyl" covers alkyl groups having one or more heteroatoms.

"alkylene" refers to an optionally substituted divalent group, which is a branched or unbranched hydrocarbon segment containing a specified number of _{carbon atoms and having two connection points. An example is propylene [-CH₂CH₂CH₂- , C₃alkylene ]} .

"Amino" refers to the group _-NH2 .

"Aryl" refers to an optionally substituted aromatic group having at least one ring with a conjugated π-electron system, including carbocyclic aryl and biaryl groups, both of which may be optionally substituted. Phenyl and naphthyl are preferred carbocyclic aryl groups.

"Arylalkyl" or "arylalkyl" refers to an alkyl-substituted aryl group. Examples of arylalkyl groups include butylphenyl, propylphenyl, ethylphenyl, methylphenyl, 3,5-dimethylphenyl, and tert-butylphenyl.

As used herein, “carbamoyl” encompasses the group of the structure in which R and ^N are selected from: hydrogen, -OH, _C1 to _C12 alkyl, _C1 to _C12 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamide.

"Carbonyl" refers to a group in a structure.

"Cycloalkyl" refers to an optionally substituted ring, which can be saturated or unsaturated and is a monocyclic, bicyclic, or tricyclic ring formed entirely of carbon atoms. An example of a cycloalkyl group is _{cyclopentenyl} ( _C5H7- ), which is a five-carbon ( _C5 ) unsaturated cycloalkyl group.

"Heterocycle" refers to a 5- to 7-membered cyclic alkyl ring system containing 1, 2 or 3 heteroatoms selected from N, O or S that may be the same or different and optionally contain a double bond.

"Halogen" refers to a group consisting of chlorine, bromine, fluorine, or iodine atoms. The term "halogen" also encompasses the terms "halo" or "halide".

"Heteroatoms" refers to non-carbon atoms, among which boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, and nitrogen, oxygen and sulfur are particularly preferred heteroatoms in the compounds of this invention.

"Heteroaryl" refers to an aryl group having 1 to 9 carbon atoms with the remaining atoms being heteroatoms, and includes those heterocyclic systems described in "Handbook of Chemistry and Physics", 49th edition, 1968, ed. R.C. Weast; The Chemical Rubber Co., Cleveland, Ohio. See in particular Chapter C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryl groups include thiophene, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazoleyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrololinyl, pyridazinyl, triazolyl, indolyl, isoindolyl, indolazinyl, benzimidazolyl, quinolinyl, isoquinolinyl, inzozolyl, benzotriazolyl, tetrazopyridazinyl, oxadiazolyl, benzooxazolyl, benzooxadiazolyl, thiazolyl, benzothiazolyl, benzothiazolyl, etc.

The "optionally substituted" portion may be substituted by 1 to 4, preferably 1 to 3, or more preferably 1 or ₂ non-hydrogen substituents. Unless otherwise stated, when the substituent is on a carbon atom, it is selected from: -OH, -CN, -NO₂, halogen, _C1 to _C12 alkyl, _C1 to _C12 heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide, and amino, none of which are further substituted. Unless otherwise stated, when the substituent is on a nitrogen atom, it is selected from: _C1 to _C12 alkyl, _C1 to _C12 heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate, and sulfonamide, none of which are further substituted.

As used herein, the term "sulfonamide" encompasses the group of the structure in which R and ^N are selected from: hydrogen, -OH, _C1 to _C12 alkyl, _C1 to _C12 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.

As used herein, the term "sulfonate ester" encompasses the group of the structure, wherein R and ^S are selected from: hydrogen, _C1 - _C10 alkyl, _C2 - _C10 alkenyl, _C2 - _C10 alkynyl, _C1 - _C10 alkanoyl, or _C1 - _C10 alkoxycarbonyl.

As used herein, “sulfonyl” alone or as part of another group refers to the _SO2 group. The _SO2 moiety may optionally be substituted.

The compounds disclosed herein can exist as stereoisomers, wherein an asymmetric or chiral center is present. Stereoisomers are referred to as (R) or (S) depending on the configuration of the substituents surrounding the chiral carbon atom. As used herein, the terms (R) and (S) are configurations as defined in Section E of IUPAC 1974 Recommendations, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45:13-30, which is incorporated herein by reference. This disclosure covers a variety of stereoisomers and mixtures thereof and is specifically included within the scope of this disclosure. Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds disclosed may be synthesized from commercially available starting materials containing an asymmetric or chiral center, or prepared by preparing a racemic mixture followed by resolution as known to those skilled in the art. These separation methods are exemplified as follows: (1) attaching an enantiomer mixture to a chiral additive, separating the resulting diastereomer mixture by recrystallization or chromatography, and precipitating the optically pure product from the additive; or (2) separating the optically enantiomer mixture directly on a chiral chromatography column.

Furthermore, the portion disclosed herein that exists in various tautomer forms includes all such forms covered by the given tautomer structure.

Individual atoms in the disclosed compounds may be any isotope of the element. For example, hydrogen may be in the form of deuterium.

"Pharmaceutical acceptable" means a substance that has been approved or is intended to be approved by a federal or state regulatory agency, or is listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals and more particularly in humans. It can be a substance that is biologically or otherwise undesirable, meaning that the substance can be administered to a subject without causing any adverse biological effects or interacting harmfully with any component of the composition.

The term "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. These salts include, for example, acid addition salts and base addition salts.

The "acid addition salt" of this invention is formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc. Acids, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucohepanoic acid, 4,4′-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucoconic acid, etc.

The "base addition salt" of this invention is formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or when it coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, thiocyanate, N-methylglucosamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. It should be understood that references to pharmaceutically acceptable salts include solvation forms or their crystalline forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are typically formed during crystallization. Hydrates are formed when the solvent is water, or alcohols are formed when the solvent is alcohol. Polymorphs include different crystalline arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, can cause a single crystal form to dominate.

The term "treatment" includes administering the compounds or agents of the present invention to a subject to prevent or delay, alleviate, or prevent or inhibit the development of symptoms or conditions associated with fatty acid synthase-related disorders, such as tumor growth associated with cancer. Skilled medical professionals should know how to use standard methods to determine whether a patient has a disease associated with fatty acid synthase activity, for example, by examining the patient and determining whether the patient has a known disease associated with fatty acid synthase activity; or by analyzing the fatty acid synthase levels in the plasma or tissues of a subject suspected of having a fatty acid synthase-related disorder and comparing the fatty acid synthase levels in the plasma or tissues of a subject suspected of having a fatty acid synthase-related disorder with those in the plasma or tissues of a healthy subject. Increased serum levels indicate disease. Therefore, the present invention specifically provides a method for administering the compounds of the present invention to a subject and measuring the fatty acid synthase activity in the subject. The fatty acid synthase activity in the subject can be measured before and/or after administration of the compound.

"Therapeutic effective amount" or "pharmaceutical effective amount" refers to the amount that, when administered to a subject, produces the desired effect. For example, a "therapeutic effective amount" is sufficient to inhibit fatty acid synthase activity when administered to a subject. Similarly, a "therapeutic effective amount" is sufficient to treat a disease when administered to a subject.

Unless otherwise stated, the terms "subject" or "patient" are used interchangeably and refer to mammals such as human patients and non-human primates, as well as laboratory animals such as rabbits, rats, mice, and other animals. Therefore, as used herein, the terms "subject" or "patient" mean any mammalian patient or subject to whom the compounds of the present invention may be administered. In an exemplary aspect of the invention, to identify subject patients for treatment according to the methods of the present invention, recognized screening methods are used to determine risk factors associated with a target or suspected disease or condition, or to determine the status of an existing disease or condition in the subject. These screening methods include, for example, routine procedures to determine risk factors associated with a target or suspected disease or condition. These and other routine methods enable clinicians to select patients for treatment using the methods and formulations of the present invention.

FASN pathway modulators

One aspect of the invention includes a method for inhibiting viral infection or treating cancer by contacting cells with an agent that regulates fatty acid synthesis pathways. This method of inhibiting viral infection or treating cancer can be carried out in vitro by contacting virus-infected cells/cancer cells with an agent that regulates fatty acid synthesis pathways, or in vivo by administering the agent to a subject infected with a virus/having cancer. In one aspect, the agent may be an inhibitor of the fatty acid synthesis pathway.

Examples of inhibitors of fatty acid synthesis pathways that can be used in the methods and compositions of the present invention are described below.

Compounds with structure (I)

In several respects, this disclosure provides compounds of structure (I) or pharmaceutically acceptable salts thereof:

in:

X, Y and Z are each independently CR or NR′, where R is hydrogen or _C1-6 alkyl and R′ is hydrogen, _C1-6 alkyl or absent;

A is CH or N;

R1 can be hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _{2R20 , R4} and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl or alkylamino;

_R17 and _R18 are each independently hydrogen or alkyl, or may optionally be bonded together to form a bond;

n is 1 or 2; and

m is 0 or 1.

In some aspects of structure (I), _R3 is F.

In some aspects of structure (I), A is CH.

In some aspects of structure (I), A is N.

In certain aspects of structure (I), X, Y, and Z are NR′.

In some aspects of structure (I), _R4 is a heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N( _R7 )C(=O) _R8 , -N _{( R9R10} ), _C1-6 alkyl, _C1-6 alkoxy, or _{R4 and R11} together with the atoms they are attached to form a heteroaryl.

In some aspects of structure (I), _R5 is hydrogen and _R6 is aryl or heteroaryl.

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have one of the following structures (I-A) or (I-B):

in:

X, Y and Z are each independently CR or NR′, where R is hydrogen or _C1-6 alkyl and R′ is hydrogen, _C1-6 alkyl or absent;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _{2R20 , R4} and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino; and

_R17 and _R18 are each independently hydrogen or alkyl, or optionally bonded together to form a bond.

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have one of the following structures (I-C) or (I-D):

in:

X, Y and Z are each independently CR or NR′, where R is hydrogen or _C1-6 alkyl and R′ is hydrogen, _C1-6 alkyl or absent;

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14 )} , _CF3 , _-OCF3 , -S(=O) _2R20 , or _R4 and _R11 together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , and _R10 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N ( _{R15 R16} ); and

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have one of the following structures: (I-E), (I-F), (I-G), (I-H):

in:

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , _R4 and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with _the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 , and _R14 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N ( _{R15, R16} ); and

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl or alkylamino.

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have one of the following structures: (I-I), (I-J), or (I-K):

in:

X and Y are each independently CR or NR′, wherein R is H or _C1-6 alkyl and R′ is H, _C1-6 alkyl or absent;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R11 can be hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

_R5 , _R6 , _R7 , _R8 , _R9 , and _R10 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N ( _{R15 R16} ); and

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have one of the following structures (I-L) or (I-M):

in:

X and Y are each independently CR or NR′, wherein R is H or _C1-6 alkyl and R′ is H, _C1-6 alkyl or absent;

R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14 )} , _CF3 , _-OCF3 , -S(=O) _2R20 , or _R4 and _R11 together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , and _R10 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N ( _{R15 R16} ); and

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have one of the following structures (I-N) or (I-O):

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have the following structures (I-P):

in:

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , _R4 and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with _the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 , and _R14 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N ( _{R15, R16} ); and

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have one of the following structures: (I-Q), (I-R), or (I-S):

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have the following structures (I-T):

in:

X, Y and Z are each independently CR or NR′, wherein R is H or _C1-6 alkyl and R′ is H, _C1-6 alkyl or absent;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _{2R20 , R4} and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 , and _R14 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N ( _{R15, R16} ); and

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have the following structures (I-U):

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have one of the following structures (I-V):

in:

X, Y and Z are each independently CR or NR′, wherein R is H or _C1-6 alkyl and R′ is H, _C1-6 alkyl or absent;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _{2R20 , R4} and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 , and _R14 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N ( _{R15, R16} ); and

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

In some respects, compounds of structure (I) or pharmaceutically acceptable salts thereof have the following structures (I-W):

In some respects, the compound of structure (I) or a pharmaceutically acceptable salt thereof has one of the following structures: (I-X), (I-Y), (I-Z), (I-AA), (I-AB), (I-AC), (I-AD), (I-AF), (I-AG), or (I-AH):

Compounds with structure (I)

In several respects, this disclosure provides compounds of structure (II) or pharmaceutically acceptable salts thereof:

in:

X, Y and Z are each independently CR or NR′, wherein R is H or _C1-6 alkyl and R′ is H, _C1-6 alkyl or absent;

L and D are each independently C or N;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _{2R20 , R4} and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 and _R14 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino or -N ( _{R15 R16} );

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl or alkylamino;

_R17 and _R18 are each independently hydrogen or alkyl, or may optionally be bonded together to form a bond;

n is 1 or 2; and

m is 0 or 1.

In some respects, compounds of structure (II) or pharmaceutically acceptable salts thereof have the following structure (II-A):

in:

X, Y and Z are each independently CR or NR′, wherein R is H or _C1-6 alkyl and R′ is H, _C1-6 alkyl or absent;

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _{2R20 , R4} and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 , and _R14 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N ( _{R15, R16} ); and

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

In some respects, compounds of structure (II) or pharmaceutically acceptable salts thereof have the following structure (II-B):

in:

X and Y are each independently CR or NR′, wherein R is H or _C1-6 alkyl and R′ is H, _C1-6 alkyl or absent;

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14 )} , _CF3 , _-OCF3 , -S(=O) _2R20 , or _R4 and _R11 together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , and _R10 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N ( _{R15 R16} ); and

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

In some respects, compounds of structure (II) or pharmaceutically acceptable salts thereof have one of the following structures: (II-C), (II-D), or (II-E):

in:

X and Y are each independently CR or NR′, wherein R is H or _C1-6 alkyl and R′ is H, _C1-6 alkyl or absent;

_R2 is hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or _R2 and _R3 together with the atoms they are attached to form a 5-membered heterocyclic group;

_R11 can be hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R5 , _R6 , _R7 , _R8 , _R9 , and _R10 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N ( _{R15 R16} ); and

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

In some respects, compounds of structure (II) or pharmaceutically acceptable salts thereof have the following structures (II-F):

Compounds with structure (III)

In several respects, this disclosure provides compounds of structure (III) or pharmaceutically acceptable salts thereof:

in:

X, Y and Z are each independently CR or NR′, wherein R is H or _C1-6 alkyl and R′ is H, _C1-6 alkyl or absent;

Q is either C or N;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, _C1-6 alkoxy, or if Q is N, then _R3 does not exist;

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _{2R20 , R4} and _R11 together with the atoms they are attached to form a heteroaryl group, or _R11 and _R12 together with the atoms they are attached to form a heteroaryl group;

_R12 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14} ), _CF3 , _-OCF3 , -S(=O) _2R20 , or _{R11 and R12} together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R13 and _R14 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino or -N ( _{R15 R16} );

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl or alkylamino;

_R17 and _R18 are each independently hydrogen or alkyl, or may optionally be bonded together to form a bond;

R ₁₉ is aryl, heteroaryl, cycloalkyl, or heterocyclic;

n is 0, 1, or 2; and

m is 0 or 1.

In some respects, compounds of structure (III) or pharmaceutically acceptable salts thereof have one of the following structures: (III-A), (III-B), or (III-C):

in:

X and Y are each independently CR or NR′, wherein R is H or _C1-6 alkyl and R′ is H, _C1-6 alkyl or absent;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R4 is hydrogen, heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N _{(R7)C(=O)R8, -N(R9R10), C1-6 alkyl, C1-6 alkoxy, -S(=O)2R20 , or R4 and R11 together with the atoms they} are attached to form a heteroaryl group;

_R11 is hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, -N ( _{R13 R14 )} , _CF3 , _-OCF3 , -S(=O) _2R20 , or _R4 and _R11 together with the atoms they are attached to form a heteroaryl group.

_R5 , _R6 , _R7 , _R8 , _R9 , and _R10 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N ( _{R15 R16} ); and

_R15 and _R16 are each independently H, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

In some respects, compounds of structure (III) or pharmaceutically acceptable salts thereof have one of the following structures: (III-D), (III-E), or (III-F):

Compounds with structure (IV)

In some respects, compounds of structure (IV) or pharmaceutically acceptable salts thereof have one of the following structures (IV-A), (IV-B), or (IV-C):

in:

_L1 , _L2 , _L3 , _L4 and A are each independently CH or N;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

_R23 is hydrogen, -N( _R13 )( _R14 ), _C1-6 alkyl, _C1-6 alkoxy. If _L1 is N, then _R23 is absent, or _R23 and _R24 together with the atoms they are attached to are bonded together to form a heterocyclic group, heteroaryl group or cycloalkyl group.

R ₂₄ is hydrogen, -N(R ₁₃ )(R ₁₄ ), C _1-6 alkyl, C _1-6 alkoxy, -(C _1-6 alkoxy)(heterocyclic), heterocyclic, or R ₂₃ and R ₂₄ together with the atoms they are attached to form a heterocyclic, heteroaryl, or cycloalkyl group.

R ₂₆ is hydrogen, heteroaryl, heterocyclic, -N(R ₁₃ )(R ₁₄ ) or -S(＝O) _{2R 20} ;

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

R ₂₅ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy; and

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

In some respects, compounds of structure (IV) or pharmaceutically acceptable salts thereof have one of the following structures (IV-D) and (IV-E):

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₂₆ is hydrogen, heteroaryl, heterocyclic, -N(R ₁₃ )(R ₁₄ ) or -S(＝O) _{2R 20} ;

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

R ₂₅ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy; and

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

In some respects, compounds of structure (IV) or pharmaceutically acceptable salts thereof have one of the following structures (IV-F) and (IV-G):

in:

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

R ₂₅ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl or alkylamino;

s is 0, 1, or 2;

_L5 is _CH2 , NH, S or O;

_L6 is CH or N;

R ₂₇ represents hydrogen, -C(=O)R″, -S(=O) ₂ R ₂₀ ;

_R28 is hydrogen, -C(=O))R″, -S(=O) _{2R20 ,} or if _L6 is O, then _R28 does not exist; and

R″ is hydrogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ) or -N( _R13 )( _R14 ).

In some aspects of the structure (IV), _R1 is hydrogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, or -C(=O)N( _R13 )( _R14 ).

In some aspects of the structure (IV), _R1 is a cyano group.

In some aspects of the structure (IV), _R2 is hydrogen or halogen; _R2 is hydrogen.

In some aspects of structure (IV), _R3 is hydrogen.

In certain aspects of the structure (IV), _R21 and _R22 are each independently hydrogen or _C1-6 alkyl.

In certain aspects of the structure (IV), _R21 and _R22 are each independently _C1-6 alkyl.

In some aspects of structure (IV), R ₂₅ is hydrogen.

In some aspects of the structure (IV), _L2 is N.

In some aspects of the structure (IV), _L1 is CH.

In some aspects of the structure (IV), _L3 is CH.

In some aspects of structure (IV), _L4 is CH.

In some aspects of the structure (IV), A is N.

In some aspects of the structure (IV), A is CH.

In some aspects of the structure (IV), R ₂₆ is a heterocyclic group.

In some aspects of the structure (IV), R ₂₄ is -N(R ₁₃ )(R ₁₄ ).

In some aspects of structure (IV), _L5 and _L6 are each independently N. In some aspects of structure (IV), s is 1.

In some aspects of the structure (IV), s is 0.

In some respects, compounds of structure (IV) or pharmaceutically acceptable salts thereof have one of the following structures: (IV-H), (IV-I), (IV-J), (IV-K), (IV-L), (IV-M), (IV-N), or (IV-O):

Compounds with structure (V)

In several respects, this disclosure provides compounds of structure (V) or pharmaceutically acceptable salts thereof:

in:

_L7 is either N or O, where if _L7 is O, then _R30 does not exist;

A is CH or N;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is a halogen, a _C1-6 alkyl group, or a _C1-6 alkoxy group;

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₂₉ and R ₃₀ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxyalkyl, heteroaryl, heterocyclic, -N(R ₁₅ R ₁₆ ), -C(=O)R ₄₆ , -R _48C (=O)R ₄₇ , or R ₂₉ and R ₃₀ together with the atoms they are attached to form a heteroaryl or heterocyclic group, wherein if L ₇ is O, then R ₃₀ is not present;

R ₄₆ and R ₄₇ are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, -N (R ₁₅ R ₁₆ ) or -S (=O) ₂ R ₂₀ ;

R ₄₈ is an alkyl group or is absent;

R ₃₁ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy;

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino; and

v is 0 or 1.

In some respects, compounds of structure (V) or pharmaceutically acceptable salts thereof have one of the following structures: (V-A), (V-B), (V-C), or (V-D):

in:

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is a halogen, a _C1-6 alkyl group, or a _C1-6 alkoxy group;

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₃₀ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxyalkyl, heteroaryl, heterocyclic, -N(R ₁₅ R ₁₆ ), -C(=O)R ₄₆ or -R _48C (=O)R ₄₇ , wherein if L ₇ is O, then R ₃₀ does not exist;

R ₄₆ and R ₄₇ are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, -N (R ₁₅ R ₁₆ ) or -S (=O) ₂ R ₂₀ ;

R ₄₈ is an alkyl group or is absent;

R ₃₁ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy;

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl or alkylamino;

_L8 , _L9 and _L10 are each independently _CH2 , NH or O;

_L11 and _L12 are each independently CH or N;

R ₃₂ and R ₃₃ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, -S(=O) _{2R 20} , -C(=O)R ₄₆ , hydroxyalkyl, hydroxyl, or absent;

u is 0, 1, or 2; and

t can be 0, 1, or 2.

In some aspects of the structure (V), _L7 is N.

In some aspects of the structure (V), _L7 is O.

In some aspects of the structure (V), A is N.

In some aspects of the structure (V), A is CH.

In some aspects of the structure (V), _R1 is hydrogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, or -C(=O)N( _R13 )( _R14 ).

In some aspects of the structure (V), _R1 is a cyano group.

In some aspects of the structure (V), _R2 is hydrogen or halogen.

In some aspects of the structure (V), _R2 is hydrogen.

In some aspects of the structure (V), _R3 is fluorine.

In certain aspects of the structure (V), _R21 and _R22 are each independently hydrogen or _C1-6 alkyl.

In certain aspects of the structure (V), _R21 and _R22 are each independently _C1-6 alkyl.

In some aspects of the structure (V), R ₃₁ is hydrogen.

In some aspects of the structure (V), _R30 is hydrogen.

In some aspects of the structure (V), _L8 is O.

In some aspects of the structure (V), _L9 is O.

In some aspects of the structure (V), _L10 is O and _L11 is N.

In some aspects of the structure (V), L ₁₂ is N.

In certain aspects of the structure (V), _R32 and _R33 are each independently hydrogen.

In some respects, compounds of structure (V) or pharmaceutically acceptable salts thereof have one of the following structures: (V-I), (V-J), (V-K), (V-L), (V-M), (V-N), or (V-O):

Compounds with structure (VI)

In some respects, compounds of structure (VI) or their pharmaceutically acceptable salts have one of the following structures (VI-A) or (VI-B):

in:

_L13 , _L14 , _L15 and A are each independently CH or N;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is a halogen, a _C1-6 alkyl group, or a _C1-6 alkoxy group;

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₃₄ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, cycloalkyl, hydroxyl, hydroxyalkyl, aryl, heterocyclic, heteroaryl, alkylamino, CF ₃ , -OCF ₃ , -S(=O) _{2R 20} or -N (R ₁₅ R ₁₆ );

R ₃₅ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy;

R ₃₆ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, -N (R ₁₅ R ₁₆ ), heterocyclic or heteroaryl;

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ; and

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

In some respects, compounds of structure (VI) or their pharmaceutically acceptable salts have one of the following structures (VI-C) or (VI-D):

in:

_R1 can be hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O))N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is a halogen, a _C1-6 alkyl group, or a _C1-6 alkoxy group;

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₃₅ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy;

R ₃₆ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, -N (R ₁₅ R ₁₆ ), heterocyclic or heteroaryl;

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino; and

R ₃₇ and R ₃₈ are each independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, hydroxyalkyl, heteroaryl, heterocyclic, or R ₃₇ and R ₃₈ together with the atoms to which they are attached to form a heteroaryl or heterocyclic group.

In some aspects of structure (VI), _R1 is hydrogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, or -C(=O)N( _R13 )( _R14 ).

In some aspects of structure (VI), _R1 is a cyano group.

In some aspects of structure (VI), _R2 is hydrogen or halogen.

In some aspects of structure (VI), _R2 is hydrogen.

In certain aspects of structure (VI), _R3 is fluorine.

In certain aspects of structure (VI), _R21 and _R22 are each independently hydrogen or _C1-6 alkyl.

In certain aspects of structure (VI), _R21 and _R22 are each independently _C1-6 alkyl.

In some aspects of structure (VI), R ₃₅ is hydrogen.

In some aspects of the structure (VI), R ₃₄ is a heteroaryl group.

In certain aspects of structure (VI), R ₃₄ is thiophene, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrololinyl, pyridazinyl, triazolyl, indoleyl, isoindoleyl, indoleazinyl, benzimidazolyl, quinolinyl, isoquinolinyl, inzolyl, benzotriazolyl, tetrazopyridazinyl, oxadiazolyl, benzooxazolyl, benzooxadiazolyl, thiazolyl, benzothiazolyl, or benzothiazolyl.

In some aspects of the structure (VI), L ₁₃ is N.

In certain aspects of structure (VI), L ₁₄ and L ₁₅ are each independently CH.

In some aspects of the structure (VI), A is N.

In some aspects of structure (VI), A is CH.

In some respects, compounds of structure (VI) or pharmaceutically acceptable salts thereof have one of the following structures: (VI-E), (VI-F), (VI-G), (VI-H), or (VI-I):

In several respects, this disclosure provides compounds of structure (VI-J) or pharmaceutically acceptable salts thereof:

in:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azircyclobutane-1-yl, or cyclopropyl;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and

R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which may be optionally substituted.

In some aspects of the structure (VI-J), ^R3 is H or a halogen.

In some aspects of the structure (VI-J), ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some aspects of the structure (VI-J), ^R22 is a _C1 - _C2 alkyl group.

In some aspects of the structure (VI-J), ^R21 is cyclobutyl and ^R22 is _C1 - _C2 alkyl.

In some aspects of the structure (VI-J), R ²¹ is cyclobutyl.

In some aspects of the structure (VI-J), R ³ is H or F.

In some aspects of the structure (VI-J), ^R1 is -CN.

In some aspects of the structure (VI-J), ^R1 is _-CF3 .

In some aspects of the structure (VI-J), R ²² is H, methyl, or ethyl.

In some aspects of the structure (VI-J), R ²² is H.

In some aspects of the structure (VI-J), R ²² is methyl.

In some aspects of the structure (VI-J), R ³⁵ is -C(O)-NHR ³⁵¹ .

In some aspects of the structure (VI-J), R ³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of the structure (VI-J), R ³⁵¹ is (R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

In some aspects of the structure (VI-J), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is H, and ^R35 is -C(O)-NHR ³⁵¹ , wherein ^R351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of the structure (VI-J), R ³⁵ is -C(O)-OR ³⁵¹ .

In some aspects of the structure (VI-J), R ³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of the structure (VI-J), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is H, and ^R35 is -C(O)-OR ³⁵¹ , wherein ^R351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of the structure (VI-J), R ³⁵¹ is (R)-3-tetrahydrofuranyl or (S)-3-tetrahydrofuranyl.

In some aspects of the structure (VI-J), the compound has a structure selected from the following:

Compounds with structure (VII)

In some respects, compounds of structure (VII) or pharmaceutically acceptable salts thereof have one of the following structures (VII-A) or (VII-B):

in:

_L16 is C or N, where if _L16 is N, then _R41 does not exist;

_L17 , _L18 and A are each independently CH or N;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₄₀ , R ₄₂ and R ₄₃ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, -S(=O) _{2R 20} , -C(=O)R, hydroxyalkyl, hydroxyl, -N (R ₁₃ R ₁₄ ), or R ₄₁ and R ₄₂ together with the atoms they are attached to form a heteroaryl or heterocyclic group;

R ₄₁ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, -S(=O) _{2R 20} , -C(=O)R, hydroxyalkyl, hydroxyl, -N (R ₁₃ R ₁₄ ). If L ₁₆ is N, then R ₄₁ is absent, or R ₄₁ and R ₄₂ together with the atoms they are attached to form a heteroaryl or heterocyclic group.

R is hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

R ₃₉ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy;

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ; and

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

In some aspects of structure (VII), _R1 is hydrogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, or -C(=O)N( _R13 )( _R14 ).

In some aspects of structure (VII), _R1 is a cyano group.

In some aspects of structure (VII), _R2 is hydrogen or halogen.

In some aspects of structure (VII), _R2 is hydrogen.

In some aspects of structure (VII), _R3 is hydrogen.

In certain aspects of structure (VII), R ₂₁ and R ₂₂ are each independently hydrogen or _C1-6 alkyl.

In certain aspects of structure (VII), R ₂₁ and R ₂₂ are each independently _C1-6 alkyl.

In some aspects of structure (VII), R ₃₉ is hydrogen.

In some aspects of structure (VII), R ₄₀ is hydrogen.

In some aspects of structure (VII), L ₁₆ is N.

In some aspects of structure (VII), L ₁₇ is N.

In some aspects of structure (VII), L ₁₈ is CH.

In some aspects of structure (VII), L ₁₈ is N.

In some aspects of structure (VII), A is N.

In some aspects of structure (VII), A is CH.

In some aspects of structure (VII), R ₄₂ is a _C1-6 alkyl group.

In some aspects of structure (VII), R ₄₁ is a _C1-6 alkyl group.

In some respects, compounds of structure (VII) or pharmaceutically acceptable salts thereof have one of the following structures (VII-C) or (VII-D):

Compounds with structure (VIII)

In some respects, compounds of structure (VIII) or their pharmaceutically acceptable salts have one of the following structures: (VIII-A), (VIII-B), or (VIII-C):

in:

L ₁₉ and A are each independently CH or N;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

R ₃₉ is hydrogen, _C1-6 alkyl, or _C1-6 alkoxy;

R ₄₄ and R ₄₅ are each independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, cycloalkyl, hydroxyalkyl, aryl, heterocyclic, heteroaryl, alkylamino, -S(=O) _2R20 , -C(=O)R, or _-N ( _R13R14 ); _and

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ; and

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

In some aspects of the structure (VIII), _R1 is hydrogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, or -C(=O)NN( _R13 )( _R14 ).

In some aspects of structure (VIII), _R1 is a cyano group.

In some aspects of structure (VIII), _R2 is hydrogen or halogen.

In some aspects of structure (VIII), _R2 is hydrogen.

In some aspects of structure (VIII), _R3 is hydrogen.

In certain aspects of the structure (VIII), _R21 and _R22 are each independently hydrogen or _C1-6 alkyl.

In certain aspects of the structure (VIII), R ₂₁ and R ₂₂ are each independently _C1-6 alkyl.

In some aspects of structure (VIII), R ₃₉ is hydrogen.

In some aspects of structure (VIII), L ₁₉ is N.

In some aspects of structure (VIII), A is N.

In some aspects of structure (VIII), A is CH.

In some respects, compounds of structure (VIII) or their pharmaceutically acceptable salts have the following structures (VIII-D):

In several respects, compounds of formula IX or pharmaceutically acceptable salts thereof are provided:

in:

^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1;

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

^L1 is either ^CR23 or N;

^L2 is CH or N;

At least one of ^L1 or ^L2 is N; and

R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group.

In some aspects of the structure (IX), R ²⁴ is a _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), where t is 0 or 1.

In some aspects of the structure (IX), R ²¹ is a halogen; _C1 - _C4 straight-chain or branched alkyl; _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; -S(O) _u- ( _C1 - _C4 straight-chain or branched alkyl), wherein u is 0 or 2; or -S(O) _u- ( _C3 - _C5 cycloalkyl), wherein u is 0 or 2.

In some aspects of the structure (IX), ^R3 is H or a halogen.

In some aspects of the structure (IX), ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some aspects of the structure (IX), both ^L1 and ^L2 are N.

In some aspects of the structure (IX), R ²¹ is a _C1 - _C2 alkyl or a _C3 - _C5 cycloalkyl and R ²² is a _C1 - _C2 alkyl.

In some aspects of the structure (IX), R ²¹ is a _C3 - _C5 cycloalkyl and R ²² is a _C1 - _C2 alkyl.

In some aspects of the structure (IX), R ²⁴ is -(C ₁ -C ₂ alkyl) _t -O-(C ₁ -C ₂ alkyl), where t is 0 or 1.

In some aspects of the structure (IX), R ²¹ is a _C3 - _C5 cycloalkyl, R ²² is a _C1 - _C2 alkyl and R ₂₄ ^is a _C1 - _C2 alkyl.

In some aspects of the structure (IX), R ²¹ is cyclobutyl, R ²² is _C1 - _C2 alkyl and R ²⁴ is _C1 - _C2 alkyl.

In some aspects of the structure (IX), R ²¹ is cyclobutyl.

In some aspects of the structure (IX), ^R3 is H or F.

In some aspects of the structure (IX), ^R1 is -CN.

In some aspects of the structure (IX), ^R1 is _-CF3 .

In some aspects of the structure (IX), R ²² is H, methyl, or ethyl.

In some aspects of the structure (IX), R ²² is H.

In some aspects of the structure (IX), R ²² is methyl.

In some aspects of the structure (IX), ^R1 is -CN, each of ^R2 is hydrogen, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 and ^L2 are N, and ^R24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of the structure (IX), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 and ^L2 are N, and ^R24 is methoxy or ethoxy.

In some aspects of the structure (IX), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 is CH, ^L2 is N, and ^R24 is methyl, ethyl, hydroxymethyl, methoxymethyl or 2-methoxyethyl.

In some aspects of the structure (IX), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 is N, ^L2 is CH, and ^R24 is methyl, ethyl, hydroxymethyl, methoxymethyl or 2-methoxyethyl.

In some aspects of structure (IX), the compound has a structure selected from the following:

In several respects, a compound of structure (X) or a pharmaceutically acceptable salt thereof is provided:

in:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ;

Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein:

t is 0 or 1, and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally including oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , _C1 - _C4 straight-chain or branched alkyl, wherein:

t is 0 or 1, and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

n is 1, 2, or 3;

m is 1 or 2;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _tO- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein:

t is 0 or 1, and

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

s is 0, 1, or 2;

Each R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and

Two of ^R26 , ^R60 , ^R50 , ^R501 and ^R601 may be joined together to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 or two ^R601 .

In some aspects of the structure (X), R ²¹ is a halogen, a _C1 - _C4 straight-chain or branched alkyl group, or a _C3 - _C5 cycloalkyl group.

In some aspects of the structure (X), ^R3 is H or a halogen.

In some aspects of the structure (X), ^R1 is -CN or _C1 - _C2 haloalkyl.

In some aspects of the structure (X), ^R3 is H or F.

In some aspects of the structure (X), ^R1 is -CN.

In some aspects of the structure (X), ^R1 is _-CF3 .

In some aspects of the structure (X), n is 1.

In some aspects of the structure (X), n is 2.

In some aspects of the structure (X), m is 1.

In some aspects of the structure (X), m is 2.

In some aspects of structure (X), ^R21 is a _C1 - _C2 alkyl or a _C3 - _C5 cycloalkyl and ^R22 is a _C1 - _C2 alkyl.

In some aspects of the structure (X), R ²¹ is a _C3 - _C5 cycloalkyl and R ²² is a _C1 - _C2 alkyl.

In some aspects of the structure (X), n is 2, m is 1, and ^L3 is -NC(O)-O-(C1-C2 alkyl).

In some aspects of the structure (X), ^L3 is ^NR50 ; ^R50 is _C1 - _C2 alkyl; ^R21 is cyclobutyl; ^R22 is H or methyl; ^R3 is H; ^R1 is -CN; m is 2 and n is 1 or 2.

In some aspects of the structure (X), n is 2, m is 1, ^L3 is 0 and s is 0.

In some aspects of the structure (X), ^R22 is H, methyl, or ethyl.

In some aspects of structure (X), R ²² is methyl.

In some aspects of structure (X), R ²² is H.

In some aspects of the structure (X), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, n is 2 and ^L3 is NR ⁵⁰ , wherein R ⁵⁰ is methyl or ethyl.

In some aspects of the structure (X), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, n is 2 and ^L3 is O.

In some aspects of structure (X), the compound has a structure selected from the following:

In several respects, compounds of structure (XI) or pharmaceutically acceptable salts thereof are provided:

in:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is cyclobutyl, azircyclobutane-1-yl, or cyclopropyl;

^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and

R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl).

In some aspects of the structure (XI), ^R3 is H or a halogen.

In some aspects of the structure (XI), ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some aspects of the structure (XI), R ²¹ is a _C3 - _C4 cycloalkyl and R ²² is a _C1 - _C2 alkyl.

In some aspects of the structure (XI), ^R21 is cyclobutyl and ^R22 is _C1 - _C2 alkyl.

In some aspects of the structure (XI), R ²¹ is cyclobutyl.

In some aspects of structure (XI), ^R3 is H or F.

In some aspects of the structure (XI), ^R1 is -CN.

In some aspects of the structure (XI), ^R1 is _-CF3 .

In some aspects of the structure (XI), R ²² is H, methyl, or ethyl.

In some aspects of structure (XI), R ²² is H.

In some aspects of the structure (XI), R ²² is methyl.

In some aspects of the structure (XI), ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is cyclobutyl, ^R22 is methyl and ^R351 is methyl or ethyl.

In some aspects of structure (XI), the compound has a structure selected from the following:

In some respects, this disclosure provides compounds having any of the structures shown in Table 1. According to this disclosure, the compounds in Table 1 are inhibitors of fatty acid synthases.

Compound Synthesis

This document also describes a method for synthesizing the compounds disclosed herein. The compounds disclosed herein can be synthesized as shown in the following synthetic procedures 1-13.

Process 1

in:

R″ is hydrogen or alkyl;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino; and

R ₁₇ is hydrogen or alkyl.

Process 2

in:

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl or alkylamino;

_R23 is hydrogen, -N( _R13 )( _R14 ), _C1-6 alkyl, _C1-6 alkoxy; if _L1 is N, then _R23 is absent; or _R23 and _R24 , together with the atoms they are attached to, are bonded together to form a heterocyclic, heteroaryl, or cycloalkyl group; and

_R24 is hydrogen, -N( _R13 )( _R14 ), _C1-6 alkyl, _C1-6 alkoxy, -( _C1-6 alkoxy)(heterocyclic), heterocyclic, or _R23 and _R24 together with the atoms they are attached to form a heterocyclic, heteroaryl, or cycloalkyl group.

Process 3

in:

LG is a leaving group;

Nu is a nucleophilic substance;

_L2 , _L3 , _L4 and L4 _′ are each independently CH or N;

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino; and

R ₁₇ is hydrogen or alkyl.

Process 4

in:

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl or alkylamino;

R ₁₇ is hydrogen or alkyl; and

_R24 is hydrogen, -N( _R13 )( _R14 ), _C1-6 alkyl, _C1-6 alkoxy, -( _C1-6 alkoxy)(heterocyclic) or heterocyclic.

Process 5

in:

_R1 is hydrogen, cyano, halogen, _C1-6 alkyl, _C1-6 alkoxy, -C(=O)N( _R13 )( _R14 ), -( _CH2 ) _qC (=O)N( _R13 )( _R14 ), _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

q can be 0, 1, 2, 3, or 4;

R ₂₀ is hydrogen or C _1-6 alkyl, C _1-6 alkoxy or -N(R ₁₃ )(R ₁₄ );

_R2 is hydrogen, halogen, _C1-6 alkoxy, or _C1-6 alkyl;

_R3 is hydrogen, hydroxyl, halogen, _C1-6 alkyl, or _C1-6 alkoxy.

_R21 and _R22 are each independently hydrogen, halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _CF3 , _-OCF3 or -S(=O) _{2R20 ;}

_R13 and _R14 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, -N ( _{R15 R16} ) or -S (=O) _{2 R20} ;

_R15 and _R16 are each independently hydrogen, _C1-6 alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl or alkylamino;

R ₁₇ is hydrogen or alkyl;

_R24 is hydrogen, -N( _R13 )( _R14 ), _C1-6 alkyl, _C1-6 alkoxy, -( _C1-6 alkoxy)(heterocyclic) or heterocyclic;

R ₂₉ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxyalkyl, heteroaryl, heterocyclic, -N (R ₁₅ R ₁₆ ), -C(=O)R ₄₆ or -R ₄₈ C(=O)R ₄₇ ;

R ₃₄ is hydrogen, _C1-6 alkyl, _C1-6 alkoxy, cycloalkyl, hydroxyl, hydroxyalkyl, aryl, heterocyclic, heteroaryl, alkylamino, _CF3 , _-OCF3 , -S(=O) _2R20 or -N ( _{R15 R16 )} ; and

m can be 0, 1, or 2.

Procedure 6-13 provides the synthesis of exemplary compounds of general formula IX, wherein:

^R1 can be H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl), or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

_C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

Each R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl;

^R3 is H, -OH, or a halogen;

R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl, or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

R ²² is H, halogen, or _C1 - _C2 alkyl;

R ²³ is an H or a _C1 - _C4 straight-chain or branched alkyl group; and

R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein:

t is 0 or 1; and the _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

Process 6

Process 7

Process 8

Process 9

Process 10

Process 11

Process 12

Process 13

Other methods for preparing specific compounds according to this disclosure are provided in the examples. Those skilled in the art will recognize that other compounds with different structures can be prepared by modifying the procedures of a specific disclosure using methods known to those skilled in the art. Other examples are shown in Table 1.

Many such techniques are well known in the art. However, many of the known techniques are detailed in Compendium of Organic Synthetic Methods (Vol. 1, 1971; Vol. 2, 1974; Vol. 3, 1977; Vol. 4, 1980; Vol. 5, 1984; and Vol. 6) and March, Advanced Organic Chemistry (1985); Comprehensive Organic Synthesis: Selection, Strategy & Efficiency in Modern Organic Chemistry. Volume 9 (1993); Advanced Organic Chemistry Part B: Reactions and Synthesis, 2nd edition (1983); Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, 2nd edition (1977); Protecting Groups in Organic Synthesis, 2nd edition; and Comprehensive Organic Transformations (1999).

Viral infection routes

Host cell targets inhibited by the compounds and methods of this invention play a role in viral replication and/or infection pathways. Targeting of these host cell targets modulates viral replication and/or infection pathways. In a preferred aspect, the compositions of this disclosure are used to directly or indirectly modulate identified host cell targets. Modulation of such host cell targets can also be achieved by targeting entities in upstream or downstream signaling pathways of the host cell targets.

According to this disclosure, viral infections can be treated by targeting fatty acid synthesis pathways, and in particular by targeting fatty acid synthases. HRV is a representative virus that can be treated according to this disclosure. Like other viruses, HRV replication comprises six stages: spread, entry, replication, biosynthesis, assembly, and exit. Entry occurs via endocytosis, replication and vRNP assembly occur in the cell nucleus, and the virus buds from the plasma membrane. In infected patients, the virus targets tracheal epithelial cells. The compounds and methods of this invention target and modulate at least one host cell target involved in these pathways.

For some viruses, significant progress has been made in elucidating the steps involved during infection of host cells. For example, experiments beginning in the early 1980s showed that influenza viruses follow a stepwise endocytic entry procedure with elements shared by other viruses such as alpha viruses and rod-shaped viruses (Marsh and Helenius 1989; Whittaker 2006). These steps include: 1) initial attachment to sialic acid-containing glycoconjugate receptors on the cell surface; 2) signal transduction induced by viral particles; 3) endocytosis via clathrin-dependent and clathrin-independent cellular mechanisms; 4) acid-induced hemagglutinin (HA)-mediated permeation from late endosomes; 5) acid-activated M2 and matrix protein (M1)-dependent uncoating of the capsid; and 6) intracytoplasmic transport and nuclear importation of vRNPs. These steps depend on the assistance of host cells in the form of sorting receptors, vesicle formation mechanisms, kinase-mediated regulation, organelle acidification, and most likely, cytoskeleton activity.

Influenza receptors attaching to cell surfaces occur via HA1 subunits to cell surface glycoproteins and glycolipids containing oligosaccharide moieties with terminal sialic acid residues (Skehel and Wiley 2000). The sialic acid-to-the-next-sugar linkage contributes to species specificity. Avian strains, including H5N1, prefer α-(2,3)-linking, while human strains prefer α-(2,6)-linking (Matrosovich 2006). In epithelial cells, binding preferably occurs at the microvilli on the apical surface, and endocytosis occurs at the base of these extensions (Matlin 1982). Although it is not known whether receptor binding induces signals that prepare the cell for invasion, it is possible that effective entry requires activation of protein kinase C and synthesis of phosphatidylinositol-3-phosphate (PI3P) (Sieczkarski et al., 2003; Whittaker 2006).

Internalization occurs within minutes of binding (Matlin 1982; Yoshimura and Ohnishi 1984). In tissue-cultured cells, influenza viruses utilize three different types of cellular processes: 1) pre-existing clathrin-coated pits; 2) virus-induced clathrin-coated pits; and 3) internalization in vesicles without a visible outer coating (Matlin 1982; Sieczkarski and Whittaker 2002; Rust et al., 2004). Video microscopy using fluorescent viruses shows that viral particles undergo rapid, actin-mediated movement in the pericellular space, followed by negative-terminal, microtubule-mediated transport to the perinuclear region of the cell. Live-cell imaging indicates that viral particles first enter a subset of moving peripheral early endosomes, which carry the viral particles deep into the cytoplasm, followed by infiltration (Lakadamyaii et al., 2003; Rust et al., 2004). The process of endocytosis is regulated by protein and lipid kinases, proteasomes, and Rabs and ubiquitin-dependent sorting factors (Khor et al., 2003; Whittaker 2006).

The membrane permeation step is mediated by the low pH-mediated activation of the trimer metastable HA and the conversion of the type I viral fusion protein to a membrane fusion-competent conformation (Maeda et al., 1981; White et al., 1982). This occurs approximately 16 minutes after internalization, and the pH threshold varies between strains in the range of 5.0–5.6. The target membrane is the restrictive membrane of the mid- or late-stage endosome. The fusion mechanism has been extensively studied (Kielian and Rey 2006). Furthermore, it has been observed that fusion itself does not appear to require any host cell components other than the lipid bilayer membrane and functional acidification systems (Maeda et al., 1981; White et al., 1982). The permeation step is inhibited by the action of lysosomal weak bases, carboxylate ionopreservators, and proton pump inhibitors (Matlin 1982; Whittaker 2006).

For the nuclear importation of vRNPs to be permitted, the capsid must be broken down. This step involves acidification of the M1 channel within the virus via amantadine-sensitive M2 channels, causing dissociation of the vRNP from the M1 channel (Bukrinskaya et al., 1982; Martin and Helenius, 1991; Pinto et al., 1992). Individual vRNPs are transported to the nuclear pore complex and translocated into the nucleus, depending on nuclear transport receptors (O'Neill et al., 1995; Cros et al., 2005). Viral RNA replication (synthesis of positive and negative strands) and transcription occur in a complex closely associated with chromatin in the nucleus. Clearly, although many steps are catalyzed by viral polymerases, cytokines are involved, including RNA polymerase activator, chaperone protein HSP90, hCLE, and human splicing factor UAP56. Viral gene expression is subject to complex cellular control at the transcriptional level (a control system dependent on cellular kinases) (Whittaker, 2006).

The final assembly of influenza particles occurs during budding at the plasma membrane. In epithelial cells, budding occurs only in the apical membrane domain (Rodriguez-Boulan 1983). First, progeny vRNPs are transported within the nucleoplasm to the nuclear envelope, then from the nucleus to the cytoplasm, and finally accumulate in the periphery. Exit from the nucleus depends on the viral proteins NEP and M1, as well as various cellular proteins, including CRM1 (nuclear export receptor), caspase, and possibly several nuclear chaperone proteins. Phosphorylation plays a role in nuclear export by regulating M1 and NEP synthesis and via the MAPK/ERK system (Bui et al., 1996; Ludwig 2006). G protein and protein kinase signaling are involved in influenza virus budding from infected host cells (Hui E. and Nayak D, 2002).

The three membrane proteins of the virus are synthesized, folded, and assembled into oligomers in the ER (Doms et al., 1993). They cross the Golgi complex and undergo maturation via modifications to their carbohydrate moiety and protein cleavage. Upon reaching the plasma membrane, they associate with M1 and vRNPs during budding, resulting in a composition including all eight vRNPs and excluding most host cell components except lipids.

Influenza infection is associated with the activation of several signaling cascades, including the MAPK pathway (ERK, INK, p38, and BMK-1/ERK5), the IkB/NF-κB signaling module, the Raf/MEK/ERK cascade, and programmed cell death (Ludwig 2006). These factors exert various effects on limiting the course of infection, such as transcriptional activation of IFNb, apoptotic cell death, and blocking viral escape from late endosomes (Ludwig 2006).

Most previous studies on virus-cell interactions have been conducted in tissue cultures using virus strains adapted to tissue culture or oocytes. In these cases, the viruses are adapted in ways that induce changes in receptor binding and tropism (Matrosovich 2006). Infection with wild-type pathogens provides a more natural picture of viral-host protein interactions. It is known that in human influenza A and B, infection first occurs in non-ciliated epithelial cells of the upper respiratory tract carrying NeuSAc α-(2,6)-Gal, while avian strains infect ciliated epithelial cells with α-(2,3)-linked sialic acid deeper in the trachea (Matrosovich et al., 2004a).

Furthermore, progress has been made in elucidating the steps involved in host cell infection with HRV. Selected events in rhinovirus infection of the normal human trachea can be considered to occur sequentially. The initial steps of the confirmed rhinovirus pathogenesis include viral entry through the nose, transport of the virus to the posterior pharynx via mucociliary tracts, and initiation of infection in the ciliated and non-ciliated epithelial cells of the upper trachea. Viral replication peaks within an average of 48 hours of initiation and persists for up to 3 weeks. Following infection, several inflammatory mechanisms are activated, which may include the release or production of interleukins, bradykinin, prostaglandins, and possibly histamine, as well as stimulation of parasympathetic reflexes. Pathophysiological processes begin, including vasodilation of nasal blood vessels, plasma exudation, glandular secretion, and stimulation of nerve fibers, causing pain and triggering sneezing and coughing reflexes. The resulting clinical conditions are sinusitis, pharyngitis, and bronchitis, which last an average of one week.

Changes in gene expression profiles during rhinovirus infection in vivo have been identified (Proud D. et al., Am J RespirCrit Care Med, Vol. 178, pp. 962-968, 2008). Nasal epithelial scrapings were obtained before and during experimental rhinovirus infection, and gene expression was assessed by microarray. Viperin was identified as an interferon (IFN)-induced antiviral protein, a virus infection, and a pathogen-associated molecule. The role of viperinin in rhinovirus infection was further evaluated using naturally acquired rhinovirus infection, cultured human epithelial cells, and short interfering RNA knockdown. Symptom scores and viral titers were measured in subjects inoculated with rhinovirus or as sham controls, and changes in gene expression were assessed at 8 and 48 hours post-inoculation. No rhinovirus-induced changes in gene expression were observed at 8 hours post-inoculation, but significant alterations were observed in 11,887 gene transcripts in scrapings obtained 2 days post-inoculation. The major upregulated gene groups included chemokines, signal transduction molecules, interferon-responsive genes, and antivirals. Rhinovirus infection significantly alters the expression of many genes associated with immune responses, including chemokines and antivirals. Some genes significantly induced by HRV-16 infection include, but are not limited to, CCL2, CCL8, CXCL11, CXCL10, CXCL13, CXCL9, CCL20, IFIT2, GBP1, IFIT1, GIP2, IFIT4, IL28B, IRF7, CIG5, NOS2A, OAS3, OASL, OAS2, OAS1, MX2, MX1, PLSCR1, SOCS1, SOCS2, MDA5, RIGI, SOCS3, ICAM-1, HAPLN3, MMP12, EPSTI1, and TNC.

Fatty acid synthesis pathway

Several aspects of this disclosure relate to compositions and methods for regulating the activity of fatty acid synthesis pathways to treat viral infections or cancer. The fatty acid synthesis pathway in humans utilizes four enzymes: 1) acetyl-CoA carboxylase (ACC), which synthesizes malonyl-CoA; 2) malic acidase, which produces NADPH; 3) citrate lyase, which synthesizes acetyl-CoA; and 4) fatty acid synthase, which catalyzes the NADPH-dependent synthesis of fatty acids from acetyl-CoA and malonyl-CoA. In several aspects, this disclosure relates to treating viral infections and cancer by regulating the activity of fatty acid synthase proteins.

The final products of fatty acid synthase are free fatty acids, which can be incorporated into other products by independent enzymatic derivatization using coenzyme A. In humans, fatty acid synthesis can occur at two sites: the liver, where palmitic acid is produced (Roncari, (1974) Can. J. Biochem., 52: 221-230); and the mammary gland, where _C10 - _C14 fatty acids are produced (Thompson et al., (1985) Pediatr. Res., 19: 139-143).

Fatty acids can be synthesized from acetyl-CoA in the cytoplasm. Acetyl-CoA is produced from pyruvate via pyruvate dehydrogenase (PDH) and through the β-oxidation of fatty acids in the mitochondria. The "citrate shuttle" transports acetyl-CoA from the mitochondria to the cytoplasm. Acetyl-CoA reacts with oxaloacetate to produce citrate, and tricarboxylic acid translocase transports citrate from the mitochondria to the cytosol. In the cytoplasm, citrate can be cleaved back into oxaloacetate and acetyl-CoA; this reaction is catalyzed by ATP-citrate lyase. Oxaloacetate can then be converted back into pyruvate for re-entry into the mitochondria.

Acetyl-CoA can be converted to malonyl-CoA. Acetyl-CoA carboxyltransferase (ACC) is a complex, biotin-containing, multifunctional enzyme system that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. This conversion is an irreversible rate-limiting step in fatty acid synthesis. ACC performs three functions: a biotin carboxyl carrier protein, a biotin carboxylase, and a carboxyltransferase. Following ATP-dependent carboxylation of biotin and its cofactor, the carboxyl group is transferred to acetyl-CoA.

_HCO3- ⁺ ATP + acetyl-CoA → ADP + _Pi + malonyl-CoA

There are two forms of ACC, α and β, encoded by two different genes. ACC-α (also known as ACC, ACAC, ACC1, ACCA, and ACACA) encodes a protein highly enriched in lipid-producing tissues. Various alternating splice transcriptomic variants have different sequences, and different isoforms have been found to encode this gene. ACC-β (also known as ACC2, ACCB, HACC275, and ACACB) encodes a protein believed to control fatty acid oxidation by inhibiting carnitine-palmitoyl-CoA transferase I (the rate-limiting step in fatty acid uptake and mitochondrial oxidation) via malonyl-CoA. ACC-β may be involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis. There is evidence of two ACC-β isoforms.

ACC can be regulated by phosphorylation/dephosphorylation of targeted serine residues. For example, AMP-activated kinase (AMPK) phosphorylates ACC, and this phosphorylation inhibits ACC's ability to produce malonyl-CoA. On ACACA, AMPK can phosphorylate Ser79, Ser1200, and Ser1215 (Park S.H. et al., (2002) J. Appl. Physiol. 92: 2475-82). AMPK can phosphorylate Ser218 on ACACB (Hardie D.G. (1992) Biochim. Biophys. Acta 1123: 231-8). In addition, cAMP-dependent protein kinases (protein kinase A or PKA) can phosphorylate ACC.

ACC can be regulated by allotropic conversion of citrate or palmitoyl-CoA. For example, citrate can be a positive effector (i.e., citrate can allotropically activate ACC). Citrate concentrations may be high when sufficient acetyl-CoA enters the Krebs cycle. Excess acetyl-CoA can then be converted to fatty acids via malonyl-CoA. Palmitoyl-CoA can be a negative effector. Palmitoyl-CoA is a product of fatty acid synthase (FASN), which promotes the inactive conversion of ACC, and the inactive conversion of ACC reduces malonyl-CoA production (a feedback inhibition process). AMP can regulate fatty acid synthesis by modulating the availability of malonyl-CoA. Insulin-binding receptors can activate phosphatases to dephosphorylate ACC, which can remove the inhibitory effect.

Fatty acid synthase genes (also known as FAS, OA-519, SDR27X1; MGC14367; MGC15706; FASN) are involved in fatty acid synthesis. The enzyme encoded by this gene is a multifunctional protein of approximately 272 kDa with multiple domains, each possessing different enzymatic activities that play a role in fatty acid biosynthesis. FASN catalyzes the synthesis of long-chain saturated fatty acids from palmitate via acetyl-CoA and malonyl-CoA in the presence of NADPH. In some cancer cell lines, the FASN protein has been found to fuse with estrogen receptor-α (ER-αt), with the N-terminus of FASN fused within the C-terminal frame of ER-α.

FASN proteins can exist in the cytosol as dimers of the same subunits. The N-terminal region of FASN consists of three catalytic domains (-ketoacyl synthase (KS), malonyl/acetyltransferase (MAT), and dehydrogenase (DH)). The N-terminal region is separated from the C-terminal domains by a core region of approximately 600 amino acids (enoyl reductase (ER), -ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase (TE)). The crystal structures of mammalian fatty acid synthases have been reported (Maier T. et al., (2008) Science 321: 1315-1322). In the method for treating viral infections provided by the invention, the catalytic domains of FASN can be targeted.

Enzymatic steps in fatty acid synthesis can include decarboxylation condensation, reduction, dehydration, and another reduction, and can produce a saturated acyl moiety. NADPH can serve as an electron donor in the reduction reaction.

Antiviral activity

In several aspects, this disclosure provides a method for treating a subject with a viral infection, the method comprising administering to a subject in need of the treatment an effective amount of a compound of structure (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1.

In several respects, this disclosure provides a method for treating viral infections, the method comprising administering a compound of the disclosure to a subject in need of the agent.

This disclosure covers any viral infection that targets the fatty acid synthesis pathway in the host, and particularly by modulating the activity of fatty acid synthases. For example, the method of the present invention can be used to treat influenza infection, adenovirus infection, respiratory syncytial virus infection, poxvirus infection, polio infection, hepatitis C infection, yellow fever infection, dengue fever infection, rhinovirus infection, etc.

In several respects, this disclosure provides a method for treating hepatitis C infection by administering one or more of the compounds disclosed herein to a subject. Hepatitis C infection is treated by modulating the FASN pathway in the subject. It has been shown that FASN expression is upregulated in human hepatocellular carcinoma cell line Huh7 when infected with HCV. Inhibition of FASN production with FASN inhibitors reduces HCV production. Therefore, the subjects are administered the compounds of this disclosure (Yang, W. et al., (2008) Hepatology 48(5): 1396-1403). Examples demonstrate that FASN inhibition is associated with HCV inhibition.

In some respects, methods for inhibiting viral infection can be performed outside the body. In other respects, methods for inhibiting viral infection can be performed inside the body.

In some respects, the compounds disclosed herein can be combined with other antiviral therapies for the treatment of viral infections.

In several respects, viral infection can cause human yellow fever. In other respects, it can cause human hepatitis C. In still other respects, it can cause human rhinovirus infection.

In several respects, the compounds disclosed herein can be used to treat infections of any of a wide range of viruses in animal subjects, such as humans.

In some respects, the compounds disclosed herein can be used to inhibit respiratory viruses in the host. Respiratory viruses are most commonly transmitted by airborne droplets or nasal secretions and can cause a variety of illnesses. Respiratory viruses include respiratory syncytial virus (RSV), influenza virus, coronaviruses (such as SARS), adenovirus, parainfluenza virus, and rhinovirus (HRV).

According to one aspect, this disclosure can be used to treat HRV infection. Rhinoviruses are members of the family Picornaviridae. Genera within this family include Enterovirus, Rhinovirus, Cardiovirus, Aphthovirus, Hepatovirus, Parechovirus, Erbovirus, Kobuvirus, and Teschovirus. Human rhinoviruses (HRVs) include the most common viruses that infect humans and cause the common cold. HRVs are cytolytic. Rhinoviruses have a single-stranded, positive-sense RNA genome of 7.2 kb to 8.5 kb in length. The 5′ end of these genomes encodes viral proteins and, like mammalian mRNA, also possesses a 3′ poly-A tail. The 5′ UMP of the viral RNA is covalently linked to the small viral protein VPg (Paul AV et al., Nature 1998, 393(6682): 280-284). The 5′ UTR contains two structural elements. One is the 5′ cloverleaf structure involved in the synthesis of the positive RNA strand and the transition from translation to replication (Huang H et al., Biochemistry 2001, 40(27): 8055-8064). The other is the internal ribosome entry site (IRES), which promotes the translation of polymerized proteins. In addition, species-specific internal cis-acting replication elements (cre) have been identified in human enteroviruses (HEV), HRV-A, and HRV-B (Gerber K, Wimmer E, Paul AV, J Virol 2001, 75(22): 10979-10990). The viral particles themselves are unenveloped and have an icosahedral structure. Rhinoviruses also grow optimally at temperatures of 33-35°C. They are also sensitive to acidic environments.

HRV viral proteins are transcribed into a single long polypeptide, which cleaves into structural and non-structural viral proteins. Rhinoviruses consist of a capsid containing four viral proteins: VP1, VP2, VP3, and VP4 (Rossmann M et al., 1985 Nature 317(6033): 145-53; Smith T et al., 1986 Science 233(4770): 1286-93). The isometric nucleocapsid has a diameter of 22-40 nm. VP1, VP2, and VP3 form the major parts of the protein capsid. The much smaller VP4 protein has a more elongated structure and is located at the interface between the capsid and the RNA genome. Sixty copies of each of these proteins assemble into an icosahedron. Human antibodies targeting epitopes located on the outer regions of VP1-VP3 play a role in the immune response to HRV.

HRV has two common modes of transmission: 1) via aerosols from respiratory droplets and 2) from contaminated surfaces, including direct person-to-person contact. The primary route of entry for rhinovirus is the upper respiratory tract. HRV then binds to ICAM-1 (Inter-Cellular Adhesion Molecule 1) on respiratory epithelial cells, a receptor also known as CD54 (Cluster of Differentiation 54). As the virus replicates and spreads, infected cells release chemokines and cytokines, which in turn activate inflammatory mediators. Infection occurs rapidly, with the rhinovirus attaching to surface receptors within 15 minutes of entering the respiratory tract. The incubation period is typically 8–10 hours, followed by the onset of symptoms. HRV is the most common cause of infection in all age groups of the human population. Replication is usually confined to the upper respiratory tract, producing self-limiting illnesses such as the common cold. However, HRV infection can exacerbate pre-existing tracheal conditions, invade the lower respiratory tract, and lead to serious complications.

On the other hand, the compounds disclosed herein can be used to treat influenza virus infection by targeting the pathways upon which viral infection or replication depends. Influenza viruses belong to the family Orthomyxoviridae. This family also includes Thogoto virus and Dhorivirus. Several types and subtypes of influenza viruses are known to exist, infecting humans and other species. Type A influenza viruses infect humans, birds, pigs, horses, seals, and other animals, but wild birds are the natural hosts of these viruses. Type A influenza viruses are divided into several subtypes and named based on two proteins on the viral surface: hemagglutinin (HA) and neuraminidase (NA). For example, “H7N2 virus” indicates a subtype A influenza virus possessing both HA7 and NA2 proteins. Similarly, “H5N1” virus possesses both HA5 and NA1 proteins. There are 16 known HA subtypes and 9 known NA subtypes. Many different combinations of HA and NA proteins are possible. Currently, only a few subtypes of influenza A (i.e., H1N1, H1N2, and H3N2) are prevalent in humans. Other subtypes are most common in other animal species. For example, H7N7 and H3N8 viruses cause disease in horses, while H3N8 has recently been shown to cause disease in dogs (see www.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Antiviral agents targeting host cell proteins involved in influenza infection can be used to protect high-risk groups (hospital facilities, nursing homes for the elderly, immunosuppressed subjects) as appropriate. A potential use of antiviral agents is to limit the spread and severity of future widespread epidemics caused by avian H5N1 or other strains of influenza virus. Avian influenza A viruses of the H5 and H7 subtypes (including H5N1, H7N7, and H7N3) are highly pathogenic, and infections with these viruses can range from mild (H7N3, H7N7) to severe and fatal (H7N7, H5N1). Human illnesses caused by low-pathogenic viruses have been documented, ranging from very mild symptoms (e.g., conjunctivitis) to influenza-like illness. Examples of low-pathogenic viruses that have infected humans include H7N7, H9N2, and H7N2 (see www.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza B virus is commonly found in humans, but can also infect seals. Unlike influenza A virus, these viruses are not classified by subtype. Influenza B virus can cause illness and death in humans, but generally produces epidemics less severe than those caused by influenza A virus. Although influenza B virus can cause epidemics in humans, it does not cause widespread epidemics (see www.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza C viruses cause mild illness in humans and do not cause epidemics or widespread outbreaks. These viruses can also infect dogs and pigs. These viruses are not classified according to subtypes (see www.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza viruses differ from one another in terms of cell surface receptor specificity and cytotropy, but they use a common entry pathway. The compounds disclosed herein advantageously target this common pathway of multiple viruses, producing broader antiviral activity. Therefore, the compounds of this invention can also demonstrate effectiveness against unrelated viruses using similar pathways. For example, these agents can protect tracheal epithelial cells from a variety of different viruses besides influenza viruses.

In some respects, the compounds disclosed herein can be used to treat adenovirus infections. Most adenoviruses commonly cause respiratory illnesses; symptoms of respiratory illnesses caused by adenovirus infection range from cold symptoms to pneumonia, croup, and bronchitis. Patients with compromised immune systems are particularly susceptible to serious complications from adenovirus infection. Acute respiratory illness (ARD), first recognized in military recruits during World War II, can be caused by adenovirus infection under crowded and stressful conditions. Adenoviruses are medium-sized (90-100 nm) non-enveloped icosahedral viruses containing double-stranded DNA. There are 49 immunologically distinct types (6 subgenera: A to F) that can cause infection in humans. Adenoviruses are generally stable to chemical or physical agents and adverse pH conditions, allowing them to survive for extended periods in vitro. Some adenoviruses (such as AD2 and Ad5 (species C)) use inclusionin-mediated endocytosis and pinocytosis for infectious entry. Other nematoviruses (such as Ad3 (species B)) use dynein-dependent endocytosis and pinocytosis for infectious entry.

In some respects, the compounds disclosed herein can be used to treat respiratory syncytial virus (RSV) infection. RSV is the most common cause of bronchiolitis and pneumonia in infants and children under 1 year of age. The initial symptoms most commonly include fever, runny nose, cough, and sometimes asthma. During their first RSV infection, 25% to 40% of infants and young children present with signs or symptoms of bronchiolitis or pneumonia, and 0.5% to 2% require hospitalization. Most children recover from the illness within 8 to 15 days. Most children hospitalized for RSV infection are under 6 months of age. RSV also causes reinfection throughout life, usually involving moderate to severe cold-like symptoms; however, severe lower respiratory tract illness can occur at any age, particularly in the elderly or in individuals with compromised heart, lungs, or immune systems. RSV is a negative-sense enveloped RNA virus. The shape and size of the viral particles (average diameter 120 nm to 300 nm) are variable, they are unstable in the environment (surviving only a few hours on environmental surfaces), and are readily inactivated by soap and water and disinfectants.

In some respects, the compounds disclosed herein can be used to treat human parainfluenza virus (HPIV) infection. HPIV is the second most common cause of lower respiratory tract illness in young children, after respiratory syncytial virus (RSV). Similar to RSV, HPIV can cause recurrent infections throughout life, usually manifesting as upper respiratory tract illnesses (such as colds and/or sore throats). HPIV can also cause serious lower respiratory tract illnesses with recurrent infections (such as pneumonia, bronchitis, and bronchiolitis), particularly in the elderly and in patients with compromised immune systems. The four types of HPIV each have distinct clinical and epidemiological characteristics. The most distinctive clinical feature of HPIV-1 and HPIV-2 is croup (i.e., laryngotracheobronchitis); HPIV-1 is the leading cause of croup in children, while HPIV-2 is rarely detected. Both HPIV-1 and HPIV-2 can cause other upper and lower respiratory tract illnesses. HPIV-3 is more commonly associated with bronchiolitis and pneumonia. HPIV-4 is rarely detected, possibly because it is unlikely to cause serious illness. The incubation period for HPIV is typically 1 to 7 days. HPIV is a negative-sense single-stranded RNA virus with fusion structures and hemagglutinin-neuraminidase glycoprotein "spikes" on its surface. There are four serologically classified types of HPIV (1 to 4) and two subtypes (4a and 4b). The size (average diameter 150 nm to 300 nm) and shape of the virus particles are variable. They are unstable in the environment (surviving on environmental surfaces for several hours) and are easily inactivated by soap and water.

In several respects, the compounds disclosed herein can be used to treat coronavirus infections. Coronaviruses belong to the genus *Coronavirus* of the family Coronaviridae. Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome and helical symmetry. The genome size of coronaviruses ranges from approximately 16 to 31 kilobases, which is very large for an RNA virus. The name "coronavirus" comes from the Latin word *corona*, meaning crown, because the viral envelope appears under an electron microscope to be adorned with characteristic rings of small spherical structures. This morphology is actually formed by viral protrusion membrane particles, which are proteins residing on the surface of the virus and determining host orientation. Coronaviruses belong to the order *Nidovirales*, named from the Latin word *nidus*, meaning nest, because all viruses in this order produce 3′ homo-nested subgenomic mRNA during infection. Proteins contributing to the overall structure of all coronaviruses are protrusions, envelope, membrane, and nucleocapsid. In the specific case of SARS, the restricted receptor-binding domain on the S-terminus mediates the viral binding to its cellular receptor, angiotensin-converting enzyme 2.

This invention covers the treatment of any viral infection targeting the fatty acid synthesis pathway in the host, and particularly by modulating the activity of fatty acid synthases. For example, the method of this invention can be used to treat infections induced by: Abelson leukemia virus, Abelson murine leukemia virus, Abelson's virus, acute laryngotracheobronchitis virus, Adelaide River virus, adeno-associated virus group, adenovirus, African horse sickness virus, African swine fever virus, AIDS virus, and Aleutian parvovirus. Mink disease parvovirus), Alpha retrovirus, Alpha virus, ALV-associated virus, Amapari virus, Aphthovirus, Aquareovirus, Arbovirus, Arbovirus C, Group A Arbovirus, Group B Arbovirus, Arenavirus, Argentine hemorrhagic fever virus, Arterivirus, Astrovirus, Atripline herpesvirus ( Atelineherpesvirus group, Aujezky's disease virus, Aura virus, Auduk disease virus, Australian batlyssavirus, avian adenovirus, avian erythroblastosis virus, avian infectious bronchitis virus, avian leukosis virus, avian leukocyte histiocytosis virus, avian lymphoma virus, avian myeloblastosis virus, avian paramyxovirus, avian pulmonary encephalitis virus, avian reticuloendotheliosis virus, avian sarcoma virus, avian type C retrovirus group, avian hepatotropic DNA virus (Avihepatotropic DNA virus). dnavirus), fowlpox virus, B virus, B19 virus, Babanki virus, baboon herpesvirus, baculovirus, Barmah Forest virus, Bebaru virus, Berrimah virus, β retrovirus, dual RNA virus, Bittner virus, BK virus, Black Creek Canal virus, bluetongue virus, Bolivian hemorrhagic fever virus Borna virus, Borna disease virus, border disease of sheep virus, Borna virus, bovine alpha herpesvirus 1, bovine alpha herpesvirus 2, bovine coronavirus, bovine ephemeral fever virus, bovine immunodeficiency virus, bovine leukemia virus, bovine leukocyte histiocytosis virus, bovine papillitis virus, bovine papillomavirus, bovine papillary stomatitis virus, bovine parvovirus, bovine fusion virus, bovine type C tumor virus, bovine viral diarrhea virus, Buggy Creek virus, bullet-shaped virus cluster, Bunyambwera virus supergroup, Bunyavirus (Avirus), Burkitt's lymphoma virus, Bwamba Fever, CA virus, Calicivirus, California encephalitis virus, camelpox virus, canarypox virus, canine herpesvirus, canine coronavirus, canine distemper virus, canine herpesvirus, canine parvovirus, canine parvovirus, Cano Delgadito virus, caprine arthritis virus, caprine encephalitis virus, caprine herpesvirus, sheep pox virus, heart virus, guinea pig herpesvirus 1, macaque herpesvirus 1 (Cecopithecid herpesvirus 1) Virus 1), Ceropithecine Herpesvirus 1, Ceropithecine Herpesvirus 2, Chandipura Virus, Changuinola Virus, Channel Catfish Virus, Charleville Virus, Varicella Virus, Chikungunya Virus, Chimpanzee Herpesvirus, Chub Reovirus, Chum Salmon Virus, Cocal Virus, Coho Reovirus Salmon reovirus, herpes virus, Colorado tick fever virus, Coltivirus, Columbia SK virus, common cold virus, infectious pustular virus, infectious pustular dermatitis virus, coronavirus, Corriparta virus, rhinitis virus, vaccinia virus, coxsackie virus, CPV (cytopolyhedrovirus), cricket paralysis virus, Crimean-Congo hemorrhagic fever virus. Fever virus, croup-associated virus, cryptovirus, cytovirus, cytomegalovirus, cytomegalovirus group, cytoplasmic polyhedrosis virus, deer papillomavirus, delta retrovirus, dengue virus, densovirus, dependovirus, polycythemia virus, diplorna virus, fruit fly C virus, duck hepatitis B virus, duck hepatitis virus 1, duck hepatitis virus 2, duovirus, Duvenhage virus, deformed wing virus s)DWV, Eastern Equine Encephalitis Virus, Eastern Equine Encephalomyelitis Virus, EB Virus, Ebola Virus, Ebola-like Virus, Echo Virus, Echovirus, Echovirus 10, Echovirus 28, Echovirus 9, Ectomyelitis Virus, EEE Virus, EIA Virus, EIA Virus, Encephalitis Virus, Encephalomyocarditis Syndrome Virus, Enterovirus, Enzyme-Enhanced Virus, Enzyme-Enhanced Virus (LDH), Epidemic Hemorrhagic Fever Virus, Livestock Epidemic Hemorrhagic Disease Virus, Epstein-Barr Virus, Equine Alpha Herpesvirus 1, Equine Alpha Herpesvirus 4, Equine Herpesvirus 2, Equine Abortion Virus, Equine Arteritis Viruses, Equine Organic Encephalopathy Virus, Equine Infectious Anemia Virus, Equine Measles Virus, Equine Rhinoplasty Virus, Equine Rhinoplasty Virus, Eubenangu Virus, European Elk Papillomavirus, European Swine Fever Virus, Everglades Virus, Eyach Virus, Feline Herpesvirus 1, Feline Calicovirus, Feline Fibrosarcoma Virus, Feline Herpesvirus, Feline Immunodeficiency Virus, Feline Infectious Peritonitis Virus, Feline Leukemia/Sarcoma Virus, Feline Leukemia Virus, Feline Panleukopenia Virus, Feline Parvovirus, Feline Sarcoma Virus, Feline Fusion Virus, Filovirus, Flanders Virus, Flavivirus, Foot-and-Mouth Disease Virus, Morganburg Virus (Fort Morgan virus), Four Comers hantavirus, Avian adenovirus 1, Fowlpox virus, Friend virus, Gamma retrovirus, GB hepatitis virus, GB virus, German measles virus, Getah virus, Gibbon leukemia virus, Adenofever virus, Sheep pox virus, Golden shinner virus, Gonometa virus, Goose parvovirus, Granulosavirus, Gross' virus, Ground squirrel hepatitis B virus, Group A arbovirus, Guanareto virus ( Guanarito virus, guinea pig cytomegalovirus, guinea pig type C virus, Hantaan virus, Hantavirus, clam reovirus, rabbit fibroma virus, HCMV (human cytomegalovirus), hemolysinic virus 2, Japanese hemagglutination virus, hemorrhagic fever virus, hendra virus, henipavirus, liver DNA virus, hepatitis A virus, hepatitis B virus group, hepatitis C virus, hepatitis D virus, delta hepatitis virus, hepatitis E virus, hepatitis F virus, hepatitis G virus, non-A non-B hepatitis virus, hepatitis virus, hepatitis virus (non-human), hepatitis encephalitis reovirus 3, hepatitis virus, heron hepatitis B virus, B Herpes simplex virus, herpes simplex virus, herpes simplex virus 1, herpes simplex virus 2, herpesvirus, herpesvirus 7, spider monkey herpesvirus, human herpesvirus, herpesvirus infection, squirrel monkey herpesvirus, swine herpesvirus, varicella herpesvirus, Highlands J virus, flounder rhabdovirus, swine cholera virus, human adenovirus 2, human alpha herpesvirus 1, human alpha herpesvirus 2, human alpha herpesvirus 3, human B lymphocyte virus, human beta herpesvirus 5, human coronavirus, human cytomegalovirus group, human foamy virus, human gamma herpesvirus 4, human gamma herpesvirus 6, human hepatitis A virus, human herpesvirus group 1, human herpesvirus group 2, human herpesvirus group 3, human herpesvirus group 4, human herpesvirus 6, human herpesvirus Virus 8, Human Immunodeficiency Virus, Human Immunodeficiency Virus 1, Human Immunodeficiency Virus 2, Human Papillomavirus, Human T-cell Leukemia Virus, Human T-cell Leukemia Virus I, Human T-cell Leukemia Virus II, Human T-cell Leukemia Virus III, Human T-cell Lymphoma Virus I, Human T-cell Lymphoma Virus II, Human T-cell Lymphoma Virus Type 1, Human T-cell Lymphoma Virus Type 2, Human T-lymphoma Virus I, Human T-lymphoma Virus II, Human T-lymphoma Virus III, Ichnovirus, Infantile Gastroenteritis Virus, Bovine Infectious Rhinotracheitis Virus, Infectious Hematopoietic Necrosis Virus, Infectious Pancreatic Necrosis Virus, Influenza Virus Type A, Influenza Virus Type B, Influenza Virus Type C, Influenza Virus Type D, Influenza Virus pr8 Insect iridovirus, insect virus, iridovirus, Japanese type B virus, Japanese encephalitis virus, JC virus, Junin virus, Kaposi's sarcoma-associated herpesvirus, Kemerovo virus, Kilham's rat virus, Klamath virus, Kolongo virus, Korean hemorrhagic fever virus, kumba virus, Kysanur forest disease virus, Kyzylagach virus, La Crosse virus Lactate dehydrogenase-enhancing virus, Lactate dehydrogenase virus, Lagos bat virus, Langur virus, Rabbit parvovirus, Lassa fever virus, Lassa virus, Latent rat virus, LCM virus, Leaky virus, Lentivirus, Leporipoxvirus, Leukemia virus, Leukovirus, Nodular dermatosis virus, Lymphoid adenosis-associated virus, Lymphoid follicle virus, Lymphocytic choroid plexus meningitis virus, Lymphoproliferative virus group, Horse Machupo virus, pruritus virus, mammalian tumor virus type B, mammalian retrovirus type B, mammalian retrovirus type C, mammalian retrovirus type D, mammary tumor virus, Mapuera virus, Marburg virus, Marburg-like virus, Mason-Pfizer monkey virus, mammalian adenovirus, Mayaro virus, ME virus, measles virus, Menangle virus, Mengo virus, Mengo virus, Middelburg virus urg virus), milker nodule virus, mink enteritis virus, mouse parvovirus, MLV-associated virus, MM virus, mokola virus, molluscum contagiosum virus, molluscum contagiosum virus, simian B virus, monkeypox virus, single-stranded negative-sense virus (Mononegavirales), measles virus, Mount Elgon bat virus, mouse cytomegalovirus, mouse encephalomyelitis virus, mouse hepatitis virus, mouse K virus, mouse leukemia virus, mouse mammary tumor virus, mouse parvovirus. Mouse pneumonia virus, mouse poliovirus, mouse polyomavirus, mouse sarcoma virus, mousepox virus, Mozambique virus, Mucambo virus, mucosal disease virus, mumps virus, murine β-herpesvirus 1, murine cytomegalovirus 2, murine cytomegalovirus group, murine encephalomyelitis virus, murine hepatitis virus, murine leukemia virus, murine root nodule-inducing virus, murine polyomavirus, murine sarcoma virus, murine cytomegalovirus, Murray Valley encephalitis virus, myxoma virus, myxovirus, polymorphic myxovirus, mumps myxovirus, Nairobi sheep disease virus (N (List of viruses including: airobi sheep disease virus, Nairovirus, Nanirnavirus, Nariva virus, Ndumo virus, Neethling virus, Nelson Bay virus, neurovirus, NewWorldArenavirus, neonatal pneumonia virus, Newcastle disease virus, Nipah virus, acellular pathogenic virus, Norwalk virus) Nucleopolyhedrovirus (NPV), papillary neck virus, O'nyong'nyong virus, Ockelbo virus, oncogenic viruses, oncogenic viral particles, oncogenic RNA viruses, Orbivirus, Orf virus, Orropouche virus, Orthohepadnavirus, Orthomyxovirus, Orthopoxvirus, Orthoreovirus, Orrungo virus, sheep papillomavirus, sheep catarrhal fever virus (ovin (e.g., catarrhal fever virus), owl monkey herpesvirus, Palyam virus, papillomavirus, hare papillomavirus, papillomavirus, parainfluenza virus, parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, parainfluenza virus type 4, paramyxovirus, parapoxovirus, paravaccinia virus, parvovirus, parvovirus B19, parvovirus group, pestivirus, phlebovirus, phozoon virus, small DNA virus, small RNA virus, porcine cytomegalovirus-pigeonpox virus, Piry virus, Pixunavirus, mouse Pneumonia virus, pneumovirus, poliomyelitis virus, poliovirus, multiDNA virus, polyhedrovirus, polyomavirus, polyomavirus, bovine polyomavirus, macaque polyomavirus, human polyomavirus 2, macaque polyomavirus 1, murine polyomavirus 1, murine polyomavirus 2, baboon polyomavirus 1, baboon polyomavirus 2, hare polyomavirus, Pongine herpesvirus 1, porcine epidemic diarrhea virus, porcine hemoglobinotropic encephalomyelitis virus, porcine parvovirus, porcine transmissible gastroenteritis virus, porcine type C virus, pox virus, poxvirus, smallpox virus variolae), Prospect Hill virus, Provirus, pseudovaccinia virus, pseudorabies virus, psittacosis virus, quailpox virus, rabbit fibroma virus, rabbit kidney vaccinia virus, rabbit papillomavirus, rabies virus, raccoon parvovirus, raccoon pox virus, Ranichet virus, rat cytomegalovirus, rat parvovirus, rat virus, Rauscher's virus, recombinant vaccinia virus, recombinant virus, reovirus, reovirus 1, reovirus 2, reovirus 3, reptile type C virus, Respiratory tract infection viruses, respiratory syncytial virus, respiratory viruses, reticuloendotheliosis virus, rod-shaped virus, carp rod-shaped virus, rhabdovirus, rhinovirus, Rhizidiovirus, Rift Valley fever virus, Riley's virus, rinderpest virus, RNA tumor virus, Ross River virus, rotavirus, rougeole virus, Rous sarcoma virus, rubella virus, rubeolavirus, Rubivir us), Russian autumn encephalitis virus, SA11 simian virus, SA2 virus, Sabia virus, Sagiyama virus, squirrel monkey herpesvirus 1, salivary gland virus, sandfly virus group, Sandjimba virus, SARS virus, SDAV (salivarius virus), phozooma virus, Semliki Forest virus, Seoul virus, sheep pox virus, Shope fibroma virus, Shope papillomavirus Sapienza papilloma virus, sapienza foam virus, sapienza hepatitis A virus, sapienza immunodeficiency virus, sapienza immunodeficiency virus, sapienza parainfluenza virus, sapienza T-cell lymphotropic virus, sapienza virus, sapienza virus 40, simplex virus, SinNombre virus, Sindbis virus, smallpox virus, South American hemorrhagic fever virus, fowlpox virus, foam virus, squirrel fibroma virus, squirrel monkey retrovirus, SSV 1 virus group, type I STLV (sapienza T-cell lymphotropic virus), type II STLV (sapienza T-cell lymphotropic virus), type III STLV (sapienza T-cell lymphotropic virus) Porcine alpha herpesvirus, swine herpesvirus 1, swine herpesvirus 2, swine poxvirus, equine infectious anemia virus, swine pox virus, Swiss mouse leukemia virus, TAC virus, Tacarib complex virus, Tacarib virus, Tanapox virus, Taterapox virus, Tench reovirus, Theiler's encephalomyelitis virus (The following are listed as viruses and their related names: tis virus, Theiler's virus, Sogoto virus, Thotapalayam virus, Tick-borne encephalitis virus, Tioman virus, Togavirus, Torovirus, Tupaia virus, Turkey rhinotracheitis virus, Turkeypox virus, C-type retrovirus, D-type tumor virus, D-type retrovirus group, Ulcerative disease rod-shaped virus, Una virus, Uukuniemi virus group, bovine) Poxvirus, vacuolating virus, varicella-zoster virus, varicella virus, smallpox virus, severe smallpox virus, smallpox virus, Vasin Gishu disease virus, VEE virus, Venezuelan equine encephalitis virus, Venezuelan equine encephalomyelitis virus, Venezuelan hemorrhagic fever virus, vesicular stomatitis virus, vesicular virus, Vilyuisk virus, viper retrovirus, viral hemorrhagic septicemia virus, Visna-Maedi virus, Visna virus, volepox virus, VSV (vesicular stomatitis virus), Wallal virus, Wariger Warrego virus, wart virus, WEE virus, West Nile virus, Western equine encephalitis virus, Western equine encephalomyelitis virus, Whataroa virus, Winter vomiting virus, Marmot hepatitis B virus, Curly macaque sarcoma virus, Wound tumor virus, WRSV virus, Yabamonkey tumor virus, Yaba virus, Yatapox virus, Yellow fever virus, and Yug Bogdanovac virus.

efficacy in metabolic disorders

In several respects, the compounds disclosed herein have therapeutic efficacy for metabolic diseases. FASN has been shown to be involved in the regulation of glucose, lipid, and cholesterol metabolism. Mice with liver-specific inactivation of FASN exhibit normal physiological function except when fed a zero-fat diet, in which case they develop hypoglycemia and fatty liver, both of which are reversed by dietary fat (Chakravarthy, M.V. et al., (2005) Cell Metabolism 1:309-322). Db/+ mice fed a high-fructose diet showed reduced liver triglyceride levels and improved insulin sensitivity after 28 days of treatment with tebufenozide (a covalent inhibitor of FASN) (Wu, M. et al., (2011) PNAS 108(13):5378-5383). Peripheral glucose levels were also reduced in db/db mice after treatment with tebufenozide. These results provide evidence that inhibition of FASN can produce therapeutic benefits in animal models of diabetes and related metabolic diseases. Therefore, the disclosed FASN inhibitors can be used to treat conditions characterized by these systemic disorders. Examples, without limitation, include sebaceous gland disorders and diabetes.

Nonalcoholic liver disease (NAFLD) is a condition in which the liver contains more than 5% fat by weight and is not caused by alcohol consumption. It currently affects approximately 20-30% of the total population in the United States and the Western world and is associated with a significantly increased risk of developing cardiovascular disease, chronic kidney disease, and malignant diseases, extending beyond the liver. Obesity and metabolic syndrome are two key risk factors for NAFLD, characterized by an imbalance between energy utilization and storage. This imbalance leads to dysregulation of metabolic pathways and inflammatory responses, resulting in other changes that cause liver damage and comorbidities. As metabolic syndrome progresses, NAFLD leads to more advanced liver disease, starting with nonalcoholic steatohepatitis (NASH) and then progressing to severe liver diseases, including cirrhosis and hepatocellular carcinoma.

In subjects with metabolic syndrome and NAFLD, fatty acid synthesis in the liver (a pathway known as de novo lipogenesis (DNL)) is increased. The DNL pathway not only produces fatty acids that contribute to increased hepatic triglyceride reserves, but also produces saturated fatty acids, primarily palmitic acid (C16:0), which contributes to signaling events that enhance liver inflammation. Free palmitic acid is also involved in liver inflammatory processes such as macrophage recruitment and endoplasmic reticulum stress response activation.

In several embodiments, the compounds of this disclosure (e.g., compound 364A) can act preventively to prevent the progression of NASH symptoms, such as elevated AST and ALT, elevated hepatic triglyceride and cholesterol levels, hepatic steatosis, hepatic inflammation, hepatic ballooning, hepatic fibrosis, and NAFLD activity scores. For example, Example 7 demonstrates that the compounds of this disclosure (e.g., compound 364A) can inhibit the progression of metabolic diseases such as liver diseases (e.g., NASH).

Furthermore, the compounds of this disclosure (e.g., compound 364A) can reverse NASH symptoms in a deterministic NASH disease model. For example, Example 10 demonstrates that the compounds of this disclosure can reduce AST, ALT, hepatic triglyceride, and cholesterol levels, as well as symptoms such as hepatic steatosis, liver inflammation, hepatic ballooning, liver fibrosis, and NAFLD activity scores in mice with deterministic NASH after a 44-week high-fat, high-fructose, high-cholesterol diet. In Example 10, NASH disease progression progressed to a level showing fibrosis before administration of the drug to the mice. Data showed dose-response for all major indicators of disease progression.

Therefore, in several aspects, this disclosure provides a method for treating a subject with NASH or NASH symptoms, the method comprising administering to a subject requiring such treatment an effective amount of a compound having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1. In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1 can be used to manufacture a pharmaceutical agent for treating NASH or NASH symptoms. In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1 can be used to treat NASH or NASH symptoms. In some embodiments, NASH is confirmed in the subject, and treatment with the compounds disclosed herein can reduce or eliminate the symptoms and causes of NASH, such as general steatosis, hepatic steatosis, steatohepatitis, inflammation, liver inflammation, lysosomal acid lipase deficiency, and cirrhosis. In other embodiments, the treatment is used prophylactically to prevent the onset of nonalcoholic fatty liver disease (NAFLD), NASH flare-ups, progression of NAFLD to NASH, or to halt the progression of NASH. Whether for prophylactic treatment or treatment of confirmed NAFLD or NASH, treatment of fatty liver disease can reduce risk factors associated with confirmed or progressive diabetes, liver cancer, cardiovascular disease, high triglycerides, kidney disease, and metabolic syndrome.

Therefore, in some embodiments, this disclosure provides a method for treating non-alcoholic steatohepatitis (NAHH), the method comprising administering to a subject in need a compound having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1, wherein the method comprises reversing at least one symptom of definitive NHA. In some embodiments, the method comprises preventing the progression of at least one symptom of NHA. In some embodiments, the symptom is selected from elevated AST levels, elevated ALT levels, elevated hepatic triglyceride levels, elevated cholesterol levels, hepatic steatosis, hepatic inflammation, hepatic ballooning, hepatic fibrosis, and NAFLD activity score.

Furthermore, as described in Example 12, the compounds of this disclosure (e.g., compound 364A) were found to reduce the expression of fibrosis genes in human liver cells. Therefore, in some embodiments, the compounds of this disclosure can reduce the expression of fibrosis genes (e.g., Col 1a1, αSMA, βPDGFR, TGFbR1, TIMP1, TIMP2, and/or MMP2). In some embodiments, gene expression can recover upon withdrawal of the compound (e.g., compound 364A). Therefore, it is not intended to be theoretically correct that downregulation of fibrosis genes is not a toxic effect of the compounds of this disclosure.

Therefore, in several aspects, this disclosure provides a method for reducing the expression of fibrosis genes in a subject (e.g., in the subject's liver cells), the method comprising administering to a subject in need of such treatment an effective amount of a compound having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1. In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1 can be used to manufacture agents for reducing the expression of fibrosis genes (e.g., in liver cells). In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1 can be used to reduce the expression of fibrosis genes (e.g., in liver cells).

Cardiovascular disease is closely associated with the progression of metabolic syndrome. However, NAFLD is also a strong predictor of cardiovascular disease, such as an increased risk of carotid atherosclerotic plaques and endothelial dysfunction, which is not associated with the presence of metabolic syndrome (Francis W.B. et al., “De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose”. Biol. Rev. (2016), 91, pp. 452-468). NAFLD has also been implicated as an independent factor contributing to the development of type 2 diabetes. In subjects with NAFLD, the incidence of prediabetes or type 2 diabetes was 2.6 times higher, suggesting an independent role in the pathogenesis of type 2 diabetes beyond initial insulin resistance (Francis W.B., Biol. Rev. (2016), pp. 452-468; Bae, J.C. et al., “Combined effect of nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetes.” Diabetes Care, 2011, 34, 727-729). Therefore, DNL is an important therapeutic intervention for reducing the consequences associated with metabolic syndrome and NAFLD (Bae, J.C., Diabetes Care, 2011, 727-729).

In individuals with high-fat and high-calorie diets, NAFLD and NASH are associated with obesity and diabetes. In subjects with metabolic syndrome and NAFLD, fatty acid synthesis in the liver (i.e., via the hepatic de novo lipogenesis (DNL) pathway) is increased. One of the key enzymes in DNL is fatty acid synthase (FASN). Although a link between FASN, DNL, and NAFLD is anticipated, there is little evidence that direct inhibition of FASN is a competent mechanism for treating NAFLD or controlling the progression of hepatic steatosis. Some literature reports that direct intervention at FASN via gene knockout or small molecule inhibitors indicates worsening of hepatic steatosis; treatment of NAFLD or NASH requires the exact opposite approach. These results suggest that FASN inhibition is not expected to alleviate hepatic steatosis or be a suitable mechanism for controlling the underlying metabolic dysregulations or inflammatory signaling that drive the progression of fatty liver disease.

For example, liver-specific FASN knockout mice have shown normal livers when maintained on a standard diet. Unexpectedly, when maintained on a zero-fat/high-carbohydrate diet, the mice developed fatty liver (hepatic steatosis) and hypoglycemia, indicating that complete inhibition of FASN in the liver of mammals on a fat-restricted diet can cause precursors to NASH, namely the development of NAFLD (Chakravarthy, M.V. et al., “New hepatic fat activates PPARalpha to maintaining glucose, lipid, and cholesterol homeostasis,” Cell Metabol. 1(5), 2005, 309-322). When the knockout mice were fed a normal diet, no effect was observed on metabolism or the development of hepatic steatosis caused by complete inhibition of FASN by knockout, indicating that FASN inhibition in the liver will have no effect on mammals consuming a fat-containing diet, or will induce fatty liver symptoms (leading to NAFLD and NASH) in mammals consuming a low-fat/high-carbohydrate diet, thus providing the opposite effect required to treat NASH.

Small molecule inhibitors of FASNs have been used to evaluate insulin resistance and hepatic steatosis. In a recent study on obese insulin-resistant Zucker rats (a type 2 diabetes model), inhibition of de novo adipogenesis with small molecule FASN inhibitors did not improve insulin sensitivity and actually increased fat levels in the liver (i.e., hepatic steatosis). FASN inhibitors have also been shown to inhibit de novo lipogenesis in the liver, but lead to hepatic steatosis or increased fat deposition in the liver (“A Novel Fatty Acid Synthase Inhibitor (FASi) Suppresses De Novo Lipogenesis but Induces Hepatic Steatosis, Dermatitis and Does Not Enhance Insulin Sensitivity in Obese Zucker Rats”, Am. Diabetes Assoc. 68th Scientific Sessions, June 6–10, 2008, San Francisco, CA, poster 58LB; WO2008059214). These studies indicate that direct inhibition of FASN reduces fat synthesis in the liver, but leads to accelerated development of NAFLD and NASH in obese diabetic mammals. Therefore, FASN inhibition is not expected to have a therapeutic effect on fatty liver disease in obese and diabetic individuals with the highest risk of NAFLD and NASH.

The activity of the FASN inhibitor of this application against NAFLD was tested. Unexpectedly, the FASN inhibitor of this application has been shown to be effective in a rodent model of NAFLD and to reduce pro-inflammatory IL-1β (IL-1β) in rats on a high-fat diet. The FASN inhibitor of this application has also shown anti-inflammatory activity in cells, specifically reducing IL-1β in human peripheral blood mononuclear cells (PBMCs) and mononuclear cells, and has been shown to regulate the differentiation of mouse and human CD4+ naive T cells, thereby reducing _Th17 (pro-inflammatory helper T cells) and stimulating T _reg (anti-inflammatory regulatory T) cells.

The FASN inhibitors of this application can be used to control NAFLD in rodents by reducing pro-inflammatory cytokines (e.g., IL-1β) and regulating the differentiation of T cells from pro-inflammatory cells (e.g., Th ₁₇ cells) to anti-inflammatory T _reg cells. The FASN inhibitors of this application can be used to treat various metabolic syndromes, including non-alcoholic liver disease (NAFLD) and the more advanced disease non-alcoholic steatohepatitis (NASH). Without treatment, these liver dysfunction symptoms can progress to serious liver diseases, including cirrhosis, i.e., the liver exhibits symptoms of steatosis, inflammation, fibrosis, steatohepatitis, and may progress to hepatocellular carcinoma (hepatocellular carcinoma). Cirrhosis can have direct health consequences due to liver dysfunction, including arachnoid angiomas or spider nevi, palmar erythema, gynecomastia, hypogonadism, ascites, hepatic halitosis, jaundice, portal hypertension leading to splenomegaly, esophageal varices, serpentine head, hepatic encephalopathy, and acute kidney injury (especially hepatorenal syndrome). In some embodiments, the compounds disclosed herein can be used to treat metabolic syndrome, non-alcoholic liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, liver fibrosis, and/or liver cancer (hepatocellular carcinoma).

The FASN inhibitor compounds of this application can also be used to treat inflammatory diseases by inducing changes in inflammation-induced cytokines. Examples of inflammatory diseases that can be treated with the FASN inhibitor compounds of this application include, but are not limited to, inflammatory diseases involving IL-1β, such as diseases that respond to IL-1β blockade or are associated with increased IL-1β expression; familial Mediterranean fever (FMF); pyogenic arthritis, pyoderma gangrenosa, acne acne (PAPA); cryptothermal protein-associated periodic syndrome (CAPS); high IgD syndrome (HIDS); Still disease in adults and adolescents; Schnitzler syndrome; TNF receptor-associated periodic syndrome (TRAPS); Blau syndrome; Sweet syndrome; IL-1 receptor Antagonist deficiency (DIRA); recurrent idiopathic pericarditis; macrophage activation syndrome (MAS); urticarial vasculitis; antisynthetic enzyme syndrome; recurrent chondritis; Behçet's disease; Erdheim-Chester syndrome (histiocytosis); synovitis, acne, impetigo, osteophyte, osteitis (SAPHO); rheumatoid arthritis; periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA); urate crystal arthritis (gout); type 2 diabetes; smoldering multiple myeloma; heart failure after myocardial infarction; osteoarthritis; transfusion-related acute lung injury; ventilator-induced lung injury; pulmonary fibrosis, including idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease (COPD); and asthma.

The FASN inhibitor of this application can also be used to treat diseases or conditions associated with elevated levels of inflammatory T cells and/or decreased or insufficient levels of anti-inflammatory T cells, or to treat diseases or conditions in which regulating leukocyte (i.e., T _cell ) differentiation away from T helper cells and increasing anti-inflammatory regulatory T cells would be beneficial. T _reg cells are essential for immune tolerance and play a key role in limiting excessive immune and inflammatory responses carried out by T helper cells (i.e., _Th1 , _Th2 , _Th9 , _Th17 , etc.). Therefore, reorganizing T helper cell differentiation into regulatory T cells through FASN inhibition can be used to treat inflammatory diseases.

Treatment with the FASN inhibitor of this application can inhibit the maturation of T cells into T helper inflammatory cells (including, but not limited to, _Th1 , _Th2 , _Th9 , and _Th17 T helper cells) and promote their differentiation into T _reg cells. Primary CD4+ cells differentiate into T helper cells and regulatory T cells to perform their immune functions. Differentiation depends on the presence of cytokines. While T helper cells, such as _Th17 cells, play an important role in protective immune responses against intracellular pathogens, excessive immune responses generated by these T helper cells can also cause autoimmune diseases and inflammatory diseases. Examples of immune-mediated diseases that can be treated with the FASN inhibitor of this application include, but are not limited to, psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), asthma, tumorigenesis, and graft rejection. (Laura, A. et al., “Th17 cells in human disease,” Immunol. Rev. 223, 2008, 87-113; Lee, Y. et al., “Unexpected targets and triggers of autoimmunity.” J. Clin. Immunol., 34, Supplement 1, 2014, pp. 56-60)

In several aspects, the disclosed FASN inhibitors can be used to treat conditions characterized by dysregulation in these systems, including but not limited to non-alcoholic fatty acid disease (NAFLD), non-alcoholic steatohepatitis (NASH), steatosis, and diabetes. In one embodiment, this disclosure relates to a method of treating non-alcoholic steatohepatitis (NASH) with a FASN inhibitor compound of the disclosure (i.e., a compound of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)).

In another embodiment, this disclosure relates to a method of treating non-alcoholic steatohepatitis non-alcoholic fatty acid disease (NAFLD) with FASN inhibitor compounds of the present disclosure (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (vII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)).

In several aspects, the disclosed FASN inhibitors can be used to treat metabolic syndrome. In one embodiment, this disclosure relates to a method of treating metabolic syndrome with compounds of the disclosed formula (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)).

In several aspects, the disclosed FASN inhibitors can be used to treat cirrhosis. In one embodiment, this disclosure relates to a method of treating cirrhosis with compounds of the disclosed formula (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)).

In several aspects, the disclosed FASN inhibitors can be used to treat liver fibrosis. In one embodiment, this disclosure relates to a method of treating liver fibrosis with compounds of the disclosed formula (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)).

In several aspects, the disclosed FASN inhibitors can be used to treat inflammation. In one embodiment, this disclosure relates to a method of treating inflammation with compounds of the disclosed formula (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)).

In several aspects, the disclosed FASN inhibitors can be used to treat diseases or conditions with elevated interleukin 1β (IL1β) levels. In one embodiment, this disclosure relates to a method of treating diseases or conditions with elevated interleukin 1β (IL1β) levels with compounds of the disclosed formula (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)). In some implementations, diseases or symptoms with elevated interleukin-1β (IL1β) levels are selected from familial Mediterranean fever (FMF), septic arthritis, pyoderma gangrenosa, acne vulgaris (PAPA), cryptothermal protein-associated periodic syndrome (CAPS), high IgD syndrome (HIDS), adult-onset Still's disease, Schnitzler syndrome, TNF receptor-associated periodic syndrome (TRAPS), Blau syndrome, Sweet's syndrome, IL-1 receptor antagonist deficiency (DIRA), recurrent idiopathic pericarditis, macrophage activation syndrome (MAS), and urticaria. Measles vasculitis, antisynergistic enzyme syndrome, relapsing chondritis, Behcet's disease, Edheimer-Chester syndrome (histiocytosis), synovitis, acne, impetigo, osteophyte, osteitis (SAPHO), rheumatoid arthritis, periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA), urate crystal arthritis (gout), type 2 diabetes, smoking multiple myeloma, heart failure after myocardial infarction, osteoarthritis, transfusion-related acute lung injury, ventilator-induced lung injury, pulmonary fibrosis (including idiopathic pulmonary fibrosis), chronic obstructive pulmonary disease, and asthma.

In several aspects, the disclosed FASN inhibitors can be used to treat diseases or conditions with elevated t-helper ( _Th ) cell levels. In one embodiment, this disclosure relates to a method of treating diseases or conditions with elevated t-helper (Th) cell levels with compounds of the disclosed formula (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)). In some embodiments, the diseases or conditions with elevated t-helper ( _Th ) cell levels are selected from psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis, and graft rejection.

In several aspects, the disclosed FASN inhibitors can be used to treat diseases or conditions in which regulatory T cells (T _regs ) are reduced or suppressed. In one embodiment, this disclosure relates to a method of treating diseases or conditions in which regulatory T cells (T regs) are reduced or suppressed with compounds of the disclosed formula (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)). In some embodiments, the diseases or conditions _{in which regulatory T cells (T regs )} are reduced or suppressed are selected from psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis, and graft rejection.

In some embodiments, the disclosed FASN inhibitors (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)) may also be combined with one or more other therapeutic agents to treat diseases or conditions associated with fatty liver or metabolic syndrome, including but not limited to steatosis, glucose metabolism and lipogenesis. These therapeutic agents include, but are not limited to: (1) stearoyl-CoA desaturase 1 (SCD1) inhibitors, such as Aramchol; (2) fibroblast growth factor (FGF) agonists, such as BMS-986036; (3) peroxisome proliferator-activated α/δ receptor agonists, such as Elafibranor, agliflozin, moggliflozin, and ticaglipizide; and (4) glucagon-like peptide-1 (GLP-1) agonists, such as liraglutide, exenatide, lixinatide, abiglutide, duraglutide, and tastiglutide. (5) Hepatic X receptor α (LXR-α) inhibitors, such as Oltipraz; (6) Dipeptidyl peptidase (DPP4) inhibitors, such as sitagliptin; (7) Peroxisome proliferator-activated receptor (PPAR)-γ agonists, such as thiazolidinediones, rosiglitazone, pioglitazone, lobeglitazone, thioglitazone, dapaglitazone, empaglitazone, neiglitazone, and repaglitazone; (8) Biguanides, such as metformin, buformin, and phenformin; (9) Statins or anti-absorption agents, such as atorvastatin, cetirizine, and cephalosporins. Vastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe, SCH-48461, niacin, taurine, and orlistat; (10) antihyperlipidemic agents and fibrates, such as gemfibrozil, bezafibrate, ciprofibrate, clofibrate, fenofibrate, crifibrate, pentoxifylline, and ursodeoxycholic acid; (11) α-glucosidase inhibitors, such as acarbose; (12) PPARα ligands, such as N-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid. (13) Hexaenoic acid (DHA); (14) FXR agonists, such as obeticholic acid (INT-747) and Px-104; (15) sodium-dependent bile acid transporter inhibitors, such as SHP626; (16) SGLT2 inhibitors, such as repaglinide, canagliflozin, dapagliflozin and empagliflozin; and (17) acetyl-CoA carboxylase (ACC) inhibitors, such as ND-630, ND-654, NDI-010976 (GS-0976), CP-640186 and PF-05175157.

In some embodiments, the disclosed FASN inhibitors (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)) may also be combined with one or more other therapeutic agents for the treatment of diseases or conditions associated with fatty liver or metabolic syndrome. These therapeutic agents include, but are not limited to, (1) immune signaling modulators; (2) TLR antagonists or TLR4 antagonists, such as JKB-121 and JKB-122; (13) TNF-α synthesis inhibitors, such as pentoxifylline; (4) angiotensin II type 1 blockers, such as telmisartan, losartan, valsartan, telmisartan, irbesartan, azisartan and olmesartan; and (5) pro-inflammatory signaling mediators, such as IMM-124E, FGF19 and NGM282.

In some embodiments, the disclosed FASN inhibitors (i.e., compounds of formulas (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) may also be combined with one or more other therapeutic agents to reduce oxidative stress in the treatment of diseases or conditions associated with fatty liver or metabolic syndrome. Such therapeutic agents include, but are not limited to, (1) apoptosis signal-regulated kinase (ASK1) inhibitors for reducing profibrotic responses to ROS and (2) other mediators of oxidative stress, such as GS-4997 and vitamin E.

In some embodiments, the disclosed FASN inhibitors (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)) may also be combined with one or more antifibrotic therapeutic agents for the treatment of diseases or conditions associated with fatty liver or metabolic syndrome. These antifibrotic agents include, but are not limited to, (1) C-C chemokine receptor inhibitors or dual inhibitors of the C-C chemokine receptor type 2 (CCR2) and C-C chemokine receptor type 5 (CCR5) pathways, such as Centicriviroc; (2) galactoglobulin antagonists or galactoglobulin-3 antagonists, such as GR-MD-02; (3) angiotensin receptor blockers (ARBs) that disrupt the renin-angiotensin system, such as losartan; (4) lysyl oxidase-like protein 2 (LOXL2) inhibitors, such as cetuzumab; and (5) fibrosis mediators, such as vitamin A, vitamin C, and vitamin D.

In some embodiments, the disclosed FASN inhibitors (i.e., compounds of formulas (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) may also be combined with one or more other apoptosis inhibitors for the treatment of diseases or conditions associated with fatty liver or metabolic syndrome. These apoptosis inhibitors include, but are not limited to, (1) apoptotic protease inhibitors, such as GS-9450 or Emricasan; and (2) galactolectin inhibitors, such as GR-MD-02 or GCS-100.

Anti-cancer activity

In several aspects, this disclosure provides a method for treating a subject with cancer, the method comprising administering to a subject in need of the treatment an effective amount of a compound having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1. In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1, can be used to prepare a medicament for treating cancer.

In some aspects, this disclosure provides a method for inhibiting the growth of tumor cells in a subject, the method comprising administering to a subject in need of the treatment an effective amount of a compound of structure (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1. In other aspects, the tumor may originate from ovarian, breast, lung, thyroid, lymph nodes, kidney, ureter, bladder, ovary, testis, prostate, bone, skeletal muscle, bone marrow, stomach, esophagus, small intestine, colon, rectum, pancreas, liver, smooth muscle, brain, spinal cord, nerve, ear, eye, nasopharynx, oropharynx, salivary gland, or heart tissue. In some aspects, the compounds of the invention may be administered concurrently with one or more additional anticancer therapies.

In several aspects, the disclosed FASN inhibitors can be used to treat liver cancer. In one embodiment, this disclosure relates to a method of treating liver cancer with compounds of the disclosed formula (i.e., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)).

Rapidly proliferating cancer cells activate fatty acid synthesis pathways to replenish high levels of lipids required for membrane assembly and oxidative metabolism (Flavin, R. et al., (2010) Future Oncology. 6(4): 551-562). Inhibitors of fatty acid synthesis have shown in vivo activity in preclinical cancer models (Orita, H. et al., (2007) Clinical Cancer Research. 13(23): 7139-7145 and Puig, T. et al., (2011) Breast Cancer Research, 13(6): R131). In addition, fatty acid synthesis supports angiogenesis, and inhibitors of this pathway are active in in vitro angiogenesis models (Browne, C.D. et al., (2006) The FASEB Journal, 20(12): 2027-2035). The compounds disclosed in this invention have demonstrated the ability to selectively induce cell cycle arrest in HUVEC cells without causing general cell death caused by apoptosis. See Examples.

The cancer treatment of the present invention includes antitumor effects that can be assessed by conventional methods, such as response rate, time to disease progression, and/or survival rate. The antitumor effects of the present invention include, but are not limited to, inhibition of tumor growth, delay of tumor growth, tumor regression, tumor shrinkage, prolonged tumor regeneration upon cessation of treatment, and slowing of disease progression. For example, it is anticipated that when the combinations of the present invention are administered to warm-blooded animals (such as humans) with solid tumors requiring cancer treatment, such a treatment will produce effects as measured by, for example, one or more of the following: the extent of antitumor effect, response rate, time to disease progression, and survival rate.

Skin fibrosis

In several aspects, this disclosure provides a method for treating skin fibrosis in a subject, the method comprising administering to a subject requiring such treatment an effective amount of a compound having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1. In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1 can be used to manufacture a medicament for treating skin fibrosis. In other aspects, compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or as provided in Table 1 can be used to treat skin fibrosis.

For example, as described in Example 11, compounds of this disclosure (e.g., compound 364A) can reduce skin collagen content in a bleomycin-induced mouse model of skin fibrosis. As described in Example 11, FASN inhibition using compounds of this disclosure can reduce skin collagen content, whether treatment is administered concurrently with bleomycin injection or initiated after bleomycin injection (e.g., 1 week or 2 weeks after injection). Therefore, compounds of this disclosure can be used to prevent the progression of skin fibrosis symptoms, such as collagen buildup. Compounds of this disclosure can also be used to reverse the symptoms of skin fibrosis.

Treatment

This document also provides pharmaceutical compositions comprising the compounds disclosed herein. The compositions and methods of this invention have antiviral and/or anticancer activity.

In several aspects, this disclosure provides pharmaceutical compositions comprising any one of the compounds having structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI) and a pharmaceutically acceptable carrier, excipient, or diluent.

In some respects, this disclosure provides pharmaceutical compositions comprising any one of the compounds in Table 1 and a pharmaceutically acceptable carrier, excipient, or diluent.

Some aspects of this invention relate to methods for inhibiting or reducing viral infections or for treating cancer using pharmaceutical compositions and kits comprising one or more agents that inhibit fatty acid synthesis pathways. Other aspects of this invention provide methods, pharmaceutical compositions, and kits for treating animal subjects suffering from or at risk of viral infections or cancer. The term "subject" as used herein includes humans and other mammals. The term "treatment" as used herein includes achieving therapeutic and/or preventative benefits. A therapeutic benefit means eradication or improvement of an underlying viral infection. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with an underlying viral infection such that improvement is observed in animal subjects, although the subjects may still suffer from the underlying virus.

In other respects, the present invention relates to a method for treating fatty liver disease in a subject in need, the method comprising administering to the subject a fatty acid synthase inhibitor having the formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX).

In other respects, the present invention relates to a method for treating a subject with non-alcoholic steatohepatitis and non-alcoholic fatty acid disease (NAFLD) in need, the method comprising administering to the subject a fatty acid synthase inhibitor having the formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX).

In other respects, the present invention relates to a method for treating non-alcoholic steatohepatitis (NASH) in a subject of need, the method comprising administering to the subject a fatty acid synthase inhibitor having formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX).

In other respects, the present invention relates to a method for treating cirrhosis in a subject in need, the method comprising administering to the subject a fatty acid synthase inhibitor having the formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX).

In other respects, the present invention relates to a method for treating liver fibrosis in a subject in need, the method comprising administering to the subject a fatty acid synthase inhibitor having the formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX).

In other respects, the present invention relates to a method for treating inflammation in a subject in need, the method comprising administering to the subject a fatty acid synthase inhibitor having the formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX).

In other respects, the present invention relates to a method for treating a disease or condition in a subject with elevated interleukin 1β (IL1β) levels, the method comprising administering to the subject a fatty acid synthase inhibitor having formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX).

In other respects, the present invention relates to a method for treating a disease or condition in which a subject in need has elevated levels of t-helper ( _Th ) cells, the method comprising administering to the subject a fatty acid synthase inhibitor having the formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX).

In other respects, the present invention relates to a method for treating a disease or condition in which regulatory T cells (T _reg ) are reduced or suppressed in a subject in need, the method comprising administering to the subject a fatty acid synthase inhibitor having the formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX).

In other respects, the present invention relates to a method for treating liver cancer in a subject in need, the method comprising administering to the subject a fatty acid synthase inhibitor having the formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I), wherein _R3 is F.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I), wherein A is CH.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I), wherein A is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I), wherein X, Y and Z are NR′.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I), wherein _R4 is a heteroaryl, heterocyclic, -C(=O)N( _R5R6 ), -N( _R7 )C(=O) _R8 , _{-N ( R9R10} ), _C1-6 alkyl, _C1-6 alkoxy, or _R4 and _R11 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-A).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-B).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-C).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-D).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formulas (I-E).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-F).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-G).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-H).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-I).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-J).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-K).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-L).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-M).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-N).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-O).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-P).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-Q).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-R).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-S).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-T).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-U).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formulas (I-V).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-W).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-X).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-Y).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-Z).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-AA).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-AB).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-AC).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-AD).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-AE).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-AF).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having formula (I-AG).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (I) having the formula (I-AH).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (II) having formula (II-A).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (II) having formula (II-B).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (II) having formula (II-C).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (II) having formula (II-D).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (II) having formula (II-E).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (II) having formula (II-F).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (III) having formula (III-A).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (III) having formula (III-B).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (III) having formula (III-C).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (III) having formula (III-D).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (III) having formula (III-E).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (III) having formula (III-F).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _R1 is hydrogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, or -C(=O)N( _R13 )( _R14 ).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _R1 is a cyano group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _R2 is hydrogen or halogen; _R2 is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _R3 is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _R21 and _R22 are each independently hydrogen or _C1-6 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _R21 and _R22 are each independently _C1-6 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein R ₂₅ is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _L2 is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _L1 is CH.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _L3 is CH.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _L4 is CH.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein A is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein A is CH.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein R ₂₆ is a heterocyclic group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _R24 is -N( _R13 )( _R14 ).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein _L5 and _L6 are each independently N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein s is 1.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV), wherein s is 0.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-A).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-B).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-C).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-D).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-E).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-F).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-G).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-H).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-I).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-J).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-K).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-L).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-M).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-N).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IV) having formula (IV-O).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _L7 is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _L7 is O.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein A is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein A is CH.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _R1 is hydrogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, or -C(=O)N( _R13 )( _R14 ).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _R1 is a cyano group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _R2 is hydrogen or halogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _R2 is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _R3 is fluorine.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _R21 and _R22 are each independently hydrogen or _C1-6 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _R21 and _R22 are each independently _C1-6 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein R ₃₁ is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein R ₃₀ is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _L8 is O.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _L9 is O.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _L10 is O and _L11 is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _L12 is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V), wherein _R32 and _R33 are each independently hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V) having formula (V-A).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V) having formula (V-B).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V) having formula (V-C).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V) having formula (V-D).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V) having formula (V-I).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V) having formula (V-K).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V) having formula (V-L).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V) having formula (V-M).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V) having formula (V-N).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (V) having formula (V-O).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein _R1 is hydrogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, or -C(=O)N( _R13 )( _R14 ).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein _R1 is a cyano group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein _R2 is hydrogen or halogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein _R2 is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein _R3 is fluorine.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein _R21 and _R22 are each independently hydrogen or _C1-6 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein _R21 and _R22 are each independently _C1-6 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein R ₃₅ is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein _R34 is a heteroaryl group;

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein R ₃₄ is thiophene, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazoleyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrololinyl, pyridazinyl, triazolyl, indoleyl, isoindoleyl, indoleazinyl, benzimidazolyl, quinolinyl, isoquinolinyl, inzolyl, benzotriazolyl, tetrazopyridazinyl, oxadiazolyl, benzooxazolyl, benzooxadiazolyl, thiazolyl, benzothiazolyl, or benzothiazolyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein L ₁₃ is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein _L14 and _L15 are each independently CH.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein A is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI), wherein A is CH.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI) having formula (VI-A).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI) having formula (VI-B).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI) having formula (VI-C).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI) having formula (VI-D).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI) having formula (VI-E).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI) having formula (VI-F).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI) having formula (VI-G).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI) having formula (VI-H).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VI) having formula (VI-I).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein _R1 is hydrogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, or -C(=O)N( _R13 )( _R14 ).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein _R1 is a cyano group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein _R2 is hydrogen or halogenated.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein _R2 is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein _R3 is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein _R21 and _R22 are each independently hydrogen or _C1-6 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein _R21 and _R22 are each independently _C1-6 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein R ₃₉ is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein R ₄₀ is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein L ₁₆ is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein L ₁₇ is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein L ₁₈ is CH.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein L ₁₈ is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein A is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein A is CH.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein R ₄₂ is a _C1-6 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII), wherein R ₄₁ is a _C1-6 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII) having formula (VII-A).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII) having formula (VII-B).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII) having formula (VII-C).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VII) having formula (VII-D).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII), wherein _R1 is hydrogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, or -C(=O)NN ( _R13 )( _R14 ).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII), wherein _R1 is a cyano group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII), wherein _R2 is hydrogen or halogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII), wherein _R2 is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII), wherein _R3 is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII), wherein _R21 and _R22 are each independently hydrogen or _C1-6 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII), wherein _R21 and _R22 are each independently _C1-6 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII), wherein R ₃₉ is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII), wherein L ₁₉ is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII), wherein A is N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII), wherein A is CH.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII) having formula (VIII-A).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII) having formula (VIII-B).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII) having formula (VIII-C).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VIII) having formula (VIII-D).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R24 is a _C1 - _C4 straight-chain or branched alkyl or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein t is 0 or 1.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein R ²¹ is a halogen, a _C1 - _C4 straight-chain or branched alkyl group, or a _C3 - _C5 cycloalkyl group, wherein the _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R3 is H or a halogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^L1 and ^L2 are both N.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R21 is a _C1 - _C2 alkyl or _C3 - _C5 cycloalkyl and ^R22 is a _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R21 is a _C3 - _C5 cycloalkyl and ^R22 is a _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R24 is -( _C1 - _C2 alkyl) _t -O-( _C1 - _C2 alkyl), where t is 0 or 1.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R21 is a _C3 - _C5 cycloalkyl, ^R22 is a _C1 - _C2 alkyl, and ^R24 is a _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R21 is cyclobutyl, ^R22 is _C1 - _C2 alkyl, and ^R24 is _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein R ²¹ is cyclobutyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R3 is H or F.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R1 is -CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R1 is _-CF3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R22 is H, methyl, or ethyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein R ²² is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein R ²² is methyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein each ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 and ^L2 are N, and ^R24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 and ^L2 are N, and ^R24 is methoxy or ethoxy.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 is CH, ^L2 is N, and ^R24 is methyl, ethyl, hydroxymethyl, methoxymethyl or 2-methoxyethyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, ^L1 is N, ^L2 is CH, and ^R24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (IX), wherein the compound is selected from:

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R21 is a halogen, a _C1 - _C4 straight-chain or branched alkyl group, or a _C3 - _C5 cycloalkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R3 is H or a halogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R1 is -CN or _C1 - _C2 haloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R3 is H or F.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R1 is -CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R1 is _-CF3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), where n is 1.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), where n is 2.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), where m is 1.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), where m is 2.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R21 is a _C1 - _C2 alkyl or _C3 - _C5 cycloalkyl and ^R22 is a _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R21 is a _C3 - _C5 cycloalkyl group and ^R22 is a _C1 - _C2 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein n is 2, m is 1, and ^L3 is...

-NC(O)-O-( _C1 - _C2 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^L3 is ^NR50 ; ^R50 is _C1 - _C2 alkyl; ^R21 is cyclobutyl; ^R22 is H or methyl; ^R3 is H; ^R1 is -CN; m is 2; and n is 1 or 2.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein n is 2, m is 1, ^L3 is 0 and s is 0.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R22 is H, methyl, or ethyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R22 is methyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R22 is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, n is 2 and ^L3 is ^NR50 , wherein ^R50 is methyl or ethyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is methyl, n is 2 and ^L3 is O.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (X), wherein the compound is selected from:

and

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein ^R3 is H or a halogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein ^R22 is a _C1 - _C2 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein ^R21 is cyclobutyl and ^R22 is _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein R ²¹ is cyclobutyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein ^R3 is H or F.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein ^R1 is -CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein ^R1 is _-CF3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein ^R22 is H, methyl, or ethyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein R ²² is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein R ²² is methyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein R ³⁵ is -C(O)-NH R ³⁵¹ .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein R ³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein R ³⁵¹ is (R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein ^R1 is -CN, each of ^R2 is hydrogen, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is H, and ^R35 is -C(O)-NHR ³⁵¹ , wherein ^R351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein R ³⁵ is -C(O)-OR ³⁵¹ .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein R ³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein R ³⁵¹ is (R)-3-tetrahydrofuranyl or (S)-3-tetrahydrofuranyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is _C3 - _C4 cycloalkyl, ^R22 is H, and ^R35 is -C(O)-OR ³⁵¹ , wherein ^R351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (VJ-I), wherein the compound is selected from:

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R3 is H or a halogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R21 is a _C3 - _C4 cycloalkyl and ^R22 is a _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R21 is cyclobutyl and ^R22 is _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R21 is cyclobutyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R3 is H or F.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R1 is -CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R1 is _-CF3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R22 is H, methyl, or ethyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R22 is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R22 is methyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein ^R1 is -CN, each of ^R2 is H, ^R3 is H or F, ^R21 is cyclobutyl, ^R22 is methyl and ^R351 is methyl or ethyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XI), wherein the compound is selected from:

and

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein L-Ar is Ar and not Ar.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein L-Ar is and Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein L-Ar is and Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R1 is -CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R2 is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R21 is a halogen, a _C1 - _C4 alkyl group, or a _C3 - _C5 cycloalkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R21 is a _C1 - _C4 alkyl or a _C3 - _C5 cycloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R21 is a _C1 - _C2 alkyl or _C3 - _C5 cycloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R21 is a _C1 - _C2 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R21 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R22 is H or _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R22 is H or _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R22 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N( ^R241 ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N( ^R241 ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is _C1 - _C4 alkyl or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is -( _C1 - _C2 alkyl)-O-( _C1 - _C2 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is _-CH2 -O- _CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is a _C1 - _C2 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is a _C3 - _C6 cycloalkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is -CN or -( _C1 - _C2 alkyl)-CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein R ²⁴ is -CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is -( _C1 - _C2 alkyl)-CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is H, _-CH3 , _-CH2OH , _-CH2OCH3 , -( _CH2 ) _2OH , _- ( _{CH2 )2OCH3 or} -( _CH2 ) _2N ( _CH3 ) ₂ .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is methyl, isopropyl, cyclopropyl, -CN, or -( _C1 - _C2 alkyl)-CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is substituted by one or more substituents selected from _C1 - _C2 alkyl, oxo, -CN, halogen, alkyl acyl, alkoxy carbonyl, -OH and _C1 - _C2 alkoxy.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is substituted with one or _more substituents selected from methyl, -F, methoxy, -C(=O) _CH3 and -C(=O)-OCH3.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is substituted by two identical or different substituents.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R24 is substituted by the same or different three substituents.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R25 is a halogen, -CN, _C1 - _C2 alkyl, or cyclopropyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R25 is a halogen, _C1 - _C2 alkyl, or cyclopropyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R25 is -CN, -Cl, or _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein R ²⁵ is -Cl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R25 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R25 is substituted with one or more substituents selected from -OH, halogen, _C1 - _C2 alkyl and alkyl carbonyloxy groups.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein ^R25 is substituted with one or more substituents selected from -F, methyl and -OC(=O) _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein R ²⁵ is substituted by two identical or different substituents.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XII), wherein R ²⁵ is substituted by the same or different three substituents.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein the compound is not:

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein when L-Ar is present, Ar is not present.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein L-Ar is and Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein L-Ar is and Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R1 is -CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R2 is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R21 is a halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R21 is a _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R21 is a _C1 - _C2 alkyl or a _C3 - _C5 cycloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R21 is a _C1 - _C2 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R21 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R22 is H or _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R22 is H or _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R22 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein each of ^R24 and ^R25 is independently H, -CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N( ^R241 ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein each of ^R24 and ^R25 is independently H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R24 is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N( ^R241 ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R24 is -CN, -Cl, _C1 - _C4 alkyl or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R24 is _C1 - _C4 alkyl or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R24 is -( _C1 - _C2 alkyl)-O-( _C1 - _C2 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R24 is a _C1 - _C4 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R24 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein R ²⁴ is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R24 is substituted with one or more substituents selected from halogens, _C3 - _C5 cycloalkyl groups, and _C1 - _C2 alkoxy groups.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R24 is substituted by one or more substituents selected from -F, cyclopropyl, and _-OCH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R24 is substituted by two identical or different substituents.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R24 is substituted by the same or different three substituents.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein R ²⁵ is halogen, methyl, ethyl or cyclopropyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein R ²⁵ is -CN, -Cl, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl) _t -O-( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R25 is -CN, -Cl, _-CH3 , -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C2 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R25 is -CN, -Cl or _C1 - _C4 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R25 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein R ²⁵ is -Cl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein ^R25 is replaced by one or more halogens.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein R ²⁵ is substituted with one or more -F.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein R ²⁵ is substituted by two substituents.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIII), wherein R ²⁵ is substituted with three substituents.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein L-Ar is and Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein L-Ar is and Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R1 is -CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R2 is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R21 is a halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R21 is H, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R21 is a _C1 - _C2 alkyl or _C3 - _C5 cycloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R21 is a _C1 - _C2 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R21 is a _C3 - _C5 cycloalkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R22 is H or _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R22 is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R22 is a _C1 - _C2 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R22 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R24 is _C1 - _C4 alkyl or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIV), wherein ^R24 is -( _C1 - _C2 alkyl) _t -O-( _C1 - _C2 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein L-Ar is and Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein L-Ar is and Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R1 is H, -CN, _-C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H or -CN, ^R1 is optionally substituted with one or more halogens.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R1 is -CN or _C1 - _C2 haloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R1 is -CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R1 is -Cl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R2 is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R21 is a halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R21 is a _C1 - _C2 alkyl or _C3 - _C5 cycloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R21 is a _C3 - _C5 cycloalkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R22 is H or _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R22 is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R22 is a _C1 - _C2 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^R22 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein ^L3 is -N( _CH3 )-.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein n is 2 and m is 2.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein n is 1 or 2.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XV), wherein n is 1 and m is 2.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVI), wherein L-Ar is Ar and not Ar.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVI), wherein L-Ar is and Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVI), wherein L-Ar is and Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVI), wherein ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVI), wherein ^R21 is a halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVI), wherein ^R21 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVI), wherein ^R22 is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein L-Ar is and Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein ^R1 is a halogen, -CN, or _C1 - _C2 haloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein ^R1 is -CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein ^R2 is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein R ²¹ is a halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein R ²¹ is a _C1 - _C2 alkyl or _C3 - _C5 cycloalkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein R ²¹ is a _C1 - _C2 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein R ²¹ is a _C3 - _C5 cycloalkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein ^R22 is H or _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein R ²² is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein ^R22 is a _C1 - _C2 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein ^R22 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein R ²⁴ is _C1 - _C4 alkyl or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVII), wherein R ²⁴ is -( _C1 - _C2 alkyl)-O-( _C1 - _C2 alkyl).

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVIII), wherein L-Ar is Ar and not Ar.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVIII), wherein ^L2 is -NHR ³⁵ .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XVIII), wherein ^L2 is -C(O)NHR ³⁵¹ .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIX), wherein Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIX), wherein Y is -CR ^26- and R ²⁶ is -N(R ²⁷ ) ₂ .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XIX), wherein X is -N-.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein the compound is not:

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein L-Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein L-Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein L-Ar is...

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein ^R3 is H.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein ^R1 is -CN or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not -CN, ^R1 is optionally substituted with one or more halogens.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein ^R1 is -CN.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein ^R1 is an -O-( _C1 - _C4 alkyl) optionally substituted with one or more halogens.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein each ^R2 is hydrogen.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein ^R21 is a _C1 - _C4 alkyl group.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein ^R22 is H or _C1 - _C2 alkyl.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein ^R24 is an -O-( _C1 - _C4 alkyl) optionally substituted with one or more hydroxyl groups or halogens.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein ^R24 is an -O-( _C1 - _C4 alkyl) optionally substituted with one or more hydroxyl groups.

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein ^R25 is _-CH3 .

In some embodiments of the above method, the fatty acid synthase inhibitor is a compound of formula (XX), wherein the compound is selected from:

For aspects requiring preventative benefits, the pharmaceutical compositions of the present invention can be administered to patients at risk of developing a viral infection (such as HRV or HIV), or to patients reporting physiological symptoms of one or more viral infections, even if a diagnosis of the condition may not have been made. Administration may prevent the development of a viral infection, or may reduce, alleviate, shorten, and/or otherwise improve an existing viral infection. The pharmaceutical compositions may modulate fatty acid synthesis pathways, such as FASN gene expression or FASN protein activity. The term "modulation" includes inhibiting, for example, FASN gene expression or FASN protein activity, fatty acid synthesis pathways, or activating, for example, FASN gene expression or FASN protein activity.

The reduction of fatty acid synthesis pathway activity, such as FASN gene expression or FASN protein activity, is also referred to as "inhibition" of fatty acid synthesis pathway activity, such as FASN gene expression or FASN protein activity. The term "inhibition" and its grammatical variations (such as "inhibitory") do not necessarily refer to complete inhibition, but rather to a reduction in fatty acid synthesis activity, such as FASN gene expression or FASN protein activity. On the other hand, such a reduction is at least 50%, at least 75%, at least 90%, and possibly at least 95% of enzyme activity in the absence of inhibition, for example, in the absence of an inhibitor. Conversely, the phrase "non-inhibitory" and its grammatical variations refer to a reduction in enzyme activity of less than 20%, less than 10%, and possibly less than 5% in the presence of an agent. Furthermore, the phrase "substantially non-inhibitory" and its grammatical variations refer to a reduction in enzyme activity of less than 30%, less than 20%, and in some respects less than 10% in the presence of an agent.

The activity of fatty acid synthesis pathways that increase, for example, FASN gene expression or FASN protein activity is also referred to as "activation" of fatty acid synthesis pathways that increase, for example, FASN gene expression or FASN protein activity. The term "activated" and its grammatical variations (such as "activated") do not require complete activation, but rather refer to an increase in fatty acid synthesis activity, for example, FASN gene expression or FASN protein activity. On the other hand, such an increase is at least 50%, at least 75%, at least 90%, and possibly at least 95% of enzyme activity in the absence of activation, for example, in the absence of an activating agent. Conversely, the phrase "inactive" and its grammatical variations refer to a situation where, in the presence of an agent, the increase in enzyme activity is less than 20%, less than 10%, and possibly less than 5%. Furthermore, the phrase "substantially inactive" and its grammatical variations refer to a situation where, in the presence of an agent, the increase in enzyme activity is less than 30%, less than 20%, and on the other hand, less than 10%.

The ability to reduce enzyme activity is a measure of the potency or activity of an agent or combination of agents against or against an enzyme. Potency can be measured by cell-free, whole-cell, and/or in vivo assays, based on IC50, _Ki , and/or ED50 values. The IC50 value represents the concentration of the agent required to inhibit enzyme activity by half (50%) under a given set of conditions. The _Ki value represents the equilibrium affinity constant for the binding of the inhibitor to the enzyme. The ED50 value represents the dose of agent required to achieve the half-maximal response in a bioanalyte. Further details of these measurements will be apparent to those skilled in the art and can be found in standard texts concerning biochemistry, enzymology, etc.

This invention also includes kits for treating viral infections or cancer. These kits contain agents or combinations of agents that inhibit fatty acid synthesis pathways, such as FASN gene expression or FASN protein activity, and optionally include instructions for teaching the use of the kit according to the various methods and pathways described herein. Such kits may also include information such as scientific literature references, drug instruction materials, clinical trial results, and/or summaries of these and others, indicating or determining the activity and/or benefits of the agents. Such information may be based on the results of various studies, such as studies using laboratory animals involving in vivo models and studies based on human clinical trials. The kits described herein may be offered, sold, and/or promoted to healthcare providers, including physicians, nurses, pharmacists, prescribing clerks, etc.

Formulation, route of administration and effective dosage

Another aspect of the invention relates to formulations, routes of administration, and effective dosages of pharmaceutical compositions comprising the active agents or combinations thereof. Such pharmaceutical compositions can be used to treat viral infections as described above.

The compounds of the present invention can be administered in pharmaceutical formulations, including those suitable for oral administration (including buccal and sublingual administration), rectal administration, intranasal administration, topical administration, percutaneous patch administration, pulmonary administration, vaginal administration, suppository administration, or non-enteric administration (including intramuscular, intra-arterial, intrathecal, intradermal, intraperitoneal, subcutaneous, and intravenous administration), or the compounds of the present invention can be administered in forms suitable for aerosol, inhalation, or inhalation administration. General information on drug delivery systems can be found in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins, Baltimore Md. (1999)).

In several respects, pharmaceutical compositions include: carriers and excipients (including, but not limited to, buffers, carbohydrates, mannitol, proteins, peptides or amino acids (such as glycine), antioxidants, antibacterial agents, chelating agents, suspending agents, thickeners and/or preservatives); water; oils, including petroleum, animal, plant or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.; physiological saline solutions; dextran aqueous solutions and glycerol aqueous solutions; flavoring agents; coloring agents; anti-sticking agents; and other acceptable additives, adjuvants or binders; and other pharmaceutically acceptable excipients required to approximate physiological conditions, such as pH buffers, tension regulators, emulsifiers, humectants, etc. Examples of excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, ethanol, etc. In another respect, pharmaceutical preparations are substantially free of preservatives. In another respect, pharmaceutical preparations may contain at least one preservative. General methods regarding drug dosage forms can be found in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins, Baltimore Md. (1999)). It should be understood that although any suitable carrier known to those skilled in the art can be used to administer the compositions of the present invention, the type of carrier will vary depending on the mode of administration.

The compounds can also be encapsulated in liposomes using known techniques. Biodegradable microspheres can also be used as carriers for the pharmaceutical compositions of the present invention. Suitable biodegradable microspheres are disclosed, for example, in U.S. Patents 4,897,268, 5,075,109, 5,928,647, 5,811,128, 5,820,883, 5,853,763, 5,814,344, and 5,942,252.

The compound can be administered in liposomes or microspheres (or particles). Methods for preparing liposomes and microspheres for administration to patients are well known to those skilled in the art. U.S. Patent No. 4,789,734 (the contents of which are incorporated herein by reference) describes a method for encapsulating biomaterials in liposomes. Essentially, the material is dissolved in an aqueous solution, with the addition of appropriate phospholipids and lipids along with surfactants (if desired), and the material is dialyzed or sonicated if necessary. A review of known methods is provided by G. Gregoriadis, Chapter 14, “Liposomes,” Drug Carriers in Biology and Medicine, Supplement 2, pp. 87-341 (Academic Press, 1979).

Microspheres formed from polymers or proteins are well known to those skilled in the art and can be modified to pass through the gastrointestinal tract and enter the bloodstream directly. Alternatively, compounds can be incorporated into microspheres or microsphere complexes for implantation to allow for slow release over a period of days to months. See, for example, U.S. Patents 4,906,474, 4,925,673, and 3,625,214, and Jein, TIPS 19:155-157 (1998), the contents of which are incorporated herein by reference.

As is known in the art, the concentration of the drug can be adjusted, the pH of the solution can be buffered, and the isotonicity can be adjusted to make it compatible with intravenous injection.

The compounds of the present invention can be formulated into sterile solutions or suspensions in suitable media known in the art. Pharmaceutical compositions can be sterilized using commonly known sterilization techniques or by sterile filtration. The resulting aqueous solutions can be packaged for use as is or lyophilized, with the lyophilized formulation being combined with the sterile solution prior to administration. Suitable formulations and other carriers are described in Remington's "The Science and Practice of Pharmacy" (20th edition, Lippincott Williams & Wilkins, Baltimore MD), the teachings of which are incorporated herein by reference in their entirety.

The active ingredient or its pharmaceutically acceptable salt may be provided alone or in combination with one or more other active ingredients or in one or more other forms. For example, a formulation may contain one or more active ingredients in specific proportions, depending on the relative potency of the individual active ingredients and the intended indication. For example, in a composition targeting two different host targets where the potency is similar, an approximately 1:1 ratio of active ingredients may be used. Two forms may be formulated together in the same dosage unit, such as a cream, suppository, tablet, capsule, aerosol spray, or powder packet to be dissolved in a beverage; or the forms may be formulated in separate units, such as two creams, two suppositories, two tablets, two capsules, one tablet and one liquid for dissolving the tablet, two aerosol sprays, or one powder packet and one liquid for dissolving the powder, etc.

The term "pharmaceutically acceptable salt" means a salt that retains the biological effects and properties of the agents used in this invention and is not biologically or otherwise unacceptable. For example, pharmaceutically acceptable salts do not interfere with the beneficial effects of the agents of this invention in inhibiting fatty acid synthesis pathways (e.g., inhibiting FASN gene expression or FASN protein activity).

Typical salts are salts of inorganic ions, such as sodium, potassium, calcium, and magnesium ions. Such salts include those that form with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid, or maleic acid. Additionally, if the agent contains a carboxyl group or other acidic group, it can be converted into a pharmaceutically acceptable addition salt with an inorganic or organic base. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine, and triethanolamine.

Pharmaceutically acceptable esters or amides are those that retain the biological effects and properties of the agents used in this invention and are not biologically or otherwise unacceptable. For example, the ester or amide does not interfere with the beneficial effects of the agents of this invention in inhibiting fatty acid synthesis pathways (e.g., inhibiting FASN gene expression or FASN protein activity). Typical esters include ethyl esters, methyl esters, isobutyl esters, ethylene glycol esters, etc. Typical amides include unsubstituted amides, alkylamides, dialkylamides, etc.

On the other hand, the active agent may be administered in combination with one or more other compounds, forms, and/or active agents, such as those described above. Pharmaceutical compositions comprising a combination of a fatty acid synthesis pathway inhibitor (e.g., an inhibitor of FASN gene expression or FASN protein activity) and one or more other active agents may be formulated to contain a specific molar ratio. For example, a molar ratio of about 99:1 to about 1:99 of the fatty acid synthesis pathway inhibitor (e.g., an inhibitor of FASN gene expression or FASN protein activity) to the other active agent may be used. In some subsets of these aspects, the range of the molar ratio of the fatty acid synthesis pathway inhibitor (e.g., an inhibitor of FASN gene expression or FASN protein activity) to the other active agent is selected from about 80:20 to about 20:80; about 75:25 to about 25:75; about 70:30 to about 30:70; about 66:33 to about 33:66; about 60:40 to about 40:60; about 50:50; and about 90:10 to about 10:90. The molar ratio of fatty acid synthesis pathway inhibitors (e.g., inhibitors of FASN gene expression or FASN protein activity) to other active agents can be approximately 1:9, and in another case, approximately 1:1. Two agents, forms, and/or compounds can be formulated together in the same dosage unit, such as a cream, suppository, tablet, capsule, or powder packet to be dissolved in a beverage; or each agent, form, and/or compound can be formulated in a separate unit, such as two creams, suppositories, tablets, two capsules, a tablet and a liquid for dissolving the tablet, an aerosol powder packet and a liquid for dissolving the powder, etc.

When necessary or required, the active ingredient and/or combination of active ingredients may be administered together with other active ingredients. The selection of active ingredients that may be administered together with the active ingredients and/or combinations of active ingredients of the present invention may depend at least in part on the condition being treated. Active ingredients specifically used in formulations of the present invention include, for example, any active ingredient that has therapeutic effects on viral infections, including, for example, drugs used to treat inflammatory conditions. For example, in HRV treatment, in some aspects, formulations of the present invention may additionally contain one or more conventional anti-inflammatory drugs, such as NSAIDs, such as ibuprofen, naproxen, acetaminophen, ketoprofen, or aspirin. In some alternative aspects for the treatment of influenza, formulations of the present invention may additionally contain one or more conventional influenza antiviral agents, such as amantadine, rimantadine, zanamivir, and oseltamivir. In the treatment of retroviral infections (such as HIV), the formulations of the present invention may additionally contain one or more conventional antiviral drugs, such as protease inhibitors (lopinavir/ritonavir (Kaletra), indinavir (Gastrosalicy), ritonavir (Norvir), nelfinavir (Viracept), saquinavir hard gel capsules (Invirase), atazanavir (Reyataz), ampravir (Agenerase), fosanavir (Telzir), telanavir (Aptivus))); reverse transcriptase inhibitors, including non-nucleoside and nucleoside/nucleotide inhibitors (AZT (zidovudine, Litovir), ddI ( Doxorinosine, Videx, 3TC (lamivudine, Empiric), d4T (stavudine, Zerit), abacavir (Ziagen), FTC (emtricitabine, Emtriva), tynofovir (Viread), efavirenz (Sustiva), and nevirapine (Viramune), fusion inhibitor T20 (Enfuvirdi, Fuzeon), integrase inhibitors (MK-0518 and GS-9137), and mutation inhibitors (PA-457 (Bevirimat)). As another example, the formulation may additionally contain one or more supplements, such as vitamin C, E, or other antioxidants.

In some respects, the compounds disclosed herein can be administered in combination with known cancer treatments. For example, these compounds can be administered in combination with: paclitaxel (available at Taxol, Bristol-Myers Squibb), doxorubicin (also known under the trade name Adriamycin), vincristine (known under the trade names Oncovin, Vincasar PES, and Vincrex), actinomycin D, hexamethylmelamine, asparaginase, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cytarabine, dacarbazine, and daunoside. Ingredients include: mycin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantryl, oxaliplatin, procarbazine, steroids, streptozotocin, temozolomide, thioguanine, thiotepa, raltitrexed, topotecan, troosufan, UFT (uracil-tegufur), vinblastine, and vindesine, etc.

The active agent (or a pharmaceutically acceptable salt, ester, or amide thereof) may be administered either directly or as a pharmaceutical composition in which the active agent is a mixture or blend of one or more pharmaceutically acceptable carriers. The pharmaceutical composition used herein may be any composition prepared for administration to a subject. Pharmaceutical compositions used according to the invention may be formulated in a conventional manner using one or more physiologically acceptable carriers containing excipients, diluents, and/or adjuvants, such as those that facilitate the formulation of the active agent into an administerable formulation. A suitable formulation may depend at least in part on the chosen route of administration. The active agent or a pharmaceutically acceptable salt, ester, or amide thereof that can be used in the invention may be delivered to a patient via a variety of routes or modes of administration, including oral administration, buccal administration, topical administration, rectal administration, transdermal administration, transmucosal administration, subcutaneous administration, intravenous administration, intramuscular administration, and inhalation.

For oral administration, the active agent can be readily formulated by combining it with a pharmaceutically acceptable carrier known in the art. Such a carrier enables the active agent of the present invention to be formulated into tablets (including chewable tablets), pills, sugar-coated pills, capsules, sugar tablets, hard candies, liquids, gels, syrups, pastes, powders, suspensions, elixirs, rice paper wafers, etc., for oral ingestion by the patient to be treated. Such formulations may contain pharmaceutically acceptable carriers, including solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Solid carriers may be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. In powders, the carrier is generally a finely divided solid mixed with the finely divided active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the necessary binding ability in a suitable proportion and compressed into the desired shape and size. Powders and tablets preferably contain about 1% to about 70% of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, xanthan gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, cocoa butter, etc. Generally, the active ingredient of the invention is included in the total composition of the oral dosage form at concentration levels of about 0.5% by weight, about 5% by weight, about 10% by weight, about 20% by weight, or about 30% by weight, to about 50% by weight, about 60% by weight, about 70% by weight, about 80% by weight, or about 90% by weight, in an amount sufficient to provide the required dose unit.

Aqueous suspensions intended for oral use may contain the active ingredients of this invention and pharmaceutically acceptable excipients, such as suspending agents (e.g., methylcellulose), humectants (e.g., lecithin, lysophosphatidylcholine, and/or long-chain fatty alcohols), as well as colorants, preservatives, flavorings, etc.

On the other hand, due to the presence of, for example, a large lipophilic portion, an oil or non-aqueous solvent may be required to dissolve the agent. Alternatively, emulsions, suspensions, or other formulations, such as liposome formulations, may be used. For liposome formulations, any known method for preparing liposomes for treating conditions may be used. See, for example, Bangham et al., J. Mol. Biol. 23: 238-252 (1965) and Szoka et al., Proc. Natl Acad. Sci. USA 75: 4194-4198 (1978), which are incorporated herein by reference. Ligands may also be attached to liposomes to direct these compositions to specific sites of action. The agents of the present invention may also be incorporated into foods such as cream cheese, butter, salad dressing, or ice cream to facilitate dissolution, administration, and/or compliance in certain patient populations.

Pharmaceutical formulations for oral use can be obtained in the form of solid excipients, optionally by grinding the resulting mixture after adding appropriate adjuvants (if desired), and processing the granular mixture to obtain tablets or sugar-coated pill cores. Suitable excipients are particularly fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; flavoring ingredients; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, xanthophyll, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). Disintegrants, such as croscarmellose, agar, or alginate or its salts, such as sodium alginate, may be added if necessary. The active agent can also be formulated into a sustained-release formulation.

Sugar-coated pill cores may have a suitable coating. For this purpose, concentrated sugar solutions may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and/or titanium dioxide, varnish, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the coating of tablets or sugar-coated pills to identify or characterize different combinations of active agents.

Orally administered pharmaceutical formulations include push-fit capsules made of gelatin and soft-sealable capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-fit capsules may contain the active ingredient mixed with fillers such as lactose, binders such as starch, and/or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All formulations for oral administration should be at a dose suitable for administration.

Other forms suitable for oral administration include liquid formulations, including emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions; or solid formulations intended to be converted into liquid form immediately before use. Emulsions may be prepared in solutions such as aqueous propylene glycol or may contain emulsifiers such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions may be prepared by dispersing a finely powdered active ingredient in water with a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other known suspending agents. Suitable fillers or carriers that may be given with the composition include agar, alcohols, fats, lactose, starch, cellulose derivatives, polysaccharides, polyvinylpyrrolidone, silica, sterile saline, etc., or mixtures thereof, used in appropriate amounts. Solid formulations include solutions, suspensions, and emulsions, and may contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc., in addition to the active ingredient.

Syrups or suspensions can be prepared by adding an active compound to a concentrated aqueous solution of sugar (e.g., sucrose), with any auxiliary ingredients also included. Such auxiliary ingredients may include flavoring agents, agents that delay sugar crystallization, or agents that increase the solubility of any other ingredient, such as polyols like glycerol or sorbitol.

When formulating the compounds of the present invention for oral administration, gastric retention formulations may be used to enhance absorption from the gastrointestinal (GI) tract. Formulations that remain in the stomach for several hours can slowly release the compounds of the present invention and provide sustained release suitable for use in the methods of the present invention. Disclosures of such gastric retention formulations can be found in Klausner, E.A.; Lavy, E.; Barta, M.; Cserepes, E.; Friedman, M.; Hoffman, A. 2003 “Novel gastroretentive dosage forms: evaluation of gastroretentivity and its effect on levodopa in humans.” Pharm. Res. 20, 1466-73; Hoffman, A.; Stepensky, D.; Lavy, E.; Eyal, S. Klausner, E.; Friedman, M. 2004 “Pharmacokinetic and pharmacodynamic aspects of gastroretentivity” See also: “Gastroretentive drug delivery systems” Int. J. Pharm. 11, 141-53; Streubel, A.; Siepmann, J.; Bodmeier, R.; 2006 “Gastroretentive drug delivery systems” Expert Opin. DrugDeliver. 3, 217-3; and Chavanpatil, M.D.; Jain, P.; Chaudhari, S.; Shear, R.; Vavia, P.R. “Novel sustained release, swellable and bioadliesive gastroretentive drug delivery system for olfoxacin” Int. J. Pharm. March 24, 2006 (electronic publication). The absorption of the compounds of this invention can be maximized using expansion, flocculation, and bioadhesion techniques.

The compounds of the present invention can be formulated for non-enteral administration (e.g., by injection, such as rapid concentration or continuous infusion) and can be present in preservative-added ampoules, pre-filled syringes, small-volume infusion or multi-dose containers in unit dosage form. The compositions can be in the form of suspensions, solutions or emulsions in oily or aqueous media, such as solutions in aqueous polyethylene glycol.

For injectable formulations, the carrier may be selected from those known in the art as suitable, including aqueous solutions or oil suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical carriers. The formulation may also contain biocompatible, biodegradable polymer compositions, such as poly(lactic acid-co-glycolic acid). These materials can be formed into microspheres or nanospheres, loaded with the drug, and further coated or derivatized to provide excellent sustained-release efficacy. Carriers suitable for periocular or intraocular injection include suspensions of therapeutic agents, for example, in injectable water, liposomes, and carriers suitable for lipophilic substances. Other carriers for periocular or intraocular injection are known in the art.

In a preferred embodiment, the composition is formulated according to conventional procedures to be a pharmaceutical composition suitable for intravenous administration to humans. Compositions for intravenous administration are typically solutions in sterile isotonic aqueous buffer solutions. If desired, the composition may also include a solubilizer and a local anesthetic such as lidocaine to relieve pain at the injection site. Generally, the components are supplied individually or mixed together in unit dosage forms, for example, as dry lyophilized powders or anhydrous concentrates in sealed containers (such as ampoules or capsules) indicating the amount of active agent. When the composition is administered by infusion, it can be dispensed using an infusion bottle containing sterile pharmaceutical-grade water or physiological saline. When the composition is administered by injection, ampoules of sterile water or physiological saline for injection can be provided so that the components can be mixed prior to administration.

When administered by injection, the active compound may be formulated in an aqueous solution, particularly in a physiologically compatible buffer such as Hanks' solution, Ringer's solution, or physiological saline buffer. The solution may contain formulation agents such as suspending agents, stabilizers, and/or dispersants. Alternatively, the active compound may be in powder form and prepared prior to use with a suitable medium (e.g., sterile, pyrogen-free water). On the other hand, the pharmaceutical composition does not contain adjuvants or any other substances added to enhance the immune response stimulated by the peptide. On the other hand, the pharmaceutical composition contains substances that inhibit the immune response to the peptide. Formulation methods are known in the art, for example, as disclosed in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton P.

In addition to the formulations previously described, the active agent may also be formulated into a reservoir formulation. These long-acting formulations can be administered via implantation or transdermal delivery (e.g., subcutaneous or intramuscular), intramuscular injection, or the use of a transdermal patch. Thus, for example, the active agent may be formulated with a suitable polymer or hydrophobic material (e.g., an emulsion in an acceptable oil) or an ion exchange resin, or formulated as a slightly soluble derivative, such as a slightly soluble salt.

On the other hand, pharmaceutical compositions comprising one or more of the agents of the present invention exert local and regional effects when applied topically or injected at or near a specific site of infection. For example, direct surface application of viscous liquids, solutions, suspensions, dimethyl sulfoxide (DMSO)-based solutions, liposome formulations, gels, jelly, creams, lotions, ointments, suppositories, foams, or aerosol sprays can be used for topical application to produce, for example, local and/or regional effects. Pharmaceutically suitable media for such formulations include, for example, low-carbon aliphatic alcohols, polyethylene glycols (e.g., glycerin or polyethylene glycol), fatty acid esters, oils, fats, silicones, etc. Such formulations may also include preservatives (e.g., parabens) and/or antioxidants (e.g., ascorbic acid and tocopherol). See also Dermatological Formulations: Percutaneous absorption, Barry (ed.), Marcel Dekker Inc., 1983. On the other hand, topical/surface formulations containing inhibitors of fatty acid synthesis pathways (such as inhibitors of FASN gene expression or FASN protein activity) are used to treat viral infections of the epidermis or mucous membranes.

The pharmaceutical compositions of the present invention may contain cosmetically or dermatologically acceptable carriers. These carriers may be compatible with skin, nails, mucous membranes, tissues, and/or hair, and may include any commonly used cosmetic or dermatological carriers that meet these requirements. Those skilled in the art can readily select such carriers. In formulating skin ointments, the active agents or combinations of active agents of the present invention may be formulated in an oily hydrocarbon matrix, an anhydrous absorbent matrix, a water-in-oil absorbent matrix, a water-in-oil removable matrix, and/or a water-soluble matrix. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glyceryl monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers (such as polyethylene glycol).

Ointments and creams may be formulated, for example, with an aqueous or oil-based base and with the addition of suitable thickeners and/or gelling agents. Lotions may be formulated with an aqueous or oil-based base and generally should also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. The construction and use of transdermal patches for delivering pharmaceuticals are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed to deliver pharmaceuticals continuously, pulsatilely, or on demand.

Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Other lubricants include, for example, silicate silica gel, coagulated aerosols of synthetic silica, or mixtures thereof. Lubricants may optionally be added in an amount less than about 1% by weight of the pharmaceutical composition.

The compositions of the present invention can be in any form suitable for surface application, including aqueous, water-alcoholic, or oily solutions, lotions or serum dispersions, aqueous, anhydrous, or oily gels, emulsions (O/W or oil-in-water) or conversely (W/O or water-in-oil) obtained by dispersing a fatty phase in an aqueous phase, microemulsions, or ionic and/or nonionic microcapsules, microparticles, or lipid vesicle dispersions. These compositions can be prepared according to conventional methods. The amounts of the various components of the compositions of the present invention, except for the active agents of the invention, are amounts commonly used in the art. These compositions particularly constitute protective, therapeutic, or care creams, lotions, lotions, gels, or foams for use on the face, hands, body, and/or mucous membranes or for cleansing the skin. The compositions may also consist of solid formulations constituting soaps or cleansing sticks.

The compositions of the present invention may also contain adjuvants commonly used in the cosmetic and dermatological fields, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, fragrances, fillers, sunscreens, odor absorbers, and dyes. The amounts of these various adjuvants are those commonly used in the fields under consideration and, for example, from about 0.01% to about 20% of the total weight of the composition. Depending on their nature, these adjuvants may be introduced into the fatty phase, the aqueous phase, and/or lipid vesicles.

On the other hand, ocular viral infections can be effectively treated with ophthalmic solutions, suspensions, ointments, or inserts containing the active ingredients or combinations thereof of the present invention. Eye drops can be prepared by dissolving the active ingredients in a sterile aqueous solution such as physiological saline or a buffer solution, or by combining a powder composition to be dissolved prior to use. Other mediators may be selected, including but not limited to: balanced salt solutions, saline solutions, water-soluble polyethers (such as polyethylene glycol), polyethylene (such as polyvinyl alcohol and povidone), cellulose derivatives (such as methylcellulose and hydroxypropyl methylcellulose), petroleum derivatives (such as mineral oil and paraffin wax), animal fats (such as lanolin), acrylic polymers (such as carboxylated polymethylene gel), vegetable fats (such as peanut oil), and polysaccharides (such as dextran) and meglumine (such as sodium hyaluronate). If necessary, additives commonly used in eye drops may be added. Such additives include isotonic agents (e.g., sodium chloride), buffers (e.g., boric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate), preservatives (e.g., benzalkonium chloride, benzyl chloride, chlorobutanol), and thickeners (e.g., sugars such as lactose, mannitol, maltose; hyaluronic acid or its salts such as sodium hyaluronate, potassium hyaluronate; mucopolysaccharides such as chondroitin sulfate; sodium polyacrylate, carboxyethylene polymers, cross-linked polyacrylates, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, or other agents known to those skilled in the art).

The solubility of the components in the compositions of the present invention can be increased by surfactants or other suitable co-solvents in the composition. Such co-solvents include polysorbates 20, 60, and 80, Pluronic F68, F-84, and P-103, cyclodextrins, or other agents known to those skilled in the art. Such co-solvents can be used at levels of about 0.01% to 2% by weight.

The compositions of the present invention can be packaged in multiple dosage forms. Preservatives are preferably used to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium EDTA, sorbic acid, Onamer M, or other agents known to those skilled in the art. In prior art ophthalmic products, such preservatives can be used at levels of 0.004% to 0.02%. In the compositions of this application, the preservative (preferably benzalkonium chloride) can be used at levels of 0.001% by weight to less than 0.01% by weight, for example, 0.001% by weight to 0.008% by weight, preferably about 0.005% by weight. It has been found that a concentration of 0.005% benzalkonium chloride is sufficient to protect the compositions of the present invention from microbial attack.

On the other hand, viral infections of the ear can be effectively treated with otomedicine solutions, suspensions, ointments or inserts containing the agents or combinations of agents of the present invention.

On the other hand, the active ingredient of the present invention is delivered in a soluble form rather than a suspension, which allows for more rapid and quantitative absorption to the site of action. Generally, formulations such as gels, creams, lotions, suppositories, and ointments provide a wider area of exposure to the active ingredient of the present invention, while solution-based formulations (e.g., sprays) provide more immediate, short-term exposure.

In another aspect concerning surface/topical application, the pharmaceutical composition may include one or more penetration enhancers. For example, the formulation may contain a suitable solid or gel phase carrier or excipient that increases penetration or facilitates the delivery of agents or combinations of agents across permeability barriers (e.g., skin). Many of these penetration-enhancing compounds are known in the field of surface formulations and include, for example, water, alcohols (e.g., terpenes such as methanol, ethanol, 2-propanol), sulfoxides (e.g., dimethyl sulfoxide, decyl methyl sulfoxide, tetradecyl methyl sulfoxide), pyrrolidones (e.g., 2-pyrrolidone, N-methyl-2-pyrrolidone, N-(2-hydroxyethyl)pyrrolidone), lauryl azone, acetone, dimethylacetamide, dimethylformamide, tetrahydrofurfuryl alcohol, L-α-amino acids, anionic, cationic, amphoteric, or nonionic surfactants (e.g., isopropyl tetradecanoate and sodium lauryl sulfate), fatty acids, fatty alcohols (e.g., oleic acid), amines, amides, clofibric acid amide, hexamethylene lauryl amide, proteolytic enzymes, α-biazinool, d-limonene, urea, and N,N-diethyl-m-toluamide, etc. Other examples include humectants (e.g., urea), glycols (e.g., propylene glycol and polyethylene glycol), glyceryl monolaurate, alkanes, alkanols, oregels, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and/or other polymers. On the other hand, pharmaceutical compositions may include one or more such penetration enhancers.

On the other hand, pharmaceutical compositions for topical/surface application may include one or more antimicrobial preservatives, such as quaternary ammonium compounds, organic mercurials, parabens, aromatic alcohols, chlorobutanol, etc.

Gastrointestinal viral infections can be effectively treated with oral or rectal solutions, suspensions, ointments, enemas, and/or suppositories containing the agents or combinations of agents of the present invention.

Respiratory viral infections can be effectively treated with aerosol solutions, suspensions, or dry powders containing the agents or combinations of agents of the present invention. Inhalation is particularly suitable for treating pulmonary viral infections, such as HRV infection. Aerosols can be administered via the respiratory system or nasal passages. For example, those skilled in the art will recognize that the compositions of the present invention can be suspended or dissolved in a suitable carrier (e.g., a pharmaceutically acceptable propellant) and administered directly to the lungs using a nasal spray or inhaler. For example, aerosol formulations containing fatty acid synthesis pathway inhibitors (e.g., inhibitors of FASN gene expression or FASN protein activity) can be dissolved, suspended, or emulsified in a propellant or a mixture of solvent and propellant, for example, administered as a nasal spray or inhaler. Aerosol formulations can contain any acceptable propellant under pressure, such as cosmetically or dermatologically or pharmaceutically acceptable propellants commonly used in the art.

Aerosol formulations for intranasal application are typically designed to be administered as drops or sprays into the nasal passages as an aqueous solution. Nasal solutions are similar to nasal secretions in that they are generally isotonic and slightly buffered to maintain a pH of approximately 5.5 to approximately 6.5, although pH values outside this range may also be used. Antimicrobial agents or preservatives may also be included in the formulation.

Aerosol formulations and inhalers for inhalation can be designed to deliver the agents or combinations of agents of the present invention into the respiratory tree of the subject when administered via the intranasal or oral respiratory route. Inhalation solutions can be administered, for example, via a nebulizer. Inhalants or inhalers comprising fine powder or liquid drugs can be delivered to the respiratory system in the form of a pharmaceutical aerosol of a solution or suspension of the agent or combination of agents in a propellant, for example, as an aid in dispensing. The propellant can be a liquefied gas, including halocarbons, such as fluorocarbons, such as chlorofluorocarbons, hydrochlorofluorocarbons, and hydrochlorocarbons, as well as hydrocarbons and hydrocarbon ethers.

Halogenated carbide propellants that can be used in this invention include fluorocarbon propellants (where all hydrogens are replaced by fluorine), chlorofluorocarbon propellants (where all hydrogens are replaced by chlorine and at least one fluorine), hydrogen-containing fluorocarbon propellants, and hydrogen-containing chlorofluorocarbon propellants. Halogenated carbide propellants are described in U.S. Patent No. 5,376,359, issued to Johnson on December 27, 1994; U.S. Patent No. 5,190,029, issued to Byron et al. on March 2, 1993; and U.S. Patent No. 5,776,434, issued to Purewal et al. on July 7, 1998. Hydrocarbon propellants that can be used in this invention include, for example, propane, isobutane, n-butane, pentane, isopentane, and neopentane. Hydrocarbon blends can also be used as propellants. Ether propellants include, for example, dimethyl ether and diethyl ether. The aerosol formulation of this invention may also contain more than one propellant. For example, the aerosol formulation may contain one or more propellants of the same kind, such as two or more fluorocarbons; or one, two, or three or more propellants of different kinds, such as fluorocarbons and hydrocarbons. The pharmaceutical compositions of the present invention may also be dispensed using a compressed gas, such as an inert gas (e.g., carbon dioxide, nitrous oxide, or nitrogen).

Aerosol formulations may also include other components such as ethanol, isopropanol, propylene glycol, and surfactants or other components such as oils and detergents. These components can be used to stabilize the formulation and/or lubricate valve assemblies.

Aerosol formulations can be packaged under pressure and can be formulated into aerosols using solutions, suspensions, emulsions, powders, and semi-solid formulations. For example, solution aerosol formulations may comprise a solution of the active agent of the present invention (such as an inhibitor of fatty acid synthesis pathways, e.g., an inhibitor of FASN gene expression or FASN protein activity) in (essentially) pure propellant or a mixture of propellant and solvent. The solvent may be used to dissolve the active agent and/or delay the evaporation of the propellant. Solvents that can be used in the present invention include, for example, water, ethanol, and glycols. Any combination of suitable solvents may be used, optionally in combination with preservatives, antioxidants, and/or other aerosol components.

Aerosol formulations may also be dispersions or suspensions. Suspension aerosol formulations may include a suspension of the active agents or combinations of active agents of the present invention (e.g., fatty acid synthesis pathway inhibitors, such as inhibitors of FASN gene expression or FASN protein activity) and a dispersant. Dispersants that can be used in the present invention include, for example, sorbitan trioleate, oleyl alcohol, oleic acid, lecithin, and corn oil. Suspension aerosol formulations may also include lubricants, preservatives, antioxidants, and/or other aerosol components.

Aerosol formulations can be similarly formulated as emulsions. Emulsion aerosol formulations may include, for example, alcohols (such as ethanol), surfactants, water, and propellants, as well as the agents or combinations of agents of the present invention, such as fatty acid synthesis pathway inhibitors, such as inhibitors of FASN gene expression or FASN protein activity. The surfactants used may be nonionic, anionic, or cationic. One example of an emulsion aerosol formulation includes, for example, ethanol, surfactants, water, and propellants. Another example of an emulsion aerosol formulation includes, for example, vegetable oils, glyceryl monostearate, and propane.

The disclosed compounds can be formulated for application in suppository form. A low-melting-point wax (such as a mixture of triglycerides, fatty acid glycerides, Wiptsol S55 (Dynamite Nobel Chemical, a trade name in Germany), or cocoa butter) is first melted and the active ingredient is uniformly dispersed, for example, by stirring. The molten, homogeneous mixture is then poured into a mold of suitable size, allowing it to cool and solidify.

The compounds disclosed herein can be formulated for vaginal application. In addition to the active ingredient, suitable formulations include pessaries, tampons, creams, gels, pastes, foams, or sprays containing such carriers known in the art.

Furthermore, the compounds of this disclosure are contemplated to releasably adhere to biocompatible polymers for use in sustained-release formulations attached to, within, or to inserts, for topical, intraocular, periocular, or systemic administration. Controlled release from biocompatible polymers can also be achieved using water-soluble polymers to form instillable formulations. Controlled release from biocompatible polymers (such as PLGA microspheres or nanospheres) can also be used in formulations suitable for intraocular implantation or injection for sustained-release administration. Any suitable biodegradable and biocompatible polymer can be used.

Pharmaceutical compositions applicable to the present invention include compositions in which the active ingredient is present in an effective amount (i.e., an amount that can effectively achieve therapeutic and/or preventive benefits in a host with at least one viral infection or in a subject with cancer). The actual amount effective for a particular application will depend on one or more conditions being treated, the condition of the subject, the formulation and route of administration, and other factors known to those skilled in the art. Based on the disclosure herein, the determination of the effective amount of fatty acid synthesis pathway inhibitors (e.g., inhibitors of FASN gene expression or FASN protein activity) is entirely within the capabilities of those skilled in the art and should be determined using conventional optimization techniques.

Effective amounts for human use can be determined based on animal models. For example, human doses can be formulated to achieve circulatory, hepatic, surface, and/or gastrointestinal concentrations found to be effective in animals. Those skilled in the art can determine effective amounts for human use, particularly based on experimental data from the animal models described herein. Based on animal data and other similar data of other types, those skilled in the art can determine effective amounts of the compositions of the present invention suitable for human use.

When referring to the active ingredient or combination of active ingredients in this invention, the effective amount generally means a range of dosages, administration methods, formulations, etc., recommended or approved by any of the various regulatory or advisory bodies in the medical or pharmaceutical field (e.g., FDA, AMA) or by the manufacturer or supplier.

Furthermore, the appropriate dosage of fatty acid synthesis pathway inhibitors (e.g., inhibitors of FASN gene expression or FASN protein activity) can be determined based on in vitro experimental results. For example, the in vitro efficacy of an agent in inhibiting components of the fatty acid synthesis pathway (e.g., FASN gene expression or FASN protein activity) provides information that can be used to develop effective in vivo doses to achieve similar biological effects.

In another aspect, the application of the agent of the present invention can be intermittent, for example, once every two days, once every three days, once every five days, once a week, once a month, or twice a month. Furthermore, the amount, form, and/or the amount of different forms can be varied at different application times.

Those skilled in the art should be able to monitor the effects of specific agent administration in patients. For example, HIV viral load levels can be determined using standard techniques in the art, such as measuring CD4 cell counts and/or viral levels as detected by PCR. Other techniques will be apparent to those skilled in the art.

Various aspects of the invention have now been generally described, and these aspects will be more readily understood by reference to the following embodiments, which are provided by way of illustration and are not intended to be limiting unless otherwise stated.

Example

Example - Synthesis of the compounds disclosed herein

Summary: All reactions and operations described herein were performed in a well-ventilated fume hood. Operations and reactions under high or low pressure were carried out behind explosion-proof shielding. Abbreviations: ACN, acetonitrile; AcOH, acetic acid; AIBN, azobisisobutyronitrile; BuLi, butyllithium; CDI, 1,1′-carbonyldiimidazole; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DCE, 1,2-dichloroethane; DCM, dichloromethane or methylene chloride; DIEA, N,N-diisopropylethylamine; DMAP, 4-dimethylaminopyridine; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; EtOAc, ethyl acetate; EtOH, ethanol; HATU, 2-hexafluorophosphate. (1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylurea; HBTU, hexafluorophosphate O-benzotriazol-N,N,N′,N′-tetramethyl-urea or hexafluorophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium; HMPA, hexamethylphosphoramide; HOAc, acetic acid; HOBT, 1-hydroxybenzotriazine; LDA, diisopropylaminolithium; MeOH, Methanol; MsCl, methanesulfonyl chloride; MsOH, methanesulfonic acid; NBS, N-bromosuccinimide; NIS, N-iodosuccinimide; PE, petroleum ether; PTAT, phenyltrimethylammonium tribromide; PTSA, p-toluenesulfonic acid; Py, pyridine; Pyr, pyridine; TEA, triethylamine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TMSCl, trichlorotrimethylsilane; TsOH, p-toluenesulfonic acid.

Compound 1.1. 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester. Under nitrogen atmosphere and at -78°C, a butyllithium solution (150 mL, 2.43 M in THF, 1.05 equivalent) was added dropwise over 30 minutes to a stirred solution of 1-bromo-4-iodobenzene (93.7 g, 331.21 mmol, 1.10 equivalent) in tetrahydrofuran (800 mL). The resulting solution was stirred at -78°C for 2 hours. Subsequently, a solution of 4-oxopiperidine-1-carboxylic acid tert-butyl ester (60 g, 301.13 mmol, 1.00 equivalent) in tetrahydrofuran (800 mL) was added dropwise over 30 minutes with stirring at -78°C. After stirring at -78°C for 1 hour, the reaction was carefully quenched with 350 mL _of H₂O. The mixture was extracted with 2 × 400 _mL of ethyl acetate, and the combined organic layers were dried ( _Na₂SO₄ ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:200–1:10) as the eluent to give 91 g (85%) of the title compound as a yellow oil.

Compound 1.2. 4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester. A solution of 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (compound 1.1, 36 g, 101.05 mmol, 1.00 equivalent), Pd( _PPh3 ) ₄ (11.7 g, 10.12 mmol, 0.05 equivalent), and Zn(CN) ₂ (17.9 g, 152.44 mmol, 1.51 equivalent) in DMF (400 mL) was stirred overnight at 80 °C under nitrogen. After reaching ambient temperature, the reaction was quenched by adding 600 mL of _FeSO4 (saturated aqueous solution) and diluted with ethyl acetate. The resulting mixture was vigorously stirred, filtered through diatomaceous earth, and washed with 1 M _FeSO4 , water, and ethyl acetate. The separated layers were extracted with 2 × 300 mL of ethyl acetate. The combined organic layers were washed sequentially with 1×200 mL of potassium carbonate (saturated aqueous solution) and 1×200 _mL of brine, dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:200–1:5) as eluent to give 23 g (75%) of the title compound as a white solid.

Compound 1.3. 4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester. A solution of 4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (compound 1.2, 2 g, 6.61 mmol, 1.00 equivalent) in pyridine (40 mL) was placed in a round-bottom flask. _POCl3 (10.16 g, 66.26 mmol, 10.02 equivalent) was carefully added. The resulting mixture was stirred overnight at room temperature under nitrogen, followed by concentration under vacuum. The residue was dissolved in 20 mL of DCM, washed with 2 × 20 mL of sodium bicarbonate (aqueous solution), dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE/EtOAc (100:1–30: ₁ ) as eluent to give 1.4 g (74%) of the title compound as a white solid.

Compound 1.4. 4-(4-cyanophenyl)piperidin-1-carboxylic acid tert-butyl ester. A round-bottom flask containing a solution of 4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (compound 1.3, 500 mg, 1.76 mmol, 1.00 equivalent) in ethyl acetate (20 mL) was purged with nitrogen. Palladium on carbon (0.1 g, 10%, 60% water) was then added to the solution, and the flask was purged with nitrogen again. The atmosphere was then changed to hydrogen, and the mixture was stirred overnight at room temperature. After purging the system with nitrogen, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure to give 0.2 g (40%) of the title compound as a yellow oil.

Compound 1.5. 4-(piperidin-4-yl)benzonitrile hydrochloride. A solution of 4-(4-cyanophenyl)piperidin-1-carboxylic acid tert-butyl ester (compound 1.4, 4 g, 13.99 mmol, 1.00 equivalent) in ethyl acetate (60 mL) was placed in a 100 mL three-necked round-bottom flask. Hydrogen chloride (gas) was bubbled through the solution while the resulting mixture was stirred at room temperature for 1 hour. The precipitate formed was collected by filtration and dried to give 2.2 g (71%) of the title compound as a white solid. m/z (ES+) 187 (M+H) ⁺ . ¹ H NMR (300 MHz, CD ₃ OD): δ 7.72 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 3.54 (d, with fine structure, J = 12.6 Hz, 2H), 3.18 (t, with fine structure, J = 12.2 Hz, 2H), 3.12–1.97 (m, 1H), 2.11 (d, with fine structure, J = 14.1 Hz, 2H), 2.04–1.84 (m, 2H).

Compound 1.6. Methyl 3-bromo-4-methylbenzoate. A solution of 3-bromo-4-methylbenzoic acid (20 g, 93.00 mmol, 1.00 equivalent) and sulfuric acid (20 mL) in methanol (100 mL) was stirred overnight at 80 °C. The mixture was then concentrated under reduced pressure and the residue was diluted with 500 mL of ethyl acetate. The resulting mixture was washed successively with 3 × 200 mL of water, 1 × 200 mL of sodium bicarbonate (aqueous solution), and 1 × 200 mL of brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried to give 20 g (94%) of the title compound as a deep red oil.

Compound 1.7. Methyl 3-cyano-4-methylbenzoate. A mixture of methyl 3-bromo-4-methylbenzoate (compound 1.6, 18 g, 78.58 mmol, 1.00 equivalent), Zn(CN) _₂ (11.1 g, 94.87 mmol, 1.20 equivalent), and Pd( _PPh₃ ) _₄ (7.3 g, 6.32 mmol, 0.08 equivalent) in N,N-dimethylformamide (250 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched by carefully adding 200 mL of _FeSO₄ (saturated aqueous solution) and diluted with ethyl acetate. The resulting mixture was vigorously stirred, filtered through diatomaceous earth, and washed with 1 M _FeSO₄ , water, and ethyl acetate. The separated layers were extracted with 2 × 500 mL of ethyl acetate. The combined organic layers were washed with 3 × 200 mL of brine, dried over _{Na₂SO₄ ,} and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:50) as eluent to give 11 g (76%) of the title compound as a grayish-white solid.

Compound 1.8. Methyl 3-(N′-hydroxymethylammonium)-4-methylbenzoate. A mixture of methyl 3-cyano-4-methylbenzoate (compound 1.7, 8 g, 43.38 mmol, 1.00 equivalent, 95%), _NH₂OH ·HCl (3.785 g, 54.86 mmol, 1.20 equivalent), and N,N-diisopropylethylamine (DIEA, 17.7 g, 136.95 mmol, 3.00 equivalent) in tetrahydrofuran (100 mL) was stirred overnight at 70 °C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in water and the pH was adjusted to 2–3 with hydrogen chloride (aqueous solution, 1 M). The mixture was washed with 3 × 40 mL of ethyl acetate, and the pH of the aqueous layer was adjusted to 8–9 with NaOH (aqueous solution, 2 M), followed by extraction with 3 × 30 mL of ethyl acetate. The combined organic layers were dried _{over Na₂SO₄} and concentrated under reduced pressure to give 2.76 g (29%) of the title compound as a white solid.

Compound 1.9. Methyl 3-formamidinyl-4-methylbenzoate. A round-bottom flask containing a solution of methyl 3-(N′-hydroxyformamidinyl)-4-methylbenzoate (compound 1.8, 8 g, 36.50 mmol, 1.00 equivalent, 95%) in methanol (150 mL) was purged with nitrogen. Palladium on carbon (9 g, 10%, 60% water) was added to the solution, and the flask was then purged with nitrogen again. The atmosphere was then changed to hydrogen, and the mixture was stirred overnight at 25 °C in a balloon. After purging the system with nitrogen, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4 g (54%) of the title compound as a brown solid.

Compound 1.10.1 3-Bromodihydro-2H-pyran-4(3H)-one. N-bromosuccinimide (17.8 g, 100.00 mmol, 1.00 equivalent) was added fractionally to a mixture of dihydro-2H-pyran-4(3H)-one (10 g, 99.88 mmol, 1.00 equivalent) and _NH₄OAc (3.56 g, 46.23 mmol) in tetrahydrofuran (100 mL) at 0 °C under nitrogen. The resulting mixture was stirred overnight at 30 °C under nitrogen. The reaction mixture was then filtered and the filtrate concentrated. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1/10–1/5) as eluent to give 15 g (50%) of the title compound as a brown oil.

Compound 1.10. Methyl 4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate. A mixture of methyl 3-formamidinyl-4-methylbenzoate (compound 1.9, 400 mg, 1.98 mmol, 1.00 equivalent, 95%), 3-bromodihydro-2H-pyrano-4(3H)-one (compound 1.10.1, 750 mg, 2.09 mmol, 1.00 equivalent) and potassium carbonate (580 mg, 4.20 mmol, 2.00 equivalent) in _CH3CN (15 mL) was stirred overnight at 80 °C under nitrogen. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 50 _mL of ethyl acetate and washed with 2 × 10 mL _H2O . The organic phase was dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and by ethyl acetate/petroleum ether (1/3) to give 0.21 g (37%) of the title compound as a white solid.

Compound 1.11. 4-Methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid. A mixture of methyl 4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate (compound 1.10, 210 mg, 0.73 mmol, 1.00 equivalent, 95%) and sodium hydroxide (92.65 mg, 2.32 mmol, 3.00 equivalent) in 12 mL methanol/ _H₂O (2:1) was stirred at 60 °C in an oil bath. After 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 5 mL _H₂O . The resulting mixture was washed with 3 × 10 mL ethyl acetate, and the pH of the aqueous layer was subsequently adjusted to 2–3 using hydrogen chloride (aqueous solution, 2 M). The resulting mixture was extracted with 3 × 30 mL ethyl acetate. The combined organic layers were dried ( _{Na₂SO₄ )} and concentrated under reduced pressure to give 0.21 g (89%) of the title compound as a white solid.

Compound 1. Methyl-4-(1-(4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. A mixture of 4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid (compound 1.11, 60 mg, 0.22 mmol, 1.00 equivalent, 95%), EDCI (88.4 mg, 0.46 mmol, 2.00 equivalent), DMAP (85.12 mg, 0.70 mmol, 3.00 equivalent) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 52 mg, 0.23 mmol, 1.00 equivalent) in DMF was stirred at room temperature. Three hours later, the reaction mixture was diluted with 40 mL of DCM and washed sequentially with 2 × 10 mL of _NH₄Cl (saturated aqueous solution) and 2 × 10 _mL of brine. The organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure. The crude product (approximately 100 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-006(Waters)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and CH₃CN (15.0% CH₃CN increased to 42.0% within 12 minutes, and to 100.0% within 1 minute); detector, UV 254/220 nm. The fractions containing the purified compound were combined and lyophilized to give 32.9 mg (34%) of the title compound as a white solid. m/z (ES+) 427 (M+H) ^⁺ . ^¹H NMR (300 MHz, _CD₃ OD): δ 7.73–7.65 (m, 4H), 7.61 (d, J = 5.7 Hz, 1H), 7.50 (d, J = 6.0 Hz, 2H), 4.89–4.78 (1H, partially obscured by water peak), 4.81 (s, 2H), 4.10 (t, J = 4.1 Hz, 2H), 3.94–3.81 (m, 1H), approximately 3.35 (1H, partially obscured by methanol solvent peak), 3.08–1.95 (m, 2H), 2.92 (t, J = 4.1 Hz, 2H), 2.52 (s, 3H), 2.08–1.92 (m, 1H), 1.92–1.65 (m, 3H). ¹H NMR (400 MHz, CD₃ OD): δ 7.73–7.65 (m, 4H), 7.61 (d, J = 5.7 Hz, 1H), 7.50 (d, J = 6.0 Hz, 2H), 4.89–4.78 ( ^1H , partially obscured by water peak), 4.81 (s, 2H), 4.10 (t, J = 4.1 Hz, 2H), 3.94–3.81 (m, 1H), approximately 3.35 (1H, partially obscured by methanol solvent peak), 1.92–1.65 (m, _3H ). ): δ7.63 (d, J=8.3Hz, 2H), 7.34 (d, J=8.3Hz, 2H), 7.30 (s, 1H), 7.50 (m, 2H), 4. 89 (d, J = 13.0Hz, 1H), 4.81 (s, 2H), 4.05 (t, J = 5.2Hz, 2H), 3.77 (d, J = 13.2Hz, 1 H), 3.30 (t, J=13.0Hz, 1H), 3.01-2.84 (m, 4H), 2.34 (s, 3H), 2.06 (d, J=13.7Hz , 1H), 1.86 (d, J=12.9Hz, 1H), 1.76 (q, J=12.8Hz, 1H), 1.57 (q, J=11.7Hz, 1H).

Compound 2.1. 5-Iodo-2,4-dimethylbenzoic acid. A solution of 2,4-dimethylbenzoic acid (20 g, 133.18 mmol, 1.00 equivalent), sodium periodate (14.27 g, 66.72 mmol, 0.50 equivalent), iodine (37.25 g, 146.76 mmol, 1.10 equivalent), and sulfuric acid (1.96 g, 19.98 mmol, 0.15 equivalent) in acetic acid (150 mL) was stirred in an oil bath at 110 °C. After 6 hours, the reaction mixture was allowed to reach ambient temperature and then diluted with 1.2 L of water. 800 mL of a _saturated aqueous solution _{of Na₂S₂O₃} was carefully added. The resulting solid was collected by filtration, dissolved in 1.2 L of ethyl acetate, and washed successively with 1 × 300 mL of _{saturated aqueous solution of Na₂S₂O₃ and 1} × 400 mL of brine. The organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure. The crude residue was recrystallized from ethanol:H₂O ( _{2 :} 1) to give 30 g (82%) of the title compound as a white solid.

Compound 2.2. Methyl 5-iodo-2,4-dimethylbenzoate. A solution of 5-iodo-2,4-dimethylbenzoic acid (compound 2.1, 10 g, 32.60 mmol, 1.00 equivalent, 90%) and sulfuric acid (10 mL) in methanol (100 mL) was stirred overnight at 80 °C. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was diluted with 200 mL of ethyl acetate. The resulting mixture was washed successively with 3 × 50 mL of water, 2 × 50 mL of sodium bicarbonate (saturated aqueous solution), and 2 × 50 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 9.2 g (88%) of the title compound as a yellow oil.

Compound 2.3. Methyl 5-cyano-2,4-dimethylbenzoate. A solution of methyl 5-iodo-2,4-dimethylbenzoate (compound 2.2, 9.2 g, 31.71 mmol, 1.00 equivalent), Zn(CN) _₂ (4.46 g, 38.12 mmol, 1.20 equivalent), and Pd( _PPh₃ ) _₄ (2.93 g, 2.54 mmol, 0.08 equivalent) in N,N-dimethylformamide (120 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched by carefully adding 100 mL of _FeSO₄ (saturated aqueous solution) and diluted with ethyl acetate. The resulting mixture was vigorously stirred, filtered through diatomaceous earth, and washed with 1 M _FeSO₄ , water, and ethyl acetate. The separated layers were extracted with 2 × 100 mL of ethyl acetate. The combined organic layers were washed with 2 × 20 mL of brine, dried ( _Na₂SO₄ ) _, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:5) as eluent to give 6.2 g (93%) of the title compound as a white solid.

Compound 2.4. Methyl 5-(N′-hydroxymethylammonium)-2,4-dimethylbenzoate. A solution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 6 g, 28.54 mmol, 1.00 equivalent, 90%) and _NH₂OH (10 mL, 5.00 equivalent, 50% in water) in EtOH (20 mL) was stirred in an oil bath at 100 °C. After 2 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate, washed with 2 × 20 _mL of brine, dried ( _Na₂SO₄ ), and concentrated under reduced pressure to give 4.66 g (66%) of the title compound as a white solid.

Compound 2.5. Methyl 5-formamidinyl-2,4-dimethylbenzoate hydrochloride. A solution of methyl 5-(N′-hydroxyformamidinyl)-2,4-dimethylbenzoate (compound 2.4, 4.66 g, 18.87 mmol, 1.00 equivalent, 90%) and _Ac₂O (2.36 g, 23.09 mmol, 1.10 equivalent) in AcOH (21 mL) was stirred at room temperature. After 5 minutes, the flask was purged with nitrogen and HCOOK (8.8 g, 104.76 mmol, 5.00 equivalent) and palladium on carbon (10%, 2.33 g) were added. The flask was purged sequentially with nitrogen and then with hydrogen. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere (gas chamber). After purging the system with nitrogen, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 50 mL of ethanol and the pH was adjusted to 5-6 with hydrogen chloride (aqueous solution, 5 M). The resulting solid was removed by filtration and the filtrate was concentrated under reduced pressure to give 4 g of the title compound as a white solid.

Compound 2.6. 2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid tert-butyl ester. A mixture of methyl 5-formamidinyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 500 mg, 90%), tert-butyl 3-bromo-4-oxopiperidin-1-carboxylic acid (860 mg, 2.78 mmol), and potassium carbonate (570 mg, 4.12 mmol) in _CH3CN (15 mL) was stirred overnight at 80 °C under nitrogen. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 25 mL of ethyl acetate and washed with 2 × 10 _{mL H2O} . The organic phase was dried ( _Na2SO4 ) and concentrated under reduced pressure. The crude product obtained therefrom was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:3) as the eluent, yielding 0.3 g of the title compound as a white solid.

Compound 2.7. 5-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoic acid. A mixture of 2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-carboxylic acid tert-butyl ester (compound 2.6, 300 mg, 0.70 mmol, 1.00 equivalent, 90%) and sodium hydroxide (62 mg, 1.55 mmol, 2.00 equivalent) in 15 mL methanol/ _H₂O (2:1) was stirred at 40 °C in an oil bath. After 2 hours, the reaction mixture was concentrated to 1/3 of its volume under reduced pressure. The pH of the remaining mixture was adjusted to 3–4 with hydrogen chloride (aqueous solution, 1 M). The obtained solid was collected by filtration and dried in an oven under reduced pressure to give 0.2 g (69%) of the title compound as a yellow solid.

Compound 2.8. 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid tert-butyl ester. A solution of compound 2.7 (125 mg, 0.30 mmol, 1.00 equivalent, 90%), DIEA (130.5 mg, 1.01 mmol, 3.00 equivalent), HBTU (256.2 mg, 0.68 mmol, 2.00 equivalent), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 75 mg, 0.30 mmol, 1.00 equivalent) in DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with 50 mL of ethyl acetate, washed with 2 × 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and by ethyl acetate/petroleum ether (1:1) to give 0.1 g (55%) of the title compound as a yellow solid.

Compound 2.9. 4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. Trifluoroacetic acid (1 mL) was added to a solution of 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-carboxylic acid tert-butyl ester (compound 2.8, 100 mg, 0.17 mmol, 1.00 equivalent, 90%) in dichloromethane (3 mL). The resulting mixture was stirred at room temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with sodium bicarbonate (saturated aqueous solution). The organic phase was dried ( _{Na₂SO₄ )} and concentrated under reduced pressure to give 0.1 g (68%) of the title compound as a yellow solid.

Compound 2.4-(1-(5-(5-acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. At 0°C, under nitrogen, a solution of Ac₂O (2.4 mg, 0.02 mmol, 1.00 equivalent, 50%) in DMF (2 mL) was added dropwise to the stirred mixture of 4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin- ₂ -yl)benzoyl)piperidin-4-yl)benzonitrile (compound 2.9, 20 mg, 0.02 mmol, 1.00 equivalent, 50%) in DMF (2 mL). The resulting solution was stirred in a water/ice bath at 0–3°C for 1 hour. The reaction mixture was then diluted with 50 mL of ethyl acetate and washed with 2 × ₂₀ mL of brine. The organic phase was dried ( _Na₂SO₄ ) and concentrated under reduced pressure. The crude residue (50 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-006(Waters)): column, Xbridge C18; mobile phase, water containing 0.05% NH₃ _{· H₂O} and _CH₃CN (5% _CH₃CN held for 2 min, increasing to 20%-46% for 10 min, increasing to 100% for 12 min, decreasing to 20% for 14 min); detector, UV 254/220 nm. The fractions containing the purified compound were combined and lyophilized to give 5.5 mg of the title compound as a white solid. m/z (ES+) 482 (M+H) ^⁺ . ^¹H NMR (300 MHz, _CD₃OD ): δ 7.69 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.39–7.28 (m, 2H), 4.90 (m, 1H, partially obscured by solvent peak), 4.67 and 4.62 (two singlets, acetamide rotational isomer, _MeCONCH₃ -imidazole, 2H), 3.92 (m, 2H), 3.66 (m, 1H), 3.23 (m, 1H), 3.00 (m, 2H), 2.85–2.76 (m, 2H), 2.48 (s, 3H), 2.41 and 2.31 (two singlets, arylamide rotational isomer, ArCH₃ ₎ , 3H), 2.25 and 2.22 (two singlets, acetamide rotational isomer, CH ₃ CON, 3H), 2.04 (m, 1H), 1.92-1.20 (m, 3H).

Compound 3. 4-(1-(3-(5-acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compounds 1 and 2. m/z(ES+)468(M+H) ⁺ .

Compound 4. 4-(1-(4-methyl-3-(5-(methanesulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare compounds 1 and 2. m/z(ES+)504(M+H) ⁺ .

Compound 5. 4-(1-(5-(5-(isopropylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compounds 1 and 2. m/z(ES+)546(M+H) ⁺ .

Compound 6. 4-(1-(2,4-dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)-2-fluorobenzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compounds 1 and 2. m/z(ES+) 459(M+H) ⁺ .

Compound 7. 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-sulfonamide. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compounds 1 and 2. m/z(ES+)547(M+H) ⁺ .

Compound 8. (2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)phenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl ketone. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compounds 1 and 2. m/z(ES+)484(M+H) ⁺ .

Compound 9. 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-N-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazolium-6-carboxamide. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compounds 1 and 2. m/z(ES+) 496(M+H) ⁺ .

Compound 11.1. 4-(4-cyanophenyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester. Deoxo- (4.4 g, 19.89 mmol, 1.20 equivalent) was added dropwise to a stirred solution of compound 1.2 (5 g, 16.54 mmol, 1.00 equivalent) in dichloromethane (250 mL) at -78 °C under nitrogen. The resulting mixture was stirred at -78 °C for 1 hour. The reaction mixture was then carefully quenched by adding 50 mL of sodium bicarbonate (saturated aqueous solution) and extracted with 3 × 100 mL of dichloromethane. The combined organic layers were washed with 150 mL of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:30) as eluent to give 2.5 g (35%) of the title compound as a white solid.

Compound 11.2. 4-(4-Fluoroperidin-4-yl)benzonitrile. Trifluoroacetic acid (6 g, 52.62 mmol, 51.66 equivalents) was added dropwise to a stirred solution of compound 11.1 (620 mg, 1.02 mmol, 1.00 equivalent, 50%) in DCM (40 mL). The mixture was stirred at ambient temperature for 2 h and concentrated under reduced pressure. The residue was dissolved in DCM and treated with an aqueous sodium bicarbonate solution. The phase was separated and the aqueous layer was extracted with 2 × 50 mL DCM. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.4 g of the title compound as a pale yellow solid. m/z(ES+)205(M+H) ⁺ .

Compound 11.2 hydrochloride, 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 1.5, with compound 11.1 replacing compound 1.4. m/z (ES+) 205 (M+H) ⁺ . ^¹H NMR (300 MHz, _CD₃OD ): δ 7.83 (d, J = 6.3 Hz, 2H), 7.68 (d, J = 6.3 Hz, 2H), 3.55–3.32 (m, 4H), 2.58–2.40 (m, 2H), 2.28–2.22 (m, 2H).

Compound 11. 4-(1-(2,4-dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compounds 1 and 2, with compound 11.2 replacing compound 1.5. m/z(ES+) 459(M+H) ⁺ .

Compound 12. (4-(4-chlorophenyl)piperidin-1-yl)(2,4-dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)phenyl) ketone. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compounds 1 and 2. m/z(ES+) 450(M+H) ⁺ .

Compound 13. 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-N-methyl-1,4,5,6-tetrahydrocyclopentadien[d]imidazolium-5-carboxamide. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compounds 1 and 2. m/z(ES+)482(M+H) ⁺ .

Compound 14. 4-(1-(2,4-dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare compounds 1 and 2. m/z(ES+)441(M+H) ⁺ .

Compound 15. (2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)phenyl)(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)methyl ketone. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare compounds 1 and 2. m/z(ES+) 500(M+H) ⁺ .

Compound 16.1. ^N₂- (2-methoxyethyl) ^-N₂ -methyl-5-nitropyridine-2,4-diamine. A solution of 2-chloro-5-nitropyridine-4-amine (500 mg, 2.88 mmol, 1.00 equivalent), triethylamine (1.167 g, 11.53 mmol, 4.00 equivalent), and (2-methoxyethyl)(methyl)amine (514 mg, 5.77 mmol, 2.00 equivalent) in DMF (20 mL) was stirred overnight at 55 °C in a sealed tube after being protected against explosion. After cooling to room temperature, the mixture was diluted with 100 mL of water and extracted with 3 × 150 _mL of ethyl acetate. The combined organic layers were dried ( _Na₂SO₄ ) and concentrated under reduced pressure to give 723 mg (crude) of the title compound as a deep red oil.

Compound 16.2. ^N2- (2-methoxyethyl) ^-N2 -methylpyridine-2,4,5-triamine. A round-bottom flask containing a solution of compound 16.1 (400 mg, 1.77 mmol, 1.00 equivalent) in methanol (30 mL) was purged with nitrogen. Palladium on carbon (40 mg, 10%, 60% water) was then added to the solution. The flask was purged again with nitrogen, and the atmosphere was subsequently changed to hydrogen. The mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. After purging the system with nitrogen, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give 300 mg (86%) of the title compound as a light brown solid. The crude product was found to be unstable and used immediately.

Compound 16.3. 5-Formyl-2,4-dimethylbenzoic acid. Under nitrogen atmosphere and at -78°C, n-BuLi (2.5M in THF, 18 mL, 2.50 equivalents) was added dropwise to a stirred solution of 5-iodo-2,4-dimethylbenzoic acid (compound 2.1, 5 g, 18.11 mmol, 1.00 equivalents) in tetrahydrofuran (150 mL). After stirring at -78°C for 1 hour, DMF (5 g, 68.4 mmol, 3.80 equivalents) was added dropwise. The resulting mixture was stirred at -78°C for another 0.5 hours and then carefully quenched by the slow addition of 50 mL of water. The pH was then adjusted to approximately 3–4 using an aqueous solution of HCl (6 M). The mixture was extracted with 3 × 200 mL of ethyl acetate. The combined organic layers were dried ( _{Na₂SO₄ )} and concentrated under reduced pressure. The residue obtained therefrom was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:10-1:5) as a gradient to give 2.4 g (74%) of the title compound as a white solid.

Compound 16.4. 4-(1-(5-formyl-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. DIEA (2.48 g, 19.19 mmol, 4.00 equivalents) was added to a stirred solution of 5-formyl-2,4-dimethylbenzoic acid (compound 16.3, 950 mg, 5.33 mmol, 1.10 equivalents) in 15 mL of DMF, followed by the addition of HBTU (3.67 g, 9.68 mmol, 2.00 equivalents) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.07 g, 4.80 mmol, 1.00 equivalents). After stirring overnight at ambient temperature, the reaction was quenched by adding 60 mL of water. The resulting mixture was extracted with 3 × 150 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:10-1:3) as the eluent to give 1.4 g (84%) of the title compound as a brown oil.

Compound 16.4-(1-(5-(6-(((2-methoxyethyl)(methyl)amino)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. A solution of compound 16.2 (300 mg, 1.53 mmol, 1.30 equivalents), compound 16.4 (407 mg, 1.17 mmol, 1.00 equivalents), and ammonium acetate (362 mg, 4.70 mmol, 4.00 equivalents) in ethanol (20 mL) was stirred overnight in an oil bath at 70 °C. The resulting mixture was then concentrated under vacuum, and the residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:10–2:1) as eluent to give approximately 200 mg of product. This product was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-006(Waters)): column, SunFire PrepC18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and CH3CN (5.0% CH3CN maintained for 2 min, increasing to 25.0% in 1 min, 55.0% in 12 min, and 100.0% in 1 min); detector, UV 254/220 nm. The fractions containing the purified compound were combined and lyophilized to give 150 mg (24%) of the title compound as a white solid. m/z (ES+) 523 (M+H) ⁺ . ^1H NMR (300MHz, _CDCl₃ ): δ 8.57–8.38 (m, 1H), 7.78–7.53 (m, 4H), 7.34 (d, J = 7.5Hz, 2H), 7.28–7.12 (m, 2H), 5.06–4.88 (m, 1H), 3.71 (app s, 5H), 3.50 (s, 3H), 3.41–3.05 (m, 4H), 3.01–2.75 (m, 2H), 2.68 (s, 3H), 2.42 and 2.31 (two singlets, amide rotational isomer, _ArCH₃ , 3H), 2.12–1.93 (m, 1H), 1.93–1.39 (m, 3H).

Compound 17. 4-(1-(2,4-dimethyl-5-(6-morpholino-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16. m/z(ES+)521(M+H) ⁺ .

Compound 18. 4-(1-(2,4-dimethyl-5-(6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16. m/z(ES+)534(M+H) ⁺ . ^¹H NMR (300 MHz, DMSO- _d₆ ): 8.73 (s, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.66 and 7.56 (two singlets, amide rotational isomer, Ar-H, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.37 (s, 1H), 7.12 (s, 1H), 4.81–4.67 (m, 1H), 4.30 (br s, 2H), 3.70–3.37 (m, 3H), 3.37–3.05 (m, 5H), 3.05–1.80 (m, 5H), 2.60 (s, 3H), 2.37 and 2.27 (two singlets, amide rotational isomer, Ar-CH₃ _). , 3H), 2.02-1.87(m, 1H), 1.87-2.40(m, 3H).

Compound 19. 4-(1-(2,4-dimethyl-5-(6-(piperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16. m/z(ES+)519(M+H) ⁺ .

Compound 20.1. 5-Nitro-2-(pyrrolidine-1-yl)pyridine-4-amine. 2-Chloro-5-nitropyridine-4-amine (2.00 g, 11.5 mmol, 1.0 equivalent), pyrrolidine (2.86 mL, 34.6 mmol, 3.0 equivalent), potassium carbonate (4.78 g, 34.6 mmol, 3.0 equivalent), and acetonitrile (50 mL) were loaded into a 500 mL round-bottom flask equipped with a reflux condenser. The mixture was heated overnight at 70 °C under nitrogen, followed by cooling to room temperature. A yellow solid was collected by filtration and washed with acetonitrile, water, and hexane. The solid was dried to give the title compound (1.43 g, batch 1) as a bright yellow solid. The solvent was removed from the filtrate, and the aqueous phase was extracted with ethyl acetate. The organic extract was dried ( _Na₂SO₄ ), filtered, and removed under vacuum to give an additional product (820 _mg , batch 2) as an orange/yellow solid. The second batch was ground with ethyl acetate (3 mL), filtered, and washed with ethyl acetate (2 × 1 mL) and diethyl ether (3 mL) to give a bright yellow solid (751 mg). The total yield of 5-nitro-2-(pyrrolidine-1-yl)pyridine-4-amine was 2.18 g (91%). m/z (ES+) 209.1 (M+H) ⁺ . ^¹H NMR (400 MHz, DMSO- _d⁶ ): δ 8.79 (s, 1H), 7.39 (br s, 2H), 5.63 (s, 1H), 3.40 (br s, 4H), 1.93 (br s, 4H).

Compound 20.2. 6-(pyrrolidone-1-yl)pyridine-3,4-diamine. 5-nitro-2-(pyrrolidone-1-yl)pyridine-4-amine (compound 20.1, 800 mg, 3.84 mmol, 1.0 equivalent) and Pd carbon (10 wt% Pd, 400 mg, 0.38 mmol, 0.1 equivalent) were added to a 100 mL round-bottom flask. The system was purged with nitrogen, and methanol (19 mL) and hydrogen were added sequentially. The mixture was stirred under hydrogen at room temperature for 4 hours, followed by purging with nitrogen. The mixture was filtered through diatomaceous earth and washed thoroughly with MeOH. The solvent was removed under vacuum to give the title compound (641 mg, 94%) as a purple solid. m/z (ES+) 179.3 (M+H) ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ): δ7.27 (s, 1H), 5.62 (s, 1H), 5.14 (br s, 2H), 3.67 (br s, 2H), 3.23-3.13 (m, 4H), 1.91-1.79 (m, 4H).

Compound 20.4-(1-(2,4-dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. 6-(pyrrolidin-1-yl)pyridine-3,4-diamine (compound 20.2, 641 mg, 3.60 mmol, 1.0 equivalent), 4-(1-(5-formyl-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 16.4, 1.25 g, 3.60 mmol, 1.0 equivalent), sodium metabisulfite (890 mg, 4.68 mmol, 1.3 equivalent), and DMF (36 mL) were added to a 100 mL round-bottom flask. The mixture was heated at 100 °C in air for 22 hours, and then cooled to room temperature. Water (80 mL) was slowly added to the stirred solution until no more product precipitated. The solid was filtered, washed with water (2 × 15 mL), and dried to a brown solid (1.42 g). After standing, an additional product precipitated from the filtrate, which was filtered and washed with water (2 × 10 mL) to give a grayish-white solid (241 mg). The reaction was repeated a second time in the exact manner and amount described above, yielding an additional product (1.26 g of brown solid initially precipitated, plus 288 mg of grayish-white solid from the additional precipitate). The aqueous filtrates from both reactions were combined and an aqueous solution of _NaHCO3 was added to adjust the pH to 7. The aqueous phase was extracted with DCM/2% MeOH (300 _mL ), dried ( _Na2SO4 ), filtered, and evaporated to give a brown solid (547 mg). All the resulting products were combined and purified by silica gel chromatography (DCM/MeOH) to give the title compound as a yellow solid (2.37 g, 65%, based on the theoretical yield of the two reactions). m/z(ES+)505.1(M+H) ⁺ . ^¹H NMR (400 MHz, DMSO- _d₆ ): δ 12.41 (br s, 1H), 8.52 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.66 and 7.56 (two broad singlets, amide rotational isomer, ArH, 1H), 7.49 (s, J = 8.2 Hz, 2H), 7.29 (s, 1H), 6.31 (br s, 1H), 4.79–4.67 (m, 1H), 3.54–3.34 (m, 5H), 3.17 (appt, J = 11.8, 1H), 2.99–2.82 (m, 2H), 2.63 (s, 3H), 2.33 and 2.24 (two singlets, amide rotational isomer, ArCH₃ ₎ ,3H), 2.03-1.87 (m,5H), 1.82-1.38 (m,3H). Elemental analysis (C ₃₁ H ₃₂ N ₆ O·1.3 H ₂ O, 528.04), experimental values (calculated values), C: 70.66 (70.51); H: 6.54 (6.60); N: 15.78 (15.92).

Compound 20 hydrochloride. 4-(1-(2,4-dimethyl-5-(6-(pyrrolidone-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile hydrochloride. Dichloromethane (about 50 mL) was added to 4-(1-(2,4-dimethyl-5-(6-(pyrrolidone-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 20 free base, 2.31 g, 4.58 mmol) until completely dissolved, followed by the addition of dioxane (5 mL, 20 mmol, 4.3 equivalences) in 4 M HCl. The solvent was removed and the residue was dissolved in DCM and removed under vacuum. The resulting hydrochloride was recrystallized from boiling ethanol (180 mL) and allowed to cool slowly to room temperature. The mixture was left to stand overnight at room temperature, followed by freezing for 4 hours. The resulting solid was filtered and washed successively with cold ethanol (25 mL) and diethyl ether (25 mL). The solid was dried to give a grayish-white to light gray solid (1.82 g, 73%). ^¹H NMR (400 MHz, DMSO- _d₆ ): δ 13.59 and 13.46 (two broad singlets, imidazole NH tautomer, ¹H), 13.29 (br s, ¹H), 8.62 (br s, ¹H), 7.83 and 7.67 (two singlets, amide rotational isomer, ArH, ¹H), 7.78 (d, J = 7.8 Hz, 2H), 7.58–7.45 (m, 2H), 7.37 (s, 1H), 6.71 (br s, 2H). s, 1H), 4.80-4.68 (m, 1H), 3.65-3.38 (m, 5H), 3.25-3.12 (m, 1H), 3.00-2.82 (m, 2H), 2.66 (s, 3H), 2.37 and 2.27 (two singlets, amide rotational isomers, ArCH ₃ , 3H), 2.13-2.01 (m, 4H), 1.98-1.87 (m, 1H), 1.82-1.40 (m, 3H). Elemental analysis (C ₃₁ H ₃₂ N ₆ O·1.0HCl·2.4H ₂ O, 584.32), experimental values (calculated values), C: 63.80 (63.72); H: 6.32 (6.52); N: 14.25 (14.38).

Compound 20 MsOH salt, 4-(1-(2,4-dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile methanesulfonate. 4-(1-(2,4-dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile hydrochloride (compound 20 hydrochloride, 1.82 g, 3.36 mmol) was added to water (100 mL) and saturated _NaHCO3 (50 mL), and extracted with 1:1 DCM/EtOAc (500 mL) and MeOH (25 mL). Once all the product was completely dissolved, the layers were separated, and the aqueous layer was extracted again with 1:1 DCM/EtOAc (100 mL). The combined organic matter was dried ( _Na₂SO₄ ), filtered, and evaporated to a pale yellow powder (1.68 g, 3.33 mmol). The free base was dissolved in hot acetonitrile (10 _mL ), followed by the addition of 1.0 M methanesulfonic acid aqueous solution (3.33 mL, 3.33 mmol, 1.0 equivalent) and mixed thoroughly. Water (6 mL) was then added, and the mixture was freeze-dried to obtain a yellow powder (1.99 g, 99%). m/z (ES⁺) 505.1 (M + H) ^⁺ . ^¹H NMR (400 MHz, DMSO- _d₆ ): δ 13.29 (br s, 1H), 13.10 (br s, 1H), 8.65 (br s, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.74 and 7.64 (two singlets, amide rotational isomer, ArH, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.37 (s, 1H), 6.74 (br s, 1H). s, 1H), 4.80-4.68 (m, 1H), 3.65-3.38 (m, 5H), 3.26-3.12 (m, 1H), 3.01-2.83 (m, 2H), 2.64 (s, 3H), 2.37 and 2.27 (two singlets, amide rotational isomers, ArCH ₃ , 3H), 2.32 (s, 3H), 2.12-2.00 (m, 4H), 1.98-1.88 (m, 1H), 1.82-1.39 (m, 3H). Elemental analysis (C ₃₁ H ₃₂ N ₆ O·1.0MsOH.1.7H ₂ O, 631.36), experimental values (calculated values), C: 60.96 (60.88); H: 6.14 (6.29); N: 13.21 (13.31); S: 5.08 (5.08).

Compound 21. 4-(1-(5-(6-(azacyclobutan-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16. m/z(ES+)491(M+H) ⁺ .

Compound 22. 4-(1-(2,4-dimethyl-5-(6-(methanesulfonyl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16. m/z(ES+)514(M+H) ⁺ .

Compound 23. 4-(1-(2,4-dimethyl-5-(6-(methanesulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 16. m/z (ES+) 514 (M+H) ⁺ . ^1H NMR (300MHz, DMSO- _d6 + _D2O ): δ 8.87 (d, J = 1.8Hz, 1H), 8.52 (d, J = 2.1Hz, 1H), 7.74 (d, J = 7.5Hz, 2H), 7.66 and 7.56 (two singlets, amide rotational isomer, Ar-H, 1H), 7.48 (d, J = 8.4Hz, 2H), 7.38 (br) s, 1H), 4.76-4.63 (m, 1H), 3.57-3.38 (m, 1H), 3.31 (s, 3H), 3.28-3.13 (m, 1H), 3.03-2.85 (m, 2H), 2.60 (s, 3H), 2.35 and 2.27 (two singlets, amide rotational isomer, Ar- _CH3 , 3H), 2.00-1.85 (m, 1H), 1.85-1.32 (m, 3H).

Compound 24. 4-(1-(5-(5-(azacyclobutan-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 16, but with 6-chloro-3-nitropyridin-2-amine and azacyclobutane hydrochloride used instead of 2-chloro-5-nitropyridin-4-amine and (2-methoxyethyl)(methyl)amine, respectively. m/z(ES+)491(M+H) ⁺ . ^1H NMR (300MHz, CD3OD): δ 8.06 (d, J = 9.0Hz, 1H), 7.70–7.42 (m, 6H), 6.60 (d, J = 9.0Hz, 1H), 4.90 (m, 1H, partially obscured by solvent peak), 4.32 (m, 4H), 3.65 (m, 1H), 3.03 (m, 1H), 2.62 (s, 3H), 2.57 (m, 3H), 2.48 and 2.38 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.04 (m, 1H), 1.96–1.68 (m, 4H).

Compound 25. 4-(1-(5-(6-(azacyclobutan-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16, with compound 11.2 replacing compound 1.5. m/z(ES+)509(M+H) ⁺ .

Compound 26.1. 4-(5-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester. Under nitrogen atmosphere and at -78°C, n-BuLi (18 mL, 2.5 M in toluene) was added dropwise to a stirred solution of 2,5-dibromopyridine (10 g, 42.19 mmol, 1.00 equivalent) in toluene (1000 mL). After 1 hour at -78°C, a solution of 4-oxopiperidin-1-carboxylic acid tert-butyl ester (10 g, 50.25 mmol, 1.19 equivalent) in toluene (200 mL) was added dropwise with stirring. After further stirring at -78°C for 2 hours, the reaction was carefully quenched by adding 300 mL of water. The resulting mixture was extracted with 3 × 500 mL of ethyl acetate. The combined organic layers were washed with 1 × 300 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:100-1:5) to give 6.5 g (42%) of the title compound as a yellow oil.

Compound 26.2. 4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester. A mixture of 4-(5-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (compound 26.1, 1 g, 2.80 mmol, 1.00 equivalent), zinc cyanide (400 mg, 3.42 mmol, 1.22 equivalent), and Pd( _PPh3 ) ₄ (200 mg, 0.17 mmol, 0.06 equivalent) in DMF (50 mL) was stirred at 100 °C for 2 hours under nitrogen. After cooling to room temperature, the reaction was quenched by carefully adding 300 mL of _FeSO4 (saturated aqueous solution) and diluted with ethyl acetate. The resulting mixture was stirred vigorously, filtered through diatomaceous earth, and washed with 1 M _FeSO4 , water, and ethyl acetate. The layers were separated, and the aqueous phase was extracted with 2 × 100 mL of ethyl acetate. The combined organic layers were washed with 1×100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100–1:4) to give 0.5 g (58%) of the title compound as a yellow oil.

Compound 26.3. 4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester. Under nitrogen atmosphere, at -78°C, a solution of bis(2-methoxyethyl)aminosulfur trifluoride (830 mg, 3.75 mmol, 1.20 equivalent, 95%) in dichloromethane (10 mL) was added dropwise over 1 minute. The resulting mixture was stirred at -78°C for 1 hour. The reaction was then carefully quenched by dropwise addition of water and washed successively with 2 × 20 mL of sodium bicarbonate (aqueous solution) and 3 × 20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:10) to give 0.38 g (38%) of the title compound as a white solid.

Compound 26.4. 6-(4-Fluoroperidin-4-yl)nicotinonitrile trifluoroacetate. TFA (3.75 g, 32.89 mmol, 1.00 equivalent, 95%) was added dropwise to a stirred solution of tert-butyl 4-(5-cyanopyridin-2-yl)-4-fluoropiperidin-1-carboxylic acid (compound 26.3, 1 g, 3.11 mmol, 1.00 equivalent, 95%) in dichloromethane (20 mL). After stirring at 25 °C for 1 hour, the mixture was concentrated under reduced pressure to give 0.5 g of the title compound as a brown oil.

Compound 26. 6-(1-(5-(6-(azacyclobutan-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)nicotinonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 16, but with compound 26.4 instead of compound 1.5. m/z(ES+)509(M+H) ⁺ .

Compound 27. 4-(1-(4-methyl-3-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 16, but with 3-bromo-4-methylbenzoic acid instead of 5-iodo-2,4-dimethylbenzoic acid. m/z(ES+)491(M+H) ⁺ .

Compound 28. 4-(1-(3-(1H-imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compounds 16 and 27. m/z(ES+)422(M+H) ⁺ . ^1H NMR (300MHz, CD ₃ OD): δ 9.35 (s, 1H), 8.60 (d, J = 6.6Hz, 1H), 8.19 (d, J = 6.6Hz, 1H), 7.92 (s, 1H), 7.73–7.58 (m, 4H), 7.50 (d, J = 8.1Hz, 1H), approximately 4.9 (1H, partially obscured by the water peak), 4.06–3.87 (m, 1H), 3.13–2.95 (m, 3H), 2.73 (s, 3H), 2.11–1.63 (m, 4H).

Compound 29. 4-(1-(3-(1H-benzo[d]imidazol-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compounds 16 and 27. m/z (ES+) 421(M+H) ⁺ . ^1H NMR (300MHz, _CD3 OD): δ 7.87–7.77 (m, 3H), 7.75–7.60 (m, 4H), 7.60–7.47 (m, 4H), c. 4.85 (1H, partially obscured by water peak), 4.04–3.89 (m, 1H), 3.13–2.95 (m, 3H), 2.61 (s, 3H), 2.11–1.69 (m, 4H).

Compound 30. 4-(1-(3-(6-chloro-3H-imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare compounds 16 and 27. m/z(ES+)456(M+H) ⁺ .

Compound 31. 4-(1-(2-methyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 16, but with 5-bromo-2-methylbenzoic acid instead of 5-iodo-2,4-dimethylbenzoic acid (compound 2.1). m/z(ES+)491(M+H) ⁺ . ^¹H NMR (300 MHz, DMSO- _d₆ ): δ 12.63 (br s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 8.01 and 7.91 (two singlets, amide rotational isomer, Ar-H, 1H), 7.81 (d, J = 6.6 Hz, 2H), 7.58–7.42 (m, 3H), 6.31 (s, 1H), 4.85 (m, 1H), 3.57–3.35 (m, 5H), 3.30–3.13 (m, 1H), 3.07–1.85 (m, 2H), 2.39 and 2.29 (two singlets, amide rotational isomer, Ar-CH₃ _). , 3H), 2.10-1.89 (m, 5H), 1.87-1.40 (m, 3H).

Compound 32. 4-(1-(2-methoxy-5-(6-(pyrrolidone-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16. m/z(ES+)507(M+H) ⁺ .

Compound 33. 2-(4-(4-cyanophenyl)piperidin-1-carbonyl)-4-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16. m/z(ES+)502(M+H) ⁺ .

Compound 34. 4-(1-(2-chloro-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16. m/z(ES+)511(M+H) ⁺ .

Compound 35. 4-(1-(5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2-(trifluoromethoxy)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16. m/z(ES+)561(M+H) ⁺ .

Compound 36. 4-(1-(3-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16. m/z(ES+)477(M+H) ⁺ . ^1H NMR (300MHz, _CD3OD ): δ 8.44 (s, 1H), 8.25–8.17 (m, 2H), 7.77–7.63 (m, 4H), 7.51 (d, J = 8.1Hz, 2H), 6.59 (s, 1H), approx. 4.85 (1H, partially obscured by water peak), 3.98–3.83 (m, 1H), 3.61–3.48 (m, 4H), approx. 3.4 (1H, partially obscured by methanol solvent peak), 3.12–2.96 (m, 2H), 2.22–2.09 (m, 4H), 2.09–1.95 (m, 1H), 1.95 (m, 3H).

Compound 37. 4-(1-(3-(6-(isopropylamino)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 16. m/z(ES+)465(M+H) ⁺ .

Compound 38.1. Methyl tetrahydrofuran-3-carboxylic acid. A solution of tetrahydrofuran-3-carboxylic acid (540 mg, 4.65 mmol, 1.00 equivalent) and TsOH (10 mg, 0.06 mmol, 0.01 equivalent) in methanol (40 mL) was stirred in an oil bath at 66 °C. After 16 hours, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 10 mL of diethyl ether, washed successively with 1 × 20 mL _{of NaHCO3} (saturated aqueous solution) and 3 × 20 mL of brine, and concentrated under reduced pressure to give 0.40 g (66%) of the title compound as a colorless oil.

Compound 38.2. Tetrahydrofuran-3-carboxylic acid hydrazide. Hydrazine hydrate (20 mL) was placed in a round-bottom flask. Methyl tetrahydrofuran-3-carboxylic acid (Compound 38.1, 390 mg, 3.00 mmol, 1.00 equivalent) was added dropwise with stirring. The mixture was stirred in an oil bath at 50 °C. After 3 hours, the reaction mixture was concentrated and dried under reduced pressure to give 0.29 g (74%) of the title compound as a colorless oil.

Compound 38.3. Methyl 3-thiocarbamoyl-4-methylbenzoate. A solution of methyl 3-cyano-4-methylbenzoate (compound 1.7, 880 mg, 5.02 mmol, 1.00 equivalent) and diethyl dithiophosphate O,O′-diethyl ester (1.41 g, 8.29 mmol, 1.50 equivalent) in THF/ _H₂O (40 mL) was stirred at 80 °C (Note: a large amount of gas was released; this reaction and all other reactions described herein should be carried out in a well-ventilated fume hood). After 3 hours, the organic solvent was removed under reduced pressure and the residual aqueous phase was extracted with 3 × 20 mL of ethyl acetate. The combined organic layers were concentrated under reduced pressure to give 0.85 g (79%) of the title compound as a pale yellow solid.

Compound 38.4. Methyl 3-(imino(methylthio)methyl)-4-methylbenzoate. Iodomethane (2.8 g, 19.73 mmol, 2.00 equivalent) was added dropwise to a stirred solution of methyl 3-thiocarbamoyl-4-methylbenzoate (compound 38.3, 2.10 g, 9.85 mmol, 1.00 equivalent) in tetrahydrofuran (30 mL). The mixture was stirred at room temperature. After 3 hours, the reaction mixture was concentrated under reduced pressure and the residue was dried under vacuum to give 1.6 g (73%) of the title compound as a pale yellow solid.

Compound 38.5. Methyl 4-methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoate. A solution of tetrahydrofuran-3-carboxylhydrazide (compound 38.2, 195 mg, 1.50 mmol, 1.50 equivalent) and compound 38.4 (223 mg, 1.00 mmol, 1.00 equivalent) was stirred in AcOH (30 mL) at 80 °C. After 4 hours, the reaction mixture was concentrated under reduced pressure and the residue was dried under high vacuum to give 153 mg (53%) of the title compound as a yellow oil.

Compound 38.6. 4-Methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoic acid. Sodium hydroxide (aqueous solution, 1M, 0.2mL) was added dropwise to a stirred solution of compound 38.5 (57 mg, 0.20 mmol, 1.00 equivalent) in methanol (20 mL). The mixture was stirred at room temperature. After 4 hours, the organic solvent was removed under reduced pressure. The residual aqueous layer was washed with 2 × 20 mL of ethyl acetate. The pH of the aqueous phase was then adjusted to 4 with hydrogen chloride (aqueous solution, 1M), and the resulting solid was collected by filtration and dried to give 23 mg (42%) of the title compound as a pale yellow solid.

Compound 38.4-(1-(4-methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. A mixture of compound 38.6 (137 mg, 0.50 mmol, 1.00 equivalent), HBTU (228 mg, 0.60 mmol, 1.20 equivalent), DIEA (162 mg, 1.25 mmol, 2.50 equivalent), and 4-(piperidin-4-yl)benzonitrile hydrochloride (1.5, 111 mg, 0.50 mmol, 1.00 equivalent) in DMF (20 mL) was stirred at room temperature. After ₁ hour, the reaction was quenched by adding 20 mL of water, and the resulting mixture was extracted with 3 × 20 mL of ethyl acetate. The combined organic phases were dried ( _Na₂SO₄ ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:100–1:3) to give 35 mg (16%) of the title compound as a brown solid. m/z(ES+)442(M+H) ⁺ .

Compound 39.1. 3-Formyl-4-methylbenzoic acid. Under nitrogen atmosphere and at -78°C, n-BuLi (10 mL, 2.5 M in THF, 2.5 M) was added dropwise to a stirred solution of 3-bromo-4-methylbenzoic acid (2.14 g, 10.00 mmol, 1.00 equivalent) in tetrahydrofuran (30 mL). After stirring for 1 hour below -70°C, DMF (5 mL) was slowly added. The resulting solution was slowly heated to room temperature and stirred for 1 hour. After carefully quenching the reaction by slowly adding 50 mL of water, the pH was adjusted to approximately 3–4 using an aqueous solution of HCl (6 M). The resulting mixture was extracted with 2 × 50 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.6 g (98%) of the title compound as a yellow solid.

Compound 39.2. 4-(1-(3-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile. A mixture of 3-formyl-4-methylbenzoic acid (compound 39.1, 660 mg, 4.02 mmol, 1.00 equivalent) and HBTU (2 g, 5.28 mmol, 1.30 equivalent) in N,N-dimethylformamide (20 mL) was stirred at room temperature. After 1 hour, 4-(piperidin-4-yl)benzonitrile hydrochloride (1.5 g, 890 mg, 4.01 mmol, 1.00 equivalent) and DIEA (1.03 g, 7.98 mmol, 2.00 equivalent) were added. The resulting mixture was stirred at room temperature for 5 hours and then stirred overnight at 60 °C. After cooling to ambient temperature, the reaction mixture was diluted with 100 mL of LEtOAc and washed sequentially with 2 × 50 mL of _NH₄Cl (saturated aqueous solution) and 2 × 50 mL of sodium bicarbonate (saturated aqueous solution). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1 g (75%) of the title compound as a brown oil.

Compound 39.3. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylbenzoic acid. A solution of KMnO₄ ( ₁ g) in water (10 mL) was added dropwise to a stirred mixture of 4-(1-(3-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 39.2, 600 mg, 1.81 mmol, 1.00 equivalent) in THF (5 mL). The resulting mixture was stirred overnight in an oil bath at 60 °C. After cooling to ambient temperature, the solids were removed by filtration, and the pH of the filtrate was adjusted to ≥10 with sodium hydroxide (aqueous solution, 1 M). The resulting mixture was washed with 20 mL of ethyl acetate. Subsequently, the pH of the aqueous layer was adjusted to approximately 4 with 1 M HCl aqueous solution. The aqueous phase was extracted with 2 × 100 mL of ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 500 mg (80%) of the title compound as a pale yellow oil.

Compound 39.4. Methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylbenzoate. Sulfuric acid (784 mg, 7.99 mmol, 2.00 equivalent) was added dropwise to a mixture of 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylbenzoic acid (compound 39.3, 1.392 g, 4.00 mmol, 1.00 equivalent) in methanol (50 mL). The resulting mixture was heated to reflux in an oil bath overnight. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residue was diluted with 20 mL of EtOAc and washed successively with 1 × 100 mL of saturated sodium bicarbonate (aqueous solution) and 1 × 100 _mL of brine. The organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure to give 1.303 g (90%) of the title compound as a white solid.

Compound 39.5. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylbenzoylhydrazine. A solution of compound 39.4 (1.503 g, 4.15 mmol, 1.00 equivalent) and hydrazine hydrate (10 mL) in ethanol (50 mL) was heated in an oil bath under reflux. After 2 hours, the mixture was concentrated under reduced pressure and the residue was dissolved in 20 mL of EtOAc. The resulting mixture was washed with 1 × 50 mL _H₂O and 1 × 50 mL brine. The organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure to give 1.353 _g (90%) of the title compound as a white solid.

Compound 39.6. 4-(1-(3-(5-amino-1,3,4-oxadiazol-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. A mixture of compound 39.5 (380 mg, 1.05 mmol, 1.00 equivalent) and sodium bicarbonate (105.8 mg, 1.26 mmol, 1.20 equivalent) in dioxane/ _H₂O (1:1) (50 mL) was stirred at room temperature. After 5 minutes, cyanogen bromide (212 mg, 2.00 mmol, 2.00 equivalent) was added. The resulting mixture was stirred at room temperature for 3 hours. The resulting solution was stirred at room temperature for 3 hours, then quenched with 30 mL of _FeSO₄ (saturated aqueous solution) and diluted with ethyl acetate. The resulting mixture was stirred vigorously, then filtered through diatomaceous earth and washed with 1 M _FeSO₄ , water, and ethyl acetate. The separated layers were extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 397 mg (98%) of off-white solid.

Compound 39.4-(1-(3-(5-ethoxy-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. A mixture of compound 39.6 (397 mg, 1.02 mmol, 1.00 equivalent) and potassium hydroxide (287 mg, 5.12 mmol, 5.00 equivalent) in ethanol (25 mL) was heated under reflux overnight. After cooling the reaction mixture to room temperature in a water bath, the pH was adjusted to approximately 7 with acetic acid. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried ( _Na₂SO₄ ) and concentrated. The crude residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:5–1: ₀ ). The product was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-006(Waters)): column, SunFire Prep C18, 5µm, 19×150mm; mobile phase, water containing 0.05% TFA and _CH3CN (5.0% _CH3CN maintained for 2 min, increasing to 30.0% in 1 min, 59.0% in 12 min, and 100.0% in 2 min); detector, UV 254/220nm. The fractions containing the purified compound were combined and lyophilized to give 51.9 mg (12%) of the title compound as a white solid. m/z (ES+) 416 (M+H) ⁺ .

Compound 40.1. 4-(4-cyanophenyl)-4-hydroxyazacycloheptan-1-carboxylic acid tert-butyl ester. A solution of 4-iodobenzonitrile (510 mg, 2.22 mmol, 1.1 equivalents) in THF (3 mL) was added to a 10 mL round-bottom flask and the system was purged with nitrogen. The mixture was cooled to -40 °C, and then isopropyl magnesium chloride (1.16 mL, 2.0 M THF solution, 2.32 mmol, 1.15 equivalents) was added dropwise over 20 minutes. The resulting mixture was stirred at -40 °C for 2 hours, and then THF containing 4-oxozylidene-1-carboxylic acid tert-butyl ester (431 mg, 2.02 mmol, 1.0 equivalents) was added dropwise over 15 minutes (0.5 mL). The resulting mixture was stirred at -40°C for 1 hour, then diluted in ethyl acetate (15 mL) and washed successively with 0.2 M HCl (10 mL), 0.1 M HCl (5 mL), saturated sodium bicarbonate (5 mL), and brine ( ₅ mL). The organic matter was dried ( _Na₂SO₄ ), filtered, and evaporated. To remove residual ketone and aldehyde byproducts, the residue was dissolved in acetonitrile (3 mL), followed by the addition of hydrazine (0.2 mL) and heating at 60°C for 4 hours. The mixture was diluted with EtOAc (20 mL) and washed successively with water (20 mL), 0.5 M phosphoric acid (3 × 20 mL), saturated sodium bicarbonate (10 mL), and brine ( ₁₀ mL). The organic matter was dried ( _Na₂SO₄ ), filtered, and evaporated. The residue was purified by silica column chromatography (hexane/ethyl acetate) to give the title compound as a pink oil that solidified upon standing (303 mg, 47%). m/z(ES+)317(M+H) ⁺ .

Compound 40.2. 4-(4-cyanophenyl)-2,3,6,7-tetrahydro-1H-acoxane-1-carboxylic acid tert-butyl ester and 5-(4-cyanophenyl)-2,3,4,7-tetrahydro-1H-acoxane-1-carboxylic acid tert-butyl ester. Pyridine (3 mL) and phosphorus oxychloride (438 μL, 4.7 mmol, 7.5 equivalents) were added to a vial containing 4-(4-cyanophenyl)-4-hydroxyazacycloheptan-1-carboxylic acid tert-butyl ester (compound 40.1, 200 mg, 0.63 mmol, 1.0 equivalent), and the mixture was stirred at room temperature for 45 hours. The solvent was removed under vacuum, and the residue was dissolved in DCM (5 mL) and washed with water (10 mL). The aqueous layer was extracted with DCM (5 mL), and the combined organic matter was washed with saturated sodium bicarbonate (2 × 10 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated to obtain a mixture of the title compounds (167 mg, 89%) as a pale yellow oil. m/z(ES+) 299(M+H) ⁺ .

Compound 40.3. 4-(4-cyanophenyl)azacycloheptan-1-carboxylic acid tert-butyl ester. To a 25 mL round-bottom flask containing a mixture of 4-(4-cyanophenyl)-2,3,6,7-tetrahydro-1H-acoxane-1-carboxylic acid tert-butyl ester and 5-(4-cyanophenyl)-2,3,4,7-tetrahydro-1H-acoxane-1-carboxylic acid tert-butyl ester (Compound 40.2, 167 mg, 0.56 mmol), 10% palladium on carbon (40 mg) and ethyl acetate (6 mL) were added. The system was purged with nitrogen, followed by the introduction of hydrogen and stirring at room temperature. After purging with nitrogen, the mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by preparative TLC to give a colorless waxy substance (77 mg, 45%). m/z (ES+) 245 (M-tert-butyl+H) ⁺ .

Compound 40.4. 4-(azacycloheptane-4-yl)benzonitrile. DCM (500 μL) and trifluoroacetic acid (198 μL, 2.57 mmol, 10 equivalents) were added to a vial containing tert-butyl 4-(4-cyanophenyl)azacycloheptane-1-carboxylic acid (compound 40.3, 77 mg, 0.257 mmol, 1.0 equivalent), and the mixture was stirred and vented for 90 _min . The mixture was diluted in ethyl acetate (5 mL) and washed with saturated sodium bicarbonate (5 mL). The aqueous phase was adjusted to pH 10–11 and extracted with additional ethyl acetate until no product remained. The combined organic matter was dried ( _Na₂SO₄ ), filtered, and concentrated to give the title compound (51 mg, theoretical value) as a yellow oil. m/z(ES+)₂₀¹(M+H) ^⁺ .

Compound 40.5. 4-(1-(3-amino-4-methylbenzoyl)azacycloheptane-4-yl)benzonitrile. 3-amino-4-methylbenzoic acid (27 mg, 0.18 mmol, 1.0 equivalent), 4-(azacycloheptane-4-yl)benzonitrile (compound 40.4, 40 mg, 0.2 mmol, 1.1 equivalent), hydroxybenzotriazole (39 mg 20 wt% H₂O, 0.23 mmol, 1.3 equivalent), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (44 mg, 0.23 mmol, 1.3 equivalent), DMF (1 mL), and N,N-diisopropylethylamine (93 μL, 0.54 mmol, 3.0 equivalent) were added to a 4 mL vial. The mixture was stirred at room temperature for 4 hours, then diluted to ethyl acetate (10 mL) and washed with brine (10 mL). The aqueous phase was extracted with ethyl acetate (3 mL), and the combined organic compounds were washed with brine (10 mL), 1 M _NaH₂PO₄ ( ₅ mL), and brine (10 _mL ). The organic compounds were dried ( _Na₂SO₄ ), filtered, and concentrated to give the title compound (45 mg, 74%) as a brown solid. m/z(ES+) 334(M+H) ⁺ .

Compound 40.6, N-(5-(4-(4-cyanophenyl)azacycloheptane-1-carbonyl)-2-methylphenyl)-6-fluoronicotinamide. Dichloromethane (1 mL) and N,N-diisopropylethylamine (35 μL, 0.20 mmol, 1.5 equivalence) were added to a 4 mL vial containing 4-(1-(3-amino-4-methylbenzoyl)azacycloheptane-4-yl)benzonitrile (compound 40.5, 44 mg, 0.13 mmol, 1.0 equivalence). A solution of 6-fluoronicotinamide (22 mg, 0.14 mmol, 1.05 equivalence) in dichloromethane (1 mL) was added dropwise over approximately 2 minutes. The resulting mixture was stirred at room temperature for 19 hours, then diluted with dichloromethane (5 mL) and washed with ₁ M _NaH₂PO₄ (3 mL), saturated sodium bicarbonate (3 mL), and brine (3 mL). The organic matter was dried ( _Na₂SO₄ ), filtered, and concentrated to obtain the title compound (64 mg, theoretical value) as a brown waxy substance. _m /z(ES+) 457(M+H) ⁺ .

Compound 40.N-(5-(4-(4-cyanophenyl)azacycloheptane-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide. Dimethyl sulfoxide (1 mL) and isopropylamine (1 mL) were added to a vial containing N-(5-(4-(4-cyanophenyl)azacycloheptane-1-carbonyl)-2-methylphenyl)-6-fluoronicotinamide (compound 40.6, 61 mg, 0.13 mmol). The mixture was stirred at 35 °C for 2 hours, followed by stirring at room temperature for 16 hours, and then stirring at 35 °C for another 4 hours. Excess isopropylamine was removed under vacuum, and the remaining solution was purified by preparative HPLC to give a product as a grayish-white powder (TFA salt, 39 mg, 49%). m/z (ES+) 496 (M+H) ⁺ .

Compound 41.1. 5-Nitro-2-(pyrrolidine-1-yl)pyridine. A mixture of 2-chloro-5-nitropyridine (1.58 g, 10.00 mmol, 1.00 equivalent), pyrrolidine (710 mg, 10.00 mmol, 1.00 equivalent), and potassium carbonate (2.76 g, 20.00 mmol, 2.00 equivalent) in _CH3CN (20 mL) was stirred in an oil bath at 60 °C. After 2 hours, the reaction mixture was allowed to reach ambient temperature. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was ground with 1 × 20 mL of petroleum ether to give 1.8 g (93%) of the title compound as a yellow solid.

Compound 41.2. 6-(pyrrolid-1-yl)pyridine-3-amine. A round-bottom flask containing a solution of 5-nitro-2-(pyrrolid-1-yl)pyridine (compound 40.1, 1.93 g, 10.00 mmol, 1.00 equivalent) in ethanol (30 mL) was purged with nitrogen. Palladium on carbon (0.4 g, 10%, 60% water) was added. After purging the system with nitrogen again, the atmosphere was changed to hydrogen and the resulting mixture was stirred overnight at room temperature. After purging the system with nitrogen, the solid was filtered off and the filtrate was concentrated under reduced pressure and dried to give 1.6 g (98%) of the title compound as a brown solid.

Compound 41. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methyl-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)benzamide. A mixture of compound 39.3 (528 mg, 1.52 mmol, 1.00 equivalent) and HBTU (635 mg, 2.28 mmol, 1.50 equivalent) in DMF (30 mL) was stirred at room temperature for 30 minutes. 6-(pyrrolidin-1-yl)pyridin-3-amine (compound 41.2, 299 mg, 1.82 mmol, 1.20 equivalent) and DIEA (50 mg) were added. The resulting mixture was stirred overnight in an oil bath at 60 °C. After cooling to room temperature, the reaction mixture was diluted with 50 mL of EtOAc and washed sequentially with 2 × 30 mL of _NH₄Cl (saturated aqueous solution) and 2 × 30 mL of sodium bicarbonate (saturated aqueous solution). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-016(Waters)): column, SunFirePrep C18, 19×150mm 5µm; mobile phase, water containing 50 mmol _{NH₄HCO₃ and CH₃CN} ( _CH₃CN increased from 10% to 32% within 3 min, to 51% within 20 min, to 100% within 1 min, and decreased to 10% within 1 min); detector, UV 220nm. The fractions containing the purified compound were combined and lyophilized to give 50 mg (7%) of the title compound as a solid. m/z (ES+) 494 (M+H) ⁺ .

Compound 42.1. 5-Amino-2,4-dimethylbenzoic acid. A mixture of methyl 5-amino-2,4-dimethylbenzoate (1.2 g, 6.70 mmol, 1.00 equivalent) and sodium hydroxide (1.5 g, 37.50 mmol, 5.60 equivalent) in methanol/ _H₂O (20/20 mL) was stirred overnight at 50 °C. After cooling to ambient temperature, the organic phase was removed under reduced pressure. The pH of the remaining aqueous layer was adjusted to approximately 4-5 with hydrogen chloride (aqueous solution, 2 M). The resulting solid was collected by filtration and dried to give 1.0 g of a yellow solid.

Compound 42.2. 4-(1-(5-amino-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. A mixture of 5-amino-2,4-dimethylbenzoic acid (compound 42.1, 2.264 g, 13.71 mmol, 1.00 equivalent), HBTU (7.803 g, 20.59 mmol, 1.50 equivalent), 4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 2.8 g, 13.71 mmol, 1.00 equivalent), and DIEA (3.541 g, 27.45 mmol, 2.00 equivalent) in DMF (50 mL) was stirred at room temperature. After 1 hour, the mixture was diluted with 100 mL of EtOAc and washed sequentially with 1 × 100 mL of water and 1 × 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3.51 g (73%) of the title compound as a white solid.

Compound 42.3. 6-Chloro-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)nicotinamide. Under nitrogen atmosphere and at 0 °C, a solution of 6-chloropyridine-3-carbonyl chloride (1.936 g, 11.00 mmol, 1.10 equivalence) in DCM (50 mL) was added dropwise to a mixture of compound 42.2 (3.51 g, 9.99 mmol, 1.00 equivalence) and triethylamine (2.02 g, 19.96 mmol, 2.00 equivalence) in DCM (50 mL). After stirring at 0 °C for 1 hour, the reaction mixture was quenched by careful addition of 50 mL of water and extracted with 2 × 50 mL of dichloromethane. The combined organic layers were washed with 2 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4.41 g (90%) of the title compound as a yellow solid.

Compound 42.N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)-6-(isopropylamino)nicotinamide. After explosion-proof shielding, a mixture of compound 42.3 (392 mg, 0.80 mmol, 1.00 equivalent), propan-2-amine (472 mg, 7.99 mmol, 10.00 equivalent), potassium carbonate (221 mg, 1.60 mmol, 2.01 equivalent), and KI (66.4 mg, 0.40 mmol, 0.50 equivalent) in DMSO (10 mL) was heated at 100 °C in a sealed tube. After 48 hours, the mixture was allowed to reach ambient temperature and subsequently diluted with 20 mL of EtOAc. The mixture was washed sequentially with 1 × 20 mL of water and 1 × 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (approximately 300 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-002 (Agilent)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and CH3CN (15.0% CH3CN increased to 40.0% within 6 min, to 100.0% within 2 min, and decreased to 15.0% within 2 min); detector, UV 220 and 254 nm. The fractions containing the purified compound were combined and lyophilized to give 158 mg (39%) of the title compound as a grayish-white solid. m/z (ES+) 514 (M+H) ⁺ . ¹ H NMR (300MHz, CD ₃ OD, ppm): δ8.49 (s, 1H), 8.32 (d, J=9.9Hz, 1H), 7.79 (d, J=8.1Hz, 2H), 7.67 (d, J=7.5Hz, 2H), 7.40-7.22 (m, 2H), 7.07 (d, J=9 .6Hz, 1H), 4.85 (m, 1H), 4.03 (m, 1H), 3.80-3.42 (m, 2H), 3.29 (m, 1H), 2.48-2.03 (m, 9H), 1.95 (m, 1H), 1.39 (d, J=6.3Hz, 6H).

Compound 43, N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)-6-morpholinylnicotinamide. A mixture of compounds 42.3 (392 mg, 0.80 mmol, 1.00 equivalent), morpholine (348 mg, 3.99 mmol, 5.00 equivalent), and potassium carbonate (221 mg, 1.60 mmol, 2.01 equivalent) in DMSO (10 mL) was stirred overnight at 100 °C in a sealed tube after explosion-proof shielding. After cooling to ambient temperature, the reaction mixture was diluted with 20 mL of EtOAc and washed successively with 1 × 20 mL of water and 1 × 20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-002 (Agilent)): column, 1#-PrepC-005 (XBridge C18 19×1501 86002979 170130047113 03), n; mobile phase, water containing 0.05% TFA and _CH3CN (15.0% _CH3CN increased to 50.0% within 10 min, increased to 100.0% within 1 min, remained at 100.0% within 1 min, and decreased to 15.0% within 2 min); detector, UV 220 and 254 nm. The fractions containing the purified compound were combined and lyophilized to give 106 mg (25%) of the title compound as a white solid. m/z (ES+) 542 (M+H) ⁺ .

Compound 44. N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)-6-((2-methoxyethyl)(methyl)amino)nicotinamide. The title compound was synthesized in a manner similar to that described with respect to compound 43, yielding a white solid (219 mg, 50%). m/z (ES+) 544 (M+H) ⁺ . ^1H NMR (300 MHz, _CD3 OD): δ 8.56 (s, with fine structure, 1H), 8.41 (d, with fine structure, J = 9.9 Hz, 1H), 7.79 (br d, J = 8.1 Hz, 2H), 7.67 (br d, J = 8.1 Hz, 2H). d, J=6.9Hz, 2H), 7.44-7.19 (m, 3H), 4.88-4.73 (m, 1H), 3.94 (t, J=5.0Hz, 2H), 3.73 (t, J=5.0Hz, 2H), 3 .70-3.47(m, 2H), 3.39(s, 3H), 3.36(s, 3H), 3.36-3.21(m, 1H), 2.46-2.22(m, 6H), 2.22-1.85(m, 4H).

Compound 45. N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)-6-(4-methylpiperazin-1-yl)nicotinamide. The title compound was synthesized in a similar manner to that described with respect to compound 43, yielding a white solid (180 mg, 44%). m/z(ES+) 555(M+H) ⁺ .

Compound 46. 6-(azacyclobutan-1-yl)-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)nicotinamide. The title compound was synthesized in a similar manner to that described with respect to compound 43, yielding a white solid (180 mg, 44%). m/z(ES+)512(M+H) ⁺ .

Compound 47.1. 6-(1-(5-amino-4-ethyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)nicotinonitrile. The title compound was synthesized in a similar manner to that described with respect to 42.2, and with compound 26.4 replacing compound 1.5, to give a brown oil (280 mg, 89%).

Compound 47.2. 6-Chloro-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidin-1-carbonyl)-2-ethyl-4-methylphenyl)nicotinamide. The title compound was synthesized in a manner similar to that described with respect to compound 42.3, yielding a brown oil (350 mg, 91%).

Compound 47. 6-(azacyclobutan-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidin-1-carbonyl)-2-ethyl-4-methylphenyl)nicotinamide. The title compound was synthesized in a similar manner to that described with respect to compound 43, yielding a white solid (187 mg, 54%). m/z(ES+)527(M+H) ⁺ . ¹ H NMR (300MHz, DMSO-d ₆ ): δ9.88 (s, 1H), 9.06 (s, 1H), 8.59 (d, J=1.8Hz, 1H), 8.43 (dd, J=8.4Hz, J=2. 1Hz, 1H), 8.23 (d, J=9.3Hz, 1H), 7.81 (d, J=8.1Hz, 1H), 7.22 (s, 1H), 7.17 (br s, 1H), 6.74 (d, J=9.0Hz, 1H), 4.68-4.53 (m, 1H), 4.23 (t, J=7.7Hz, 4H), 3.54-3.32 (m, 2H), 3 .22-3.05 (m, 1H), 2.59 (q, J=7.5Hz, 2H), 2.50-2.38 (m, 2H), 2.35-1.80 (m, 7H), 1.14 (t, 3H).

Compound 48.1. Methyl 2-ethyl-4-methylbenzoate. Under nitrogen atmosphere and at 0 °C, EtMgBr (19.5 mL, 3 M in THF) was added dropwise to a stirred mixture of _ZnBR₂ (13 g, 57.72 mmol, 2.00 equivalent) in THF (230 mL). After 30 minutes at 0 °C, the temperature was lowered to -78 °C and Pd(dppf) _Cl₂ (2 g, 2.73 mmol, 0.09 equivalent) was added, followed by dropwise addition of methyl 2-bromo-4-methylbenzoate (6.6 g, 28.81 mmol, 1.00 equivalent) in tetrahydrofuran (200 mL). The resulting mixture was allowed to slowly reach ambient temperature and stirred overnight under nitrogen atmosphere. The reaction mixture was quenched by careful addition of 20 mL of _NH₄Cl (saturated aqueous solution) and extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were washed with 1 × 200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:30) as eluent to give 3.7 g (72%) of the title compound as a colorless oil.

Compound 48.2. 2-Ethyl-4-methylbenzoic acid. A mixture of compound 48.1 (3.7 g, 20.76 mmol, 1.00 equivalent) and sodium hydroxide (4 g, 100.01 mmol, 4.82 equivalent) in methanol/ _H₂O (30/20 mL) was stirred overnight at 50 °C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The pH of the residual aqueous layer was adjusted to 3–4 with hydrogen chloride (aqueous solution, 1 M). The resulting precipitate was collected by filtration and dried to give 3.0 g (83%) of the title compound as a white solid.

Compound 48.3. 2-Ethyl-4-methyl-5-nitrobenzoic acid. At -10°C, a solution of nitric acid (1.6 g, 16.50 mmol, 2.08 equivalents) in sulfuric acid (30 mL) was added dropwise to a stirred mixture of 2-ethyl-4-methylbenzoic acid (compound 48.2, 2 g, 12.18 mmol, 1.00 equivalents) in sulfuric acid (30 mL). After stirring at -10°C for 30 min, 200 mL of _H₂O /ice was carefully added and the mixture was extracted with 50 mL of ethyl acetate. The organic phase was washed with 2 × 50 mL of brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by recrystallization from ethyl acetate/petroleum ether in a 1:10 ratio to give 1.0 g (37%) of 2-ethyl-4-methyl-5-nitrobenzoic acid as a pale yellow solid.

Compound 48.4. 5-Amino-2-ethyl-4-methylbenzoic acid. The title compound was synthesized from 48.3 (1 g, 4.78 mmol) using a procedure similar to that described in section 1.9, yielding the title compound as a light pink solid (900 mg, 97%).

Compound 48.5. 4-(1-(5-amino-2-ethyl-4-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. A mixture of 5-amino-2-ethyl-4-methylbenzoic acid (compound 48.4, 100 mg, 0.56 mmol, 1.00 equivalent), 4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 140 mg, 0.69 mmol, 1.23 equivalent), HBTU (320 mg, 0.84 mmol, 1.51 equivalent), and DIEA (150 mg, _1.16 mmol, _2.08 equivalent) in DMF (20 mL) was stirred at room temperature for 48 hours. Water (30 mL) was added, and the mixture was extracted with 3 × 20 mL ethyl acetate. The combined organic layers were washed with 1 × 50 mL brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE:EtOAc (1:1) to give 130 mg (38%) of the title compound as a pale yellow solid.

Compound 48.6. 6-Chloro-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-4-ethyl-2-methylphenyl)inamide. The title compound was synthesized in a similar manner to that described with respect to compound 42.3, but with compound 48.5 instead of compound 42.2, to give a pale yellow solid (200 mg, 87%).

Compound 48.N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-4-ethyl-2-methylphenyl)-6-(isopropylamino)nicotinamide. The title compound was synthesized in a similar manner to that described with respect to compound 43, but with compound 48.6 replacing compound 42.3, to give a grayish-white solid (32 mg, 30%). m/z(ES+)528(M+H) ⁺ .

Compound 49. N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 43. m/z(ES+) 500(M+H) ⁺ .

Compound 50.1. 5-Cyanopyridin-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-tert-butyl carboxylate. Phosphorus oxychloride (2.5 g, 16.34 mmol, 9.90 equivalent) was added dropwise to a stirred mixture of 4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound 26.2, 500 mg, 1.65 mmol, 1.00 equivalent) and pyridine (20 mL) at 10–15 °C. The resulting solution was stirred at 15–20 °C for 18 h. The reaction was then carefully quenched by adding 20 mL of water and extracted with 3 × 100 mL of ethyl acetate. The combined organic phases were washed successively with 2 × 50 mL of 1 M aqueous HCl solution and 1 × 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:100 to 1:7) as the eluent to give 0.3 g (64%) of the title compound as a yellow solid.

Compound 50.2. 4-(5-cyanopyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester. A round-bottom flask containing a solution of compound 50.1 (300 mg, 1.05 mmol, 1.00 equivalent) in ethyl acetate (20 mL) was purged with nitrogen. Palladium on carbon (40 mg, 10%) was then added to the solution, and the flask was purged with nitrogen again. The atmosphere was then changed to hydrogen, and the mixture was stirred at 15–20 °C for 16 hours. After purging the system with nitrogen, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure to give 0.2 g (66%) of the title compound as a yellow oil.

Compound 50.3. 6-(piperidin-4-yl)nicotinonitrile hydrochloride. HCl gas was bubbled through a solution of tert-butyl 4-(5-cyanopyridin-2-yl)piperidin-1-carboxylic acid (compound 50.2, 200 mg, 0.70 mmol, 1.00 equivalent) in ethyl acetate (20 mL). The resulting mixture was stirred at 5–10 °C for 40 min. The precipitate was collected by filtration and dried to give 150 mg (97%) of the title compound as a white solid.

Compound 50.N-(5-(4-(5-cyanopyridin-2-yl)piperidin-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 43, but with compound 50.3 instead of compound 11.2. m/z(ES+)483(M+H) ⁺ .

Compound 51.1. 4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester. Under nitrogen atmosphere, n-BuLi (19 mL, 2.4 M in THF) was added dropwise to a solution of 2,5-dibromopyridine (10 g, 42.55 mmol, 1.00 equivalent) in tetrahydrofuran (400 mL). After 1 hour at -78 °C, a solution of 4-oxopiperidin-1-carboxylic acid tert-butyl ester (9.5 g, 47.74 mmol, 1.12 equivalent) in tetrahydrofuran (100 mL) was added dropwise. The resulting mixture was stirred at -78 °C for another 1 hour. The reaction was then heated to -30 °C and carefully quenched by adding 300 mL of water. The mixture was extracted with 3 × 200 mL of ethyl acetate, and the combined organic layers were washed with 1 × 200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:3) as the eluent to give 5 g (33%) of the title compound as a yellow solid.

Compound 51.2. 4-(6-cyanopyridin-3-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester. Under nitrogen atmosphere, at 50 °C, Zn(CN)₂ (400 mg, 3.42 mmol, 1.22 equivalents) was added to a mixture of 4-(6-bromopyridin-3-yl) _-4 -hydroxypiperidine-1-carboxylic acid tert-butyl ester (compound 51.1, 1 g, 2.81 mmol, 1.00 equivalents) in DMF (50 mL), followed by the addition of Pd( _PPh₃ ) _₄ (200 mg, 0.17 mmol, 0.06 equivalents) at 80 °C. The resulting mixture was then stirred at 120 °C for 1 hour. After cooling to ambient temperature, the reaction was quenched by adding 200 mL of _FeSO₄ (saturated aqueous solution) and diluted with ethyl acetate. The resulting mixture was vigorously stirred, then filtered through diatomaceous earth and washed with 1M _FeSO₄ , water, and ethyl acetate. The separated layers were extracted with 2 × 100 mL of ethyl acetate. The combined organic layers were washed with 1 × 200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:5–1:3) as the eluent to give 0.6 g (70%) of the title compound as a pale yellow oil.

Compound 51.3. 6-Cyanopyridin-5′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-tert-butyl carboxylate. Under nitrogen atmosphere and at 10–15 °C, POCl₃ (3 g, 19.74 mmol, 9.97 equivalents) was carefully added to a solution of 4-(6-cyanopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (compound 51.2, ₆₀₀ mg, 1.98 mmol, 1.00 equivalent) in pyridine (15 mL). After stirring overnight in a water/ice bath under nitrogen atmosphere, the mixture was concentrated and the residue was dissolved in 50 mL of ethyl acetate. The organic phase was washed sequentially with 1 × 50 mL of hydrogen chloride (1 M aqueous solution) and 1 × 50 mL of sodium bicarbonate (saturated aqueous solution). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:10) as the eluent to give 0.26 g (46%) of the title compound as a white solid.

Compound 51.4. 4-(6-cyanopyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester. A round-bottom flask containing a solution of compound 51.3 (260 mg, 0.91 mmol, 1.00 equivalent) in ethyl acetate (40 mL) was purged with nitrogen. Palladium on carbon (0.1 g, 10%, 60% water) was then added to the solution, and the flask was purged with nitrogen again. The atmosphere was then changed to hydrogen, and the mixture was stirred at 15–20 °C for 16 hours. After purging the system with nitrogen, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:5). This yielded 0.18 g (69%) of the title compound as a colorless oil.

Compound 51.5. 5-(piperidin-4-yl)-2-cyanopyridine hydrochloride. Hydrogen chloride gas was bubbled into a solution of tert-butyl 4-(6-cyanopyridine-3-yl)piperidin-1-carboxylic acid (51.4, 180 mg, 0.63 mmol, 1.00 equivalent) in ethyl acetate (30 mL) after cooling (5-10 °C). The mixture was stirred at 5-10 °C for 30 min, and the resulting solid was collected by filtration and dried to give 0.11 g (78%) of 5-(piperidin-4-yl)-2-cyanopyridine hydrochloride as a white solid.

Compound 51.N-(5-(4-(6-cyanopyridin-3-yl)piperidin-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 43, but with compound 51.5 instead of compound 11.2. m/z(ES+)483(M+H) ⁺ .

Compound 52. N-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)pyridazin-3-yl)-6-(isopropylamino)nicotinamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 43. m/z(ES+)470(M+H) ⁺ .

Compound 53. 2-(azacyclobutan-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)piperidin-1-carbonyl)-2-methylphenyl)pyrimidine-5-carboxamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 50. m/z(ES+)482(M+H) ⁺ .

Compound 54. 2-(azacyclobutan-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidin-1-carbonyl)-2-methylphenyl)pyrimidine-5-carboxamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 47. m/z(ES+)500(M+H) ⁺ .

Compound 55. 6-(azacyclobutan-1-yl)-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-ethylphenyl)nicotinamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 43. m/z(ES+)512(M+H) ⁺ .

Compound 56. 6-(azacyclobutan-1-yl)-N-(5-(4-fluoro-4-(5-methoxypyridin-2-yl)piperidin-1-carbonyl)-2-methylphenyl)nicotinamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 43. m/z(ES+)504(M+H) ⁺ .

Compound 57. 6-(azacyclobutan-1-yl)-N-(2-chloro-5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)phenyl)nicotinamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 43. m/z(ES+)518(M+H) ⁺ .

Compound 58. N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-ethyl-4-methylphenyl)-6-morpholinylnicotinamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 43. m/z(ES+)556(M+H) ⁺ .

Compound 60.N-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-ethyl-4-methylphenyl)-6-((2-methoxyethyl)(methyl)amino)nicotinamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 43. m/z(ES+)558(M+H) ⁺ .

Compound 61. N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)-2-morpholinylpyrimidine-5-carboxamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 47. m/z(ES+)544(M+H) ⁺ .

Compound 62.N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidin-1-carbonyl)-2-ethyl-4-methylphenyl)-2-morpholinylpyrimidine-5-carboxamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 47. m/z(ES+)558(M+H) ⁺ .

Compound 63. N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidin-1-carbonyl)-2-ethyl-4-methylphenyl)-6-morpholinylnicotinamide. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 47. m/z(ES+)557(M+H) ⁺ .

Compound 64.(R)-1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea. Under nitrogen atmosphere, at room temperature, a mixture of 4-(1-(5-amino-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile (compound 42.2, 150 mg, 0.43 mmol, 1.00 equivalent), DIEA (560 mg, 4.33 mmol, 10.15 equivalent), and CO(OCCl3)2 (160 mg, 0.54 mmol, 1.26 equivalent) in DCM (50 mL) was stirred. After 0.5 hours, (R)-(tetrahydrofuran-2-yl)methylamine (52 mg, 0.51 mmol, 1.20 equivalent) was added. After stirring at room temperature for 2 hours, the mixture was washed with 2 × 50 mL of water and 1 × 50 mL of brine. The organic phase was concentrated under reduced pressure and the residue (approximately 200 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-006(Waters)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and CH3CN (5.0% CH3CN maintained for 2 minutes, increasing to 35.0% in 1 minute, 65.0% in 12 minutes, and 100.0% in 1 minute); detector, UV 254/220 nm. The fractions containing the purified compound were combined and lyophilized to give 110 mg (54%) of the title compound as a pale yellow solid. m/z (ES+) 479 (M+H) ⁺ . ¹ H NMR (300MHz, DMSO, ppm): δ7.91 (d, J=8.1Hz, 2H), 7.77-7.69 (m, 4H), 7.04 (s, 1H), 6.68 (s, 1H), 4.64 (m, 1H), 3.89-3 .82 (m, 2H), 3.71 (m, 1H), 3.33-3.23 (m, 3H), 3.11-3.09 (m, 2H), 2.18-2.03 (m, 8H), 1.97-1.84 (m, 4H), 1.57 (m, 1H).

Compound 65. 1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)-3-(tetrahydro-2H-pyran-3-yl)urea. The title compound was synthesized in a similar manner to that described with respect to compound 64, yielding a yellow solid (111 mg, 53%). m/z (ES+) 479 (M+H) ⁺ . ¹ H NMR (300MHz, CD ₃ OD): δ7.80 (d, J=8.1Hz, 2H), 7.78-7.50 (m, 3H), 7.13 (s, 1H), 4.88-4.72 (m, 1H), 3.94-8.82 (m, 1H), 3.82-3 .68(m, 2H), 3.68-3.33(m, 3H), 3.33-3.19(m, 2H), 2.42-2.08(m, 8H), 2.08-1.74(m, 4H), 1.74-1.54(m, 2H).

Compound 66.(R)-1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)-3-(tetrahydrofuran-3-yl)urea. The title compound was synthesized in a similar manner to that described with respect to compound 64, yielding a pale yellow solid (105 mg, 53%). m/z(ES+)465(M+H) ⁺ .

Compound 67.(R)-1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-4-ethyl-2-methylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea. The title compound was synthesized in a similar manner to that described with respect to compound 64, but with compound 48.5 replacing compound 42.2. m/z(ES+)493(M+H) ⁺ .

Compound 68.1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-4-ethyl-2-methylphenyl)-3-(tetrahydro-2H-pyran-3-yl)urea. The title compound was synthesized in a similar manner to that described with respect to compound 64, but using compound 48.5 instead of compound 42.2. m/z(ES+)493(M+H) ⁺ .

Compound 69. 1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)urea. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 64. m/z(ES+)465(M+H) ⁺ .

Compound 70. 1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-methylphenyl)-3-(tetrahydro-2H-pyran-3-yl)urea. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 64. m/z(ES+)465(M+H) ⁺ .

Compound 71. 1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-methylphenyl)-3-cyclopentylurea. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 64. m/z(ES+)449(M+H) ⁺ .

Compound 72. (R)-1-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidin-1-carbonyl)-2-methylphenyl)-3-(tetrahydrofuran-3-yl)urea. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 64. m/z(ES+)452(M+H) ⁺ .

Compound 73. (R)-1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-methylphenyl)-3-(tetrahydrofuran-3-yl)urea. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 64. m/z(ES+)451(M+H) ⁺ .

Compound 74. 1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-methoxyphenyl)-3-(tetrahydrofuran-3-yl)urea. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 64. m/z(ES+)467(M+H) ⁺ .

Compound 75. 1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-fluorophenyl)-3-(tetrahydrofuran-3-yl)urea. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 64. m/z(ES+)455(M+H) ⁺ .

Compound 76. 1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-ethylphenyl)-3-(tetrahydrofuran-3-yl)urea. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 64. m/z(ES+)465(M+H) ⁺ .

Compound 77. 1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-(trifluoromethyl)phenyl)-3-(tetrahydrofuran-3-yl)urea. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 64. m/z(ES+)505(M+H) ⁺ .

Compound 78. (R)-1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-methylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 64. m/z(ES+)465(M+H) ⁺ .

Compound 79. 1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-methylphenyl)-3-(2-methoxyethyl)urea. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 64. m/z(ES+)439(M+H) ⁺ .

Compound 80.1. (R)-Tetrahydrofuran-3-yl 1H-imidazol-1-carboxylic acid ester. A solution of (R)-tetrahydrofuran-3-ol (500 mg, 5.68 mmol, 1.00 equivalent) and CDI (2 g, 12.33 mmol, 2.17 equivalent) in tetrahydrofuran (50 mL) was stirred overnight at 60 °C under nitrogen. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in 30 mL of LCM and washed with 1 × 50 _mL of _H₂O . The organic layer was dried ( _Na₂SO₄ ) and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:1) to give 0.95 g (92%) of the title compound as a white solid.

Compound 80. (R)-tetrahydrofuran-3-yl(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)carbamate. A mixture of compound 42.2 (200 mg, 0.57 mmol, 1.00 equivalent), (R)-tetrahydrofuran-3-yl1H-imidazolium-1-carboxylic acid ester (80.1, 124 mg, 0.68 mmol, 1.20 equivalent), and DBU (2.6 mg, 0.02 mmol, 0.03 equivalent) in DMF (50 mL) was stirred at 120 °C for 16 hours under nitrogen. After cooling to ambient temperature, the reaction was quenched by adding 200 mL of water. The resulting mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were washed with 1 × 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue (200 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-002 (Agilent)): column, SunFire Prep C18, 19×150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (40.0% _CH3CN to 45.0% within 8 min, maintained at 45.0% within 2 min, increased to 100.0% within 1 min, decreased to 40.0% within 2 min); detector, UV 220 254 nm. 47.4 mg of product was obtained. The fractions containing the purified compound were combined and lyophilized to give 47.4 mg (18%) of the title compound as a white solid. m/z (ES+) 466 (M+H) ⁺ .

Compound 81. (5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)carbamate 1-acetylpyrrolidine-3-yl ester. The title compound was synthesized in a manner similar to that described with respect to compound 80, yielding a white solid (113 mg, 39%). m/z (ES+) 507 (M+H) ⁺ . ^1H NMR (300MHz, CD ₃ OD): δ 7.80 (d, J = 8.1Hz, 2H), 7.77–7.61 (m, 2H), 7.52 and 7.33 (two broad singlets, amide rotational isomers, Ar-H, 1H), 7.17 (s, 1H), 5.41–5.28 (m, 1H), 4.87–4.72 (m, 1H), 3.88–3.42 (m, 6H), 3.33–3.19 (m, 1H), 2.42–1.82 (m, 15H).

Compound 82. (R)-Tetrahydrofuran-3-yl(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-methylphenyl)carbamate. The title compound was synthesized using readily available reagents and a procedure similar to that described with respect to compound 80. m/z(ES+)452(M+H) ⁺ .

Prepare the compounds in the table below using standard chemical procedures, readily available starting materials, and procedures similar to those used to prepare compounds 1 and 2:

Compound 105. 4-(1-(2,4-dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 20, but with compound 11.2 hydrochloride instead of compound 1.5. m/z(ES+)523(M+H) ⁺ .

Compound 106. 4-(1-(5-(6-(azacyclobutan-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 20, but with 4-fluoro-2-methylbenzoic acid and azacyclobutane used instead of 2,4-dimethylbenzoic acid and pyrrolidine, respectively. m/z(ES+) 495(M+H) ⁺ .

Prepare the compounds in the table below using standard chemical procedures, readily available starting materials, and a procedure similar to that used to prepare compound 20:

Compound 118.1. Tetramethyl 2-(4-methoxyphenyl)propane-1,1,3,3-tetracarboxylic acid. A mixture of (E)-N-(4-methoxybenzyl)-4-methylbenzenesulfonamide (2.89 g, 10 mmol), dimethyl malonate (3.43 mL, 30 mmol), and t-BuOK (2.24 g, 20 mmol) in anhydrous t-BuOH (20 mL) was heated at 50 °C for 4 h. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution _{of NH₄Cl} and extracted with _CH₂Cl₂ (3×). The combined organic layers were dried over _MgSO₄ , filtered, and subsequently concentrated. The residue was purified by rapid column chromatography using hexane containing EtOAc (10%, 20%, 30%, then 40%) to give the title compound (3.255 g, 85% yield) as a clear oil.

Compound 118.2. 3-(4-methoxyphenyl)glutaric acid and 3-(4-hydroxyphenyl)glutaric acid. A mixture of 2-(4-methoxyphenyl)propane-1,1,3,3-tetracarboxylic acid tetramethyl ester (compound 118.1, 6.0 g, 15.7 mmol) in concentrated hydrochloric acid (37%, 80 mL) was heated under reflux overnight. After cooling to room temperature, the suspension was filtered. The filtrate was washed with water and dried under vacuum to give 2.66 g of the product as a mixture of 3-(4-methoxyphenyl)glutaric acid (major, LCMS observation [M-H]-237) and 3-(4-hydroxyphenyl)glutaric acid (minor, LCMS observation [M-H]-223).

Compound 118.3. Dimethyl 3-(4-methoxyphenyl)glutarate. A mixture of the product obtained from the previous step (compound 118.2) (2.66 g), _K₂CO₃ (6.56 _g , 47.5 mmol), and _CH₃I (3 mL, 47.5 mmol) in DMF (10 mL) was heated overnight at 50 °C in a pressure tube. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution _{of NaHCO₃} and extracted with EtOAc (3×). The combined organic extracts were dried over _MgSO₄ , filtered, and concentrated. The residue was purified by rapid column chromatography using hexane containing EtOAc (20%, 30%, 40%, then 50%) to give the title compound (2.0 g, 48% yield, in two steps) as a clear oil.

Compound 118.4. Dimethyl 3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylic acid. Dimethyl 3-(4-methoxyphenyl)glutarate (2.0 g, 7.52 mmol) was added dropwise to a solution of LDA (18.8 mmol) in THF (60 mL) at -78 °C. After stirring at -78 °C for 14 hours, the dry ice-acetone bath was removed. The reaction mixture was stirred for 30 minutes, then cooled to -78 °C. Solid AgCl (2.2 g, 15.4 mmol) was added in a single addition. The reaction mixture was stirred at -78 °C for 14 hours, then stirred overnight at room temperature. A saturated aqueous solution of _NH₄Cl was added. The mixture was stirred vigorously for 10 minutes. The suspension was filtered through diatomaceous earth. The filtrate was extracted with EtOAc (3×). The combined organic extracts were dried over _MgSO₄ , filtered, and concentrated. The residue was purified by rapid column chromatography using hexane containing EtOAc (10%, 15%, 20%, followed by 30%) to give the title compound (0.87 g, 44% yield) as a pale yellow solid. ^¹H NMR ( _CDCl₃ , 400 Hz) δ 7.09 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.77 (s, 6H), 3.17 (t, J = 7.6 Hz, 1H), 2.36 (d, J = 7.6 Hz, 2H).

Compound 118.5. 3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylic acid. A mixture of dimethyl 3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylic acid (0.88 g, 3.33 mmol) and LiOH (2 M in _H₂O , 10 mL) in THF (30 mL) was stirred overnight at 55 °C. After cooling to room temperature, the reaction mixture was poured into 1 N HCl and extracted with EtOAc (3×). The combined organic extracts were dried over _MgSO₄ , filtered, and concentrated to give the title compound as a pale yellow solid.

Compound 118.6. 6-(4-methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2,4-dione. A mixture of 3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylic acid (from the crude product of the previous step) in _Ac₂O (20 mL) was heated under reflux for 1 hour. Excess _Ac₂O was removed under reduced pressure. The crude product was used in the next step without further purification.

Compound 118.7. 3-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione. A mixture of 6-(4-methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2,4-dione (from the crude product of the previous step) and (4-methoxyphenyl)methylamine was heated at 180 °C for 1.5 h. After cooling to room temperature, the reaction mixture was dissolved _{in CH₂Cl₂} and purified by rapid column chromatography using hexane containing EtOAc (20%, 30%, then 40%) to give the title compound as a yellow solid (0.71 g, 63% yield, in three steps). MS [M+H] ^⁺ : 338.

Compound 118.8. 3-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane. A mixture of 3-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (0.86 g, 2.6 mmol), _NaBH₄ (0.296 g, 7.8 mmol), and etherified _BF₃ (1.0 mL, 7.8 mmol) in THF was heated under reflux overnight. After cooling to 0 °C, a solution of piperazine (2 g) in _H₂O (20 mL) was added. The mixture was stirred at room temperature for 2 hours, poured into _H₂O , and extracted with EtOAc (3×). The combined organic extracts were dried over _MgSO₄ , filtered, and subsequently concentrated. The residue was purified by rapid column chromatography with hexane containing EtOAc (10%, 20%, then 30%) to give a white solid. Piperazine (3 g) was added to a suspension of this solid in THF (20 mL) and _H₂O (10 mL). The mixture was heated under reflux overnight, then poured into brine and extracted with EtOAc (3×). The combined organic extracts were dried over _MgSO₄ , filtered, and concentrated to give the title compound (0.51 g, 65% yield) as a white solid. MS [M+H] ^⁺ : 310.

Compound 118.9. 6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane. 1-Chloroethyl chloroformate (0.21 mL, 1.9 mmol, 1.2 equivalents) was added to a solution of (1R,5S,6S)-3-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane (0.5 g, 1.6 mmol) in DCE (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, heated under reflux for 1 h, and then concentrated under reduced pressure. MeOH (20 mL) was added. The resulting mixture was heated under reflux for 40 min and then concentrated. The residue was purified by preparative TLC to give the title compound (155 mg, 51% yield) as a white crystalline solid. MS [M+H] ⁺ : 190.

Compound 118.10. (3-Amino-4-methylphenyl)(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl) ketone. A mixture of 6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane (0.124 g, 0.82 mmol), 3-amino-4-methylbenzoic acid (0.155 g, 0.82 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 0.172 g, 0.90 mmol), 1-hydroxybenzotriazole (approximately 20% _H₂O , 0.122 g, 0.90 mmol), and diisopropylethylamine (0.71 mL, 4.1 mmol) in DMF (3 mL) was stirred overnight at room temperature. The reaction mixture was poured into a saturated aqueous solution of _NaHCO₃ and extracted with EtOAc (3×). The combined organic extracts were dried over _MgSO4 , filtered, and concentrated. The residue was purified by rapid column chromatography with hexane containing EtOAc (60%, then 100%) to give the title compound (0.15 g, 57% yield) as a white foam.

Compound 118.11. 6-Chloro-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide. 6-Chloronicotinamide (106 mg, 0.6 mmol) was added to a solution of (3-amino-4-methylphenyl)(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl) ketone (150 mg, 0.47 mmol) and _Et3N (0.25 mL, 1.8 mmol) in _CH2Cl2 ( ₄ mL) at 0 °C. The ice bath was removed after the addition. The reaction mixture was stirred at room temperature for 1.5 h and subsequently purified by rapid column chromatography using hexane (60%, then 100%) containing EtOAc to give the title compound (0.172 g, 80% yield) as a white foam. MS[M+H] ⁺ : 462, 464.

Compound 118. 6-(isopropylamino)-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide. A mixture of 6-chloro-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide (compound 118.11, 0.107 g, 0.23 mmol) and isopropylamine (1.5 mL) in DMSO (1.5 mL) was heated overnight at 120 °C in a sealed pressure tube. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution of _NaHCO3 and extracted with EtOAc (3×). The combined organic extracts were dried over _MgSO4 , filtered, and concentrated. The residue was ground with hexane to give the title compound (40 mg, 36% yield) as a white powder. MS[M+H] ⁺ :485. ¹ H-NMR (DMSO-d6, 400Hz) δ9.63 (s, 1H), 8.69 (d, J=3Hz, 1H), 7.95-7.90 (m, 1H), 7. 55-7.51 (m, 1H), 7.39-7.30 (m, 2H), 7.10-7.03 (m, 3H), 6.84 (d, J=9.2Hz, 2H), 6.5 2(d, J=9.2Hz, 1H), 4.17-4.07(m, 2H), 3.85-3.77(m, 1H), 3.74(s, 3H), 3.65-3.5 1 (m, 2H), 2.30 (s, 3H), 1.87 (s, 2H), 1.69 (t, J=3.7Hz, 1H), 1.20 (d, J=7.2Hz, 6H).

Compound 119. 6-(ethylamino)-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 118. MS [M+H] ⁺ : 471 ^. HNMR (DMSO-d6, 400Hz) δ9.62 (s, 1H), 8.66 (d, J=2.4Hz, 1H), 7.91 (dd, J=2.4, 9.0Hz, 1H), 7.50 (s, 1H), 7.34-7.24 (m, 2H), 7.18 (t, J=6.0Hz, 1H), 7.02 (d, J=8.8Hz, 2H), 6.81 (d, J=8.8Hz, 2H), 6.50 (d, J=9.2 Hz, 1H), 4.08 (d, J=12.4Hz, 1H), 3.81-3.75 (m, 1H), 3.70 (s, 3H), 3.59 (d, J=11.2Hz, 1H), 3.52 (d, J-13 .2Hz, 1H), 3.37-3.30 (m, 2H), 2.26 (s, 3H), 1.84 (s, 2H), 1.66 (t, J=3.2Hz, 1H), 1.16 (t, J=8.4Hz, 3H).

Compound 120. 1-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)-3-(tetrahydrofuran-3-yl)urea. The title compound was prepared using readily available reagents and a procedure similar to that used to prepare compounds 64 and 118. m/z(ES+)436(M+H) ⁺ .

Compound 121.1. 4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 3-amino-4-methylbenzoic acid (1.36 g, 9.0 mmol), (4-(piperidin-4-yl)benzonitrile hydrochloride (1.5 g, 2.0 g, 9.0 mmol), EDCI (1.89 g, 9.9 mmol), HOBT (1.66 g, 9.9 mmol, containing 20% _H₂O ), and DIEA (3.13 mL, 18.0 mmol) in DMF (50 mL) was stirred overnight at room temperature. The reaction mixture was poured into cold water (300 mL) and a grayish-white solid precipitated. The precipitate was filtered, washed with water, and dried in an oven under reduced pressure to give 2.88 g (100%) of the title compound. m/z (ES+) 320 (M+H) ⁺ .

Compound 121. 6-((5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylphenyl)amino)-N-isopropylnicotinamide. A mixture of 6-chloro-N-isopropylnicotinamide (0.055 g, 0.26 mmol), 4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (121.1 g, 0.31 mmol) _{, K₂CO₃} (0.171 g, 1.24 mmol), Pd(OAc) _₂ (6.7 mg, 0.03 mmol) and a ligand (10.2 mg, 0.03 mmol) in toluene (5 mL) was heated at 90 °C for 3 hours under argon. After cooling to room temperature, the reaction mixture was diluted with _H₂O and extracted with EtOAc. The combined organic extracts were dried over _MgSO₄ , filtered, and concentrated. The residue was purified by rapid column chromatography using hexane containing EtOAc (60%, 80%, then 100%), and the title compound (11.2 mg, 9% yield) was obtained as a grayish-white powder after lyophilization from _CH3CN / _H2O . m/z(ES+)482(M+H) ⁺ .

Compound 122. 4-(1-(4-methyl-3-((5-(4-methylpiperazin-1-carbonyl)pyridin-2-yl)amino)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 121, with t-BuONa replacing _{K₂CO₃ .} m/z(ES+) 524(M+H) ⁺ .

Compound 123, N-(4-(4-(4-(4-cyanophenyl)piperidin-1-carbonyl)pyridin-2-yl)-6-(pyrrolidine-1-yl)nicotinamide. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 43, but with 2-aminoisonicotinic acid instead of 3-amino-4-methylbenzoic acid. m/z(ES+)481(M+H) ⁺ .

Compound 124, 1-(4-(4-(4-cyanophenyl)piperidin-1-carbonyl)pyridin-2-yl)-3-isobutylurea. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 64, but with 2-aminoisonicotinic acid instead of 3-amino-4-methylbenzoic acid. m/z(ES+)406(M+H) ⁺ .

Compound 125, N-(4-(4-(4-(4-cyanophenyl)piperidin-1-carbonyl)pyridin-2-yl)pyrrolidine-1-carboxamide. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 64, but with 2-aminoisonicotinic acid instead of 3-amino-4-methylbenzoic acid. m/z(ES+)404(M+H) ⁺ .

Compound 126,N-(3-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2,4-dimethylphenyl)-6-(isopropylamino)nicotinamide. The title compound was prepared using readily available reagents and a similar procedure to that used to prepare compound 43, but with 3-amino-2,6-dimethylbenzoic acid used instead of 3-amino-4-methylbenzoic acid. m/z(ES+)514(M+H) ⁺ .

Compound 127. 4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 39. m/z(ES+)445(M+H) ⁺ .

Compound 128. 4-(1-(3-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(4-methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 38). m/z(ES+)416(M+H) ⁺ .

Compound 129. 4-(1-(3-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 38. m/z(ES+)402(M+H) ⁺ .

Compound 130.1. Methyl 5-thiocarbamoyl-2,4-dimethylbenzoate. A solution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 1.78 g, 9.41 mmol, 1.00 equivalent) in tetrahydrofuran/ _H₂O (30/3 mL) was added to a round-bottom flask. O,O′-diethyl dithiophosphate (3.30 g, 17.7 mmol, 2.00 equivalent) was added, and the resulting mixture was stirred at 85 °C for 2 days (Note: a large amount of gas is released; this reaction, and all other reactions described herein, should be carried out in a well-ventilated fume hood). After cooling to ambient temperature, the mixture was extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:10) as the eluent to give 1.20 g (57%) of the title compound as a yellow solid.

Compound 130.2. Methyl 5-(imino(methylthio)methyl)-2,4-dimethylbenzoate. CH₃I (3.95 g, 27.8 mmol, 2.00 equivalent) was added to a solution of methyl ₅ -thiocarbamoyl-2,4-dimethylbenzoate (compound 130.1, 3.10 g, 12.5 mmol, 1.00 equivalent, 90%) in tetrahydrofuran (30 mL) _, and the resulting mixture was stirred overnight at 25 °C. The organic layer was washed with 2 × 30 mL _{Na₂S₂O₄} (aqueous solution) and 1 × 30 mL brine, dried over anhydrous sodium sulfate _, and concentrated under vacuum. 2.10 g (64%) of methyl 5-(imino(methylthio)methyl)-2,4-dimethylbenzoate was obtained as a yellow oil.

Compound 130.3. Methyl 2-(tetrahydrofuran-3-yl)acetate. A mixture of 2-(tetrahydrofuran-3-yl)acetic acid (2.00 g, 15.4 mmol, 1.00 equivalent) and sulfuric acid (2 mL) in methanol (20 mL) was stirred in an oil bath at 80 °C for 3 hours. After cooling to ambient temperature, the mixture was diluted with 50 mL of diethyl ether and washed with 2 × 20 mL of water, 2 × 20 mL of sodium bicarbonate (saturated aqueous solution; note: gas escape), and 2 × 20 mL of brine. The organic phase was then dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.50 g (68%) of the title compound as a yellow oil.

Compound 130.4. 2-(tetrahydrofuran-3-yl)acetylhydrazine. A solution of methyl 2-(tetrahydrofuran-3-yl)acetate (compound 130.3, 1.50 _{g, 10.4 mmol, 1.00 equivalent) and NH₂NH₂·H₂O ( 1.04} g, 20.8 mmol, 2.00 equivalent) in methanol (15 mL) was added to a round-bottom flask. The resulting mixture was stirred overnight in an oil bath at 80 °C. After cooling to ambient temperature, the mixture was concentrated under vacuum to give 1.20 g (80%) of the title compound as a yellow oil.

Compound 130.5. Methyl 2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoate. A solution of 2-(tetrahydrofuran-3-yl)acetylhydrazine (Compound 130.4, 1.20 g, 8.32 mmol, 1.50 equivalent) in acetic acid (4 mL) was added to a round-bottom flask. Methyl 2,4-dimethyl-5-(methylthioalkyl)carbamoimide benzoate (Compound 130.2, 1.30 g, 5.48 mmol, 1.00 equivalent) was added, and the resulting mixture was stirred overnight in an oil bath at 100 °C. After cooling to ambient temperature, the mixture was concentrated under vacuum. The residue was diluted with 50 mL of ethyl acetate, followed by washing with 2 × 20 mL of water and 2 × 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (0:1 to 1:10 to 1:1) as the eluent to give 0.600 g (35%) of the title compound as a yellow solid.

Compound 130.6. 2,4-Dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoic acid. A solution of methyl 2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoate (compound 130.5, 600 mg, 1.90 mmol, 1.00 equivalent) in methanol (10 mL) was added to a round-bottom flask. A solution of sodium hydroxide (381 mg, 9.53 mmol, 5.00 equivalent) in water (5 mL) was added, and the resulting mixture was stirred in an oil bath at 70 °C for 3 hours. After cooling to room temperature, the organic solvent was removed under reduced pressure, and the pH of the remaining aqueous phase was adjusted to 3–4 with hydrogen chloride (aqueous solution, 1 M). The solid obtained was collected by filtration and dried in an oven under reduced pressure to give 0.500 g (87%) of the title compound as a yellow solid.

Compound 130.4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. A mixture of compound 130.6 (200 mg, 0.660 mmol, 1.00 equivalent), EDCI (253 mg, 1.32 mmol, 2.00 equivalent), DMAP (243 mg, 1.99 mmol, 3.00 equivalent) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 148 mg, 0.660 mmol, 1.00 equivalent) in DMF (5 mL) was stirred at 25 °C for 3 hours, followed by dilution with 50 mL of ethyl acetate. The organic layer was washed with 2 × 10 mL of water and 2 × 10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (approximately 300 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (28% _CH3CN increased to 52% within 8 min, to 100% within 1 min, and decreased to 28% within 1 min); detector, Waters 2489254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 168 mg (52%) of the title compound as a white solid. m/z (ES+) 470 (M+H) ⁺ . ^1H -NMR (400Hz, _CD3 OD): δ 7.68 (d, J = 8.0Hz, 2H), 7.61 (s, 1H), 7.50–7.49 (m, 2H), 7.33–7.31 (m, 1H), 4.90–4.88 (m, 1H), 3.95–3.92 (m, 2H), 3.90–3.81 (m, 1H), 3.79–3.77 (m, 1H), 3.69–3.55 (m, 1H), 3.28–3.25 (m, 1H), 3.03–2.94 (m, 4H), 2.81–2.73 (m, 1H), 2.53 (s, 3H), 2.43 and 2.33 (2s, amide rotational isomer, ArCH3 ₎ , 3H), 2.19-2.15(m, 1H), 2.13-2.05(m, 1H), 1.94-1.68(m, 4H).

Compound 131. 4-(1-(5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), with 3-methoxypropionylhydrazine (compound 143.1) instead of 2-(tetrahydrofuran-3-yl)acetylhydrazine (compound 130.4). m/z(ES+)444(M+H) ⁺ .

Compound 132. 4-(1-(5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), except that 2-methoxyacetylhydrazine (compound 190.6) was used instead of 2-(tetrahydrofuran-3-yl)acetylhydrazine (compound 130.4). m/z(ES+)430(M+H) ⁺ .

Compound 133.1. (R)-Tetrahydrofuran-2-formylhydrazine. A mixture of (R)-tetrahydrofuran-2-carboxylic acid (5.00 g, 43.1 mmol, 1.00 equivalent), EDCI (12.4 g, 64.6 mmol, 1.50 equivalent), and HOBt (8.70 g, 64.4 mmol, 1.50 equivalent) in dichloromethane (100 mL) was stirred at 25 °C for 30 min. Hydrazine (2.00 g, 62.4 mmol, 1.50 equivalent) was then added dropwise to the mixture. The resulting mixture was stirred overnight at 25 °C. The solid was removed by filtration, and the filtrate was concentrated under vacuum to give 25.0 g (crude) of (R)-tetrahydrofuran-2-formylhydrazine as a yellow oil.

Compound 133.(R)-4-(1-(2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), with (R)-tetrahydrofuran-2-carboxylhydrazine (compound 133.1) instead of 2-(tetrahydrofuran-3-yl)acetylhydrazine (compound 130.4). m/z(ES+)446(M+H) ⁺ .

Compound 134.1. Ethyl 2-hydrazino-2-glyoxylate. A solution of diethyl oxalate (10.0 g, 68.4 mmol, 1.00 equivalent) in ethanol (100 mL) was added to a round-bottom flask. Hydrazine hydrate (2.75 g, 85.8 mmol, 1.00 equivalent) was added, and the resulting mixture was stirred at 80 °C for 3 hours. After cooling to ambient temperature, the solid was removed by filtration, and the filtrate was concentrated under vacuum to give 8.00 g (80%) of the title compound as a colorless oil.

Compound 134.2. 2-Hydroxy-N-methyl-2-acetaldehyde amide. A solution of ethyl 2-hydrazino-2-acetaldehyde (compound 134.1, 300 mg, 2.04 mmol, 1.00 equivalent, 90%) in methanol (10 mL) was added to a round-bottom flask. Methylamine (10 mL, 40% in water) was added, and the resulting mixture was stirred overnight at 70 °C. After cooling to ambient temperature, the solid was collected by filtration and dried to give 250 mg (94%) of the title compound as a white solid.

Compound 134. 5-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-N-methyl-4H-1,2,4-triazol-3-carboxamide. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 130, with compound 134.2 replacing compound 130.4. m/z(ES+)443(M+H) ⁺ . ^1H NMR (300MHz, _CD3OD ): δ7.69 (d, J = 8.1Hz, 2H), 7.62–7.43 (m, 3H), 7.32 (s, 1H), approximately 4.9 (1H, partially obscured by water peak), 3.73–3.58 (m, 1H), 3.32–3.18 (m, 1H, partially obscured by methanol solvent peak), 3.07–1.91 (m, 5H), 2.58 (s, 3H), 2.43 and 2.33 (two singlets, amide rotational isomer, Ar- _CH3 , 3H), 2.10–1.93 (m, 1H), 1.93–1.52 (m, 3H).

Compound 135.1. 2-Hydroxy-N,N-dimethyl-2-acetaldehyde amide. Ethyl 2-hydrazino-2-acetaldehyde (compound 134.1, 2.00 g, 13.6 mmol, 1.00 equivalent, 90%) was added to a round-bottom flask. Dimethylamine (10 mL) was added to the reaction mixture, which was then stirred overnight in an oil bath at 70 °C. The mixture was cooled to room temperature and concentrated under vacuum to give 1.50 g (76%) of the title compound as a colorless oil.

Compound 135. 5-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-4H-1,2,4-triazol-3-carboxamide. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), with 2-hydrazino-N,N-dimethyl-2-acetaldehyde amide (compound 135.1) instead of 2-(tetrahydrofuran-3-yl)acetylhydrazine (compound 130.4). m/z(ES+) 457(M+H) ⁺ .

Compound 136.1. (S)-Tetrahydrofuran-2-formylhydrazide. A solution of (S)-tetrahydrofuran-2-carboxylic acid (3.00 g, 23.3 mmol, 1.00 equivalent, 90%) in dichloromethane (40 mL) was added to a round-bottom flask. _NH₂⁺ ( ₂ mL, 2.00 equivalent), HOBt (5.20 g, 38.5 mmol, 1.50 equivalent), and EDCI (7.50 g, 39.1 mmol, 1.50 equivalent) were added, and the resulting mixture was stirred overnight at 25 °C. The solid was removed by filtration, and the filtrate was concentrated under vacuum to give 2.50 g (74%) of (S)-tetrahydrofuran-2-formylhydrazide as a yellow oil.

Compound 136. (S)-4-(1-(2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), with (S)-tetrahydrofuran-2-carboxylhydrazine (compound 136.1) instead of 2-(tetrahydrofuran-3-yl)acetylhydrazine (compound 130.4). m/z(ES+)456(M+H) ⁺ .

Compound 137.1. Methyl tetrahydro-2H-pyran-4-carboxylic acid. PTSA (35.0 mg, 0.200 mmol) was added to a solution of tetrahydro-2H-pyran-4-carboxylic acid (520 mg, 4.00 mmol, 1.00 equivalent) in methanol (50 mL). The resulting mixture was stirred overnight in an oil bath at 80 °C, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with 30 mL of water and extracted with 3 × 30 mL DCM. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum. This yielded 500 mg (87%) of methyl tetrahydro-2H-pyran-4-carboxylic acid as a colorless oil.

Compound 137.2. Tetrahydro-2H-pyran-4-carboxylic acid methyl ester (compound 137.1, 5.00 g, 31.2 mmol, 1.00 equivalent, 90%) in methanol (50 mL) was added to a round-bottom flask. Hydrazine hydrate (5.20 g, 83.2 mmol, 3.00 equivalent) was added, and the resulting mixture was stirred overnight in an oil bath at 40 °C. After cooling to ambient temperature, the mixture was concentrated under vacuum to give 4.00 g (80%) of tetrahydro-2H-pyran-4-carboxylic acid hydrazide as a white solid.

Compound 137. 4-(1-(2,4-dimethyl-5-(5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), with tetrahydro-2H-pyran-4-carboxylhydrazine (compound 137.2) instead of 2-(tetrahydrofuran-3-yl)acetylhydrazine (compound 130.4). m/z(ES+) 470(M+H) ⁺ .

Compound 138.1. 2-(tetrahydrofuran-2-yl)acetylhydrazine. A solution of 2-(tetrahydrofuran-2-yl)ethyl acetate (2.00 g, 12.6 _mmol , 1.00 equivalent) in ethanol (20 mL) was added to a round-bottom flask. _NH₂ · _H₂O (1.27 g, 25.4 mmol, 2.00 equivalent) was added to the reaction mixture. The resulting solution was stirred overnight in an oil bath at 80 °C, then cooled to room temperature and concentrated under vacuum. This yielded 2.10 g (92%) of 2-(tetrahydrofuran-2-yl)acetylhydrazine as a yellow oil.

Compound 138. 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-2-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), except that 2-(tetrahydrofuran-2-yl)acetylhydrazine (compound 138.1) was used instead of 2-(tetrahydrofuran-3-yl)acetylhydrazine (compound 130.4). m/z(ES+) 470(M+H) ⁺ .

Compound 139.1. 2-Cyanoacetylhydrazine. A solution of methyl _2- cyanoacetate (7.00 g, 70.0 mmol, 1.00 equivalent) in ethanol (5 mL) was added dropwise to a solution of _NH₂NH₂ · _H₂O (3.50 g, 70.0 mmol, 1.00 equivalent) in a solvent mixture of ethanol and _Et₂O (35/35 mL). The resulting mixture was stirred at room temperature for 3 hours, followed by washing with 2 × 30 mL of diethyl ether. The solid was collected by filtration to give 5.00 g (68%) of 2-cyanoacetylhydrazine as a white solid.

Compound 139. 4-(1-(5-(5-(cyanomethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), with 2-cyanoacetylhydrazine (compound 139.1) instead of 2-(tetrahydrofuran-3-yl)acetylhydrazine (compound 130.4). m/z(ES+) 425(M+H) ⁺ . ^1H -NMR (300Hz, _CD3 OD): δ7.70 (d, J＝8.4Hz, 2H), 7.54–7.42 (m, 3H), 7.35 (s, 1H), 4.87–4.80 (m, 1H), 4.12 (s, 2H), 3.77–3.65 (m, 1H), 3.27–3.23 (m, 1H), 3.09–2.99 (m, 2H), 2.55 (s, 3H), 2.43 and 2.33 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.05–2.00 (m, 1H), 1.83–1.76 (m, 3H).

Compound 140.1. 3-Cyanopyranohydrazide. A solution of _NH₂ · _H₂O (1.25 _g , 25.1 mmol, 1.00 equivalent) in diethyl ether/EtOH (8/8 mL) was added to a round-bottom flask. Methyl 3-cyanopyranate (2.84 g, 25.1 mmol, 1.00 equivalent) was added dropwise to the solution. The resulting solution was stirred at room temperature for 2 hours, followed by concentration under vacuum. This yielded 1.40 g (49%) of 3-cyanopyranohydrazide as a colorless oil.

Compound 140. 4-(1-(5-(5-(2-cyanoethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), with 3-cyanopropionylhydrazine (compound 140.1) instead of 2-(tetrahydrofuran-3-yl)acetylhydrazine (compound 130.4). m/z(ES+) 439(M+H) ⁺ . ^1H -NMR (300Hz, _CD3 OD): δ 7.68 (d, 2H), 7.58–4.47 (m, 3H), 7.30 (s, 1H), 4.89–4.80 (m, 1H), 3.65–3.62 (m, 1H), 3.32–3.30 (m, 1H), 3.15 (t, 2H), 3.03–2.95 (m, 4H), 2.50 (s, 3H), 2.42 and 2.32 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.03–2.00 (m, 1H), 1.83–1.78 (m, 3H).

Compound 141. 4-(1-(2,4-dimethyl-5-(5-(oxetane-3-ylmethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130). m/z(ES+) 456(M+H) ⁺ .

Compound 142.1. Methyl 4-cyclopropyl-2-methylbenzoate. Potassium carbonate (6.10 g, 44.1 mmol, 2.00 equivalence), cyclopropylboronic acid (2.30 g, 26.8 mmol, 1.20 equivalence), Pd( _dppf )Cl₂ (900 mg, 1.23 mmol, 0.05 equivalence), and Pd(OAc) _₂ (250 mg, 1.12 mmol, 0.05 equivalence) were added to a solution of methyl 4-bromo- ₂ -methylbenzoate (5.00 g, 20.7 mmol, 1.00 equivalence, 95%) in a mixture of toluene and H₂O (20 mL/1 mL). The reaction mixture was purged with nitrogen and stirred overnight at 80 °C. After cooling to room temperature, the mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:50) as eluent to give 2.68 g (61%) of methyl 4-cyclopropyl-2-methylbenzoate as a colorless oil.

Compound 142.2. Methyl 4-cyclopropyl-5-iodo-2-methylbenzoate. NaIO₄ (1.51 g, 7.08 mmol, 0.50 equivalent), _I₂ (3.58 g, 14.1 mmol, 1.00 equivalent), and sulfuric acid (201 mg, 2.01 mmol, 0.15 equivalent, 98%) were added to a solution of methyl ₄ -cyclopropyl-2-methylbenzoate (compound 142.1, 2.68 g, 13.4 mmol, 1.00 equivalent) in AcOH (50 mL ₎ . The reaction mixture was stirred overnight at 110 °C. After cooling to ambient temperature, 100 mL of water was added. The resulting mixture was diluted with 100 mL of ethyl acetate, followed by washing with 3 × 30 mL _{of Na₂S₂O₃} (saturated aqueous solution) and 1 × 30 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1/50) as eluent to give 2.00 g (45%) of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate as a colorless oil.

Compound 142.3. Methyl 5-cyano-4-cyclopropyl-2-methylbenzoate. Zn(CN) _₂ (890 mg, 7.58 mmol, 1.27 equivalents) and Pd(PPh₃) _₄ (731 mg, 0.630 mmol, 0.11 equivalents) were added to a solution of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate (compound 142.2, 2.00 g, 6.01 mmol, 1.00 equivalents, 95%) in DMF ( _{16 mL} ). The resulting solution was stirred overnight at 100 °C under nitrogen. After cooling to ambient temperature, the reaction was quenched by adding 100 mL of _FeSO₄ (saturated aqueous solution) and diluted with ethyl acetate. The resulting mixture was vigorously stirred, filtered through diatomaceous earth, and washed with ₁ M FeSO₄, water, and ethyl acetate. The layers were separated, and the aqueous phase was extracted with 2 × 100 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1/50) as the eluent to give 1.10 g (81%) of methyl 5-cyano-4-cyclopropyl-2-methylbenzoate as a pale yellow oil.

Compound 142.4. Methyl 5-thiocarbamoyl-4-cyclopropyl-2-methylbenzoate. To a solution of methyl 5-cyano-4-cyclopropyl-2-methylbenzoate (Compound 142.3, 1.65 g, 7.28 mmol, 1.00 equivalent, 95%) in a mixture of tetrahydrofuran and _H₂O (20 mL/5 mL), diethyl dithiophosphate O,O′-diethyl ester (3.79 g, 22.3 mmol, 2.00 equivalent) was added. The resulting mixture was stirred overnight at 80 °C (Note: a large amount of gas is released; this reaction and all other reactions described herein should be carried out in a well-ventilated fume hood). After cooling to ambient temperature, the reaction was quenched with 100 mL of water. The resulting solution was extracted with 100 mL of ethyl acetate. The combined organic layers were washed with 3 × 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1/5) as the eluent to give 0.880 g (46%) of methyl 5-thiocarbamoyl-4-cyclopropyl-2-methylbenzoate as a white solid.

Compound 142.5. Methyl 4-cyclopropyl-2-methyl-5-(methylthioalkyl)carbonimide benzoate. A solution of methyl 5-thiocarbamoyl-4-cyclopropyl-2-methylbenzoate (Compound 142.4, 880 mg, 3.35 mmol, 1.00 equivalent, 95%) in tetrahydrofuran (10 mL) was added to a round-bottom flask. Iodomethane (1.00 g, 7.05 mmol, 2.00 equivalent) was added, and the resulting mixture was stirred overnight at room temperature. The mixture was then concentrated under vacuum to give 0.800 g (86%) of methyl 4-cyclopropyl-2-methyl-5-(methylthioalkyl)carbonimide benzoate as a colorless liquid.

Compound 142.6. Methyl 3-(dimethylamino)propionate hydrochloride. A solution of 3-(dimethylamino)propionic acid (2.00 g, 17.1 mmol, 1.00 equivalent) in methanol (60 mL) was added to a round-bottom flask. Hydrogen chloride (gas) was bubbled into the reaction mixture, and the resulting solution was stirred at 25 °C for 4 hours. The reaction mixture was concentrated under vacuum to give 2.00 g of the title compound as a colorless oil.

Compound 142.7. 3-(dimethylamino)propionylhydrazide. Hydrazine hydrate (6 mL, 6.00 equivalent) was added to a solution of methyl 3-(dimethylamino)propionate hydrochloride (compound 142.6, 2.00 g, 15.3 mmol, 1.00 equivalent) in methanol (40 mL). The reaction mixture was stirred at 70 °C for 3 h. The mixture was concentrated under vacuum and subsequently dissolved in 50 mL of _H₂O and washed with 2 × 10 mL of ethyl acetate. The aqueous solution was layered and concentrated under vacuum to give 1.30 g (65%) of 3-(dimethylamino)propionylhydrazide as a colorless oil.

Compound 142.8. Methyl 4-cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate. A solution of 3-(dimethylamino)propionylhydrazine (compound 142.7, 1.20 g, 9.15 mmol, 5.00 equivalents) and methyl 4-cyclopropyl-2-methyl-5-(methylthioalkyl)carbamoimide benzoate (compound 142.5, 600 mg, 2.28 mmol, 1.00 equivalents) in AcOH (30 mL) was stirred overnight at 80 °C. After cooling to ambient temperature, the pH was adjusted to 8-9 with sodium hydroxide (aqueous solution, 1 M). The resulting mixture was extracted with 2 × 100 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was purified by silica column chromatography using dichloromethane/methanol (10/1) as the eluent to give 504 mg (67%) of the title compound as a white solid.

Compound 142.9. 4-Cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. A solution of sodium hydroxide (97.6 mg, 2.44 mmol, 4.00 equivalent) in water (1 mL) was added to a solution of compound 142.8 (200 mg, 0.610 mmol, 1.00 equivalent) in a mixture of methanol and _H₂O (6 mL/3 mL). After stirring overnight at 60 °C, the organic solvent was removed under reduced pressure. The residual aqueous layer was washed with 20 mL of ethyl acetate. The pH was then adjusted to 4–5 with HCl (aqueous solution, 3 M), and the resulting mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried ( _Na₂SO₄ ) and concentrated under vacuum to give 280 _mg (73%) of the title compound as a brown solid.

Compound 142. 4-(1-(4-cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of compound 2661.9 (250 mg, 0.800 mmol, 1.00 equivalent) in N,N-dimethylformamide (3 mL) was mixed with 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 175 mg, 0.790 mmol, 1.00 equivalent), EDCI (302 mg, 1.58 mmol, 2.00 equivalent), and DMAP (194 mg, 1.59 mmol, 2.00 equivalent). The resulting mixture was stirred overnight at 25 °C and subsequently diluted with water. The mixture was extracted with 3 × 50 mL of ethyl acetate. The combined organic layers were washed with 2 × 20 mL _NH₄Cl (aqueous solution) and 2 × 20 mL brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using dichloromethane/methanol (10/1) as the eluent. The product (approximately ₁₅₀ mg) was further purified by preparative HPLC under the following conditions [(1#-Pre-HPLC-001(SH IMADZU)): column, Xbridge Prep C18, 5 μm, 19 × 150 mm; mobile phase, water containing 0.03% _NH₃ ·H₂O and _CH₃CN ( _CH₃CN increased from 32.0% to 47.0% within 7 min, to 100.0% within 1 min, and decreased to 32.0% within 1 min); detector, Waters 2 489 254 and 220 nm] The fractions containing the pure compound were combined and lyophilized to give 70.3 mg (18%) of the title compound as a white solid. m/z(ES+)483(M+H) ⁺ .

Compound 143.1. 3-Methoxypropionylhydrazine. A mixture of methyl 3-methoxypropionate (5.0 g, 42.33 mmol) and hydrazine (1.36 g, 42.33 mmol) was heated at 50 °C for two hours. The mixture was concentrated and dried under reduced pressure to give a clear oily product. Yield: 5.0 g, 100%. m/z (ES+) 119 (M+H) ⁺ . ^1H NMR (400 MHz, chloroform-d) δ 7.86 (br, 1H), 4.05–3.71 (m, 2H), 3.63 (t, 2H), 3.34 (s, 3H), 2.42 (t, 2H).

Compound 143. 4-(1-(4-cyclopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 142, with compound 143.1 replacing 142.7. m/z(ES+)471(M+H) ⁺ .

Compound 144. 4-(1-(4-cyclopropyl-5-(5-((dimethylamino)methyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 142. m/z (ES+) 469 (M+H) ⁺ . ^¹H NMR (300 MHz, _CD3 OD): δ 7.69 (d, J = 6.3 Hz, 2H), 7.49 (d, J = 6.0 Hz, 2H), 7.47 and 7.39 (two singlets, amide rotational isomer, Ar-H, 1H), 7.03 (s, 1H), ca. 4.9 (1H, partially obscured by water peak), 3.74 (s, 2H), 3.72–3.57 (m, 1H), 3 0.32–3.22 (m, 1H, partially obscured by methanol solvent peak), 3.00 (t, with fine structure, J = 8.9 Hz, 2H), 2.49–2.27 (m, 2H), 2.10–1.98 (m, 2H), 1.93–1.51 (m, 3H), 1.05–0.90 (m, 2H), 0.79–0.64 (m, 2H).

Compound 145. 4-(1-(5-(5-(azacyclobutane-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-4-cyclopropyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 142. m/z(ES+)481(M+H) ⁺ .

Compound 146. 2-(5-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclopropyl-4-methylphenyl)-4H-1,2,4-triazol-3-yl)-N,N-dimethylacetamide. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 142. m/z(ES+)497(M+H) ⁺ .

Compound 147.1. Methyl 4-ethyl-2-methylbenzoate. Under nitrogen atmosphere and at 0°C, EtMgBr (6.6 mL, 2.00 equivalence, 3 M in THF) was added dropwise to a stirred mixture of _ZnBr₂ (4.50 g, 20.0 mmol, 2.00 equivalent) in tetrahydrofuran (50 mL). After stirring at 0°C for 30 minutes, the temperature was lowered to -78°C and Pd(dppf)Cl₂ (1.08 g, 1.48 mmol, 0.30 equivalent) was added, followed by a solution of methyl 4-bromo-2-methylbenzoate (compound 152.1, 2.30 g, 10.0 mmol, 1.00 equivalent) in tetrahydrofuran (20 mL). The resulting mixture was stirred at -78°C for 30 minutes, then heated to room temperature and stirred overnight. The reaction mixture was carefully quenched with 60 mL of _NH₄Cl (aqueous solution) and extracted with 3 × 50 _mL of ethyl acetate. The combined organic phases were dried ( _Na₂SO₄ ) and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:100–1:5) as eluent to give 1.50 g (84%) of methyl 4-ethyl-2-methylbenzoate as a brown oil.

Compound 147.2. 4-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 142.9, with compounds 147.1 and 143.1 replacing compounds 142.1 and 142.7.

Compound 147. 4-(1-(4-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. EDCI (132 mg, 0.690 mmol, 2.00 equivalent) and DMAP (85.0 mg, 0.700 mmol, 2.00 equivalent) were added to a solution of compound 147.2 (100 mg, 0.350 mmol, 1.00 equivalent) in DMF (10 mL) under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 30 min, followed by the addition of 4-(piperidin-4-yl)benzonitrile (compound 1.5, 129 mg, 2.77 mmol, 2.00 equivalent). The reaction mixture was stirred at 25 °C for 25 h, then quenched with 40 mL of ice water and extracted with 3 × 50 mL ethyl acetate. The combined organic layers were washed with 1×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:100–1:1) as the eluent. The crude product (50 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, Xbridge Prep C18, 5 μm, 19×150 mm; mobile phase, water containing 0.03% _NH₃H₂O and _CH₃CN ( _CH₃CN increased from 33% to 52% within 10 min, to 100% within 1 min, and decreased to 33% within 1 min); detector, Waters 2489 254 and 220 _nm . The fractions containing the purified compound were combined and lyophilized to give 20.2 mg (12%) of the title compound as a white solid. m/z (ES+) 458 (M+H) ⁺ .

Compound 148. 4-(1-(4-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 147, with compound 11.2 hydrochloride substituted for compound 1.5. m/z(ES+)476(M+H) ⁺ .

Compound 149. 4-(1-(5-(5-(ethoxymethyl)-4H-1,2,4-triazol-3-yl)-4-ethyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compounds 147 and 148. m/z(ES+)476(M+H) ⁺ .

Compound 150. 4-(1-(4-ethyl-2-methyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(4-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 147). m/z(ES+) 470(M+H) ⁺ .

Compound 151. 4-(1-(4-ethyl-5-(5-(isopropoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compounds 147 and 148. m/z(ES+) 490(M+H) ⁺ . ^1H -NMR (300MHz, _CD3 OD): δ7.78 (d, 2H), 7.69–7.34 (m, 4H), 4.82–4.78 (m, 1H), 4.72 (s, 2H), 3.80 (quintet, 1H), 3.57–3.55 (m, 2H), 3.30–3.25 (m, 1H), 2.94 (q, 2H), 2.46 and 2.35 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.35–2.1 (m, 3H), 2.0–1.95 (m, 1H), 1.30 (d, 6H), 1.14 (t, 3H).

Compound 152.1. Methyl 4-bromo-2-methylbenzoate. Sulfuric acid (2.0 mL) was added dropwise to a solution of 4-bromo- ₂ -methylbenzoic acid (5.11 g, 23.8 mmol, 1.0 equivalent) in methanol (25 mL) over approximately 3 minutes (slightly exothermic). The resulting mixture was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was carefully quenched in a saturated aqueous solution of NaHCO3 (100 mL) (note: a large amount of gas escaped) and extracted with dichloromethane (200 mL × 1, followed by 50 mL × 1). The combined organic phases were washed with a mixture of brine/saturated NaHCO3 (9: ₁ ) (50 mL), dried (N2 _{2 SO4} ) and concentrated under reduced pressure to give the title compound (5.28 g, 97%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.78 (d, J=8.0Hz, 1H), 7.42 (d, J=1.6Hz, 1H), 7.38 (dd, J=1.6Hz, 1H), 3.89 (s, 3H), 2.58 (s, 3H).

Compound 152.2. Methyl 4-cyclobutyl-2-methylbenzoate. Zinc(II) cyclobutyl bromide (50 mL, 0.5 M in THF, 25.0 mmol) was added to a mixture of methyl 4-bromo-2-methylbenzoate (Compound 152.1, 5.2 g, _22.7 mmol) and _PdCl₂ (dppf) _CH₂Cl₂ (1.85 g, 2.27 mmol). The mixture was degassed and flasks were filled with argon via a gasket. The mixture was heated at 65 °C for 24 hours under argon. The mixture was cooled to 0 °C and quenched with water (10 mL). The mixture was diluted with EtOAc (200 mL) and washed successively with water and brine. The _EtOAc layer was dried ( _Na₂SO₄ ), concentrated under reduced pressure, and purified by column chromatography (silica gel) (hexane:EtOAc 30:1 to 20:1). Yield: 4.1 g, transparent oil, 89.1%. ^¹H NMR (400 MHz, chloroform-d) δ 7.86 (d, 1H), 7.12–7.02 (m, 2H), 3.88 (s, 3H), 3.59–3.48 (m, 1H), 2.59 (s, 3H), 2.35 (m, 2H), 2.22–1.96 (m, 3H), 1.86–1.84 (m, 1H).

Compound 152.3. Methyl 4-cyclobutyl-5-iodo-2-methylbenzoate. N-iodosuccinimide (3.52 g, 15.6 mmol) was added fractionally to a solution of methyl 4-cyclobutyl-2-methylbenzoate (compound 152.2, 3.2 g, 15.6 mmol) in concentrated sulfuric acid (25 ml) at 0 °C. The mixture was stirred at 0 °C for 30 min and then at room temperature for 2 h. The mixture became very viscous. The mixture was then cooled to 0 °C and MeOH (30 ml) was added. The mixture was heated at 60 °C for 2 h. Methanol was removed under reduced pressure, and the residue was poured into ice water (100 ml). The mixture was extracted with EtOAc (2×). The combined organic layers were washed successively with brine and 1 N _NaHCO3 aqueous solution (note: a large amount of gas escaped), _dried ( _Na2SO4 ), and concentrated. The residue was purified by column (silica gel) chromatography (hexane:EtOAc 30:1 to 20:1). Yield: 4.17 g, pale yellow oil, 81%. ^¹H NMR (400 MHz, chloroform-d) δ 8.33 (s, 1H), 7.14 (s, 1H), 3.87 (s, 3H), 3.67–3.54 (m, 1H), 2.57 (s, 3H), 2.51–2.40 (m, 2H), 2.14–1.97 (m, 3H), 1.82–1.79 (m, 1H).

Compound 152.4. Methyl 5-cyano-4-cyclobutyl-2-methylbenzoate. A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 152.3, 4.17 g, 12.64 mmol), Zn(CN) _₂ (2.96 g, 25.21 mmol), and Pd( _PPh₃ ) _₄ (0.73 g, 0.63 mmol) in DMF (30 ml) was degassed and flasks were filled with argon gas via a gasket. The mixture was heated overnight at 100 °C under argon gas. After cooling to ambient temperature, the mixture was quenched with a saturated aqueous solution of _FeSO₄ (20 ml) and diluted with EtOAc (200 ml). The pale green solid was removed by filtration through diatomaceous earth. The filtrate was partitioned between water and EtOAc. The EtOAc layer was washed with brine, _dried ( _Na₂SO₄ ), and concentrated. The residue was purified by column (silica gel) chromatography (hexane:EtOAc 30:1 to 20:1). Yield: 2.55 g, white solid, 88%. ^¹H NMR (400 MHz, chloroform-d) δ 8.16 (s, 1H), 7.28 (s, 1H), 3.90 (s, 3H), 3.86–3.82 (m, 1H), 2.68 (s, 3H), 2.55–2.45 (m, 2H), 2.27–2.04 (m, 3H), 1.89–1.87 (m, 1H).

Compound 152.5. Methyl 5-thiocarbamoyl-4-cyclobutyl-2-methylbenzoate. Methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (compound 152.4, 3.63 g, 0.015 mol), O,O′-diethyl dithiophosphate (10 mL), and water (1 mL) were added to a round-bottom flask. The reaction mixture was heated to 80 °C for 3 hours (Note: a large amount of gas was released; this reaction and all other reactions described herein should be carried out in a well-ventilated fume hood). After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The combined organic layers were washed successively with saturated aqueous solution of _NaHCO3 (50 mL) and brine (50 _mL ), dried over _Na2SO4 , and concentrated under vacuum. Purification by rapid _SiO₂ chromatography (hexane/ethyl acetate = 80/20 to 50/50) yielded methyl 5-thiocarbamoyl-4-cyclobutyl-2-methylbenzoate (3.06 g, 78% yield) as a yellow solid. m/z (ES+) 264 (M+H) ⁺ . ^¹H NMR (400 MHz, _CDCl₃ ): δ 7.93 (s, 1H), 7.82 (s, 1H), 7.26 (s, 1H), 6.92 (s, 1H), 4.19 (m, 1H), 3.89 (s, 3H), 2.64 (s, 3H), 2.40 (m, 2H), 2.29–2.15 (m, 2H), 2.12–2.00 (m, 1H), 1.95–1.84 (m, 1H).

Compound 152.6. Methyl 4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate. THF (10 mL) containing methyl 5-thiocarbamoyl-4-cyclobutyl-2-methylbenzoate (Compound 152.5, 861 mg, 3.27 mmol) was added to a round-bottom flask. Iodomethane (912 mg, 6.42 mmol) was added dropwise while the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under vacuum and purified by rapid _SiO₂ chromatography (ethyl acetate to ethyl acetate/methanol = 95/5) to give methyl 4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate (807 mg, 89% yield) as a pale yellow oil. m/z (ES+) 278 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.67(s, 1H), 7.40(s, 1H), 3.88-3.71(m, 4H), 2.57(s, 3H), 2.44(s, 3H ), 2.22-2.19(m, 2H), 2.12(m, 2H), .1.98-1.86(m, 1H), 1.82-1.70(m, 1H).

Compound 152.7. Methyl 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate. 6 mL of acetic acid containing methyl 4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate (compound 152.6, 556 mg, 0.002 mol) and acetylhydrazine (223 mg, 0.003 mol) was added to a round- _bottom flask. The reaction mixture was heated to 90 °C for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with brine (2 × 50 mL), dried over _Na₂SO₄ , and concentrated under vacuum. Purification by rapid _SiO₂ chromatography (hexane/ethyl acetate = 50/50 to 30/70) gave the title compound (243 mg, 43% yield) as a white solid. m/z(ES+)286(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ8.23(s, 1H), 7.32(s, 1H), 4.24-4.05(m, 1H), 3.89(s, 3H), 2.69(s, 3H), 2.54(s , 3H), 2.23-2.20(m, 2H), 2.16-2.05(m, 2H), 2.05-1.88(m, 1H), 1.88-1.71(m, 1H).

Compound 152.8. 4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid. A solution of methyl 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate (compound 152.7, 240 mg, 0.842 mmol) in methanol (5 mL) was mixed with 6 mL of aqueous NaOH solution (1 M). The resulting mixture was heated to 50 °C for 6 hours. After cooling to ambient temperature, the reaction mixture was acidified to pH 2 with 1 N HCl and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over _Na₂SO₄ , and concentrated under vacuum to give 260 mg of ₄ -cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid as a white solid. m/z(ES+)272(M+H) ⁺ .

Compound 152. 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. To a solution of 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid (compound 152.8, 260 mg, 0.95 mmol) in DMF (4 mL), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 232 mg, 1.045 mmol), EDC (272 mg, 1.425 mmol), HOBt (39 mg, 0.285 mmol), and DIEA (367.7 mg, 2.85 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched with saturated aqueous solution of _NaHCO3 (20 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50 _mL ), dried over _Na2SO4 , filtered, and concentrated under vacuum. Purification by _SiO2 column chromatography (dichloromethane/methanol = 95/5) yielded 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (193 mg, 44% yield) as a white solid. m/z (ES+) 440 (M+H) ⁺ . ^¹H NMR (300 MHz, _CD₃OD ): δ 7.69 (d, J = 5.4 Hz, 2H), 7.56–7.30 (m, 4H), one proton is masked by the methanol solvent peak, 4.10–3.98 (m, 1H), 3.64 (t, J = 10.7 Hz, 1H), 3.33–3.21 (m, 1H), 3.00 (t, J = 8.9 Hz, 2H), 2.58 (s, 3H), 2.48 and 2.38 (two singlets, amide rotational isomer, _ArCH₃ , 3H), 2.28–1.92 (m, 6H), 1.92–1.55 (m, 4H). ¹ H NMR (400MHz, DMSO-d ₆ ): δ 13.66 (s, 1H), 7.77 (d, J=8.0Hz, 2H), 7.62-7.34 (m, 4H), 4.78-4.63 (m, 1H), 4.31 (br s, 1H), 3.45 (br s, 1H), 3.15 (app t, J=12.3Hz, 1H), 2.99-2.78 (m, 2H), 2.44-1.80 (m, 12H), 1.80-1.37 (m, 4H).

Compound 153. 4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), but using 3-methoxypropionylhydrazine (compound 143.1) instead of acetylhydrazine. m/z (ES+) 484 (M+H) ⁺ , 967 (2M+H) ⁺ . ^¹H NMR (400 MHz, chloroform-d) δ 11.50–11.33 (br s, 1H), 7.66–7.44 (m, 3H), 7.33–7.27 (m, 3H), 4.98 (d, 1H), 4.24–4.12 (m, 1H), 3.78 (t, 2H), 3.70 (d, 1H), 3.44 (s, 3H), 3.14–3.03 (m, 3H), 2.90–2.75 (m, 2H), 2.42 and 2.34 (two singlets, amide rotational isomer, _ArCH₃ , 3H), 2.17 (d, 2H), 2.08–1.88 (m, 3H), 1.84–1.51 (m, 5H).

Compound 154. 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), but using 2-methoxyacetylhydrazine (compound 190.6) instead of acetylhydrazine. m/z(ES+) 470(M+H) ⁺ . ^¹H NMR (400 MHz, _CDCl₃ ): δ 12.15 (br s, 1H), 7.64–7.57 (m, 2H), 7.43 and 7.33 (two singlets, amide rotational isomer, Ar-H, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.20 (s, 1H), 5.04–4.92 (m, 1H), 4.65 (s, 2H), 4.18–4.03 (m, 1H), 3.63 (br d, J = 13.2 Hz, 1H), 3.51 (s, 3H), 3.08 (t, with fine structure, J = 12.8 Hz, 1H), 2.93–2.77 (m, 2H), 2.38 and 2.30 (two singlets, amide rotational isomer, ArCH₃ ₎ , 3H), 2.25-1.84(m, 6H), 1.84-1.43(m, 4H).

Compound 155. 4-(1-(4-cyclobutyl-5-(5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 152, but with 2-hydroxyacetylhydrazine instead of acetylhydrazine. m/z(ES+)456(M+H) ⁺ .

Compound 156. 4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 153), except that 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2 hydrochloride) was used instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5). m/z(ES+) 501.8(M+H) ⁺ . ^1H NMR (400MHz, _CDCl₃ ): δ 11.46 (br s, 1H), 7.75–7.45 (m, 3H), 7.49 (d, J = 8.4Hz, 2H), 7.32 (s, 1H), 4.89 (br d, J = 13.2Hz, 1H), 4.28–4.15 (m, 1H), 3.79 (t, J = 6.0Hz, 2H), 3.70–3.45 (m, 2H), 3.46 (s, 3H), 3.31–3.17 (m, 1H), 3.13 (t, J = 6.0Hz, 2H), 2.45 and 2.38 (two broad singlets, amide rotational isomer, Ar- _CH₃ , 3H), 2.30–1.68 (m, 10H).

Compound 157. (4-Cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl) methyl ketone. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 153), using 4-(4-(trifluoromethyl)phenyl)piperidin hydrochloride instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5). m/z(ES+)527(M+H) ⁺ . ^¹H NMR (400MHz, chloroform-d) δ 11.30–11.10 (br, 1H), 7.60–7.47 (m, 3H), 7.35–7.28 (m, 3H), 5.10–4.93 (m, 1H), 4.24–4.13 (m, 1H), 3.78 (t, 2H), 3.70 (d, 1H), 3.45 (s, 3H), 3.12 (t, 2H), 3.15–3.05 (m, 1H), 2.90–2.75 (m, 2H), 2.44 and 2.35 (two singlets, amide rotational isomers, ArCH ₃₎ , 3H), 2.25-2.13(m, 2H), 2.13-1.85(m, 4H), 1.87-1.66(m, 4H).

Compound 158. 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), with compound 11.2 hydrochloride substituted for compound 1.5. m/z(ES+)458(M+H) ⁺ . ^¹H NMR (400MHz, DMSO- _d₆ ) δ 13.66 (s, 1H), 7.66 (d, 2H), 7.51 (d, 3H), 7.38 (s, 1H), 4.72 (d, 1H), 4.30 (br s, 1H), 3.46 (br s, 1H), 3.16 (dd, 1H), 3.04–2.78 (m, 2H), 2.38 and 2.36 (two singlets, amide rotational isomer, _ArCH₃ , 3H), 2.35–2.27 (m, 3H), 2.22–1.82 (m, 6H), 1.81–1.56 (m, 3H).

Compound 159. (4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl ketone. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152). m/z(ES+) 483(M+H) ⁺ .

Compound 160. 4-(1-(4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 152, but with propionyl hydrazine instead of acetyl hydrazine. m/z(ES+)454(M+H) ⁺ . ^¹H NMR (400 MHz, chloroform-d) δ 7.75–7.43 (m, 3H), 7.40–7.17 (m, 3H), 5.18–4.81 (m, 1H), 4.30–3.91 (m, 1H), 3.84–3.55 (m, 1H), 3.21–2.99 (m, 1H), 2.92–2.69 (m, 4H), 2.40 and 2.32 (two singlets, amide rotational isomer, ArCH₃, _3H ), 2.25–1.84 (m, 7H), 1.83–1.42 (m, 3H), 1.32 (t, 3H).

Compound 161. 4-(1-(4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152). m/z(ES+)472(M+H) ⁺ . ^¹H NMR (400 MHz, chloroform-d) δ 7.79–7.57 (m, 2H), 7.57–7.18 (m, 4H), 4.86 (dd, 1H), 4.14 (s, 1H), 3.62–3.40 (m, 4H), 3.22 (t, 1H), 2.77 (q, 2H), 2.31 and 2.41 (two singlets, amide rotational isomer, 3H), 2.29–1.47 (m, 8H), 1.30 (t, 3H).

Compound 162. 4-(1-(4-cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152). m/z(ES+) 468(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ⁶ )δ13.67(s, 1H), 7.77(d, 2H), 7.49-7.47(m, 3H), 7.36(s, 1H), 4.72(d, 1H), 4.29(s, 1H), 3.46(d, 1H ), 3.12(m, 2H), 2.98-2.75(m, 2H), 2.31(d, 3H), 2.23-1.81(m, 6H), 1.83-1.36(m, 4H), 1.31(d, 6H).

Compound 163. 4-(1-(4-cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152). m/z(ES+) 486(M+H) ⁺ .

Compound 164.1. 4-(1-(4-cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 152.7, with propionyl hydrazine used instead of acetyl hydrazine.

Compound 164.2. Methyl 4-cyclobutyl-5-(5-ethyl-N-methyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate. Methyl 4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate (Compound 164.1, 87 mg, 0.29 mmol) was dissolved in methanol and dichloromethane (1:1 v/v) (6 mL). ((trimethylsilyl)methyl)diazomethane (2.0 M in diethyl ether) (220 μL, 0.44 mmol) was added. The mixture was stirred for 16 hours and quenched with HOAc (300 μL). The volatiles were removed under vacuum to give an oil (85 mg). The residue was presented as crude material without further purification and proceeded to the next step. m/z (ES+) 314 (M+H) ⁺ .

Compound 164. 4-(1-(4-cyclobutyl-5-(5-ethyl-N-methyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound (a mixture of N-methyl isomers) was prepared using standard chemical procedures and a similar process to that used to prepare compound 152, with compound 164.2 replacing compound 152.7. m/z(ES+) 468(M+H) ⁺ .

Compound 165. 4-(1-(4-cyclobutyl-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152). m/z (ES+) 494.0 (M+H) ⁺ .

Compound 166. 4-(1-(4-cyclobutyl-5-(5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152). m/z(ES+) 476(M+H) ⁺ .

Compound 167. 4-(1-(4-cyclobutyl-5-(5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-[1-[4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl]-4-piperidinyl]benzonitrile (compound 152). m/z(ES+) 494(M+H) ⁺ .

Compound 168.1. Methyl 4-cyclobutylbenzoate. Over 20 minutes, under nitrogen atmosphere and at 0°C, a solution of magnesium _bromo (cyclobutyl)magnesium (242 mL, 364 mmol, 1.5 M in THF) was added dropwise to a mixture of stirred ZnBr₂ (83.0 g, 368.53 mmol, 4.00 equivalent) in 500 mL THF. Pd(dppf) _Cl₂ (2.00 g, 0.10 equivalent) and methyl 4-bromobenzoate (20 g, 93.00 mmol, 1.00 equivalent) were added to the resulting mixture at -40°C. The resulting mixture was stirred under nitrogen atmosphere and at -40°C for 1 hour, and then carefully quenched with 500 mL of _NH₄Cl (saturated aqueous solution). The mixture was extracted with 3 × 500 mL of ethyl acetate. The combined organic layers were washed with 3 × 500 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 18.0 g (crude) of the title compound as a pale yellow oil.

Compound 168.2. Methyl 4-cyclobutyl-3-iodobenzoate. Sodium periodate (1.00 g, 4.68 mmol, 0.50 equivalent), iodine (3.00 g, 11.8 mmol, 1.10 equivalent), and sulfuric acid (0.15 g, 0.15 equivalent) were carefully added to a solution of methyl 4-cyclobutylbenzoate (168.1, 2.00 g, 10.5 mmol, 1.00 equivalent) in acetic acid ( ₃₀ mL). The resulting mixture was stirred overnight at 100 °C. After cooling to room temperature, the reaction was quenched by careful addition of 30 mL _{of Na₂S₂O₃} (saturated aqueous solution), and the mixture was extracted with 3 × 20 mL of ethyl acetate. The combined organic layers were washed with 3 × 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.50 g (45%) of the title compound as a yellow oil.

Compound 168.3. Methyl 3-cyano-4-cyclobutylbenzoate. The title compound (2.60 g (95%), white solid) was prepared using standard chemical operations and a procedure similar to that used to prepare compound 152.4, with compound 168.2 (4.00 g, 12.7 mmol) instead of compound 152.3.

Compound 168. 4-(1-(4-cyclobutyl-3-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using a similar procedure to that used to prepare compound 152, with 168.3 replacing 152.4. m/z(ES+)458(M+H) ⁺ .

Compound 169. 4-(1-(4-cyclobutyl-3-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using a similar procedure to that used to prepare compound 152, with 168.3 replacing 152.4. m/z(ES+)440(M+H) ⁺ . ¹ H NMR (300MHz, CD ₃ OD)δ7.88(d,2H),7.67-7.50(m,3H),7.47(d,2H),4.89-4.75(m,1H),4.25-3.73(m,2H),3.3 5-3.25 (m, 1H), 3.16-2.75 (m, 4H), 2.30-1.94 (m, 6H), 1.93-1.56 (m, 4H), 1.51-1.32 (m, 3H).

Compound 170. 4-(1-(4-cyclobutyl-3-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using a similar procedure to that used to prepare compound 152, with compounds 168.3 and 11.2 hydrochlorides substituted for compounds 152.4 and 1.5, respectively. m/z(ES+)444(M+H) ⁺ .

Compound 171. 4-(1-(4-cyclobutyl-3-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using a similar procedure to that used to prepare compounds 152 and 156, with 168.3 replacing 152.4. m/z(ES+)488(M+H) ⁺ .

Compound 172.1. (S)-Tetrahydrofuran-2-formylhydrazine. A solution of (S)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00 equivalent) in dichloromethane (40 mL) was added to a round-bottom flask. EDC·HCl (7.50 g, 39.1 mmol, 1.50 equivalent), HOBT (5.20 g, 38.5 mmol, 1.50 equivalent), and hydrazine hydrate (2 mL, 2.00 equivalent, 99%) were added to the reaction mixture. The resulting solution was stirred overnight at room temperature. The solid was removed by filtration, and the filtrate was concentrated under vacuum to give 5.38 g (80%) of the title compound as a yellow oil.

Compound 172. (S)-4-(1-(4-cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), with (S)-tetrahydrofuran-2-carboxylhydrazine (compound 172.1) instead of acetylhydrazine. m/z(ES+) 496(M+H) ⁺ .

Compound 173. (S)-4-(1-(4-cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using a similar procedure to that used to prepare compound 172, but with compound 11.2 hydrochloride substituted for compound 1.5. m/z(ES+)514(M+H) ⁺ .

Compound 174.1. (R)-Tetrahydrofuran-2-formylhydrazine. A solution of (R)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00 equivalent) in dichloromethane (60 mL) was added to a round-bottom flask. EDC·HCl (7.37 g, 38.5 mmol, 1.50 equivalent), HOBt (5.24 g, 38.8 mmol, 1.50 equivalent), and hydrazine hydrate (2.60 g, 51.9 mmol, 2.00 equivalent) were added to the reaction mixture. The resulting solution was stirred overnight at 25 °C. The solid was removed by filtration. The filtrate was concentrated under vacuum to give 2.00 g (59%) of (R)-tetrahydrofuran-2-formylhydrazine as a yellow oil.

Compound 174.(R)-4-(1-(4-cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), with (R)-tetrahydrofuran-2-carboxylhydrazine (compound 174.1) instead of acetylhydrazine. m/z(ES+) 496(M+H) ⁺ . ¹ H NMR (300MHz, CD ₃ OD)δ7.70(d,2H),7.49-7.41(m,4H),5.15(t,1H),4.89-4.80(m,1H),4.14-3.92(m,3H),3.65-3.51(m , 1H), 3.33-3.27(m, 1H), 3.03-2.95(m, 2H), 2.47-2.37(m, 4H), 2.24-1.91(m, 9H), 1.83-1.71(m, 4H).

Compound 175.1. 4-Cyclopentyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid. The title compound was synthesized using standard chemical procedures and a similar process to that used to prepare compound 152.8, but with magnesium bromo(cyclopentyl)magnesium instead of magnesium bromo(cyclobutyl)magnesium.

Compound 175. 4-(1-(4-cyclopentyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was synthesized using a similar procedure to that used to prepare compound 152, with compound 175.1 replacing compound 152.8. m/z(ES+) 495(M+H) ⁺ .

Compound 176.1. 4-(4-bromophenyl)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester. The title compound was synthesized using a similar procedure to that used to prepare compound 1.1, but with 2-methyl-4-oxoperidine-1-carboxylic acid tert-butyl ester instead of 4-oxoperidine-1-carboxylic acid tert-butyl ester.

Compound 176.2. 4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester. The title compound was synthesized using a similar procedure to that used to prepare compound 1.4, with compound 176.1 replacing compound 1.1.

Compound 176.3. 4-(2-methylpiperidin-4-yl)benzonitrile. TFA (1 mL) was added dropwise to a solution of tert-butyl 4-(4-cyanophenyl)-2-methylpiperidin-1-carboxylic acid (compound 176.2, 500 mg, 1.50 mmol, 1.00 equivalent, 90%) in dichloromethane (3 mL). The resulting mixture was stirred at room temperature for 1.5 hours, followed by dilution with 30 mL of dichloromethane. The resulting mixture was washed with sodium bicarbonate (aqueous solution, 1 M; note: significant gas escaping). The aqueous phase was extracted with 2 × 50 mL of dichloromethane, and the combined organic layers were dried ( _Na₂SO₄ ) and concentrated under vacuum. The residue was purified by silica gel column chromatography using methanol/dichloromethane (1:50–1: ₂₀ ) as eluent to give 280 mg (93%) of 4-(2-methylpiperidin-4-yl)benzonitrile as a colorless oil.

Compound 176.4. 4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester. The title compound was synthesized using a similar procedure to that used to prepare compound 152.8, with compound 164.1 replacing compound 152.7.

Compound 176. 4-(1-(4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-2-methylpiperidin-4-yl)benzonitrile. Add a solution of 4-(2-methylpiperidin-4-yl)benzonitrile (compound 176.3, 210 mg, 0.940 mmol, 1.00 equivalent, 90%) in N,N-dimethylformamide (2 mL) to a round-bottom flask. EDC·HCl (404 mg, 2.11 mmol, 2.00 equivalent), 4-dimethylaminopyridine (257 mg, 2.10 mmol, 2.00 equivalent), and 4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 176.4, 300 mg, 1.05 mmol, 1.00 equivalent) were added to the reaction mixture. The resulting solution was stirred at 25 °C for 4 hours, followed by dilution with 50 mL of ethyl acetate. The resulting mixture was washed with 2 × 30 mL of _NH₄Cl (saturated aqueous solution) and 2 × 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using dichloromethane/methanol (20:1) as the eluent. The crude product (approximately 20 mg) was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN ( _CH3CN increased from 48% to 49% within 8 min, to 100% within 3 min, and decreased to 48% within 2 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 3.8 mg (1%) of the title compound as a white solid. m/z (ES+) 468 (M+H) ⁺ .

Compound 177.1. 4-Chloro-5-iodo-2-methylbenzoic acid. A solution of 4-chloro-2-methylbenzoic acid (30.0 g, 176 mmol, 1.00 equivalent) in acetic acid (300 mL) was added to a round- _bottom flask. _NaIO₄ (19.0 g, 88.8 mmol, 0.50 equivalent), _I₂ (49.0 g, 193 mmol, 1.10 equivalent), and sulfuric acid (3 mL) were added to the reaction mixture. The resulting mixture was stirred overnight at 110 °C. After cooling to ambient temperature, the reaction was carefully quenched with 500 mL _{of Na₂S₂O₃} (saturated aqueous solution). The resulting solid was collected by filtration and subsequently dissolved in 500 mL of ethyl acetate. The organic phase was washed with 2 × 200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This yielded 20.0 g (38%) of 4-chloro-5-iodo-2-methylbenzoic acid as a white solid.

Compound 177.2. Methyl 4-chloro-5-iodo-2-methylbenzoate. Sulfuric acid (5 mL) was added dropwise to a solution of 4-chloro-5-iodo-2-methylbenzoic acid (compound 177.1, 20.0 g, 67.5 mmol, 1.00 equivalent) in methanol (100 mL). The resulting mixture was stirred overnight at 75 °C. After cooling to ambient temperature, the methanol was removed under reduced pressure. The pH of the remaining aqueous layer was carefully adjusted to 7 with sodium bicarbonate (aqueous solution, 1 M; note: a large amount of gas escapes). The aqueous phase was extracted with 2 × 200 mL of ethyl acetate, and the combined organic layers were washed with 2 × 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:50) as the eluent to give 20.0 g (95%) of methyl 4-chloro-5-iodo-2-methylbenzoate as a pale yellow liquid.

Compound 177.3. 4-Chloro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 152.8, but with compounds 177.2 and 143.1 used instead of compounds 152.3 and acetylhydrazine, respectively.

Compound 177. 4-(1-(4-chloro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 152, but with compound 177.3 instead of compound 152.8. m/z(ES+)464(M+H) ⁺ .

Compound 178.1. 2-Bromo-4-chlorobenzoate. The title compound (17.0 g pale yellow solid, 80%) was prepared using a similar procedure to that used to prepare compound 177.2, but with 2-bromo-4-chlorobenzoic acid (20.0 g) instead of compound 177.1.

Compound 178.2. Methyl 4-chloro-2-ethylbenzoate. The title compound (2.20 g bright colorless liquid, 55%) was prepared using a similar procedure to that used to prepare compound 48.1, but with compound 178.1 (5.00 g) instead of methyl 2-bromo-4-methylbenzoate.

Compound 178.3. 4-Chloro-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic acid. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 152.8, with compounds 178.2 and 3-methoxypropionylhydrazine (compound 143.1) replacing compounds 152.2 and acetylhydrazine, respectively.

Compound 178. 4-(1-(4-chloro-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using a similar procedure to that used to prepare compound 152, but with compound 178.3 instead of compound 152.8. m/z(ES+)478(M+H) ⁺ .

Compound 179. 4-(1-(4-chloro-2-ethyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compounds 38 and 178. m/z(ES+) 490(M+H) ⁺ .

Compound 180.1. Methyl 4-bromo-2-fluorobenzoate. A solution of 4-bromo-2-fluorobenzoic acid (30.0 g, 137 mmol, 1.00 equivalent) in methanol (200 mL) was added to a 500 mL three-necked round-bottom flask. _SOCl₂ (24.0 g, 202 mmol, 1.50 equivalent) was added dropwise at 0 °C. The resulting solution was stirred at 0 °C for 10 min, at 25 °C for 30 min, and then at 50 °C for 3 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous phase was extracted with 100 mL of ethyl acetate. The combined organic layers were washed with 1 × 100 mL of water, 1 × 100 mL of sodium bicarbonate (saturated aqueous solution), and 1 × 100 mL of brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 30.0 g (94%) of the title compound as a pale yellow solid.

Compound 180.2. Methyl 4-ethyl-2-fluorobenzoate. The title compound (3.80 g bright colorless oil, 97%) was prepared using a similar procedure to that used to prepare compound 48.1, but with compound 180.1 (5.00 g) instead of methyl 2-bromo-4-methylbenzoate.

Compound 180.3. 4-Ethyl-2-fluoro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic acid. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 152.8, with compounds 180.2 and 143.1 replacing compounds 152.2 and acetylhydrazine, respectively.

Compound 180. 4-(1-(4-ethyl-2-fluoro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 152, but with compound 180.3 instead of compound 152.8. m/z(ES+)462(M+H) ⁺ .

Compound 181.1. 4-Bromo-2-ethylbenzoic acid. 4-Bromo-2-fluorobenzoic acid (50.0 g, 228 mmol, 1.00 equivalent) in tetrahydrofuran (500 mL) was added to a 1 L three-necked round-bottom flask purged and maintained under a nitrogen atmosphere. Ethyl magnesium bromide solution (250 mL, 3 M in THF) was added dropwise at 0 °C. The resulting solution was stirred at 0 °C for 3–4 h. The mixture was then carefully quenched at 0 °C by adding water dropwise. After complete quenching, water was added again and the pH was adjusted to 2–3 with hydrogen chloride (aqueous solution, 2 M). The mixture was extracted with 2 × 200 mL of ethyl acetate, and the organic layers were combined. The pH was adjusted to 7–8 with sodium hydroxide (2 N, aqueous solution). The resulting mixture was washed with 2 × 200 mL of ethyl acetate. The pH of the aqueous solution was adjusted to 2–3 with 2 N hydrogen chloride, followed by extraction with 2 × 200 mL of ethyl acetate. The combined organic layers were dried with anhydrous sodium sulfate and concentrated under vacuum. This yielded 30.0 g (57%) of 4-bromo-2-ethylbenzoic acid as a yellow solid.

Compound 181.2. Methyl 4-bromo-2-ethylbenzoate. The title compound (25.0 g bright yellow liquid, 79%) was prepared using a similar procedure to that used to prepare compound 177.2, but with compound 181.1 (30.0 g) instead of compound 177.1.

Compound 181.3. Methyl 4-cyclobutyl-2-ethylbenzoate. Under nitrogen atmosphere and at 0°C, a solution of magnesium cyclobutyl bromide (148 mmol in 50 mL THF) was added dropwise to a stirred mixture of _ZnBr₂ (33.5 g, 149 mmol, 4.00 equivalents) in THF (350 mL). After stirring at 0°C for 0.5 hours, the temperature was lowered to -78°C and Pd(dpPf) _Cl₂ (2.00 g, 2.73 mmol, 0.07 equivalents) was added, followed by the dropwise addition of a solution of methyl 4-bromo-2-ethylbenzoate (compound 181.2, 9.00 g, 37.0 mmol, 1.00 equivalents) in tetrahydrofuran (10 mL) at the same temperature. The reaction mixture was allowed to slowly reach ambient temperature and then stirred overnight. The reaction was carefully quenched with a saturated aqueous solution of _NH₄Cl (100 mL). The mixture was extracted with 500 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50) to give 8.00 g (99%) of the desired product as a pale yellow oil.

Compound 181.4. Methyl 4-cyclobutyl-2-ethyl-5-iodobenzoate. Iodine (8.98 g, 35.4 mmol, 1.00 equivalent), NaIO₄ (3.78 g, 17.7 mmol, 0.50 equivalent), and sulfuric acid (0.870 g, 8.87 mmol, 0.25 equivalent) were added to a solution of methyl ₄ -cyclobutyl-2-ethylbenzoate (compound 181.3, 7.70 g, 35.3 mmol, 1.00 equivalent) in acetic acid (80 _{mL). The reaction mixture was stirred overnight at 60 °C. After cooling to room temperature, the reaction was slowly quenched with Na₂S₂O₃ (} saturated aqueous solution). The mixture was extracted with 200 _mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50) to obtain 10.5 g (86%) of the desired product as a colorless solid.

Compound 181.5. Methyl 5-cyano-4-cyclobutyl-2-ethylbenzoate. A solution of methyl 4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 5.50 g, 16.0 mmol, 1.00 equivalent) in N,N-dimethylformamide (150 mL) was added to a round-bottom flask purged and maintained under a nitrogen atmosphere. Zinc cyanide (2.78 g, 23.7 mmol, 1.50 equivalent) and Pd( _PPh3 ) ₄ (1.83 g, 1.59 mmol, 0.10 equivalent) were added to the reaction mixture. The resulting solution was stirred under nitrogen at 100 °C for 15 hours. After cooling to ambient temperature, the reaction was carefully quenched with 300 mL of _FeSO4 (saturated aqueous solution) and diluted with ethyl acetate. The resulting mixture was vigorously stirred, then filtered through diatomaceous earth and washed with 1 M _FeSO4 , water, and ethyl acetate. The separated layers were extracted with 2 × 300 mL of ethyl acetate from the aqueous phase. The combined organic layers were washed with 2 × 300 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:100–1:50) as the eluent to give 3.20 g (82%) of methyl 5-cyano-4-cyclobutyl-2-ethylbenzoate as a pale yellow oil.

Compound 181.6. Methyl 5-thiocarbamoyl-4-cyclobutyl-2-ethylbenzoate. A solution of methyl 5-cyano-4-cyclobutyl-2-ethylbenzoate (compound 181.5, 3.00 g, 12.3 mmol, 1.00 equivalent) in a solvent mixture of tetrahydrofuran and _H₂O (80 mL/40 mL) was added to a round-bottom flask. Diethyl dithiophosphate O,O′-diethyl ester (6.69 g, 35.9 mmol, 3.00 equivalent) was added dropwise with stirring. The resulting solution was stirred at 85 °C for 48 hours (Note: a large amount of gas was released; this reaction and all other reactions described herein should be carried out in a well-ventilated fume hood). After cooling to ambient temperature, the mixture was then concentrated under vacuum. The crude product was purified by recrystallization from petroleum ether to obtain 1.30 g (38%) of methyl 5-thiocarbamoyl-4-cyclobutyl-2-ethylbenzoate as a light yellow solid.

Compound 181.7. Methyl 4-cyclobutyl-2-ethyl-5-(imino(methylthio)methyl)benzoate. A solution of methyl 5-thiocarbamoyl-4-cyclobutyl-2-ethylbenzoate (compound 181.6, 1.50 g, 5.41 mmol, 1.00 equivalent) in tetrahydrofuran (30 mL) was added to a round-bottom flask. Iodomethane (3.80 g, 26.8 mmol, 5.00 equivalent) was then added dropwise with stirring. The resulting solution was stirred at 25 °C for 15 hours, followed by concentration under vacuum. This yielded 1.80 g (97%) of the title compound as a yellow oil.

Compound 181.8. Methyl 4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoate. A solution of methyl 4-cyclobutyl-2-ethyl-5-(methylthioalkyl)carbamoimide benzoate (compound 181.7, 900 mg, 3.09 mmol, 1.00 equivalent) in AcOH (20 mL) was added to a round-bottom flask. Propionylhydrazine (880 mg, 9.99 mmol, 3.00 equivalent) was added and the resulting mixture was stirred at 90 °C for 2 h. After cooling to ambient temperature, the mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:50–1:3) as eluent to give 0.360 g (37%) of the title compound as a clear oil.

Compound 181.9. 4-Cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoic acid. A solution of methyl 4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoate (compound 181.8, 360 mg, 1.15 mmol, 1.00 equivalent) in methanol (20 mL) was added to a round-bottom flask. A solution of sodium hydroxide (460 mg, 11.5 mmol, 10.0 equivalent) in water (10 mL) was added to the reaction mixture. The resulting solution was stirred at 25 °C for 15 hours. The organic solvent was then removed under reduced pressure. The pH of the remaining aqueous phase was adjusted to 2–3 with hydrogen chloride (aqueous solution, 2 M). The resulting precipitate was collected by filtration and dried under high vacuum to give 320 mg (93%) of the title compound as a white solid.

Compound 181. 4-(1-(4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. EDCI (113 mg, 0.590 mmol, 1.11 equivalents), DMAP (197 mg, 1.62 mmol, 3.03 equivalents), and HOBT (87.5 mg, 0.650 mmol, 1.21 equivalents) were added to a solution of 4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoic acid (compound 181.9, 160 mg, 0.530 mmol, 1.00 equivalents) in N,N-dimethylformamide (20 mL). After 5 minutes, 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 110 mg, 0.590 mmol, 1.10 equivalent) was added. The resulting mixture was stirred at 25 °C for 15 hours, followed by quenching with 100 mL of ice water. The mixture was extracted with 2 × 150 mL of ethyl acetate. The combined organic layers were washed with 3 × 150 mL of brine, dried over anhydrous sodium sulfate, and concentrated. The crude product (approximately 150 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (47% _CH3CN increased to 61% within 6 minutes, to 100% within 1.5 minutes, and decreased to 47% within 1.5 minutes); detector, Waters 2489 254 and 220 nm. The fractions containing the pure compound were combined and lyophilized to give 99.5 mg (40%) of the title compound as a white solid. m/z (ES+) 468 (M+H) ⁺ . ^¹H -NMR (300 MHz, _CD₃OD ): δ 7.71–7.69 (m, 2H), 7.50–7.32 (m, 4H), 4.03–3.99 (m, 1H), 3.65–3.5 (m, 1H), 3.32–3.20 (m, 1H), 2.90–2.95 (m, 4H), 2.70–2.74 (m, 2H), 2.20–1.98 (m, 6H), 1.98–1.79 (m, 4H), 1.41 (t, 3H), 1.39–1.28 (m, 3H).

Compound 182. 4-(1-(4-cyclopropyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compounds 143 and 181. m/z (ES+) 484 (M+H) ⁺ . ^1H -NMR (300MHz, CD3 ₎ OD): δ7.67 (d, 2H), 7.49-7.37 (m, 3H), 7.11-7.05 (m, 1H), 4.89-4.80 (m, 1H) , 3.81(t, 2H), 3.77-3.60(m, 1H), 3.4(s, 3H), 3.37-3.32(m, 1H), 3.14(t, 2H ), 3.15-2.9(m, 2H), 2.92-2.5(m, 2H), 2.39-2.36(m, 1H), 2.02-1.85(m, 1H) , 1.85-1.69 (m, 3H), 1.32-1.21 (m, 3H), 1.0-0.95 (m, 2H), 0.77-0.69 (m, 2H).

Compound 183. 4-(1-(4-cyclopropyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compounds 143 and 181. m/z(ES+) 470(M+H) ⁺ .

Compound 184. 4-(1-(4-cyclobutyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compounds 143 and 181, with compound 11.2 hydrochloride substituted for compound 1.5. m/z(ES+)502(M+H) ⁺ .

Compound 185. 4-(1-(4-cyclobutyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compounds 143 and 181. m/z(ES+)484(M+H) ⁺ .

Compound 186. 4-(1-(4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 181, with compound 11.2 hydrochloride substituted for compound 1.5. m/z(ES+)486(M+H) ⁺ .

Compound 187. 4-(1-(4-cyclobutyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compounds 143 and 181, with compound 11.2 hydrochloride substituted for compound 1.5. m/z(ES+)516(M+H) ⁺ . ¹ H-NMR (300MHz, CD ₃ OD): δ7.77(d, 2H), 7.66-7.47(m, 2H), 7.47-7.35(m, 2H), 4.89-4.83(m, 1H), 4.08-4.03(t, 1H), 3.79(t, 2H), 3 .55(t, 2H), 3.33(s, 3H), 3.28-3.20(m, 1H), 3.12(t, 2H), 2.80-2.68(m, 2H), 2.27-1.68(m, 10H), 1.27(t, 3H).

Compound 188. 4-(1-(4-cyclobutyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compounds 143 and 181. m/z(ES+) 498(M+H) ⁺ . ¹ H-NMR (300MHz, CD ₃ OD): δ7.67 (d, 2H), 7.44-7.31 (m, 4H), 4.89 (s, 1H), 4.04-3.98 (m, 1H), 3.79 (t, 2H), 3.66-3.60 (m, 1H), 3.33 (s, 3H), 3. 23-3.12 (m, 1H), 3.10 (t, 2H), 3.02 (t, 2H), 2.77-2.66 (m, 2H), 2.19-2.04 (m, 6H), 1.80-1.68 (m, 4H), 1.31-1.26 (m, 3H).

Compound 189.1. Methyl 4-(cyclobutylmethyl)-2-methylbenzoate. The title compound (4.00 g, yellow oil, 84%) was prepared by using a similar procedure to that used to prepare compound 181.3, with compound 152.1 (5.00 g) and cyclobutylmethyl magnesium bromide in place of compounds 181.2 and cyclobutyl magnesium bromide, respectively.

Compound 189.2. Methyl 4-(cyclobutylmethyl)-5-iodo-2-methylbenzoate. A solution of methyl 4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.1, 8.40 g, 38.5 mmol, 1.00 equivalent) in AcOH (150 mL) was added to a round-bottom flask. _NaIO₄ (5.00 g, 23.4 mmol, 0.50 equivalent), iodine (10.0 g, 39.4 mmol, 1.00 equivalent), and sulfuric acid (0.3 mL) were added to the reaction mixture. The resulting solution was stirred at 60 °C for 12 hours. After cooling to room temperature, the reaction was quenched with 200 mL _of NaHSO₃ (aqueous solution). The mixture was extracted with 2 × 200 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (20:1) as the eluent to give 8.00 g (60%) of methyl 4-(cyclobutylmethyl)-5-iodo-2-methylbenzoate as a white solid.

Compound 189.3. Methyl 5-cyano-4-(cyclobutylmethyl)-2-methylbenzoate. The title compound (5.0 g, pale yellow oil, 88%) was prepared by using a similar procedure to that used to prepare compound 181.5, but in place of compound 181.4 with compound 189.2 (8.00 g).

Compound 189.4. Methyl 5-thiocarbamoyl-4-(cyclobutylmethyl)-2-methylbenzoate. Add a solution of methyl 5-cyano-4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.3, 5.00 g, 20.6 mmol, 1.00 equivalent) in a solvent mixture of THF and _H₂O (50 mL/25 mL). Add diethyl dithiophosphate O,O′-diethyl ester (15.0 g, 80.5 mmol, 4.00 equivalent) to the reaction flask. Stir the resulting solution at 80 °C for 48 hours (Note: A large amount of gas is released; this reaction and all other reactions described herein should be carried out in a well-ventilated fume hood). After cooling to ambient temperature, carefully quench the reaction with 50 mL of brine. Extract the mixture with 3 × 50 mL ethyl acetate, and dry the combined organic layers with anhydrous sodium sulfate and concentrate under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:4) as the eluent to give 1.20 g (21%) of the title compound as a yellow oil.

Compound 189.5. Methyl 4-(cyclobutylmethyl)-2-methyl-5-(methylthioalkyl)carbonimide benzoate. A solution of methyl 5-thiocarbamoyl-4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.4, 1.20 g, 4.33 mmol, 1.00 equivalent) in tetrahydrofuran (25 mL) was added to a round-bottom flask. Iodimide (5.00 g, 35.2 mmol, 8.00 equivalent) was added to the reaction mixture. The resulting solution was stirred at 20 °C for 12 hours and then concentrated under vacuum. This yielded 1.10 g (87%) of methyl 4-(cyclobutylmethyl)-2-methyl-5-(methylthioalkyl)carbonimide benzoate as a yellow oil.

Compound 189.6. Methyl 4-(cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate. A solution of methyl 4-(cyclobutylmethyl)-2-methyl-5-(methylthioalkyl)carbamoimide benzoate (compound 189.5, 1.00 g, 3.43 mmol, 1.00 equivalent) in AcOH (25 mL) was added to a round-bottom flask. Propionylhydrazine (1.20 g, 13.6 mmol, 4.00 equivalent) was added, and the resulting mixture was stirred at 100 °C for 1 hour. After cooling to ambient temperature, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:5) as eluent to give 300 mg (28%) of the title compound as a white solid.

Compound 189.7. 4-(cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. The title compound (260 mg, white solid, 91%) was prepared by using a similar procedure to that used to prepare compound 181.9, but in place of compound 181.8, with compound 189.6 (300 mg).

Compound 189. 4-(1-(4-(cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound (28 mg, white solid, 18%) was prepared by substituting compound 189.7 (100 mg) for compound 181.9 using a similar procedure as that used to prepare compound 181. m/z (ES+) 468 (M+H) ⁺ . ^1H -NMR (300MHz, _CD3 OD): δ 7.67 (d, 2H), 7.52–7.47 (m, 3H), 7.26 (s, 1H), 3.66–3.22 (m, 1H), 3.33–3.22 (m, 1H), 3.05–2.99 (m, 4H), 2.97 (q, 2H), 2.53–2.47 (m, 1H), 2.47 and 2.45 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.00–1.50 (m, 10H), 1.41 (t, 3H).

Compound 190.1. Methyl 2-bromo-5-iodo-4-methylbenzoate. A mixture of methyl 2-bromo-4-methylbenzoate (2.00 g, 7.86 mmol, 1.00 equivalent) in AcOH (20 mL) was added to a round-bottom flask. _I₂ (2.45 g, 9.65 mmol, 1.10 equivalent), _NaIO₄ (950 mg, 4.42 mmol, 0.50 equivalent), and sulfuric acid (0.1 mL, 0.15 equivalent) were added, and the mixture was stirred overnight at 100 °C. After cooling to ambient temperature, the reaction was carefully quenched with _{Na₂S₂O₃} (saturated aqueous _solution ). The mixture was extracted with 2 × 50 _mL of ethyl acetate. The combined organic layers were dried ( _Na₂SO₄ ) and concentrated under vacuum to give 2.50 _g (81%) of the title compound as a grayish-white solid.

Compound 190.2. Methyl 2-bromo-5-cyano-4-methylbenzoate. The title compound (1.10 g, white solid, 61%) was prepared by using a similar procedure to that used to prepare compound 181.5, but instead of compound 181.4, using compound 190.1 (2.50 g).

Compound 190.3. Methyl 5-cyano-2-cyclopropyl-4-methylbenzoate. A solution of methyl 2-bromo-5-cyano-4-methylbenzoate (compound 190.2, 600 mg, 2.13 mmol, 1.00 equivalent, 90%) in toluene (20 mL) was added under nitrogen to a solution of cyclopropylboronic acid (552 mg, 6.43 mmol, 2.00 equivalent), potassium carbonate (876 mg, 6.34 mmol, 2.00 equivalent) in water (1 mL), Pd(dppf) _Cl₂ (252 mg, 0.10 equivalent), and Pd(OAc)₂ (70 mg, 0.10 equivalent). The resulting mixture was stirred overnight under nitrogen at 100 °C. After cooling to ambient temperature, the mixture was diluted with 20 mL of _H₂O and then extracted with 3 × 50 mL of ethyl acetate. The combined organic layers were dried ( _Na₂SO₄ ) and concentrated under vacuum to give 450 _mg (89%) of methyl 5-cyano-2-cyclopropyl-4-methylbenzoate as a white solid.

Compound 190.4. Methyl 5-thiocarbamoyl-2-cyclopropyl-4-methylbenzoate. Add a solution of methyl 5-cyano-2-cyclopropyl-4-methylbenzoate (Compound 190.3, 220 mg, 0.920 mmol, 1.00 equivalent, 90%) in tetrahydrofuran (6 mL) to a round-bottom flask. Add a solution of diethyl dithiophosphate O,O′-diethyl ester (300 mg, 1.61 mmol, 2.00 equivalent) in water (1.5 mL), and stir the resulting mixture overnight in an oil bath at 80 °C (Note: a large amount of gas will be released; this reaction and all other reactions described herein should be carried out in a well-ventilated fume hood). After cooling to ambient temperature, concentrate the mixture under vacuum. Purify the residue by silica gel column chromatography using ethyl acetate/petroleum ether (5:1) as the eluent. The collected fractions were combined and concentrated under vacuum to obtain 100 mg (39%) of methyl 5-thiocarbamoyl-2-cyclopropyl-4-methylbenzoate as a yellow solid.

Compound 190.5. Methyl 2-cyclopropyl-4-methyl-5-(methylthioalkyl)carboimide benzoate. Iodimide (1 mL) was added dropwise to a solution of methyl 5-thiocarbamoyl-2-cyclopropyl-4-methylbenzoate (compound 190.4, 600 mg, 2.17 mmol, 1.00 equivalent, 90%) in THF (55 mL). The resulting mixture was stirred overnight at 25 °C, then concentrated and dried under reduced pressure to give 400 mg (56%) of the title compound as a yellow solid.

Compound 190.6. 2-Methoxyacetylhydrazine. A solution _of ethyl 2-methoxyacetylhydrazine (10.0 g, 76.2 mmol, 1.00 equivalent, 90%) and _NH₂NH₂ · _H₂O (12 mL, 3.00 equivalent) in ethanol (100 mL) was added to a round-bottom flask. The resulting solution was stirred in an oil bath at 80 °C for 3 hours, then concentrated and dried under reduced pressure to give 6 g (68%) of 2-methoxyacetylhydrazine as a white solid.

Compound 190.7. Methyl 2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate. A solution of methyl 2-cyclopropyl-4-methyl-5-(methylthioalkyl)carbamoimidobenzoate (Compound 190.5, 400 mg, 1.37 mmol, 1.00 equivalent, 90%) and 2-methoxyacetylhydrazine (Compound 190.6, 889 mg, 7.69 mmol, 5.00 equivalent) in AcOH (25 mL) was stirred overnight at 90 °C. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (2:1) as the eluent. The collected fractions were combined and concentrated under vacuum to obtain 200 mg (44%) of methyl 2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate as a white solid.

Compound 190.8. 2-Cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoic acid. A solution of methyl 2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate (Compound 190.7, 200 mg, 0.600 mmol, 1.00 equivalent, 90%) in methanol (4 mL) was added to a round-bottom flask. A solution of sodium hydroxide (106 mg, 2.65 mmol, 4.00 equivalent) in water (2 mL) was added to the reaction mixture. The resulting solution was stirred at 60 °C for 2 hours. After cooling to ambient temperature, the organic solvent was removed under reduced pressure, and the pH of the remaining aqueous layer was adjusted to 2–3 with hydrogen chloride (aqueous solution, 6 M). The resulting solid was collected by filtration and dried to give 170 mg (89%) of the title compound as a white solid.

Compound 190. 4-(1-(2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound (115.5 mg, white solid, 51%) was prepared by substituting compound 181.9 with compound 190.8 (150 mg) using a similar procedure as that used to prepare compound 181. m/z (ES+) 456 (M+H) ⁺ .

Compound 191.1. 2-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoic acid. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 190.8.

Compound 191. 4-(1-(2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound (74.8 mg, white solid, 33%) was prepared by substituting compound 181.1 (145 mg) for compound 181.9 using a similar procedure as that used to prepare compound 181. m/z (ES+) 458 (M+H) ⁺ .

Compound 192. 4-(1-(2-ethyl-4-methyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 191. m/z(ES+) 470(M+H) ⁺ .

Compound 193. 4-(1-(2-ethyl-5-(5-(1-methoxypropyl-2-yl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 191. m/z(ES+)472(M+H) ⁺ .

Compound 194. 4-(1-(2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 191. m/z(ES+)444(M+H) ⁺ .

Compound 195. 4-(1-(2-cyclobutyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 190. m/z(ES+) 470(M+H) ⁺ .

Compound 196.1. Methyl 2-isopropyl-4-methylbenzoate. Under nitrogen atmosphere and at -48°C, isopropyl magnesium bromide (3M in THF, 170 mmol) was added dropwise to a stirred mixture of zinc dibromo (39.0 g, 173 mmol, 4.00 equivalents) in 500 mL of THF over 30 minutes. Pd(dppf) _Cl₂ (0.5 g, 0.05 equivalents) and methyl 2-bromo-4-methylbenzoate (10.0 g, 43.7 mmol, 1.00 equivalents) were added to the reaction mixture. After stirring at -48°C for 1 hour, the reaction mixture was quenched by careful addition of 500 mL of _NH₄Cl (aqueous solution). The resulting mixture was extracted with 3 × 500 mL of ethyl acetate. The combined organic layers were washed with 3 × 500 mL of brine and concentrated under vacuum. The residue was purified by silica gel column chromatography using petroleum ether (1:1) as the eluent. This produces 6.50g (77%) of methyl 2-isopropyl-4-methylbenzoate, which is a yellow oil.

Compound 196.2. Methyl 2-isopropyl-4-methylbenzoate. A solution of methyl 2-isopropyl-4-methylbenzoate (compound 196.1, 6.50 g, 33.8 mmol, 1.00 equivalent) in acetic acid (60 mL) was added to a round-bottom flask. Iodide (9.50 g, 37.4 mmol, 1.10 equivalent), sodium periodate (3.60 g, 16.8 mmol, 0.50 equivalent), and sulfuric acid (0.500 g, 0.15 equivalent) were added to the reaction mixture. The resulting solution was stirred overnight at 100 °C. After cooling to room temperature, the reaction was quenched with _{Na₂S₂O₃} (saturated aqueous solution). The mixture was extracted with 3 × 100 _mL of ethyl acetate. The combined organic layers were washed with 3 × 100 mL _of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This produces 6.00g (56%) of methyl 5-iodo-2-isopropyl-4-methylbenzoate, which is a yellow oil.

Compound 196.3. Methyl 5-cyano-2-isopropyl-4-methylbenzoate. The title compound (0.8 g, white solid, 37%) was prepared by using a similar procedure to that used to prepare compound 181.5, but instead of compound 181.4, using compound 196.2 (3.20 g).

Compound 196.4. Methyl 5-thiocarbamoyl-2-isopropyl-4-methylbenzoate. Add a solution of methyl 5-cyano-2-isopropyl-4-methylbenzoate (compound 196.3, 800 mg, 3.68 mmol, 1.00 equivalent) in tetrahydrofuran/ _H₂O (10/5 mL) to a round-bottom flask. Add diethyl dithiophosphate O,O′-diethyl ester (2.05 g, 11.0 mmol, 3.00 equivalent) to the reaction mixture. Stir the resulting solution in an oil bath at 85 °C for 15 hours (Note: a large amount of gas is released; this reaction and all other reactions described herein should be carried out in a well-ventilated fume hood). After cooling to ambient temperature, extract the mixture with 2 × 100 mL of ethyl acetate. The combined organic layers are dried ( _Na₂SO₄ ) and concentrated under _vacuum . The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:100-1:50-1:0) as the eluent to give 0.800 g (86%) of methyl 5-thiocarbamoyl-2-isopropyl-4-methylbenzoate as a yellow oil.

Compound 196.5. Methyl 5-(imino(methylthio)methyl)-2-isopropyl-4-methylbenzoate. The title compound (0.800 g, yellow oil, 92%) was prepared by using a similar procedure to that used to prepare compound 181.7, but in place of compound 181.6 with compound 196.4 (820 mg).

Compound 196.6. Methyl 2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate. A solution of methyl 5-(imino(methylthio)methyl)-2-isopropyl-4-methylbenzoate (compound 196.5, 800 mg, 3.01 mmol, 1.00 equivalent) and 2-methoxyacetylhydrazine (compound 190.6, 1.90 g, 18.3 mmol, 5.00 equivalent) in acetic acid (30 mL) was stirred in an oil bath at 80 °C for 2 hours, and then concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:50-1:2) as the eluent to give 250 mg (27%) of methyl 2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate as a clear oil.

Compound 196.7. 2-Isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoic acid. The title compound (0.20 g, white solid, 84%) was prepared by using a similar procedure to that used to prepare compound 181.9, but instead of compound 181.8, using compound 196.6 (250 mg).

Compound 196. 4-(1-(2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile and compound 197. 4-(1-(5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methyl-2-propylbenzoyl)piperidin-4-yl)benzonitrile. To a solution of 2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoic acid (compound 196.7, 200 mg, 0.690 mmol, 1.00 equivalent) in DMF (20 mL), EDCI (200 mg, 1.04 mmol, 1.51 equivalent), DMAP (250 mg, 2.05 mmol, 2.96 equivalent), and HOBT (110 mg, 0.810 mmol, 1.18 equivalent) were added. After stirring at room temperature for 30 min, compound 1.5 (142 mg, 0.640 mmol, 0.92 equivalent) was added, and the resulting solution was stirred at 25 °C for 15 h, followed by quenching with 100 mL of ice water. The resulting mixture was extracted with 2 × 200 mL of ethyl acetate. The combined organic layers were washed with 2 × 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:50-1:1-1:0) as the eluent. The crude product (approximately 120 mg) was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19×150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (40.0% _CH3CN rising to 55.0% within 8 min, to 100.0% within 1 min, and falling to 40.0% within 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compounds were combined and lyophilized to give 57.4 mg (18%) of compound 196 and 11.7 mg (4%) of compound 197 as white solids. Compound 196. m/z (ES+) 458 (M+H) ⁺ . ^¹H -NMR (300MHz, _CD₃OD ): δ 7.65–7.62 (m, 2H), 7.55–7.28 (m, 4H), 4.61 (s, 2H), 3.67–3.62 (m, 1H), 3.44 (s, 3H), 3.27–3.20 (m, 1H), 3.04–2.86 (m, 3H), 2.51 (s, 3H), 1.99–1.68 (m, 5H), 1.31–1.26 (m, 6H). Compound 197. m/z (ES+) 458 (M+H) ⁺ . ¹ H-NMR (300MHz, CD ₃ OD): δ7.66-7.63(m, 2H), 7.55(s, 1H), 7.46-7.37(m, 2H), 7.28(m, 1H), 4.61(s, 2H), 3.62-3.58(m, 1H), 3. 44(s, 3H), 3.19-3.05(m, 2H), 3.04-2.91(m, 2H), 2.73-2.45(m, 5H), 1.98-1.54(m, 6H), 1.05-0.85(m, 3H).

Compound 198.1. Methyl 4-isopropyl-2-methylbenzoate. A dry round-bottom flask with a stir bar was purged with nitrogen and loaded with diisopropylzinc (25 mL 1M THF solution, 25 mmol, 2.0 equivalent). 1,4-Dioxane (25 mL) of methyl 4-bromo-2-methylbenzoate (compound 152.1, 2.86 g, 12.5 mmol, 1.0 equivalent) was added, followed by Pd(dppf) _₂Cl₂ ·DCM ( _1.02 g, 1.25 mmol, 0.1 equivalent) (exothermic during catalyst addition). The system was then purged sequentially with nitrogen and argon and heated to 100 °C for 4 hours, followed by stirring at room temperature for 12 hours. The mixture was carefully quenched with 1M HCl (aqueous solution, 12 mL) (some bubbling occurred), and then diluted and mixed with water (100 mL) and ethyl acetate (150 mL). The mixture was filtered through diatomaceous earth and washed _with water and ethyl acetate (2 × 25 mL each). The separated layers were then extracted with ethyl acetate (50 mL). The combined organic compounds were washed with brine (50 mL), dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane to 6% ethyl acetate) to give the title compound (2.31 g, 96%) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ): δ 7.86 (d, with fine structure, J = 8.8 Hz, 1H), 7.12–7.07 (m, 2H), 3.87 (s, 3H), 2.90 (septet, J = 6.8 Hz, 1H), 2.59 (s, 3H), 1.25 (d, J = 6.8 Hz, 6H).

Compound 198.2. Methyl 5-iodo-4-isopropyl-2-methylbenzoate. TFA (24 mL) was carefully added to methyl 4-isopropyl-2-methylbenzoate (Compound 198.1, 2.31 g, 12.0 mmol, 1.0 equivalent) in a 100 mL round-bottom flask, and the mixture was cooled to 0 °C. N-iodosuccinimide (2.70 g, 12.0 mmol, 1.0 equivalent) was added fractionally over 2 minutes, and the resulting mixture was added under nitrogen atmosphere and stirred at 0 °C for 20 minutes, followed by stirring at room temperature for 15 hours. The mixture was carefully diluted to a dichloromethane mixture (50 mL) and added to a saturated aqueous solution of disodium phosphate to maintain a pH above 3 (total disodium phosphate approximately 500 mL). The mixture was thoroughly shaken, separated, and the aqueous phase was extracted again with DCM (5 × 25 mL). The combined organic matter was washed sequentially with a mixture of saturated sodium sulfite (10 mL) and water (40 mL), followed by brine (50 _mL ), dried ( _Na₂SO₄ ), filtered, and removed under vacuum. The crude product was purified by silica column chromatography (hexane to 3% ethyl acetate) to give the title compound (3.59 g, 94%) as a light brown oil. ^¹H NMR (400 MHz, _CDCl₃ ): δ 8.35 (s, 1H), 7.08 (s, 1H), 3.87 (s, 3H), 3.17 (septet, J = 6.8 Hz, 1H), 2.59 (s, 3H), 1.23 (d, J = 6.8 Hz, 6H).

Compound 198.3. Methyl 5-cyano-4-isopropyl-2-methylbenzoate. Methyl 5-iodo-4-isopropyl-2-methylbenzoate (Compound 198.2, 2.00 g, 6.29 mmol, 1.0 equivalent), zinc cyanide (1.48 g, 12.6 mmol, 2.0 equivalent), DMF (20 mL), and Pd( _PPh3 ) ₄ (364 mg, 0.315 mmol, 0.05 equivalent) were added to a dry round-bottom flask. The system was purged sequentially with nitrogen and argon, and the mixture was heated at 100 °C for 15 hours. The reaction was cooled to room temperature, then diluted with ethyl acetate (50 mL) and quenched with ₁ M FeSO4 (25 mL). The mixture was stirred vigorously for 40 minutes, then filtered through diatomaceous earth and washed with 1 M _FeSO4 (15 mL), water (50 mL), and ethyl acetate (150 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (4 × 100 mL), dried ( _Na₂SO₄ ), filtered _, and concentrated under vacuum. The product was purified by silica column chromatography (hexane to 8% ethyl acetate) to give the title compound (1.14 g, 83%). ^¹H NMR (400 MHz, _CDCl₃ ): δ 8.19 (s, 1H), 7.25 (s, 1H), 3.91 (s, 3H), 3.37 (septet, J = 6.8 Hz, 1H), 2.67 (s, 3H), 1.32 (d, J = 6.8 Hz, 6H).

Compound 198.4. Methyl 5-((ethylthio)(imino)methyl)-4-isopropyl-2-methylbenzoate. Methyl 5-cyano-4-isopropyl-2-methylbenzoate (compound 198.3, 1.12 g, 5.16 mmol, 1.0 equivalent), diethyl dithiophosphate O,O′-diethyl ester (90%) (2.0 mL, 10.7 mmol, 2.1 equivalent), and water (200 μL) were added to a 16 mL vial and the mixture was heated at 80 °C for 85 hours with the cap loosened (Note: A large amount of gas is released; this reaction and all other reactions described herein should be carried out in a well-ventilated fume hood). Note that additional diethyl dithiophosphate O,O′-diethyl ester (0.5 mL, 2.7 mmol, 0.5 equivalent) and water (50 μL) were added at 6 and 14 hours. The intermediate thioamide was also observed by LC/MS during the reaction and heated until completely converted to the desired product. The reaction mixture was diluted with ethyl acetate (75 mL) and washed successively with saturated aqueous _NaHCO3 solution (20 mL), 1 M _NaH₂PO₄ ( ₁₀ mL), and brine (10 _mL ). The organic matter was dried ( _Na₂SO₄ ), filtered, and removed under vacuum. The crude product was purified by silica column chromatography (hexane to 25% ethyl acetate) to give a colorless oil (1.12 g, 78%). m/z (ES+) 280 (M+H) ⁺ .

Compound 198.5. Methyl 4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate. Methyl 5-((ethylthio)(imino)methyl)-4-isopropyl-2-methylbenzoate (Compound 198.4, 33 mg, 0.12 mmol, 1.0 equivalent), 3-methoxypropionylhydrazine (Compound 143.1, 21 mg, 0.18 mmol, 1.5 equivalent), and acetic acid (1.2 mL) were added to a 4-mL vial and heated at 80 °C for 4 hours with the cap loose. The solvent was removed under vacuum, and the residue was dissolved in DCM (10 mL) and washed successively with saturated _NaHCO3 (5 mL) and brine (5 _mL ), dried ( _Na2SO4 ), filtered, and evaporated to a colorless oil (theoretical yield). m/z(ES+)318(M+H) ⁺ .

Compound 198.6. 4-Isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. Lithium hydroxide monohydrate (10.1 mg, 0.24 mmol, 2.0 equivalent), methanol (0.9 mL), and water (0.3 mL) were added to crude methyl 4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate (compound 198.5, 0.12 mmol, 1.0 equivalent) from the previous step in a 4-mL vial. The resulting mixture was stirred at room temperature for 3 hours, followed by stirring at 50°C for 3 hours and then at 40°C for 17 hours. The solvent was removed under vacuum, and the residue was diluted with saturated _NaHCO3 (1 mL) in water (7 mL) and washed with diethyl ether (2 mL). The organic phase was back-extracted from the mixture of water (2 mL) and saturated _NaHCO3 (0.5 mL). The combined aqueous phases were acidified to pH ₃ with 1 _{M H3PO4} and extracted with dichloromethane (3 × 5 mL). The organic matter was dried ( _Na2SO4 ), filtered, and removed under vacuum to give the title compound (31.5 mg, 88%, in 2 steps) as a white, waxy solid. m/z(ES+)304(M+H) ⁺ .

Compound 198. 4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. Add 4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 1 98.6, 31 mg, 0.10 mmol, 1.0 equivalent), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 23 mg, 0.10 mmol, 1.0 equivalent), l-hydroxybenzotriazole hydrate (20 wt% water) (22 mg, 0.13 mmol, 1.25 equivalent), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.5 mg, 0.11 mmol, 1.1 equivalent), DMF (1 mL), and DIEA (71 μL, 0.41 mmol, 4 equivalent) to 4-mL vials. The mixture was stirred at room temperature for 24 hours, then diluted with ethyl acetate (10 mL) and washed with brine (10 mL). The aqueous phase was back-extracted with ethyl acetate (3 mL) and the combined organic matter was washed with saturated _NaHCO3 (5 mL), 1 M _NaH2PO4 ( ₅ mL), and brine ( ₅ mL). The organic matter was dried ( _Na2SO4 ), filtered, and removed under vacuum. The crude residue was purified by preparative TLC (DCM/8% MeOH) to give the title compound (23 mg, 48%) as a grayish-white solid. m/z (ES+) 472 (M+H) ⁺ .

Compound 199. 4-(1-(4-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 198). m/z(ES+) 458(M+H) ⁺ .

Compound 200. 4-(1-(4-isopropyl-3-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 198). m/z(ES+) 458(M+H) ⁺ .

Compound 201. 4-(1-(4-isopropyl-3-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 198). m/z(ES+)444(M+H) ⁺ .

Compound 202.1. Methyl 5-carbamoyl-4-cyclobutyl-2-methylbenzoate. Methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (152.4 mg, 100 mg, 0.436 mmol, 1.0 equivalent), potassium carbonate (181 mg, 1.31 mmol, 3.0 equivalent), and DMSO (2.2 mL) were added to an 8-mL vial and stirring was started. Hydrogen peroxide (50 wt%) (176 μL, 3.05 mmol, 7.0 equivalent) was added over approximately 1 minute. The mixture was stirred at room temperature for 29 hours, then diluted to 10 _mL of brine in 1 M _H₃PO₄ (1.5 mL). The mixture was extracted with ethyl acetate (10 mL × 1, 3 mL × 1). The combined organic layers were washed with brine (10 mL) with a few drops _of 1 M _H₃PO₄ , followed by washing with a mixture of water (10 mL) and saturated _NaHCO₃ ( ₁ mL), and finally with brine (5 mL). The organic matter was dried ( _Na₂SO₄ ), filtered, and evaporated to give the title compound (59 mg, 55%) as a white solid. m/z (ES+) 248.0 (M+H) ⁺ .

Compound 202.2. Methyl 4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoate. Methyl 5-carbamoyl-4-cyclobutyl-2-methylbenzoate (compound 202.1, 59 mg, 0.24 mmol, 1.0 equivalent) and N,N-dimethylformamide dimethyl acetal (1 mL) were added to a vial. The mixture was heated at 80 °C for 5 hours, followed by removal of the solvent under vacuum. Acetic acid (400 μL) and a solution of anhydrous hydrazine (8.2 μL, 0.26 mmol, 1.1 equivalent) in acetic acid (100 μL) were added to the residue. Acetic acid (500 μL) was added to the resulting thick suspension, and the mixture was stirred at 80 °C for 1.5 hours, followed by removal of the solvent under vacuum. Ethyl acetate (5 mL) and DCM (5 mL) (containing some undissolved solids) were added. The organic matter was washed with saturated _NaHCO3 (10 mL) and brine (5 mL) and removed under vacuum to give the title compound as a white solid (theoretical yield). m/z(ES+)272(M+H) ⁺ .

Compound 202.3. 4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid. Methanol (1.5 mL), water (0.5 mL), and lithium hydroxide monohydrate (20 mg, 0.48 mmol, 2.0 equivalent) were added to a 4-mL vial of crude 4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoate from the previous step. The resulting mixture was stirred at 40 °C for 42 hours. The reaction mixture was diluted to water (5 mL), acidified to pH ₃ with 1 M _H₃PO₄ , and extracted with DCM (3 × 5 _mL ). The organic matter was dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum to give the title compound (61 mg, 98%, in 2 steps) as a white solid. m/z(ES+)258(M+H) ⁺ .

Compound 202. 4-(1-(4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. Add 4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid (compound 202.3, 31 mg, 0.12 mmol, 1.0 equivalent), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 27 mg, 0.12 mmol, 1.0 equivalent), 1-hydroxybenzotriazole hydrate (20 wt% water) (25 mg, 0.15 mmol, 1.25 equivalent), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg, 0.13 mmol, 1.1 equivalent), DMF (0.6 mL), and DIEA (83 μL, 0.48 mmol, 4 equivalent) to ₄ -mL vials. The mixture was stirred at room temperature for 4 hours, then diluted with ethyl acetate (10 mL) and washed with ₁ M NaH₂PO₄ (5 mL). The aqueous phase was back-extracted with ethyl acetate (3 mL), and the combined organic matter was washed with brine (5 mL), saturated _NaHCO3 (5 mL), and brine (5 _mL ). The organic matter was dried ( _Na2SO4 ), filtered, and removed under vacuum. The crude residue was purified by preparative TLC (DCM/8% MeOH) to give the title compound (23 mg, 46%) as a white solid. m/z (ES+) 426 (M+H) ⁺ .

Compound 203. 4-(1-(4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. Add 4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid (compound 202.3, 31 mg, 0.12 mmol, 1.0 equivalent), 4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 31 mg, 0.13 mmol, 1.1 equivalent), 1-hydroxybenzotriazole hydrate (20 wt% water) (25 mg, 0.15 mmol, 1.25 equivalent), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg, 0.13 mmol, 1.1 equivalent), DMF (0.6 mL), and DIEA (83 μL, 0.48 mmol, 4 equivalent) to ₄ -mL vials. The mixture was stirred at room temperature for 4 hours, then diluted with ethyl acetate (10 mL) and washed with 1 _M NaH₂PO₄ (5 mL). The aqueous phase was back-extracted with ethyl acetate (3 mL) _, and the combined organic matter was washed with brine (5 mL), saturated _NaHCO3 (5 mL), and brine (5 mL). The organic matter was dried ( _Na2SO4 ), filtered, and removed under vacuum. The crude residue was purified by preparative TLC (DCM/8% MeOH) to give the title compound (30 mg, 56%) as a white solid. m/z(ES+)444(M+H) ⁺ .

Compound 204.1.2, methyl 2,4-dibromobenzoate. A solution of 2,4-dibromobenzoic acid (52.0 g, 176 mmol, 1.00 equivalent, 95%) and sulfuric acid (20 mL) in methanol (400 mL) was stirred overnight at 90 °C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with 500 mL of ethyl acetate and washed successively with 3 × 100 mL of _H₂O and 1 × 100 mL of _NaHCO₃ (saturated aqueous solution; note: gas escape occurred). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This yielded 45.0 g (78%) of methyl 2,4-dibromobenzoate as a yellow oil.

Compound 204.2.2, methyl 4-diethylbenzoate. Under nitrogen atmosphere and at 0°C, EtMgBr (60 mL, 3 M in THF) was added dropwise to a stirred mixture of _ZnBr₂ (40.0 g, 176 mmol, 5.44 equivalents, 99%) in 100 mL of THF. After 0.5 hours at 0°C, the temperature was lowered to -78°C and _PdCl₂ (dppf) (3.72 g, 5.03 mmol, 0.16 equivalents, 99%) was added, followed by dropwise addition of methyl 2,4-dibromobenzoate (compound 204.1, 10.0 g, 32.3 mmol, 1.00 equivalents, 95%) in 200 mL of THF. The reaction mixture was stirred overnight at room temperature, followed by careful quenching sequentially with water and then with HCl (1 M aqueous solution). The mixture was extracted with 3 × 500 mL of ethyl acetate, and the combined organic layers were washed with 3 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:60) as the eluent to give 6.30 g (96%) of methyl 2,4-diethylbenzoate as a colorless oil.

Compound 204.3. Methyl 2,4-diethyl-5-iodobenzoate. The title compound (4.0 g, pale yellow oil, 69%) was prepared by using a similar procedure to that used to prepare compound 181.4, but instead of compound 181.3, using compound 204.2 (3.50 g).

Compound 204.4. 2,4-Diethyl-5-iodobenzoic acid. The title compound (3.24 g, white solid, 85%) was prepared by using a similar procedure to that used to prepare compound 181.9, but instead of compound 181.8, using compound 204.3 (4.00 g).

Compound 204.5. 2,4-Diethyl-5-(methoxycarbonyl)benzoic acid. At -78°C, under nitrogen, n-BuLi solution (1.73 mL, 4.10 mmol, 2.36 M in THF) was added dropwise to a stirred solution of 2,4-diethyl-5-iodobenzoic acid (compound 204.4, 500 mg 1.64 mmol, 1.00 equivalent, 90%) in tetrahydrofuran (20 mL). After 5 minutes, methyl chloroformate (0.315 mL, 4.10 mmol, 2.50 equivalent) in THF (5 mL) was added dropwise to the reaction at -78°C for another 5 minutes. The reaction was stirred at -78°C for another 5 minutes and then carefully quenched with 10 mL of water. The pH was adjusted to 1–2 with hydrochloric acid (6 M) and the resulting mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate-petroleum ether (1:20) as the eluent to give 96 mg (25%) of the title compound as a grayish-white solid.

Compound 204.6. Methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-diethylbenzoate. A solution of 2,4-diethyl-5-(methoxycarbonyl)benzoic acid (compound 204.5, 500 mg, 2.12 mmol, 1.00 equivalent), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 470 mg, 2.12 mmol, 1 equivalent), EDC·HCl (810 mg, 4.24 mmol, 2.00 equivalent), and 4-dimethylaminopyridine (520 mg, 4.24 mmol, 2 equivalent) in N,N-dimethylformamide (15 mL) was added to a round-bottom flask. The reaction mixture was stirred overnight at 25 °C. After the reaction was complete, the reaction mixture was diluted with 30 mL of ethyl acetate, followed by washing with 1 × 20 mL of _NH₄Cl (aqueous solution) and 1 × 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography using a solvent mixture of ethyl acetate and petroleum ether (1:1) to give 500 mg (60%) of the title compound as a pale yellow solid.

Compound 204.7. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-diethylbenzoylhydrazine. Hydrazine hydrate (3 mL) was added to a solution of compound 204.6 (500 mg, 1.05 mmol, 1.00 equivalent, 85%) in ethanol (6 mL). The resulting solution was stirred overnight at 90 °C. After cooling to ambient temperature, the mixture was concentrated under vacuum. The residue was diluted with 20 mL of ethyl acetate, washed with 1 × 5 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using dichloromethane-methanol (20:1) as the eluent to give 260 mg (55%) of the desired compound as a yellow solid.

Compound 204.8. 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-diethylbenzoylhydrazine (compound 204.7, 100 mg, 0.220 mmol, 1.00 equivalent, 90%) in a solvent mixture of water (2 mL) and dioxane (3 mL) was added to a round-bottom flask. Sodium bicarbonate (62 mg, 0.740 mmol, 3.00 equivalent) was added to the reaction mixture at room temperature and stirred for 5 minutes. BrCN (75 mg, 0.740 mmol, 3.00 equivalent) was then added to the reaction mixture at room temperature. The resulting solution was stirred at room temperature for 2 hours, then quenched with 30 mL of _FeSO₄ (saturated aqueous solution) and diluted with ethyl acetate. The resulting mixture was vigorously stirred, then filtered through diatomaceous earth and washed with 1M _FeSO₄ , water, and ethyl acetate. The separated layers were extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 100 mg (89%) of the title compound as a yellow solid. This compound was used in the next reaction step without further purification.

Compound 204.9. 4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzamide. A mixture of compound 204.8 (100 mg, 0.200 mmol, 1.00 equivalent, 85%) and potassium hydroxide (132 mg, 2.35 mmol, 10.0 equivalent) in ethanol (10 mL) was stirred overnight at 85 °C. After cooling to ambient temperature, the pH was adjusted to 7 with acetic acid and the resulting solution was concentrated under vacuum. The residue was diluted with 50 mL of ethyl acetate, washed with 2 × 20 mL of brine, and then concentrated under vacuum. The crude product was dried in a vacuum oven, then loaded onto a silica gel column and purified using dichloromethane-methanol (20:1) to give 100 mg (85%) of the title compound as a yellow solid.

Compound 204. 4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzamide (compound 204.9, 100 mg, 0.170 mmol, 1.00 equivalent) in 10 mL of dichloromethane was added to a round-bottom flask. Triethylamine (170 mg, 1.68 mmol, 8.00 equivalent) was added to the reaction mixture at room temperature, followed by dropwise addition of ( _CF3CO ) _2O (160 mg, 0.760 mmol, 4.50 equivalent) in 0.5 mL of dichloromethane at 0 to 5 °C. The resulting solution was stirred for another 2 hours at room temperature. The mixture was diluted with 60 mL of ethyl acetate and then washed with ₃ × 20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC (SunFire Prep C18, 19 × 150 mm, 5 μm, with water containing 0.05% TFA and CH3CN ( _CH3CN increased from 53.0% to 65.0% in 8 min, to 100.0% in 2 min, and decreased to 53.0% in 1 min). The fractions containing the pure compound were combined and lyophilized to give 50 mg (50%) of the title compound as a white solid. m/z (ES+) 458 (M+H) ⁺ . ¹ H NMR (300MHz, CD ₃ OD): δ7.63 (d, 2H), 7.45-7.30 (m, 4H), 4.89-4.80 (m, 1H, overlap), 4.36 (q, 2H), 3.60-3.57 (m, 1H), 3.29-3.23 (m, 1H), 3.19 -2.85(m, 4H), 2.74-2.56(m, 2H), 2.00-1.82(m, 1H), 1.77-1.66(m, 3H), 1.40(t, 3H), 1.30-1.21(m, 3H), 1.11(t, 3H).

Compound 205. 4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile (compound 204). m/z(ES+) 430(M+H) ⁺ . ^1H NMR (300MHz, _CD3 OD): δ 7.69 (d, 2H), 7.52–7.47 (m, 3H), 7.29 (s, 1H), 4.89–4.80 (m, 1H, overlapping), 4.42–4.40 (m, 2H), 3.64–3.61 (m, 1H), 3.02–2.96 (m, 2H), 2.51 (s, 3H), 2.41 and 2.31 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.05–2.02 (m, 1H), 1.77–1.46 (m, 3H), 1.45 (t, 3H).

Compound 206. 4-(1-(5-(5-(2-methoxyethoxy)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile (compound 204). m/z(ES+) 460(M+H) ⁺ .

Compound 207. 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)oxy)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile (compound 204). m/z(ES+)472(M+H) ⁺ . ^¹H NMR (300 MHz, _CD₃ OD): δ 7.69 (d, J = 6.0 Hz, 2H), 7.58–7.37 (m, 3H), 7.30 (br s, 1H), 5.40 (br s, 1H), approximately 4.9 (1H, partially obscured by water peak), 4.08–3.96 (m, 3H), 3.96–3.88 (m, 1H), 3.71–3.58 (m, 1H), 3.33–3.22 (m, 1H), 3.00 (t, with fine structure, J = 9.0 Hz, 2H), 2.52 (s, 3H), 2.42 and 2.32 (two singlets, amide rotational isomer, Ar-CH₃ ₎ , 3H), 2.38-2.20(m, 2H), 2.08-1.97(m, 1H), 1.93-1.55(m, 3H).

Compound 208. 4-(1-(2,4-diethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile (compound 204.8, 80.0 mg, 0.150 mmol, 1.00 equivalent, 80%) and potassium hydroxide (104 mg, 1.85 mmol, 10.00 equivalent) in methanol (10 mL) was added to a round-bottom flask. The resulting mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography using dichloromethane/methanol (20:1) as the eluent. The crude product (50 mg) was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19×150 mm, 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (40% _CH3CN to 64% within 8 min, to 100% within 1 min, and to 40% within 1 min); detector, Waters 2489254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 1.7 mg (3%) of the title compound as a white solid. m/z (ES+) 444 (M+H) ⁺ . ¹ H NMR (300MHz, CD ₃ OD): δ7.63 (d, J=5.7Hz, 2H), 7.45-7.30 (m, 4H), 4.85-4.80 (m, 1H), 4.02 (s, 3H), 3.65-3.62 (m, 1H), 3.15-3.10 (m, 1H), 2.90-2.84(m, 4H), 2.72-2.60(m, 2H), 2.02-2.00(m, 1H), 1.72-1.65(m, 3H), 1.30-1.25(m, 3H), 1.11(t, 3H).

Compound 209.1. 2,4-Diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic acid. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 198.6, but with methyl 2,4-diethyl-5-iodobenzoate (compound 204.3) instead of compound 198.2 as the starting material.

Compound 209.4-(1-(2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. A solution of 2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic acid (compound 209.1, 300 mg, 0.940 mmol, 1.00 equivalent, 95%) in N,N-dimethylformamide (20 mL) was added to a round-bottom flask. 4-(piperidin-4-yl)benzonitrile hydrochloride (1.5 mg, 243 mg, 1.09 mmol, 1.10 equivalents), EDC·HCl (380 mg, 1.98 mmol, 2.00 equivalents), and 4-dimethylaminopyridine (240 mg, 1.96 mmol, 2.09 equivalents) were added to the reaction mixture. The resulting solution was stirred overnight at room temperature and then diluted with 100 mL of ethyl acetate. The organic layer was washed with 3 × 15 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate as the eluent. The crude product (300 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19×150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN ( _CH3CN increased from 35% to 60% in 8 min, to 100% in 1 min, and decreased to 35% in 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 188 mg (42%) of the title compound as a white solid. m/z (ES+) 472 (M+H) ⁺ .

Compound 210. 4-(1-(2,4-diethyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 209), but using tetrahydrofuran-3-carboxylhydrazide (compound 38.2) instead of 3-methoxypropionylhydrazide (compound 143.1). m/z (ES+) 484.05 (M+H) ⁺ .

Compound 211.2. Methyl 2-ethyl-5-iodo-4-methylbenzoate. A solution of methyl 2-ethyl-4-methylbenzoate (compound 48.1, 12.5 g, 70.1 mmol, 1.00 equivalent) in 100 mL AcOH was added to a round-bottom flask. _NaIO₄ (7.51 g, 35.1 mmol, 0.50 equivalent) and _I₂ (21.4 g, 84.3 mmol, 1.20 equivalent) were added dropwise at 25 °C. Sulfuric acid (1.60 g, 16.3 mmol, 0.20 equivalent) was then added dropwise to the reaction mixture at 25 _° C. The resulting solution was stirred in an oil bath at 110 °C for 12 hours and then cooled to ambient temperature. The reaction was quenched with 150 mL _{of Na₂S₂O₃} (saturated aqueous solution). The aqueous phase was extracted with 2 × 200 mL of ethyl acetate. The combined organic layers were washed with 3 × 300 mL of sodium bicarbonate (aqueous solution) and 1 × 150 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This yielded 20.0 g (94%) of methyl 2-ethyl-5-iodo-4-methylbenzoate as a yellow oil.

Compound 211.3. 2-Ethyl-5-iodo-4-methylbenzoic acid. A solution of methyl 2-ethyl-5-iodo-4-methylbenzoate (compound 211.2, 10.0 g, 32.9 mmol, 1.00 equivalent) in methanol (40 mL) was added to a round-bottom flask. A solution of NaOH (5.26 g, 132 mmol, 4.00 equivalent) in water (20 mL) was added dropwise. After stirring at 40 °C for 12 hours, the organic solvent was removed under reduced pressure. The pH of the remaining aqueous phase was adjusted to 4 with hydrogen chloride (aqueous solution, 6 M), followed by extraction with 2 × 100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This yielded 9.30 g (97%) of 2-ethyl-5-iodo-4-methylbenzoic acid as a white solid.

Compound 211.4. 2-Ethyl-5-formyl-4-methylbenzoic acid. n-BuLi (17 mL, 2 M in THF, 2.00 equivalence) was added dropwise to a stirred solution of 2-ethyl-5-iodo-4-methylbenzoic acid (compound 211.3, 5.00 g, 17.2 mmol, 1.00 equivalence) in tetrahydrofuran (100 mL) at -78 °C under nitrogen atmosphere. After 1 hour at -78 °C, DMF (7.00 g, 95.8 mmol, 3.00 equivalence) was added dropwise at -78 °C. The resulting solution was slowly heated to 25 °C, then carefully quenched with water, followed by the addition of 10 mL of HCl (aqueous solution, 6 M). The aqueous phase was extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (2:1) as the eluent to give 450 mg (14%) of 2-ethyl-5-formyl-4-methylbenzoic acid as a yellow solid.

Compound 211.5. 4-(1-(2-ethyl-5-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4, 450 mg, 2.34 mmol, 1.00 equivalent) in N,N-dimethylformamide (5 mL) was added to a round-bottom flask. DIEA (907 mg, 7.02 mmol, 3.00 equivalent) and HBTU (1.30 g, 3.43 mmol, 1.50 equivalent) were added to the reaction mixture. The resulting solution was stirred at 25 °C for 30 minutes. A solution of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 624 mg, 2.80 mmol, 1.20 equivalent) in DIEA (2 mL) was added dropwise. The resulting solution was stirred at 25 °C for 30 minutes, then quenched with 20 mL of water. The aqueous phase was extracted with 3 × 30 mL of ethyl acetate. The combined organic layers were washed with 1 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (5:1) as the eluent to give 720 mg (85%) of the title compound as a yellow solid.

Compound 211.6. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-4-ethyl-2-methylbenzoic acid. A solution of 4-(1-(2-ethyl-5-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 211.5, 720 mg, 2.00 mmol, 1.00 equivalent) in tetrahydrofuran (20 mL) was added dropwise. A solution of _KMnO₄ (640 mg, 4.05 mmol, 2.00 equivalent) in water (20 mL) was added dropwise. The resulting solution was stirred at 60 °C for 15 hours, then cooled to room temperature in a water bath. The solid was removed by filtration. The filtrate was extracted with 3 × 30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This produces 600 mg (80%) of 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-4-ethyl-2-methylbenzoic acid as a pale yellow solid.

Compound 211.7. Methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-4-ethyl-2-methylbenzoate. A solution of 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-4-ethyl-2-methylbenzoic acid (compound 211.6, 600 mg, 1.59 mmol, 1.00 equivalent) in methanol (30 mL) was added to a round-bottom flask. Sulfuric acid (500 mg, 5.10 mmol, 3.20 equivalent) was added dropwise. The resulting solution was stirred at 60 °C for 15 hours. After cooling to ambient temperature, the mixture was concentrated under vacuum. The residue was diluted with 20 mL of _H₂O . The aqueous phase was extracted with 3 × 20 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This produces 500 mg (80%) of methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-4-ethyl-2-methylbenzoate in a yellow oil.

Compound 211.8. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-4-ethyl-2-methylbenzoylhydrazine. A solution of methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-4-ethyl-2-methylbenzoate (compound 211.7, 500 mg, 1.28 mmol, 1.00 equivalent) in ethanol (20 mL) was added to a round-bottom flask. Hydrazine (4 mL) was added to the reaction mixture. The resulting solution was stirred at 80 °C for 15 hours, followed by concentration under vacuum. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give 400 mg (80%) of 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-4-ethyl-2-methylbenzoylhydrazine as a pale yellow solid.

Compound 211.9.N-(morpholine-4-thiocarbonyl)benzamide. A solution of morpholine (1.00 g, 11.5 mmol, 1.00 equivalent) in acetone (10 mL) was added to a 50 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. TEA (1.74 g, 17.2 mmol, 1.50 equivalent) was added to the reaction mixture, and the resulting solution was stirred at 25 °C for 30 min. Benzoyl isothiocyanate (1.87 g, 11.5 mmol, 2.00 equivalent) was added dropwise to the reaction mixture at 0 °C. The resulting solution was stirred at 0 °C for 30 min, followed by quenching with 20 mL of water. The mixture was extracted with 2 × 30 _mL of ethyl acetate. The combined organic layers were dried ( _Na₂SO₄ ) and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:10-1:3) as the eluent to give 2.30 g (80%) of N-(morpholine-4-thiocarbonyl)benzamide as a yellow solid.

Compound 211.10. Morpholine-4-thiocarboxamide. A solution of N-(morpholine-4-thiocarbonyl)benzamide (compound 211.9, 3.00 g, 12.0 mmol, 1.00 equivalent) in methanol (20 mL) was added to a round-bottom flask. A solution of sodium hydroxide (1.44 g, 36.0 mmol, 3.00 equivalent) in water (20 mL) was added to the reaction mixture. The resulting solution was stirred overnight at 60 °C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residue was extracted with 2 × 20 mL ethyl acetate/petroleum ether (1:1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This yielded 430 mg (25%) of morpholine-4-thiocarboxamide as a yellow solid.

Compound 211.11. 4-(methylthioalkyl)carboimide morpholine. A solution of morpholine-4-thiocarboxamide (compound 211.10, 430 mg, 2.94 mmol, 1.00 equivalent) and iodomethane (1.25 g, 8.81 mmol, 3.00 equivalent) in tetrahydrofuran (10 mL) was stirred at 25 °C for 4 hours, followed by concentration under vacuum. This yielded 471 mg (100%) of 4-(methylthioalkyl)carboimide morpholine as a yellow solid.

Compound 211. 4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. A solution of 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-4-ethyl-2-methylbenzoylhydrazine (compound 211.8, 225 mg, 0.580 mmol, 1.00 equivalent) in pyridine (10 mL) was added to a 20 mL sealed tube. 4-(methanesulfonyl)carbamoimide morpholine (compound 211.11, 200 mg, 1.25 mmol, 1.00 equivalent) was added to the reaction mixture. The resulting solution was stirred at 100 °C for 3 days after being shielded from explosion. After cooling to room temperature, the mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography using chloroform/methanol (30:1) as the eluent. The crude product (approximately 100 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, Xbridge Prep C18, 5 _{μm, 19 × 150 mm; mobile phase, water containing 0.03% NH₃H₂O and CH₃CN (CH₃CN increased from 32} % to 55% within 8 min, to 100% within 2 min, and decreased to 32% within 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 67.7 mg (24%) of the title compound as a white solid. m/z (ES+) 485 (M+H) ^⁺ . ¹ H-NMR (300MHz, CD ₃ OD): δ7.69 (d, 2H), 7.49-7.31 (m, 4H), 4.90-4.80 (m, 1H), 3.83-3.81 (m, 4H), 3.79-3.65 (m, 1H), 3.60-3.41 (m, 4H), 3.40- 3.31 (m, 1H), 3.08-2.97 (m, 2H), 2.76-2.71 (m, 2H), 2.51 (s, 3H), 2.02-1.98 (m, 1H), 1.85-1.80 (m, 3H), 1.33-1.30 (m, 3H).

Compound 212. 4-(1-(5-(5-(((2-methoxyethyl)(methyl)amino)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 211). m/z(ES+)473(M+H) ⁺ .

Compound 213. 4-(1-(2,4-dimethyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 211). m/z(ES+)471(M+H) ⁺ .

Compound 214. 4-(1-(2,4-dimethyl-5-(5-(pyrrolidin-1-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 211). m/z(ES+)455(M+H) ⁺ .

Compound 215.3. 4-Cyclobutyl-2-ethyl-5-iodobenzoic acid. A solution of methyl 4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 10.3 g, 30.0 mmol, 1.00 equivalent) in methanol (100 mL) was added to a round-bottom flask. A solution of sodium hydroxide (3.60 g, 3.00 equivalent) in water (10 mL) was added dropwise to the stirred reaction mixture. The resulting mixture was stirred at 60 °C for 2 hours. After cooling to ambient temperature, the volatiles were removed under reduced pressure. The pH of the remaining aqueous mixture was adjusted to approximately 4 using HCl (aqueous solution, 1 M). The resulting precipitate was collected by filtration and dried to give 9.00 g (91%) of 4-cyclobutyl-2-ethyl-5-iodobenzoic acid as a white solid.

Compound 215.4. 4-Cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid. n-BuLi (2.5 M, 9.50 mL, 2.38 equivalents) was added dropwise to a solution of 4-cyclobutyl-2-ethyl-5-iodobenzoic acid (compound 215.3, 3.30 g, 10.0 mmol, 1.00 equivalents) in THF (40 mL) at -78 °C under a nitrogen atmosphere. The resulting solution was stirred at the same temperature for another 20 minutes, followed by dropwise addition of dimethyl carbonate (2.70 g, 30.0 mmol, 3.00 equivalents) in tetrahydrofuran (2 mL). The reaction temperature was slowly increased to 25 °C and stirred for another 1 hour, followed by slow quenching with 50 mL of water. The pH was adjusted to approximately 4 with HCl (aqueous solution, 1 M), and the mixture was extracted with 100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:3) as the eluent to obtain 1.80 g (69%) of the desired product as a white solid.

Compound 215.5. Methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate. A solution of 4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4, 1.15 g, 4.38 mmol, 1.00 equivalent), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.07 g, 4.80 mmol, 1.10 equivalent), HBTU (2.50 g, 6.59 mmol, 1.50 equivalent), and DIEA (1.07 g, 8.28 mmol, 3.00 equivalent) in N,N-dimethylformamide (10 mL) was added to a round-bottom flask. The resulting solution was stirred at 25 °C for 1 hour. The reaction was then quenched by adding 20 mL of water. The resulting mixture was extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:3) to give 1.80 g (95%) of methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate as a yellow solid.

Compound 215.6. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-ethylbenzoylhydrazine. Hydrazine hydrate (80%, 15 mL) was added batch-wise to a solution of methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate (compound 215.5, 2.15 g, 4.99 mmol, 1.00 equivalent) in methanol (20 mL). The reaction was stirred overnight at 80 °C. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane (2 × 100 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography with dichloromethane/methanol (100:1) to give 1.13 g (53%) of the desired product as a pale pink solid.

Compound 215.7. 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile. To a solution of 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-ethylbenzoylhydrazine (compound 215.6, 600 mg, 1.39 mmol, 1.00 equivalent) in 1,4-dioxane (10 mL), 10 mL of an aqueous solution of sodium bicarbonate (350 mg, 4.17 mmol, 1.00 equivalent) was added. Cyanogen bromide (220 mg, 2.08 mmol, 1.50 equivalent) was added dropwise to the reaction mixture. The reaction mixture was stirred at 25 °C for 2 hours, then quenched with 20 mL of _FeSO₄ (saturated aqueous solution) and diluted with DCM. The resulting mixture was vigorously stirred, then filtered through diatomaceous earth and washed with 1M _FeSO₄ , water, and ethyl acetate. The separated layers were extracted with 2 × 50 mL DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This yielded 600 mg (95%) of 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile as a grayish-white solid.

Compound 215.8. 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide. A solution of 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile (compound 215.7, 228 mg, 0.500 mmol, 1.00 equivalent) in ethanol (5 mL) was added to a 10 mL sealed tube purged and maintained under an inert nitrogen atmosphere. Potassium hydroxide (280 mg, 4.99 mmol, 10.0 equivalent) was then added in portions. The resulting solution was stirred at 80 °C for 5 hours after being shielded from explosion. After cooling to ambient temperature, the reaction was quenched with 15 mL of water and extracted with 2 × 20 mL of ethyl acetate. The combined organic layers were dried with anhydrous sodium sulfate and concentrated under vacuum. This yielded 200 mg (80%) of 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide as a yellow solid.

Compound 215.4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile. A solution of compound 215.8 (251 mg, 0.500 mmol, 1.00 equivalent) in dichloromethane (5 mL) was added to a round-bottom flask. Then, ( _CF3CO ) _2O (158 mg, 1.50 equivalent) was added dropwise with stirring. Triethylamine (101 mg, 1.00 mmol, 2.00 equivalent) was added dropwise with stirring. The resulting mixture was stirred at 25 °C for 1 h, followed by concentration under vacuum. The residue was purified by silica gel column chromatography using dichloromethane/methanol (20:1) as the eluent. The crude product (120 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire PrepC18, 19×150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN ( _CH3CN increased from 54.0% to 64.0% in 6 min, to 100.0% in 1 min, and decreased to 54.0% in 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 60 mg (25%) of the title compound as a white solid. m/z (ES+) 484 (M+H) ⁺ . ¹ H-NMR (300MHz, CD ₃ OD): δ7.64 (d, 2H), 7.45-7.21 (m, 4H), 4.37 (q, 2H), 4.02-3.96 (m, 1H), 3.60-3.53 (m, 1H), 3.29-3.19 (m, 2H), 2.98-2.9 0 (m, 2H), 2.76-2.61 (m, 2H), 2.15-2.12 (m, 2H), 2.07-1.92 (m, 4H), 1.80-1.68 (m, 4H), 1.35 (t, 3H), 1.29-1.20 (m, 3H).

Compound 216. 4-(1-(4-cyclobutyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile (compound 215). m/z (ES+) 470 (M+H) ⁺ . ^1H -NMR (300MHz, _CD3OD ): δ 7.64 (d, 2H), 7.45–7.38 (m, 3H), 7.32 and 7.21 (two singlets, amide rotational isomer, 1H), 4.0 (s, 3H), 4.00–3.95 (m, 1H), 3.63–3.56 (m, 1H), 3.29–3.19 (m, 2H), 2.98 (app t, 2H), 2.76–2.61 (m, 2H), 2.17–1.89 (m, 6H), 1.80–1.64 (m, 4H), 1.32–1.20 (m, 3H).

Compound 217.1. Methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate. A solution of 4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4, 70.0 mg, 0.270 mmol, 1.00 equivalent) in N,N-dimethylformamide (5 mL) was added to a round-bottom flask. HBTU (210 mg, 0.550 mmol, 2.07 equivalent) and DIEA (150 mg, 1.16 mmol, 4.35 equivalent) were added to the reaction mixture at 0 °C, and the mixture was stirred for 30 minutes. Subsequently, 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2 hydrochloride, 80.0 mg, 0.330 mmol, 1.20 equivalent) was added. The resulting solution was stirred at 25°C for 15 hours and then quenched with 20 mL of ice water. The mixture was extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were washed with 1 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:100–1:5) as the eluent to give 100 mg (84%) of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate as a white solid.

Compound 217.2. 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoylhydrazine. A solution of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate (compound 217.1, 1.10 g, 2.45 mmol, 1.00 equivalent) in ethanol (40 mL) was added to a round-bottom flask. Hydrazine hydrate (20 mL) was added to the reaction mixture, and the mixture was stirred at 80 °C for 15 h. After cooling to ambient temperature, the mixture was concentrated under vacuum and then diluted with 50 mL _H₂O . The resulting mixture was extracted with 3 × 50 mL dichloromethane. The combined organic layers were washed with 2 × 50 mL brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:1-1:0) as the eluent to give 900 mg (82%) of 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoylhydrazine as a white solid.

Compound 217.3. 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. A solution of 5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-cyclobutyl-4-ethylbenzoylhydrazine (compound 217.2, 450 mg, 1.00 mmol, 1.00 equivalent) in 1,4-dioxane (10 mL) was added to a round-bottom flask. A solution of sodium bicarbonate (252 mg, 3.00 mmol, 2.99 equivalent) in water (10 mL) and BrCN (128 mg, 1.21 mmol, 1.20 equivalent) were added to the reaction mixture. The resulting solution was stirred at room temperature for 3 hours, then quenched with ₃₀ mL of FeSO4 (saturated aqueous solution) and diluted with ethyl acetate. The resulting mixture was vigorously stirred, then filtered through diatomaceous earth and washed with 1M _FeSO₄ , water, and ethyl acetate. The separated layers were then extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 400 mg (84%) of 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile as a light brown solid.

Compound 217. 4-(1-(4-cyclobutyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. A solution of 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile (compound 217.3, 200 mg, 0.420 mmol, 1.00 equivalent) in methanol (20 mL) was added to a round-bottom flask purged and maintained under a nitrogen atmosphere. Potassium hydroxide (237 mg, 4.22 mmol, 10.0 equivalent) was added to the reaction mixture. The resulting solution was stirred at 70 °C for 15 hours. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residue was diluted with 30 mL of _H₂O and then extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (50 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH₃CN (49.0% _CH₃CN increased to 63.0% within 8 min, to 100.0% within 1 min, and decreased to 49.0% within 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 20 mg (10%) of the title compound as a white compound. m/z (ES+) 488 (M+H) ⁺ . ¹ H-NMR (300MHz, CD ₃ OD): δ7.72 (d, 2H), 7.64-7.61 (m, 2H), 7.39-7.25 (m, 2H), 4.85-4.78 (m, 1H), 4.00-3.93 (m, 4H), 3.54-3.49 (m, 2H), 3.28-3.22 (m, 1H), 2.80-2.65 (m, 2H), 2.26-1.84 (m, 10H), 1.45-1.27 (m, 3H).

Compound 218. 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile (compound 215), with the hydrochloride of compound 11.2 used instead of compound 1.5. m/z (ES+) 502[M+H] ⁺ , 543[M+ _CH3CN +H] ⁺ . ¹ H-NMR (300MHz, CD ₃ OD): δ7.73 (d, 2H), 7.64-7.58 (m, 2H), 7.39-7.26 (m, 2H), 4.89-4.82 (m, 1H), 4.35 (q, 2H), 4.10-3.95 (m, IH), 3.50-3.38(m, 2H), 3.30-3.27(m, 1H), 2.75-2.65(m, 2H), 2.22-1.86(m, 10H), 1.41(t, 3H), 1.35-1.20(m, 3H).

Compound 219.1 Methyl 2-bromo-4-methylbenzoate. Concentrated sulfuric acid (10 ml) was added dropwise to a solution of 2-bromo-4-methylbenzoic acid (10 g) in MeOH (50 ml) at 0 °C. The mixture was heated at 70 °C for 2 hours. After cooling to ambient temperature, methanol was removed under reduced pressure. The residue was poured into ice water (100 ml). The mixture was extracted with EtOAc (×2). The combined organic layers were washed with _NaHCO3 (saturated aqueous solution; note: gas escape), brine, dried over _MgSO4 , filtered, and concentrated to give a clear, oily product. Yield: 10.5 g, 99%. ^¹H NMR (400 MHz, chloroform-d) δ 7.73 (d, 1H), 7.50 (d, 1H), 7.19–7.11 (m, 1H), 3.92 (s, 3H), 2.36 (s, 3H).

Compound 219.22-Cyclobutyl-4-methylbenzoate. Cyclobutylzinc bromide(II) (50 mL, 0.5 M in THF, 25.0 mmol) was added to a mixture of methyl 2-bromo-4-methylbenzoate (219.1, 5.0 g, 21.8 mmol) _{and PdCl₂} (dppf) _CH₂Cl₂ (1.78 g, 2.20 mmol). The mixture was degassed and flasks were filled with argon via a gasket. The mixture was heated at 65 °C for 24 hours under argon, then cooled to 0 °C and quenched with water (10 mL). The mixture was diluted with EtOAc (200 mL) and washed successively with water and brine. The EtOAc layer was dried ( _Na₂SO₄ ), concentrated, and purified by column chromatography (silica gel) (hexane:EtOAc 30:1 to 20:1). Yield: 3.6 _g , 81%. ^¹H NMR (400 MHz, chloroform-d) δ 7.68 (d, 1H), 7.23–7.17 (s, 1H), 7.03 (d, 1H), 4.16 (m, 1H), 3.86 (s, 3H), 2.39 (s, 3H), 2.34 (m, 2H), 2.16–1.96 (m, 3H), 1.80 (m, 1H).

Compound 219.3, methyl 2-cyclobutyl-5-iodo-4-methylbenzoate. N-iodosuccinimide (5.25 g, 23.3 mmol) was added fractionally to a solution of methyl 2-cyclobutyl-4-methylbenzoate (219.2 g, 4.77 g, 23.3 mmol) in concentrated sulfuric acid (100 ml) at 0 °C. The mixture was stirred at 0 °C for 30 min and then at room temperature for 2 hours until it became very viscous. The mixture was then cooled to 0 °C and MeOH (100 ml) was added. The mixture was heated at 60 °C for 2 hours. Methanol was removed under reduced pressure, and the residue was poured into ice water (200 ml). The mixture was extracted with EtOAc (2×). The combined organic layers were washed successively with brine and _1N NaHCO3 aqueous solution, dried ( _Na2SO4 ), and _concentrated . The residue was purified by column (silica gel) chromatography (hexane:EtOAc 30:1 to 20:1). Yield: 5.0 g, clear oil, 65%. ^¹H NMR (400 MHz, chloroform-d) δ 8.19 (s, 1H), 7.24 (s, 1H), 4.17–4.04 (m, 1H), 3.86 (s, 3H), 2.48–2.44 (s, 3H), 2.40–2.28 (m, 2H), 2.13–1.92 (m, 3H), 1.85–1.75 (m, 1H).

Compound 219.4 methyl 5-cyano-2-cyclobutyl-4-methylbenzoate. A mixture of methyl 2-cyclobutyl-5-iodo-4-methylbenzoate (219.3, 3.0 g, 9.1 mmol), Zn(CN)₂ (2.3 g, 19.6 mmol), and Pd( _PPh₃ ) _₄ (0.55 g, 0.47 mmol) in DMF (50 mL) was degassed and passed through a gasket filled with argon. The mixture was heated overnight at 100 °C under argon atmosphere. After cooling to ambient temperature, the reaction was quenched with a saturated aqueous solution of _FeSO₄ (20 mL) and diluted with EtOAc (200 mL). The mixture was vigorously stirred, then filtered through diatomaceous earth and washed with 1 M _FeSO₄ , water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, _dried ( _Na₂SO₄ ), and concentrated. The residue was purified by column (silica gel) chromatography (hexane:EtOAc 30:1 to 20:1). Yield: 2.0 g, 96%. ^¹H NMR (400 MHz, chloroform-d) δ 8.03 (s, 1H), 7.34 (s, 1H), 4.26–4.13 (m, 1H), 3.89 (s, 3H), 2.59 (s, 3H), 2.46–2.32 (m, 2H), 2.16–1.98 (m, 3H), 1.90–1.78 (m, 1H).

Compound 219.5. 5-Cyano-2-cyclobutyl-4-methylbenzoylhydrazine. Anhydrous hydrazine (2 ml, excess) was added to a solution of methyl 5-cyano-2-cyclobutyl-4-methylbenzoate (219.4, 2.0 g, 8.73 mmol) in EtOH (10 ml) at room temperature. The mixture was heated overnight at 90 °C. After cooling to ambient temperature, the mixture was partitioned between water (60 ml) and EtOAc (200 ml). The EtOAc layer was washed with water (×2) and brine, dried over _Na₂SO₄ and concentrated to give a product as a white solid. Yield: 1.9 g, 95%. m/z (ES+) 230 ( _M +H) ⁺ . ^¹H NMR (400 MHz, chloroform-d) δ 7.52 (s, 1H), 7.32 (s, 1H), 6.91 (br, 1H), 4.08 (br, 2H), 3.89 (m, 1H), 2.61–2.52 (m, 3H), 2.42–2.28 (m, 2H), 2.18–1.98 (m, 3H), 1.91–1.78 (m, 1H).

Compound 219.6. 5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile. The title compound (0.55 g, white solid, 100%) was prepared using a similar procedure to that used to prepare compound 217.3, but with compound 219.5 (0.50 g) instead of compound 217.2. m/z (ES+) 255 (M+H) ⁺ . ^1H NMR (400 MHz, chloroform-d) δ 7.93 (s, 1H), 7.45 (s, 1H), 5.10 (br, 2H), 4.38 (m, 1H), 2.61 (s, 3H), 2.48–2.34 (m, 2H), 2.17–1.98 (m, 3H), 1.91–1.79 (m, 1H).

Compound 219.7. 4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile. KOH (1.11 g, 20.0 mmol) was added to a solution of 5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile (219.6, 0.5 g, 2.0 mmol) in EtOH (40 mL ₎ . The mixture was heated overnight at 85 °C. After cooling to ambient temperature, the mixture was neutralized to pH 7 with 1 N HCl at 0 °C and subsequently extracted with EtOAc (×2). The combined organic layers were dried ( _Na₂SO₄ ) and concentrated. The residue was purified by column chromatography (silica gel) (hexane:EtOAc 1:1 to EtOAc). Yield: 0.2 g, white solid, 34%. m/z(ES+)283(M+H) ⁺ 。 ¹ H NMR (400MHz, chloroform-d) δ 7.84(s, 1H), 7.35(s, 1H), 4.48(t, 2H), 4.19-4.10(m, 1H), 2.58(s, 3H), 2.30-2.19(m, 2H), 2.11-1.95(m, 3H), 1.85-1.76(m, 1H), 1.45(t, 3H).

Compound 219.8. 4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide. _NH₄OH (0.18 ml, 2.66 mmol, 14.8 N in _H₂O ) was added to a solution of 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile (219.7, 0.15 g, _{0.53 mmol} ) in EtOH (10 ml), followed by the addition _{of H₂O₂} (1.8 ml, 26.6 mmol, 50% in _H₂O ). The mixture was stirred overnight at room temperature. The mixture was cooled to 0 °C and carefully quenched with 1 N _{Na₂S₂O₃} solution (26 ml). The mixture was extracted with EtOAc (×2), and the combined organic layers were dried over _Na₂SO₄ , _filtered , and concentrated. The residue was purified by preparative TLC ( _CH₂Cl₂ containing 5% _MeOH ). Yield: 0.1 g, white solid, 62.5%. m/z (ES-) 299 (MH) ^- .

Compound 219.9. 4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. _NaNO₂ (0.046 g, 0.66 mmol) was added to a solution of 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide (219.8, 0.1 g, 0.33 mmol) in TFA (5 ml) at 0 °C. The mixture was stirred at 0 °C for 14 hours, followed by stirring at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc. The combined organic layers were dried ( _Na₂SO₄ ) and concentrated to give a clear oil. Yield: 0.1 g, 100%. _m /z (ES-) 300 (MH) ^- .

Compound 219. 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 219.9, 40 mg, 0.13 mmol), DIEA (0.07 mL, 0.39 mmol), HOBT (34 mg, 0.19 mmol, containing 20% water), EDCI (38 mg, 0.19 mmol), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 36 mg, 0.16 mmol) in N,N-dimethylformamide (3 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with 50 mL of ethyl acetate and washed with 2 × 20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was coated onto a silica gel preparative TLC plate and developed using ethyl acetate/hexane (1:1) to give 0.1 g (68%) of the title compound as a white solid. m/z (ES+) 470 (M+H) ⁺ .

Compound 220. 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used in the preparation of 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 219), with compound 11.2 hydrochloride substituted for compound 1.5. m/z(ES+)488(M+H) ⁺ . ^1H NMR (400MHz, _CDCl3 ): δ 11.10 (br s, 1H), 7.72–7.63 (m, 2H), 7.47 (d, J = 8.4Hz, 2H), 7.42 and 7.33 (two singlets, amide rotational isomer, Ar-H, 1H), 7.25 (s, 1H), 4.86 (brd, J = 11.2Hz, 1H), 4.41 (q, J = 7.1Hz, 2H), 4.17–4.03 (m, 1H), 3.61–3.38 (m, 2H), 3.29–3.14 (m, 1H), 2.46–1.70 (m, 13H), 1.45 (t, J = 7.2Hz, 3H).

Compound 221. (4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-fluoro-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl) methyl ketone. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 219). m/z(ES+)531(M+H) ⁺ .

Compound 222.1. 4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile (compound 219.7), but with MeOH used instead of EtOH as the solvent. m/z(ES+) 269(M+H) ⁺ . ^¹H NMR (400 MHz, chloroform-d) δ 10.96 (br, ¹H), 7.82 (s, ¹H), 7.35 (s, ¹H), 4.11 (s, ³H), 4.15–4.05 (m, ¹H), 2.59 (s, ³H), 2.31–2.16 (m, ²H), 2.14–1.89 (m, ³H), 1.87–1.71 (m, ¹H).

Compound 222.2. 4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide. The title compound was prepared using standard chemical procedures and a similar procedure to that used for the preparation of 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide (compound 219.8), but using compound 222.1 instead of compound 219.7. m/z(ES+)287(M+H) ⁺ . ^1H NMR (400MHz, methanol-d4) δ 7.50 (s, 1H), 7.33 (s, 1H), 4.03 (s, 3H), 3.95–4.05 (m, 1H), 2.51 (s, 3H), 2.23–2.11 (m, 2H), 2.11–1.88 (m, 3H), 1.83–1.71 (m, 1H).

Compound 222.3. 4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 219.9), but using compound 222.2 instead of compound 219.8. m/z(ES+)287(M+H) ⁺ .

Compound 222. 4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 222.3, 60 mg, 0.21 mmol), DIEA (0.11 mL, 0.63 mmol), HOBT (53 mg, 0.32 mmol, containing 20% water), EDCI (60 mg, 0.32 mmol), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 47 mg, 0.21 mmol) in N,N-dimethylformamide (3 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with 50 mL of ethyl acetate and washed with 2 × 20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was coated onto a silica gel preparative TLC plate and developed using ethyl acetate/hexane (1:1) to give 21.0 mg (22%) of the title compound as a white solid. m/z (ES+) 456 (M+H) ⁺ . ^¹H NMR (400 MHz, chloroform-d) δ 11.54–10.86 (br s, 1H), 7.60 (d, 2H), 7.38–7.20 (m, 4H), 5.04–4.92 (m, 1H), 4.06 (s, 3H), 4.14–4.00 (m, 1H), 3.62 (d, 1H), 3.15–3.03 (m, 1H), 2.93–2.76 (m, 2H), 2.38 and 2.30 (two singlets, amide rotational isomer, _ArCH₃ , 3H), 2.34–2.22 (m, 1H), 2.20–2.06 (m, 2H), 2.05–1.84 (m, 3H), 1.61–1.45 (m, 1H).

Compound 223. 4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 222), but using compound 11.2 hydrochloride instead of compound 1.5. m/z(ES+)474(M+H) ⁺ .

Compound 224. (4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl ketone. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (222). m/z(ES+)499(M+H) ⁺ .

Compound 225. (4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-fluoro-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl) methyl ketone. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 222). m/z(ES+)517(M+H) ⁺ .

Compound 226.3. Methyl 4-cyclopropyl-2-ethylbenzoate. Magnesium bromo(cyclopropyl)methyl benzoate (3.28 M in THF, 50 mL, 4.00 equivalent) was added dropwise to a stirred mixture of _ZnBr₂ (37.0 g, 164 mmol, 3.99 equivalents) in tetrahydrofuran (150 mL) under nitrogen atmosphere at 0 °C. After stirring at 0 °C for 15 minutes, the temperature was lowered to -30 °C, and then a solution of Pd(dppf) _Cl₂ (2.00 g, 2.73 mmol, 0.07 equivalents) in tetrahydrofuran (50 mL) and a solution of methyl 4-bromo-2-ethylbenzoate (compound 181.2, 10.0 g, 41.1 mmol, 1.00 equivalents) in tetrahydrofuran (50 mL) were added dropwise. The resulting solution was slowly heated to 25°C and stirred for 15 hours, then carefully quenched by the slow addition of 100 mL of _NH₄Cl (saturated aqueous solution). The mixture was extracted with 2 × 100 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:30) as the eluent to give 7.50 g (89%) of methyl 4-cyclopropyl-2-ethylbenzoate as a pale yellow oil.

Compound 226.4. Methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate. A solution of methyl 4-cyclopropyl-2-ethylbenzoate (compound 226.3, 5.00 g, 24.5 mmol, 1.00 equivalent) in AcOH (40 mL) was added to a round-bottom flask. _I₂ (6.80 g, 26.8 mmol, 1.10 equivalent), _NaIO₄ (2.60 g, 12.2 mmol, 0.50 equivalent), and sulfuric acid (400 mg, 4.08 mmol, 0.15 equivalent) were added to the reaction mixture. The resulting solution was stirred at 50 °C for 2 hours. After cooling to ambient temperature, the reaction was carefully quenched with _{Na₂S₂O₃} (saturated aqueous solution). The mixture was extracted with ₂ × 100 mL of ethyl acetate, and the combined organic layers _were dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (20:1) as the eluent to give 4.00 g (49%) of methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate as a yellow oil.

Compound 226.5. 4-Cyclopropyl-2-ethyl-5-iodobenzoic acid. An aqueous solution of sodium hydroxide (3.10 g, 77.5 mmol, 10.0 equivalent in 10 mL of water) was added to a solution of methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate (compound 226.4, 2.50 g, 7.57 mmol, 1.00 equivalent) in methanol (40 mL). The resulting mixture was stirred in an oil bath at 60 °C for 15 hours. After cooling to ambient temperature, the organic solvent was removed under reduced pressure, and the pH of the remaining aqueous layer was adjusted to 4 with hydrogen chloride (aqueous solution, 1 M). The solid was collected by filtration and dried in an oven under reduced pressure to give 2.20 g (92%) of 4-cyclopropyl-2-ethyl-5-iodobenzoic acid as a white solid.

Compound 226.6. 4-Cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid. Under nitrogen atmosphere, n-butyllithium (2.5 M, 1.88 mL, 3.00 equivalent) was added dropwise to a solution of 4-cyclopropyl-2-ethyl-5-iodobenzoic acid (compound 226.5, 500 mg, 1.58 mmol, 1.00 equivalent) in THF/ _Et₂O (10/10 mL) over 3 minutes at -78 °C. After stirring at -78 °C for 10 minutes, methyl chloroformate (230 mg, 2.43 mmol, 1.50 equivalent) was added dropwise at -78 °C. The resulting solution was stirred at -78 °C for 40 minutes, followed by a slow warming to -35 °C. The reaction was carefully quenched with 2 mL of water. The pH was adjusted to approximately 4–5 with hydrogen chloride (aqueous solution, 1 M). The mixture was extracted with 3 × 20 mL of ethyl acetate, and the combined organic layers were dried ( _Na₂SO₄ ) and concentrated under reduced pressure to give 400 _mg of the title compound as a yellow solid.

Compound 226.7. Methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate. A solution of 4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 226.6, 150 mg, 0.600 mmol, 1.00 equivalent) in N,N-dimethylformamide (15 mL) was supplemented with 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2, 150 mg, 0.620 mmol, 1.00 equivalent), DIPEA (450 mg, 3.49 mmol, 6.00 equivalent), and HBTU (300 mg, 0.790 mmol, 1.30 equivalent). The resulting solution was stirred at 20 °C for 4 hours, followed by quenching with 20 mL of brine. The mixture was extracted with 4 × 30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:3) as the eluent. This yielded 0.200 g (76%) of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate as a pale yellow solid.

Compound 226.8. 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoylhydrazine. Hydrazine hydrate (80%, 5 mL) was added to a solution of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate (compound 226.7, 200 mg, 0.460 mmol, 1.00 equivalent) in ethanol (15 mL). The resulting solution was stirred at 80 °C for 15 hours. After cooling to ambient temperature, the reaction was quenched with 50 mL of water, followed by extraction with 3 × 50 mL of dichloromethane. The combined organic layers were dried with anhydrous sodium sulfate and concentrated under vacuum to give 150 mg (75%) of 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoylhydrazine as a colorless oil.

Compound 226.9. 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclopropyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound (50 mg, white solid, 95%) was prepared using a similar procedure to that used to prepare compound 217.3, but with compound 226.8 (50 mg) instead of compound 217.2.

Compound 226. 4-(1-(4-cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound (50 mg, white solid, 95%) was prepared using a similar procedure to that used to prepare compound 219.7, but with compound 226.9 (300 mg) instead of compound 219.6. The crude product (approximately 30 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire PrepC18, 19×150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (46.0% _CH3CN increased to 57.0% within 8 min, to 100.0% within 1 min, and decreased to 46.0% within 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 15 mg of the title compound as a white solid. m/z (ES+) 474 (M+H) ⁺ . ¹ H-NMR (300MHz, CD ₃ OD, ppm): δ7.73 (d, 2H), 7.65-7.57 (m, 2H), 7.46-7.32 (m, 1H), 7.03 (s, 1H), 4.85-4.73 (m, 1H), 4.00 (s, 3H), 3.48-3.32 (m, 2H), 3.2 8-3.21 (m, 1H), 2.71-2.62 (m, 2H), 2.28-2.14 (m, 2H), 2.10-1.80 (m, 3H), 1.28-1.20 (m, 3H), 0.97-0.94 (m, 2H), 0.75-0.50 (m, 2H).

Compound 227. 4-(1-(4-cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile (compound 226). m/z(ES+)488(M+H) ⁺ . ¹ H-NMR (300MHz, CD ₃ OD): δ7.80-7.78 (m, 2H), 7.70-7.63 (m, 2H), 7.51 (m, 1H), 7.07 (s, 1H), 4.89-4.82 (m, 1H), 4.40 (app t, 2H), 3.57-3.52 (m, 2H), 3.28-3.25 (m, 1H), 2.80-2.50 (m, 2H), 2.40-2.10 (m, 4H), 1. 95-1.80 (m, 1H), 1.45 (t, 3H), 1.32-1.22 (m, 3H), 1.01-0.99 (m, 2H), 0.73-0.73 (m, 2H).

Compound 228.1. Methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate. A solution of 4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 226.6, 500 mg, 2.01 mmol, 1.00 equivalent) in N,N-dimethylformamide (20 mL) was added to a round-bottom flask purged and maintained under a nitrogen atmosphere. HBTU (1.53 g, 4.03 mmol, 2.00 equivalent) and DIEA (780 mg, 6.04 mmol, 3.00 equivalent) were added to the reaction solution, and the mixture was stirred at 25 °C for 5 min. 4-(piperidin-4-yl)benzonitrile (compound 1.5, 410 mg, 2.20 mmol, 1.10 equivalent) was added to the mixture. After stirring at 25 °C for 15 hours, the reaction was quenched by adding water. The mixture was extracted with 100 mL of ethyl acetate, and the combined organic layers were washed with 4 × 40 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (4:1) as the eluent to give 0.830 g (99%) of methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate as a colorless oil.

Compound 228.2. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclopropyl-4-ethylbenzoylhydrazine. A solution of methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate (compound 228.1, 830 mg, 1.99 mmol, 1.00 equivalent) in ethanol (15 mL) was added to a round-bottom flask. Hydrazine (5 mL, 100 equivalent) was added to the reaction mixture. The resulting solution was stirred at 100 °C for 15 hours, followed by concentration under vacuum. The residue was extracted with 100 mL of dichloromethane, and the combined organic layers were washed with 1 × 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This produces 0.800 g (96%) of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoylhydrazine as a white solid.

Compound 228.3. 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclopropyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound (750 mg, light brown solid, 94%) was prepared using a similar procedure to that used to prepare compound 217.3, but with compound 228.2 (750 mg) substituted for compound 217.2.

Compound 228.4. 4-(1-(4-cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide. The title compound (80 mg, yellow solid, 36%) was prepared using a similar procedure to that used to prepare compound 219.7, but with compound 228.3 (200 mg) instead of compound 219.6.

Compound 228. 4-(1-(4-cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-(4-cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide (compound 228.4, 80.0 mg, 0.160 mmol, 1.00 equivalent) in dichloromethane (10 mL) was added to a round-bottom flask purged and maintained under a nitrogen atmosphere. Trifluoroacetic anhydride (34.0 mg, 0.160 mmol, 1.00 equivalent) and triethylamine (33.0 mg, 0.330 mmol, 2.00 equivalent) were added dropwise to the stirred mixture. The resulting solution was stirred at 25°C for 2 hours, followed by washing with 1×10 mL of brine. The aqueous layer was extracted with 2×20 mL of dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (30 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19×150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (42% _CH3CN increased to 57% within 8 min, to 100% within 1.5 min, and decreased to 42% within 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 15 mg (20%) of the title compound as a grayish-white solid. m/z (ES+) 470 (M+H) ⁺ . ^1H -NMR (300 MHz, CD3 ₎ OD, ppm): δ7.64 (d, 2H), 7.46-7.28 (m, 3H), 7.02-7.01 (m, 1H), 4.89-4.80 (m , 1H), 4.40-4.33(m, 2H), 3.58-3.56(m, 1H), 3.27-3.25(m, 1H), 3.04-2.90(m , 2H), 2.73-2.58(m, 2H), 2.31-2.29(m, 1H), 1.94-1.96(m, 1H), 1.82-1.78(m , 3H), 1.45 (t, 3H), 1.32-1.12 (m, 3H), 0.98-0.88 (m, 2H), 0.71-0.68 (m, 2H).

Compound 229. 4-(1-(4-cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 228. m/z(ES+)456(M+H) ⁺ . ¹ H-NMR (300MHz, CD ₃ OD, ppm): δ7.64 (d, 2H), 7.43-7.27 (m, 3H), 7.03-7.02 (m, 1H), 4.0 (s, 3H), 3.59-3.55 (m, 1H), 3.28-3.27 (m, 1H), 3.04-2.98 (m, 2H), 2.97-2.56(m, 2H), 2.53-2.29(m, 1H), 2.0-1.98(m, 1H), 1.76-1.42(m, 3H), 1.30-1.16(m, 3H), 0.99-0.94(m, 2H), 0.70-0.64(m, 2H).

Compound 230.1. 4-Cyclobutyl-5-iodo-2-methylbenzoic acid. Sodium hydroxide aqueous solution (12.7 g, 318 mmol, 3.00 equivalent in 100 mL of water) was added dropwise to a solution of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 152.3, 35.0 g, 106 mmol, 1.00 equivalent) in methanol (200 mL) at 0–5 °C. The resulting mixture was stirred at 60 °C for 3 hours. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The pH of the remaining aqueous phase was adjusted to approximately 4 with hydrogen chloride (aqueous solution, 2 M). The resulting solid was collected by filtration and dried in an oven under reduced pressure to give 31.0 g (93%) of the title compound as a white solid.

Compound 230.2. 4-Cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid. Under nitrogen atmosphere, n-BuLi (9.5 mL, 2.50 M, 2.5 M, in THF) was added dropwise to a solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 230.1, 3.00 g, 9.49 mmol, 1.00 equivalent) in THF (40 mL) at -78 °C. After 10 minutes, dimethyl carbonate (2.56 g, 28.4 mmol, 3.00 equivalent) was added dropwise to a solution of THF (10 mL) at -78 °C. The resulting solution was stirred at -78 °C for 1 hour, followed by careful quenching with the slow addition of 50 mL of water. The pH was adjusted to approximately 4 with hydrogen chloride (aqueous solution, 1 M). The resulting mixture was extracted with 2 × 80 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:10-1:2) as the eluent to give 1.30 g (55%) of 4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid as a white solid.

Compound 230.3. Methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylbenzoate. A solution of 4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid (compound 230.2, 2.10 g, 8.46 mmol, 1.00 equivalent) in N,N-dimethylformamide (10 mL) was added to a round-bottom flask. 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.88 g, 8.44 mmol, 1.00 equivalent), EDC·HCl (3.22 g, 16.8 mmol, 2.00 equivalent), and 4-dimethylaminopyridine (3.10 g, 25.4 mmol, 3.00 equivalent) were added to the reaction mixture. The resulting solution was stirred overnight at 25 °C and then diluted with 100 mL of ethyl acetate. The mixture was washed with 2 × 30 mL of _NH₄Cl (saturated aqueous solution) and 2 × 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (0:1–1:3) as eluent to give 3.20 g (91%) of methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylbenzoate as a white solid.

Compound 230.4. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylbenzoylhydrazine. The title compound (660 mg, white solid, 66%) was prepared using a similar procedure to that used to prepare compound 219.5, but with compound 230.3 (1.00 g) instead of compound 219.4.

Compound 230. 4-(1-(4-cyclobutyl-5-(5-ethyl-1,3,4-oxadiazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylbenzoylhydrazine (compound 230.4, 150 mg, 0.360 mmol, 1.00 equivalent) in dioxane (5 mL) was added to a round-bottom flask. MeSO₃⁻ _⇌ H₂ (7 mg, 0.07 mmol, 0.20 equivalent) and 1,1,1-triethoxypropane (190 mg, 1.08 mmol, 3.00 equivalent) were added to the reaction mixture. The resulting solution was stirred at 110 °C for 20 min, then cooled to room temperature and diluted with 50 mL of ethyl acetate. The organic layer was washed with 2 × 20 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19×150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN ( _CH3CN increased from 64.0% to 76.0% in 6 min, to 100.0% in 4 min, and decreased to 64.0% in 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 129 mg (79%) of the title compound as a white solid. m/z (ES+) 455 (M+H) ⁺ . ^1H -NMR (300MHz, _CD3OD , ppm): δ 7.73-7.67 (m, 3H), 7.52-7.48 (m, 3H), 5-4.94 (m, 1H), 4.25-4.20 (m, 1H), 3.60-3.58 (m, 1H), 3.33-3.24 (m, 1H), 3.05-2.97 (m, 4H), 2.49 and 2.30 (two singlets, amide rotational isomer, _CH3 , 3H), 2.39-2.34 (m, 2H), 2.19-1.91 (m, 4H), 1.88-1.66 (m, 4H), 1.49-1.42 (t, 3H).

Compound 231.1. Methyl 4-vinyl-2-methylbenzoate. A solution of methyl 4-bromo-2-methylbenzoate (compound 152.1, 14.0 g, 61.1 mmol, 1.00 equivalent) in N,N-dimethylformamide (150 mL) was added to a round-bottom flask purged and maintained under a nitrogen atmosphere. Tributyl(vinyl)stanane (29.3 g, 92.4 mmol, 2.00 equivalent) and Pd( _PPh3 ) ₄ (7.10 g, 6.14 mmol, 0.10 equivalent) were added to the reaction mixture. The resulting mixture was stirred overnight in an oil bath at 100 °C. After cooling to room temperature, the mixture was diluted with 400 mL of ethyl acetate. The organic layer was washed with 2 × 400 mL of _NH4Cl (aqueous solution) and 2 × 400 mL of brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The crude product was purified by CombiFlash under the following conditions (IntelFlash-1): mobile phase, petroleum ether/ethyl acetate = 1:0 increased to petroleum ether/ethyl acetate = 100:1 over 20 minutes; detector, UV 254 nm. This yielded 6.81 g (63%) of methyl 4-vinyl-2-methylbenzoate as a colorless oil.

Compound 231.2. Methyl 2-methyl-4-(3-oxocyclobutyl)benzoate. Under nitrogen atmosphere, at -15°C, a solution of trifluoromethanesulfonic anhydride (10 mL) in DCE (50 mL) was added dropwise to a solution of N,N-dimethylacetamide (5.5 mL) in DCE (20 mL). The mixture was then stirred at -15°C for 10 minutes to prepare solution A. Methyl 4-vinyl-2-methylbenzoate (compound 231.1, 5.30 g, 0.03 mol, 1.00 equivalent) was added to another flask. A solution of 2,4,6-trimethylpyridine (5.5 mL) in DCE (80 mL) was added dropwise at -15°C. The resulting mixture was added dropwise to solution A under an inert nitrogen atmosphere. The resulting solution was stirred overnight at 80°C. After cooling to ambient temperature, the mixture was carefully quenched with water. The mixture was extracted with 2 × 200 mL of ethyl acetate, and the combined organic layers were washed with 3 × 400 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:50–1:5) as the eluent to give 2.95 g (45%) of methyl 2-methyl-4-(3-oxocyclobutyl)benzoate as a brown oil.

Compound 231.3. Methyl 4-(3,3-difluorocyclobutyl)-2-methylbenzoate. A solution of methyl 2-methyl-4-(3-oxocyclobutyl)benzoate (compound 231.2, 3.00 g, 13.8 mmol, 1.00 equivalent) in dichloromethane (100 mL) was added to a round-bottom flask purged and maintained under an inert nitrogen atmosphere. DAST (22.2 g, 137 mmol, 10.00 equivalent) was added to the reaction mixture. The resulting solution was stirred overnight at 25 °C, and then carefully quenched by the slow addition (initially dropwise) of 500 mL of sodium bicarbonate (aqueous solution) and ice. The mixture was extracted with 300 mL of ethyl acetate, and the combined organic layers were washed with 2 × 300 mL of sodium bicarbonate (aqueous solution) and 2 × 300 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:20) as the eluent to give 3.00 g (91%) of methyl 4-(3,3-difluorocyclobutyl)-2-methylbenzoate as a brown oil.

Compound 231.4. Methyl 4-(3,3-difluorocyclobutyl)-5-iodo-2-methylbenzoate. The title compound (3.02 g, yellow solid, 66%) was prepared using a similar procedure to that used to prepare compound 181.4, but with compound 231.3 (3.00 g) instead of compound 181.3.

Compound 231.5. 4-(3,3-difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. The title compound was synthesized using standard chemical procedures and a similar process to that used to prepare compound 164.1, with compound 231.4 replacing compound 152.3.

Compound 231. 4-(1-(4-(3,3-difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. Add a solution of 4-(3,3-difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 231.5, 211 mg, 0.660 mmol, 1.00 equivalent) in N,N-dimethylformamide (5 mL) to a round-bottom flask. 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 146 mg, 0.660 mmol, 1.00 equivalent), EDC·HCl (252 mg, 1.31 mmol, 2.00 equivalent), and 4-dimethylaminopyridine (160 mg, 1.31 mmol, 2.00 equivalent) were added to the reaction mixture. The resulting solution was stirred in an oil bath at 30 °C for 3 hours, followed by dilution with 30 mL of ethyl acetate. The mixture was washed with 3 × 40 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (448 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19×150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (48.0% _CH3CN increased to 62.0% within 6 min, 100.0% within 4 min, and decreased to 48.0% within 2 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 186 mg (58%) of the title compound as a white solid. m/z (ES+) 490 (M+H) ⁺ . ^1H -NMR (300MHz, _CD3 OD, ppm): δ 7.68 (d, J = 8Hz, 2H), 7.59–7.44 (m, 4H), 4.89–4.80 (m, 1H), 4.03–3.98 (m, 1H), 3.67–3.61 (m, 1H), 3.28–3.24 (m, 1H), 3.04–3.00 (m, 2H), 2.97–2.89 (m, 2H), 2.87–2.83 (m, 2H), 2.62–2.60 (m, 2H), 2.48 and 2.38 (two singlets, amide rotational isomers, ArCH3 ₎ , 3H), 2.05-2.00 (m, 1H), 1.88-1.58 (m, 3H), 1.41 (t, 3H).

Compound 232.1. Methyl 5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoate. A mixture of 3-bromo-N,N-dimethyl-2-oxopropionamide (246 mg), methyl 5-formamidinyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 237 mg), and potassium carbonate (311 mg) in acetonitrile (12 mL) was heated to reflux for 48 hours. After cooling to ambient temperature, the mixture was concentrated. The residue was dissolved in EtOAc and washed with brine, dried over _MgSO4 , concentrated, and purified by rapid chromatography ( _SiO2 ; EtOAc) to give 88 mg of the title compound. m/z(ES+)302(M+H) ⁺ .

Compound 232.2. 5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoic acid. Methyl 5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoate (compound 232.1, 113 mg, 0.37 mmol) was dissolved in 2N LiOH aqueous solution (1 ml) and tetrahydrofuran (THF) (5 ml) and heated to 50 °C for 16 hours. After cooling to ambient temperature, the organic solvent was removed under vacuum. The pH of the remaining aqueous layer was adjusted to pH 3-4 with 2N HCl. The precipitate was collected by filtration and dried to give 56 mg of 5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoic acid (53%). m/z(ES+)288(M+H) ⁺ .

Compound 232. 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-1H-imidazolium-5-carboxamide. A mixture of the above acid (compound 232.2, 56 mg, 0.2 mmol), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 45 mg, 0.2 mmol), HBTU (152 mg, 0.4 mmol), and DIEA (105 μL, 0.6 mmol) in DMF (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with brine and extracted with EtOAc. The organic layer was washed with brine, dried over _MgSO4 , and concentrated. The residue was purified by rapid chromatography ( _SiO2 ; EtOAc containing 4% methanol) to give 44 mg of foamy substance (48%). m/z (ES+) 456 (M+H) ⁺ .

Compound 233. 4-(1-(2,4-dimethyl-5-(5-(morpholin-4-carbonyl)-1H-imidazolyl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-1H-imidazol-5-carboxamide (compound 232). m/z(ES+) 498(M+H) ⁺ .

Compound 234. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylbenzoic acid. Sodium hydroxide aqueous solution (577 mg, 14.4 mmol, in 5 mL of water) was added dropwise to a solution of methyl 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylbenzoate (compound 230.3, 1.50 g, 3.60 mmol, 1.00 equivalent) in methanol (10 mL) at 0 °C. The resulting solution was stirred in an oil bath at 60 °C for 2 h. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The pH of the remaining aqueous layer was adjusted to 3–4 with hydrogen chloride (aqueous solution, 2 M). The resulting solid was collected by filtration and dried in an oven under reduced pressure to give 1.20 g (83%) of the title compound as a white solid. m/z(ES+)403(M+H) ⁺ .

Compound 235.1. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylbenzoyl chloride. A solution of 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylbenzoic acid (compound 234, 500 mg, 1.24 mmol, 1.00 equivalent) in dichloromethane (5 mL) was added dropwise to the mixture. Oxythiocyanate chloride (317 mg, 2.50 mmol, 2.00 equivalent) and N,N-dimethylformamide (about 5 mg) were added dropwise to the mixture. The resulting solution was stirred at 40 °C for 1 hour, then concentrated and dried under reduced pressure to give 480 mg (92%) of the title compound as a pale yellow oil.

Compound 235.2. 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile. Under nitrogen atmosphere, at 0°C, a solution of 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylbenzoyl chloride (compound 235.1, 200 mg, 0.480 mmol, 1.00 equivalence) in dichloromethane (3 mL) was added dropwise to a solution of TMSCHN2 (2 M in hexane) (0.476 mL, 2.00 equivalence) in dichloromethane (3 mL). The resulting mixture was stirred overnight at 25°C. Subsequently, HBr (40%) (0.154 mL, 1.50 equivalence) was added dropwise at 0°C, and the mixture was stirred at 0°C for another 2 hours, followed by dilution with 50 mL of dichloromethane. The organic layer was washed with 2 × 20 mL of water and 1 × 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (0:1-1:50-1:5) as the eluent to give 200 mg (88%) of 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile as a yellow oil.

Compound 235. 4-(1-(4-cyclobutyl-5-(2-ethyl-1H-imidazol-5-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 235.2, 100 mg, 0.210 mmol, 1.00 equivalent) in _CH3CN (5 mL) was added to a round-bottom flask purged and maintained under an inert nitrogen atmosphere. Propanamine hydrochloride (22.8 mg, 1.00 equivalent) and potassium carbonate (86.6 mg, 0.63 mmol, 3.00 equivalent) were added to the reactants. The resulting solution was stirred at 80 °C for 3 hours, then cooled to room temperature and concentrated under vacuum. The residue was dissolved in 20 mL of water. The mixture was extracted with 2 × 20 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (approximately 100 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (29.0% _CH3CN to 43.0% within 7 min, to 100.0% within 3 min, and to 29.0% within 2 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 43 mg (44%) of the title compound as a white solid. m/z (ES+) 453 (M+H) ⁺ . ^¹H NMR (300 MHz, _CD₃OD ): δ 7.68 (d, with fine structure, J = 7.8 Hz, 2H), 7.56–7.53 (m, 4H), 7.30 and 7.20 (two singlets, amide rotational isomer, Ar-H, 1H), approximately 4.9 (1H, partially obscured by water peak), 3.84–3.70 (m, 1H), 3.70–3.53 (m, 1H), 3.33–3.19 (m, 1H, partially obscured by methanol solvent peak), 3.13–2.92 (m, 4H), 2.48 and 2.38 (two singlets, amide rotational isomer, Ar-CH₃ ₎ , 3H), 2.29-2.11(m, 4H), 2.11-1.93(m, 2H), 1.93-1.72(m, 3H), 1.72-1.53(m, 1H), 1.45(t, 3H).

Compound 236.1. 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 235.2), but using compound 11.2 hydrochloride instead of compound 1.5.

Compound 236. 4-(1-(4-cyclobutyl-2-methyl-5-(2-methyl-1H-imidazol-5-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. A solution of 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile (compound 236.1, 40 mg, 0.08 mmol, 1.00 equivalent) in _CH3CN (10 mL) was added to a round-bottom flask purged and maintained under an inert nitrogen atmosphere. Acetamidinium hydrochloride (7.6 mg, 0.08 mmol, 1.00 equivalent) and potassium carbonate (33.4 mg, 0.24 mmol, 3.00 equivalent) were added to the reaction mixture. The resulting solution was stirred in an oil bath at 80 °C for 2 hours, then cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate. The organic layer was washed with 2 × 20 mL of water and 2 × 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (approximately 50 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN ( _CH3CN increased from 29.0% to 43.0% within 8 min, to 100.0% within 2 min, and decreased to 29.0% within 2 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 13 mg (35%) of the title compound as a white solid. m/z (ES+) 457 (M+H) ⁺ . ^1H NMR (400MHz, _CD3 OD): δ 7.78 (d, 2H), 7.65 (d, 2H), 7.50–7.46 (m, 2H), 7.35 and 7.23 (2s, amide rotational isomer, 1H), 4.91–4.83 (m, 1H), 3.76–3.63 (m, 1H), 3.54–3.49 (m, 2H), 3.32–3.30 (m, 1H), 2.70 (s, 3H), 2.49 and 2.39 (two singlets, amide rotational isomer, ArCH3, 3H), 2.34–2.28 (m, 7H), 1.98–1.80 (m, 3H).

Compound 237.1. N′-hydroxy-3-methoxypropanediamine. A solution of 3-methoxypropionitrile (10.0 g, 118 mmol, 1.00 equivalent) in ethanol (20 mL) was placed in a round-bottom flask. _NH₂OH (50% in _H₂O ) (10 mL) was added to the reactants. The resulting solution was stirred overnight in an oil bath at 90 °C, then cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with 30 mL of _H₂O and washed with 2 × 20 mL of ethyl acetate. The aqueous layers were combined and concentrated under reduced pressure to give 10.0 g (65%) of the title compound as a colorless oil.

Compound 237.2. 3-Methoxypropanediamine hydrochloride. A solution of N′-hydroxy-3-methoxypropanediamine (compound 237.1, 10.0 g, 76.2 mmol, 1.00 equivalent, 90%) in AcOH (50 mL) was placed in a round-bottom flask. Acetic anhydride (9.50 g, 93.1 mmol, 1.10 equivalent) was added dropwise, and the resulting mixture was stirred at room temperature for 30 minutes. After purging the flask with nitrogen, palladium on carbon (10%, 60% water, 5 g) was added. The flask was then carefully purged with nitrogen, and the atmosphere was subsequently changed to hydrogen. The mixture was stirred overnight at 20 °C under hydrogen atmosphere pressure. After purging the system with nitrogen, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with 50 mL of _H₂O . The pH of the solution was adjusted to 2–3 with hydrogen chloride (12 mol/L), followed by washing with 2 × 30 mL of ethyl acetate. The aqueous layers were combined and concentrated under reduced pressure to give 5.00 g (40%) of the title compound as a grayish-white solid.

Compound 237. 4-(1-(4-cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoyl)-4-fluoropiperidine-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare 4-(1-(4-cyclobutyl-2-methyl-5-(2-methyl-1H-imidazol-5-yl)benzoyl)-4-fluoropiperidine-4-yl)benzonitrile (compound 236), with 237.2 used instead of acetamiprid hydrochloride. m/z(ES+)501(M+H) ⁺ .

Compound 238.1. Methyl 5-acetyl-4-cyclobutyl-2-methylbenzoate. Under nitrogen atmosphere, a solution of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (152.3 g, 5.00 g, 15.1 mmol, 1.00 equivalent) in DMSO (50 mL) was supplemented with 1-(vinyloxy)butane (3.03 g, 30.3 mmol, 2.00 equivalent), DPPP (624 mg, 1.51 mmol, 0.10 equivalent), Pd(OAc)₂ (324 mg, 1.51 mmol, 0.10 equivalent), and TEA (3.06 g, 30.2 mmol, 2.00 equivalent). The resulting mixture was stirred overnight under nitrogen atmosphere at 120 °C, then cooled to ambient temperature and diluted with water. The pH was adjusted to 1 with hydrogen chloride (aqueous solution, 6 M). The resulting mixture was diluted with 200 mL of ethyl acetate, washed with brine (3 × 200 _mL ), dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:30) as the eluent to give 2.28 g (61%) of the title compound as a yellow oil.

Compounds 238.2 and 238.3: Methyl 5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoate and methyl 4-cyclobutyl-5-(2,2-dibromoacetyl)-2-methylbenzoate. Br₂ (325 mg, 2.03 mmol, 1.00 equivalent) was added dropwise to a solution of methyl 5-acetyl-4-cyclobutyl- ₂ -methylbenzoate (238.1, 500 mg, 1.83 mmol, 1.00 equivalent, 90%) in chloroform (5 mL) (Note: an exothermic reaction with significant HBr emission). The resulting mixture was stirred at 25 °C for 3 hours, and subsequently quenched by adding 5 mL of _H₂O . The mixture was then extracted with 50 mL of ethyl acetate. The organic phase was washed sequentially with 2×10 mL _{of Na₂S₂O₃} (saturated aqueous solution) and 1×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 500 mg of a mixture of the title compound in _a yellow oily form.

Compound 238.4. Methyl 4-cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoate. A solution of a mixture of compounds 238.2 and 238.3 (500 mg, about 0.6 mmol, 80%), potassium carbonate (640 mg, 3.00 equivalent), and 3-methoxypropanediamine hydrochloride (compound 237.2, 213 mg, 1.54 mmol) in acetonitrile was placed in a round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight in an oil bath at 80 °C, then cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with 60 mL of ethyl acetate. The organic layer was washed with 2 × 25 mL of water and 2 × 25 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (2:1) as the eluent to give 90 mg (43%) of the title compound as a yellow solid.

Compound 238.5. 4-Cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoic acid. A mixture of compound 238.4 (90 mg, 0.25 mmol, 1.00 equivalent, 90%) and an aqueous solution of sodium hydroxide (44 mg, 1.10 mmol, 4.00 equivalent in 1 mL of water) in methanol (3 mL) was stirred at 60 °C for 2 hours. After cooling to ambient temperature, the methanol was removed under reduced pressure. The pH of the residual aqueous layer was adjusted to 3–4 with hydrogen chloride (aqueous solution, 2 M). The resulting mixture was concentrated under reduced pressure to give 80 mg (crude) of the title compound as a yellow solid.

Compound 238. 4-(1-(4-cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of compound 238.5 (80 mg, 0.23 mmol, 1.00 equivalent, 90%) in N,N-dimethylformamide (2 mL) was placed in a round-bottom flask purged and maintained under an inert nitrogen atmosphere. 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 54 mg, 0.24 mmol, 1.00 equivalent), EDC·HCl (93 mg, 0.49 mmol, 2.00 equivalent), and 4-dimethylaminopyridine (59 mg, 0.48 mmol, 2.00 equivalent) were added to the solution. The resulting mixture was stirred at 30 °C for 3 hours, and then diluted with 50 mL of ethyl acetate. The organic layer was washed with 2 × 20 mL of water and 2 × 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform/methanol (20:1) as the eluent. The product (approximately 50 mg) was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (29% _CH3CN increased to 43% within 8 min, to 100% within 6 min, and decreased to 29% within 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 20.6 mg (19%) of the title compound as a white solid. m/z (ES+) 483 (M+H) ⁺ .

The compounds in the table below shall be prepared using standard chemical procedures, readily available starting materials, and procedures similar to those used to prepare compounds 236, 237, and 238:

Compound 245.1. Methyl 5-formamidinyl-4-cyclobutyl-2-methylbenzoate hydrochloride. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare methyl 5-(N′-hydroxyformamidinyl)-2,4-dimethylbenzoate (compound 2.4) and methyl 5-formamidinyl-2,4-dimethylbenzoate hydrochloride (compound 2.5), with methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (compound 152.4) instead of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3).

Compound 245.2. Methyl 4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate. A solution of methyl 5-formamidinyl-4-cyclobutyl-2-methylbenzoate hydrochloride (compound 245.1, 350 mg, 1.11 mmol, 1.00 equivalent, 90%) in 50 mL of ACN was added to a round-bottom flask purged and maintained under an inert nitrogen atmosphere. 1-Bromobut-2-one (186 mg, 1.23 mmol, 1.00 equivalent) and potassium carbonate (513 mg, 3.53 mmol, 3.00 equivalent, 95%) were added to the reaction mixture. The resulting solution was stirred overnight at 80 °C. After cooling to ambient temperature, the mixture was diluted with ethyl acetate, washed with 3 × 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:5) as the eluent to give 290 mg (83%) of methyl 4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate as a yellow solid.

Compound 245.3. 4-Cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoic acid. A mixture of methyl 4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate (compound 245.2, 200 mg, 0.600 mmol, 1.00 equivalent, 90%) and sodium hydroxide (107 mg, 2.68 mmol, 4.00 equivalent) in a solvent mixture of methanol and water (4/2 mL) was stirred at 60 °C for 3 hours. After cooling to ambient temperature, the pH was adjusted to 3-4 with hydrogen chloride (aqueous solution, 6 M). The resulting mixture was concentrated under vacuum to give 150 mg of a white solid.

Compound 245. 4-(1-(4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoic acid (compound 245.3, 153 mg, 0.480 mmol, 1.00 equivalent, 90%) in N,N-dimethylformamide (5 mL) was added to a round-bottom flask. 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 132 mg, 0.590 mmol, 1.10 equivalent), EDC·HCl (204 mg, 1.01 mmol, 2.00 equivalent, 95%), and 4-dimethylaminopyridine (131 mg, 1.02 mmol, 2.00 equivalent, 95%) were added to the reaction mixture. The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (2:1) as the eluent. The crude product (approximately 150 mg) was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH4CN (28% _CH3CN rising to 43% within 7 min, rising to 100% within 2 min, and falling to 28% within 2 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 62 mg (29%) of the title compound as a white solid. m/z (ES+) 453 (M+H) ⁺ . ^¹H NMR (400MHz, _CD₃OD ) δ 7.75–7.67 (m, 2H), 7.49–7.34 (m, 5H), 4.89–4.80 (m, 1H), 3.75–3.72 (m, 1H), 3.64–3.59 (m, 1H), 3.27–3.23 (m, 1H), 3.05–2.90 (m, 2H), 2.83 (q, 2H), 2.40 and 2.30 (two singlets, amide rotational isomer, _ArCH₃ , 3H), 2.27–1.97 (m, 6H), 1.90–1.70 (m, 4H), 1.40 (t, 3H).

Compound 246.1. 2-Methoxyacetyl chloride. N,N-dimethylformamide (0.1 mL) of (COCl) _₂ (5.65 g, 2.00 equivalent) was added dropwise to a solution of 2-methoxyacetic acid (2.00 g, 22.2 mmol, 1.00 equivalent) in dichloromethane (20 mL) (gas escaping was observed). The reaction mixture was stirred at 40 °C for 1 hour. The resulting mixture was then concentrated under reduced pressure to give 2.10 g (70%) of 2-methoxyacetyl chloride as a yellow oil.

Compound 246.2. 1-Bromo-3-methoxypropane-2-one. 2-Methoxyacetyl chloride (compound 246.1, 2.10 g, 15.5 mmol, 1.00 equivalent, 80%) was added dropwise to a solution of TMSCHN ₂ (2 M in hexane) (16 mL, 2.00 equivalent) in dichloromethane (40 mL) at 0 °C. After stirring for 20 min, HBr (48%, 2 mL) was added to the reaction. The resulting solution was stirred at 25 °C for 30 min. The mixture was washed with 1 × 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 2.30 g (71%) of 1-bromo-3-methoxypropane-2-one as a yellow oil.

Compound 246.3. Methyl 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate. A solution of 1-bromo-3-methoxyprop-2-one (compound 246.2, 505 mg, 1.81 mmol, 1.00 equivalent, 60%) in _CH3CN (16 mL) was added to a round-bottom flask. Methyl 5-formamidinyl-4-cyclobutyl-2-methylbenzoate hydrochloride (compound 245.1, 450 mg, 1.59 mmol, 1.00 equivalent) and potassium carbonate (554 mg, 3.61 mmol, 3.00 equivalent, 90%) were added to the reaction mixture. The resulting solution was stirred overnight at 80 °C under nitrogen. After cooling to ambient temperature, the reaction was carefully quenched by adding water. The resulting mixture was extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were dried ( _Na₂SO₄ ) and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:2) as eluent to give 170 _mg (24%) of methyl 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate as a white solid.

Compound 246.4. 4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acid. A solution of methyl 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate (compound 246.3, 150 mg, 0.430 mmol, 1.00 equivalent, 90%) and an aqueous solution of sodium hydroxide (76.0 mg, 1.90 mmol, 4.00 equivalent in 2 mL of water) in methanol (4 mL) was stirred at 60 °C for 2 hours. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The pH of the remaining aqueous phase was adjusted to approximately 4 with hydrogen chloride (aqueous solution, 4 M) _. The resulting mixture was extracted with 2 × 50 mL of ethyl acetate, and the combined organic layers were dried ( _Na₂SO₄ ) and concentrated under vacuum. This produces 120 mg (84%) of 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acid as a white solid.

Compound 246. 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acid (compound 246.4, 50.0 mg, 0.150 mmol, 1.00 equivalent, 90%) in N,N-dimethylformamide (3 mL) was added to a round-bottom flask. 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 41.0 mg, 0.170 mmol, 1.10 equivalents), EDC·HCl (64.0 mg, 0.330 mmol, 2.00 equivalents), and 4-dimethylaminopyridine (41.0 mg, 0.340 mmol, 2.00 equivalents) were added to the reaction mixture. The resulting solution was stirred at 25 °C for 3 hours, then quenched with water and extracted with 2 × 30 mL of ethyl acetate. The combined organic layers were concentrated under vacuum. The crude product (approximately 50 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19×150 mm 5 μm; mobile phase, water containing 0.05% TFA and CH3CN (CH3CN increased from 26.0% to 42.0% within 7 min, to 100.0% within 2 min, and decreased to 26.0% within 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 18 mg (25%) of the title compound as a white solid. m/z (ES+) 469 (M+H) ⁺ . ^¹H NMR (300 MHz, _CD₃OD ): δ 7.73–7.64 (m, 3H), 7.52–7.32 (m, 4H), approximately 4.9 (1H, partially obscured by water peak), 4.60 (s, 2H), 3.81–3.68 (m, 1H), 3.68–3.52 (m, 1H), 3.46 (s, 3H), 3.35–3.22 (m, 1H, partially obscured by methanol solvent peak), 3.09–2.95 (m, 2H), 2.52 and 2.41 (two singlets, amide rotational isomer, Ar- _CH₃ , 3H), 2.16–1.97 (m, 6H), 1.94–1.58 (m, 4H).

Compound 247. 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 246), except that 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2 hydrochloride) was used instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5). m/z(ES+)487(M+H) ⁺ . ^1H NMR (400MHz, _CD3 OD): δ 7.79–7.67 (m, 2H), 7.66 (d, 3H), 7.53–7.39 (m, 2H), 4.99–4.93 (m, 1H), 4.85 (s, 2H), 3.76–3.56 (m, 3H), 3.50 (s, 3H), 2.42 and 2.34 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.27–1.97 (m, 8H), 1.92–1.81 (m, 2H), 1.35–1.26 (m, 1H).

Compound 248. 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-4-methyl-1H-imidazol-2-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 246). m/z(ES+)501(M+H) ⁺ . ^1H NMR (400MHz, _CD3 OD): δ 7.79–7.77 (m, 2H), 7.66 (d, 2H), 7.52–7.38 (m, 2H), 4.87–4.80 (m, 1H), 4.55 (s, 2H), 3.78–3.74 (m, 1H), 3.62–3.56 (m, 2H), 3.50 (s, 3H), 3.44–3.32 (m, 1H), 2.52 and 2.42 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.44 (s, 3H), 2.11–1.99 (m, 8H), 1.93–1.83 (m, 2H).

Compound 249. 4-(1-(4-cyclobutyl-5-(4,5-dimethyl-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 246). m/z(ES+)453(M+H) ⁺ . ^1H NMR (400MHz, _CD3 OD): δ 7.68 (d, 2H), 7.51 (d, 2H), 7.31 (d, 1H), 7.32 and 7.30 (two singlets, amide rotational isomer, ArH, 1H), 4.90–4.88 (m, 1H), 3.96–3.87 (m, 1H), 3.70–3.62 (m, 1H), 3.32–3.29 (m, 1H), 3.02 (t, 2H), 2.44 and 2.33 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.20 (s, 6H), 2.18–1.90 (m, 7H), 1.88–1.78 (m, 3H).

Compound 250. 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-1H-imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 246). m/z(ES+) 439(M+H) ⁺ . ^1H NMR (400MHz, _CD3 OD): δ 7.68 (d, 2H), 7.49–7.39 (m, 4H), 7.36 and 7.34 (two singlets, amide rotational isomer, ArH, 1H), 4.90–4.86 (m, 1H), 3.75–3.70 (m, 1H), 3.63–3.55 (m, 1H), 3.33–3.24 (m, 1H), 3.04–2.99 (m, 2H), 2.51 and 2.41 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.44 (s, 3H), 2.28–1.96 (m, 6H), 1.89–1.81 (m, 3H), 1.77–1.74 (m, 1H).

Compound 251. 4-(1-(4-cyclobutyl-2-methyl-5-(5-(trifluoromethyl)-1H-imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 246). m/z(ES+) 493(M+H) ⁺ .

Compound 252. 4-(1-(5-(5-chloro-1H-imidazol-2-yl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 246). m/z(ES+) 459(M+H) ⁺ .

Compound 253. 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-1H-imidazol-5-carboxynitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 246. m/z(ES+) 450(M+H) ⁺ .

Compound 254. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide. EDCI (36 mg, 0.186 mmol), HOBt (10 mg, 0.5 mmol), diisopropylethylamine (54 mg, 0.434 mmol), and methylamine (125 μL, 2.5 M in THF) were added to a solution of 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylbenzoic acid (compound 234, 50 mg, 0.124 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 12 hours and quenched with a saturated aqueous solution of _NaHCO3 (50 mL). After extraction with ethyl acetate (2 × 50 mL), the combined organic layers were dried over _Na2SO4 , filtered _, and concentrated under vacuum. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide (28.3 mg, 55% yield) was obtained as a white solid by rapid SiO2 chromatography using ethyl acetate to ethyl acetate/methanol = 98/2. m/z (ES+) 416 (M+H) ⁺ . ^¹H NMR (400 MHz, DMSO-d6): δ 8.13 (q, J = 4.5 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.55–7.45 (m, 2H), 7.26 (br s, 1H), 7.12 and 6.99 (two singlets, amide rotational isomer, Ar-H, 1H), 4.70 (br s, 1H). d, J = 11.9 Hz, 1H), 3.86-3.72 (m, 1H), 3.50-3.35 (m, 1H), 3.13 (t, with fine structure, J = 12.3 Hz, 1H), 2.99-2.78 (m, 2H), 2.72 (d, J = 4.6 Hz, 3H), 2.39-2.17 (m, 5H), 2.17-1.98 (m, 2H), 1.98-1.81 (m, 2H), 1.81-1.35 (m, 4H).

Compound 255. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-N-(2-methoxyethyl)-4-methylbenzamide. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide (compound 254). m/z (ES+) 460 (M+H) ⁺ . ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.27 (t, 1H), 7.78 (d, 2H), 7.49 (d, 2H), 7.26 (s, 1H), 7.12 and 6.98 (two singlets, amide rotational isomer, 1H), 4.70 (d, 1H), 3.85–3.75 (m, 1H), 3.44 (t, 3H), 3.39–3.33 (m, 2H), 3.30 (s, 3H), 3.19–3.03 (m, 1H), 3.02–2.71 (m, 2H), 2.32 and 2.26 (two singlets, amide rotational isomer, ArCH₃ ₎ , 3H), 2.38-2.17(m, 2H), 2.15-2.00(m, 2H), 1.98-1.81(m, 2H), 1.83-1.47(m, 4H).

Compound 256. 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-N-ethyl-4-methylbenzamide. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide (compound 254). m/z(ES+) 430(M+H) ⁺ . ^¹H NMR (400MHz, DMSO- _d₆ ) δ 8.21 (t, ¹H), 7.78 (d, 2H), 7.56–7.45 (m, 2H), 7.31–7.20 (m, ¹H), 7.11 and 6.98 (two singlets, amide rotational isomer, ¹H), 4.74–4.65 (m, ¹H), 3.85–3.74 (m, 1H), 3.50–3.37 (m, 1H), 3.22 (q, 2H), 3.20–3.05 (m, 2H), 2.32 and 2.22 (two singlets, amide rotational isomer, ArCH₃ ₎ , 3H), 3.01-2.76(m, 2H), 2.38-2.17(m, 2H), 2.18-1.97(m, 2H), 1.98-1.84(m, 2H), 1.81-1.38(m, 3H), 1.10(t, 3H).

Compound 257.1. (S)-Tetrahydrofuran-2-carbonyl chloride. A solution of (S)-tetrahydrofuran-2-carboxylic acid (4.64 g, 40.0 mmol, 1.00 equivalent) in dichloromethane (25 mL) was added to a round-bottom flask. N,N-dimethylformamide (0.05 mL, 0.05 equivalent) and (COCl)₂ (5.2 mL, 1.50 equivalent) were added dropwise to the reaction. The resulting solution was stirred at 25 °C for 1 hour, and then concentrated under vacuum to give 5.00 g (93%) of (S)-tetrahydrofuran-2-carbonyl chloride as a yellow oil.

Compound 257.2. (S)-2-bromo-1-(tetrahydrofuran-2-yl)ethyl ketone. A solution of (diazomethyl)trimethylsilane (20 mL, 2 M in hexane) in 150 mL diethyl ether was added to a 250 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. A solution of (S)-tetrahydrofuran-2-carbonyl chloride (compound 257.1, 5.00 g, 37.2 mmol, 1.00 equivalent) in ether/DCM (25/10 mL) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 20 min. Hydrogen bromide (48%) (8 mL, 1.50 equivalent) was added dropwise. The resulting solution was stirred at 10 °C for 30 min, followed by washing with 2 × 100 mL water and 1 × 50 mL brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:50) as the eluent to give 2.50 g (35%) of (S)-2-bromo-1-(tetrahydrofuran-2-yl)ethyl ketone as a yellow oil.

Compound 257.3. (S)-Methyl-2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate. A solution of methyl 5-formamidinyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 1.30 g) in _CH3CN (30 mL) was added to a round-bottom flask. (S)-2-bromo-1-(tetrahydrofuran-2-yl)acetone (compound 257.2, 1.92 g, 9.95 mmol) and potassium carbonate (4.20 g, 30.4 mmol) were added to the reaction mixture. The resulting solution was stirred at 75 °C for 3 days under nitrogen. After cooling to ambient temperature, the solid was removed by filtration. The filtrate was concentrated under vacuum and diluted with 30 mL _H2O . The aqueous phase was extracted with 3 × 50 mL ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and then concentrated under vacuum. The mixture was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:2) as the eluent to give 400 mg (25%) of (S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate as a pale yellow solid.

Compound 257.4. (S)-2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoic acid. A solution of (S)-methyl-2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate (compound 257.3, 400 mg, 1.33 mmol, 1.00 equivalent) and sodium hydroxide (300 mg, 7.50 mmol, 5.63 equivalent) in a solvent mixture of methanol and _H₂O (20/10 mL) was added to a round-bottom flask. The resulting solution was stirred at 70 °C for 2 hours. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residual aqueous layer was washed with 2 × 50 mL of ethyl acetate. The pH of the aqueous layer was adjusted to 5–6 with hydrogen chloride (aqueous solution, 6 M), followed by extraction with 3 × 50 mL of ethyl acetate. The combined organic layers were dried with anhydrous sodium sulfate and concentrated under vacuum. This yielded 340 mg (90%) of (S)-methyl-2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate as a yellow solid.

Compound 257. (S)-4-(1-(2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. A solution of (S)-methyl-2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate (compound 257.4, 143 mg, 0.500 mmol, 1.00 equivalent) in N,N-dimethylformamide (10 mL) was added to a round-bottom flask. HBTU (285 mg, 0.750 mmol, 1.50 equivalent) was added to the reaction mixture, and the mixture was stirred at 25 °C for 30 minutes. 4-(piperidin-4-yl)benzonitrile hydrochloride (1.5 mg, 133 mg, 0.600 mmol, 1.20 equivalents) and DIEA (390 mg, 3.02 mmol, 6.04 equivalents) were added dropwise. The resulting solution was stirred at 25 °C for 30 min, followed by quenching with 20 mL of water. The mixture was extracted with 3 × 25 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using methanol/ethyl acetate (1:30) as the eluent. The product (approximately 100 mg) was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, Xbridge PrepC18, 5 μm, 19 × 150 mm; mobile phase, water containing 0.03% _NH₃H₂O and _CH₃CN ( _CH₃CN increased from 35% to 52% within 8 min, to 100% within 1 min, and decreased to 35% within 1 min); detector, Waters 2489 254 and 220 _nm . The fractions containing the purified compound were combined and lyophilized to give 34.6 mg (15%) of the title compound as a white solid. m/z (ES+) 455 (M+H) ⁺ .

Compound 258.1. 5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoic acid. The title compound was synthesized using standard chemical procedures and a similar process to that used to prepare compound 152.8, with 4-fluoro-2-methylbenzoic acid instead of 4-bromo-2-methylbenzoic acid and propionylhydrazine instead of acetylhydrazine.

Compound 258.2. 4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile. Add a solution of 5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoic acid (Compound 258.1, 125 mg, 0.500 mmol, 1.00 equivalent) in 10 mL of DMF to a round-bottom flask. Add EDC·HCl (143 mg, 0.750 mmol, 1.50 equivalent), 4-(piperidin-4-yl)benzonitrile hydrochloride (Compound 1.5, 122 mg, 0.550 mmol, 1.10 equivalent), and 4-dimethylaminopyridine (183 mg, 1.50 mmol, 3.00 equivalent) in portions. The resulting solution was stirred in an oil bath at 40°C for 1 hour, followed by quenching with 50 mL of _NH₄Cl (saturated aqueous solution). The mixture was extracted with 40 mL of ethyl acetate, and the combined organic layers were washed with 3 × 30 mL of _NH₄Cl (saturated aqueous solution), dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 180 mg (86%) of 4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile as a white solid.

Compound 258. 4-(1-(4-(azacyclobutan-1-yl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-[[5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylphenyl]carbonyl]piperidin-4-yl)benzonitrile (compound 258.2, 83.5 mg, 0.200 mmol, 1.00 equivalent) in 1,4-dioxane (5 mL) was added to a 10-mL sealed tube. Azacyclobutane hydrochloride (93.0 mg, 0.990 mmol, 5.00 equivalent) was added to the reaction mixture in portions. Potassium carbonate (276 mg, 2.00 mmol, 10.0 equivalent) was also added to the mixture. The resulting solution was shielded against explosion and stirred overnight at 105°C, then cooled to room temperature. The reaction was quenched with 20 mL of water. The mixture was extracted with 30 mL of ethyl acetate, and the organic layer was dried over anhydrous sodium _sulfate and concentrated under reduced pressure. The product (80 mg) was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19×150 mm 5 μm; mobile phase, water containing 50 mL of _NH₄CO₃ and _CH₃CN ( _CH₃CN increased from 41.0% to 43.0% in 8 min, to 100.0% in 2 min, and decreased to 41.0% in 2 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 18.0 mg (20%) of the title compound as a white solid. m/z (ES+) 455 (M+H) ⁺ . ^¹H NMR (300 MHz, _CD₃OD ): δ 7.68 (d, J = 6.3 Hz, 2H), 7.48 (d, J = 5.7 Hz, 2H), 7.24 and 7.13 (two singlets, amide rotational isomer, Ar-H, 1H), 6.52 (s, 1H), 4.91–7.77 (m, 1H, partially obscured by water peak), 3.81–3.67 (m, 1H), 3.68 ( t, J=5.6Hz, 4H), 3.32-3.18 (m, 1H), 3.05-1.91 (m, 2H), 2.84 (q, J=5.8Hz, 2H), 2 .45-2.19 (m, 5H), 2.09-1.91 (m, 1H), 1.91-1.49 (m, 3H), 1.39 (t, J=5.7Hz, 3H).

Compound 259. 4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methyl-4-(methylthio)benzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 258.2, 20 mg, 0.050 mmol, 1.0 equivalent) in N,N-dimethylformamide (3 mL) was added to a round-bottom flask. Sodium thiomethoxide (70 mg, 0.10 mmol, 2.0 equivalent) was added to the reaction mixture. The resulting mixture was stirred in an oil bath at 110 °C for 15 hours, then cooled to ambient temperature and quenched with 100 mL of ice water. The mixture was extracted with 50 mL of ethyl acetate, and the combined organic layers were washed with 2 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product (50 mg) was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (37% _CH3CN increased to 49% within 7 min, to 100% within 3 min, and decreased to 37% within 2 min); detector, Waters 2489254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 4 mg (19%) of the title compound as a white solid. m/z (ES+) 446 (M+H) ⁺ . ^¹H NMR (300 MHz, _CD₃OD ): δ 7.69 (d, J = 8.4 Hz, 2H), 7.61–7.43 (m, 3H), 7.35 (br s, 1H), approximately 4.85 (1H, partially obscured by the water peak), 3.77–3.60 (m, 1H), approximately 3.3 (1H, partially obscured by the methanol solvent peak), 3.08–2.94 (m, 2H), 2.91 (q, J = 7.7 Hz, 2H), 2.51 (s, 3H), 2.47 and 2.37 (two singlets, amide rotational isomer, Ar- _CH₃ , 3H), 2.10–1.97 (m, 1H), 1.88–1.55 (m, 3H), 1.40 (t, 3H).

The compounds in the table below were prepared using standard chemical procedures, readily available starting materials, and a procedure similar to that used to prepare compound 5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide (compound 254):

The compounds in the table below shall be prepared using standard chemical procedures, readily available starting materials, and procedures similar to those used to prepare compounds 27, 38, and 211:

Compound 280.1, N-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylphenyl)-2-isonicotinamide. A solution of 4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 121.1, 0.1 g, 0.31 mmol) and triethylamine (0.09 mL, 0.62 mmol) in DCM (5 mL) was added to a solution of carbamate (20% in toluene, 0.31 mL, 0.62 mmol) in DCM (5 mL). The resulting reaction mixture was stirred at room temperature for 1.5 hours, and then all solvent was removed under reduced pressure. The residue was dried under high vacuum for 30 minutes and then reconstituted in EtOH (5 mL). Isonicotinamide (0.05 g, 0.34 mmol) was added. The mixture was heated at 80 °C overnight. Ethanol was removed and the residue was purified by preparative TLC (DCM of 10% MeOH) to give a product as a light brown solid. Yield: 0.14 g, 93%. m/z (ES+) 483.2 (M+H) ⁺ .

Compound 280, 4-(1-(4-methyl-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. Triethylamine (0.061 ml, 0.43 mmol) and CCl4 (0.08 ml, 0.87 mmol) were added sequentially to a solution of N-(5-(4-(4-cyanophenyl)piperidin- ₁ -carbonyl)-2-methylphenyl) _-2 -isonicotinylhydrazine carboxamide (compound 280.1, 0.14 g, 0.29 mmol) and PPh3 (0.09 g, 0.35 mmol) in DCM (10 ml). The mixture was refluxed for 3 hours. TLC and LCMS showed the reaction was complete. The mixture was cooled to room temperature, diluted with DCM (100 ml), and washed with water (20 ml). The organic layer _was dried over _Na₂SO₄ , concentrated, and purified by preparative TLC ( _CH₂Cl₂ in 5% _MeOH ) to give 54 mg (42%) of white solid. m/z (ES⁺) 465.0 (M + H) ^⁺ . ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 10.00 (br, 1H), 8.77 (d, 2H), 7.92 (s, 1H), 7.81–7.73 (m, 4H), 7.50 (d, 2H), 7.33 (d, 1H), 7.14 (d, 1H), 4.64 (m, 1H), 3.81 (m, 1H), 3.17 (m, 1H), 3.00–2.80 (m, 2H), 2.35 (s, 3H), 1.95–1.57 (m, 4H).

Compound 281.1.N-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylphenyl)-1H-imidazol-1-thiocarboxamide. 1,1′-thio-CDI (0.056 g, 0.32 mmol) was added to a solution of 4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (121.1 g, 0.32 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 3 hours. LC-MS showed the reaction was complete. The mixture was carried out in a single vessel without further treatment or purification. m/z (ES+) 430 (M+H) ⁺ .

Compound 281.2. 1-(4-aminopyridin-3-yl)-3-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylphenyl)thiourea. Pyridine-3,4-diamine (0.034, 0.32 mmol) was added to a solution of N-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylphenyl)-1H-imidazolium-1-thiocarboxamide (281.1) continuously from the previous step in DMF. The mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reactants were proceeded to the next step without further treatment or purification. m/z (ES+) 471 (M+H) ⁺ .

Compound 281. 4-(1-(3-((1H-imidazo[4,5-c]pyridin-2-yl)amino)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. EDCI (0.12 g, 0.64 mmol) was added to a solution of 1-(4-aminopyridin-3-yl)-3-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylphenyl)thiourea (281.2) in DMF. The mixture was stirred overnight at room temperature. The DMF was removed under high vacuum and the residue was purified by preparative TLC (EtOAc in 5% MeOH) to give 76 mg (56%, 3 steps) of white powder. m/z (ES+) 437 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ8.84(br,1H),8.48(s,1H),8.40(s,1H),8.08(d,1H),7.78(d,2H),7.53(d,2H),7.29(d,2H),7.0 5 (d, 1H), 4.65 (m, 1H), 3.91 (m, 1H), 3.17 (m, 1H), 3.04-3.72 (m, 2H), 2.36 (s, 3H), 1.97-1.60 (m, 4H).

Compound 282.1, N-((5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylphenyl)thiocarbamoyl)isobutyramide. A solution of _NH₄SCN (72 mg, 0.95 mmol, 2.00 equivalent) in acetone (10 mL) was placed in a round-bottom flask. A solution of 2-methylpropionyl chloride (50 mg, 0.47 mmol, 1.00 equivalent) in acetone (5 mL) was added dropwise at 25 °C, and the reaction mixture was stirred overnight in an oil bath at 40 °C. 4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 121.1, 150 mg, 0.42 mmol, 1.00 equivalent) was added to the mixture at 25 °C. The resulting solution was stirred at 25 °C for 2 hours, and then concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate. The organic layer was washed with 2 × 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (20:1) as the eluent to give 150 mg (64%) of the title compound as a brown oil.

Compound 282. 4-(1-(3-(((5-isopropyl-4H-1,2,4-triazol-3-yl)amino)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of N-((5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylphenyl)thiocarbamoyl)isobutyramide (compound 282.1, 200 mg, 0.40 mmol, 1.00 equivalent, 90%) in ethanol (3 mL) was placed in a 10 mL sealed tube. _{NH₂NH₂HCl} (234 mg, _2.23 mmol, 5.00 equivalent) and potassium carbonate (185 mg, 1.34 mmol, 3.00 equivalent) were added to the reaction mixture. The resulting solution was stirred overnight in an oil bath at 80 °C after being shielded from explosion. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, _dried ( _Na₂SO₄ ), and concentrated. The crude product (approximately 50 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-006(Waters)): column, SunFire Prep C18, 5 μm, 19 × 150 mm; mobile phase, water containing 0.05% TFA and _CH₃CN (5.0% _CH₃CN held for 2 min, increasing to 30.0% in 1 min, 60.0% in 12 min, and 100.0% in 1 min); detector, UV 254/220 nm. The fractions containing the purified compound were combined and lyophilized to give 10.3 mg (6%) of the title compound as a white solid. m/z (ES+) 429 (M+H) ⁺ .

The compounds in the table below shall be prepared using standard chemical operations, readily available starting materials, and procedures similar to those used to prepare compounds 280, 121, 281, and 282:

The compounds in the table below shall be prepared using standard chemical operations, readily available starting materials, and procedures similar to those used to prepare compounds 26, 43, 48, 50, 51, 64, and 80:

Compound 346.1. 2-(1-Benzyl-4-hydroxypiperidin-4-yl)-5-bromobenzoic acid. Under nitrogen atmosphere, n-BuLi (2.5 M) (88 mL, 2.20 equivalents) was added dropwise to a stirred solution of 2,5-dibromobenzoic acid (27.8 g, 100 mmol, 1.00 equivalents) in THF/Et ₂ O (450/50 mL) at -78 °C. After 2 hours at -78 °C, 1-benzylpiperidin-4-one (26.5 g, 140 mmol, 1.40 equivalents) was added. The resulting solution was stirred at -78 °C for 0.5 hours and then cooled to room temperature and stirred overnight. The reaction was quenched by careful addition of 200 mL of water. The pH of the mixture was adjusted to 2–3 with hydrogen chloride (aqueous solution, 2 M). The aqueous phase was extracted with 3 × 500 mL of ethyl acetate and 3 × 500 mL of tetrahydrofuran. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 38.9 g (crude) of the title compound as a yellow solid.

Compound 346.2. 1′-Benzyl-5-bromo-3H-spiro[isobenzofuran-1,4′-piperidine]-3-one. A solution of crude compound 346.1 (38.9 g, 100 mmol, 1.00 equivalent) in tetrahydrofuran (800 mL) was placed in a round-bottom flask. Sulfuric acid (8 mL) was added dropwise. The resulting solution was stirred overnight under reflux in an oil bath. The pH of the solution was slowly adjusted to 10 with LiOH (saturated aqueous solution). The aqueous phase was extracted with 3 × 500 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:8 to 1:5) as eluent to give 8.00 g (22%) of the title compound as a white solid.

Compound 346.3. 1′-Benzyl-5-bromo-3H-spiro[isobenzofuran-1,4′-piperidine]. Under nitrogen atmosphere, BH3 _- THF (135 mL, 5.00 equivalent) was added dropwise to a solution of compound 346.2 (10.0 g, 26.9 mmol, 1.00 equivalent) in tetrahydrofuran (150 mL) at -10 °C. The resulting solution was stirred at room temperature for 30 min and then heated overnight at reflux. After cooling to -10 °C, hydrogen chloride (6 M, 60 mL aqueous solution) was added dropwise at -10 °C. The resulting solution was heated to reflux in an oil bath for 5 h. The reaction mixture was cooled and the pH of the solution was adjusted to 10 with potassium hydroxide (1 M aqueous solution). The aqueous phase was extracted with 2 × 200 mL of ethyl acetate, and the combined organic layers were washed with 2 × 300 mL of brine, dried over sodium sulfate, and concentrated under reduced pressure to give 15.0 g (crude) of the title compound as a yellow oil.

Compound 346.4. 1′-Benzyl-3H-spiro[isobenzofuran-1,4′-piperidine]-5-carboxynitrile. A solution of compound 346.3 (12.0 g, 33.6 mmol, 1.00 equivalent) in N,N-dimethylformamide (150 mL) was placed in a three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Zn(CN) _₂ (4.50 g, 38.5 mmol, 1.14 equivalent) and Pd( _PPh₃ ) _₄ (4.00 g) were added to the reaction mixture. The resulting solution was stirred overnight in an oil bath at 90 °C. The reaction mixture was cooled to room temperature, then quenched with 200 mL of _FeSO₄ (saturated aqueous solution) and diluted with ethyl acetate. The resulting mixture was stirred vigorously, then filtered through diatomaceous earth and washed with 1 M _FeSO₄ , water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2 × 200 mL of ethyl acetate. The combined organic layers were washed with 2 × 100 mL of sodium chloride (saturated aqueous solution), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (10:1 to 5:1) as the eluent to give 9.12 g (89%) of the title compound as a yellow oil.

Compound 346.5. 3H-spiro[isobenzofuran-1,4′-piperidine]-5-carboxynitrile. 1-Chloroethyl chloroformate (8.52 g, 60.0 mmol, 2.00 equivalent) was added dropwise to a solution of 346.4 (9.12 g, 30.0 mmol, 1.00 equivalent) in a DCE (150 mL) at 0 °C. After stirring at ambient temperature for 30 min, triethylamine (9.09 g, 3.00 equivalent) was carefully added to the mixture. The resulting solution was heated to reflux in an oil bath for 2 h, followed by concentration under reduced pressure. The residue was dissolved in 100 mL of methanol and then heated to reflux in an oil bath for 1 h. The resulting mixture was concentrated under reduced pressure, and the residue was dissolved in water (100 mL). The pH of the mixture was adjusted to 10 with sodium hydroxide (aqueous solution, 1 M). The aqueous phase was extracted with 3 × 200 mL of ethyl acetate, and the combined organic layers were washed with 2 × 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/methanol (100:0 to 3:1) as the eluent to give 3.50 g (46%) of the title compound as a yellow solid.

Compound 346.N-(5-(5-cyano-3H-spiro[isobenzofuran-1,4′-piperidin]-1′-carbonyl)-2-methylphenyl)-6-(pyrrolidone-1-yl)nicotinamide. The title compound was prepared using a similar procedure to that used to prepare compound 43, with compound 346.5 replacing compound 11.2. m/z(ES+)522(M+H) ⁺ .

Compound 347.1. 4-(4-cyanophenyl)-2-oxopiperidin-1-carboxylic acid tert-butyl ester. A solution of 4-(4-cyanophenyl)piperidine-1-carboxylic acid tert-butyl ester (compound 1.4, 515 mg, 1.80 mmol, 1.00 equivalent) in ethyl acetate (5 mL) was placed in a round-bottom flask. A solution of _NaIO₄ (963 mg, 4.50 mmol, 2.50 equivalent) in water (5 mL) and _RuCl₃ (74.7 mg, 0.36 mmol, 0.20 equivalent) were carefully added. The resulting mixture was stirred overnight at room temperature. The solid was removed by filtration, and the filtrate was washed with 2 × 20 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 432 mg (80%) of the title compound as a pale yellow oil.

Compound 347.2. 4-(2-oxopiperidin-4-yl)benzonitrile. A solution of compound 347.1 (432 mg, 1.44 mmol, 1.00 equivalent) in 10 mL of ethyl acetate was placed in a round-bottom flask. Hydrogen chloride gas was bubbled through the solution while the resulting mixture was stirred at room temperature for 0.5 h. The solid was collected by filtration and then dissolved in 50 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 254 mg (88%) of the title compound as a white solid.

Compound 347.3. 4-(6-methoxy-2,3,4,5-tetrahydropyridin-4-yl)benzonitrile. A solution of 4-(2-oxopiperidin-4-yl)benzonitrile (347.2, 220 mg, 1.10 mmol, 1.00 equivalent) in dichloromethane (10 mL) was placed in a round-bottom flask. Trimethyloxonium tetrafluoroborate (244.2 mg, 1.65 mmol, 1.50 equivalent) was slowly added while the mixture was stirred at room temperature for 2 hours. The pH was carefully adjusted to 8 with sodium bicarbonate (aqueous solution). The organic layer was washed with 2 × 20 mL _H₂O , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 212 mg (90%) of the title compound as a white solid.

Compound 347.4. 3-Amino-4-methylbenzoylhydrazide. A solution of methyl 3-amino-4-methylbenzoate (6.60 g, 40.0 mmol, 1.00 equivalent) in ethanol (100 mL) was placed in a round-bottom flask. Hydrazine hydrate (10.0 g, 200 mmol, 5.00 equivalent) was added to the reaction mixture. The resulting solution was stirred in an oil bath at 100 °C for 2 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate (20 mL). The aqueous layer was extracted with 4 × 20 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under high vacuum to give 4.60 g (70%) of the title compound as a brown solid.

Compound 347.5. 4-(3-(3-amino-4-methylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile. 3-amino-4-methylbenzoylhydrazine (compound 347.4, 4.63 g, 28.0 mmol, 1.00 equivalent) was added to a solution of 4-(6-methoxy-2,3,4,5-tetrahydropyridin-4-yl)benzonitrile (compound 347.3, 5.00 g, 23.36 mmol, 1.00 equivalent) in 1,2-dichlorobenzene (100 mL). The resulting solution was stirred overnight in an oil bath at 150 °C. After cooling to ambient temperature, the mixture was purified by silica gel column chromatography using dichloromethane/methanol (1:0 to 100:1) as the eluent to give 2.40 g (31%) of the title compound as a white solid.

Compound 347.N-(5-(7-(4-cyanophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methylphenyl)-6-(isopropylamino)nicotinamide. The title compound was prepared using a similar procedure to that used to prepare compound 43, with compound 347.5 replacing compound 42.2. m/z(ES+)492(M+H) ⁺ .

Compound 348.1. 2-Hydroxy-6-methyl-5-nitronicotinic acid. A solution of _HNO₃ (12.0 g, 190 mmol, 2.00 equivalent) in concentrated sulfuric acid (140 mL) was added dropwise to a solution of 2-hydroxy-6-methylnicotinic acid (14.0 g, 91.5 mmol, 1.00 equivalent) in concentrated sulfuric acid (140 mL) at 0 °C. The resulting mixture was then stirred at 90 °C for 2 h, cooled to ambient temperature, and subsequently quenched with 250 mL of ice water. The resulting solid was collected by filtration and dried in an oven under reduced pressure to give 15.8 g (87%) of the title compound as a yellow solid.

Compound 348.2. Methyl 2-chloro-6-methyl-5-nitronicotinic acid. Phosphorus oxychloride (45.0 g, 296 mmol, 4.00 equivalent) and N,N-dimethylformamide (1.5 mL, 0.10 equivalent) were carefully added to a solution of 2-hydroxy-6-methyl-5-nitronicotinic acid (compound 348.1, 15.0 g, 75.8 mmol, 1.00 equivalent) in chlorobenzene (150 mL). The resulting mixture was stirred at 135 °C for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 20 mL of DCM. Methanol (20 mL) was added dropwise to the solution. The resulting solution was stirred at 25 °C for 3 hours and then concentrated under reduced pressure. 100 mL of water was carefully added to the residue, and the pH of the resulting mixture was slowly adjusted to 8 with sodium bicarbonate (aqueous solution). The aqueous phase was extracted with 2 × 200 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 17.6 g (crude) of the title compound as a yellow solid.

Compound 348.3. 5-Amino-6-methylnicotinic acid methyl ester. A round-bottom flask containing a solution of 2-chloro-6-methyl-5-nitronicotinic acid methyl ester (12.8 g, 55.5 mmol, 1.00 equivalent) in methanol (120 mL) was purged with nitrogen. Triethylamine (15.0 g, 149 mmol, 2.68 equivalent) and palladium on carbon (1.30 g) were added. After further purging the flask with nitrogen, the atmosphere was changed to hydrogen and the resulting solution was stirred at atmospheric pressure for 2 days at room temperature. After purging the system with nitrogen, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:50–1:5) as eluent to give 3.50 g (38%) of the title compound as a yellow solid.

Compound 348.4. 5-Amino-6-methylnicotinic acid. A solution of methyl 5-amino-6-methylnicotinic acid (5.00 g, 30.1 mmol, 1.00 equivalent) and sodium hydroxide (20 g) in MeOH/ _H₂O (80/200 mL) was placed in a round-bottom flask. The resulting solution was heated under reflux overnight. After cooling to ambient temperature, methanol was removed under reduced pressure. The pH of the remaining aqueous phase was adjusted to 4 with an aqueous hydrogen chloride solution (2 M). The resulting mixture was then concentrated under reduced pressure to give 5.00 g (crude) of the title compound as a yellow solid.

Compound 348.N-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-methylpyridin-3-yl)-6-(pyrrolidine-1-yl)nicotinamide. The title compound was prepared using a similar procedure to that used to prepare compound 43, with compounds 348.4 and 1.5 replacing 5-amino-2,4-dimethylbenzoic acid and compound 11.2, respectively. m/z(ES+)495(M+H) ⁺ .

Compound 349.1. 1-Oxy-2-bromo-5-methylpyridine. A solution of 2-bromo-5-methylpyridine (10.0 g, 58.1 mmol, 1.00 equivalent) in dichloromethane (250 mL) was placed in a round-bottom flask. mCPBA (15.0 g, 86.9 mmol, 1.50 equivalent) was added in batches at room temperature. The resulting solution was stirred overnight at 30 °C, and then diluted with 50 mL of 2N sodium hydroxide (aqueous solution). The pH of the solution was adjusted to 10 with 2N sodium hydroxide (aqueous solution). The aqueous phase was extracted with 3 × 100 mL of dichloromethane, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 11.0 g (91%) of 2-bromo-5-methylpyridine-1-onthium-1-acid salt as a yellow solid.

Compound 349.2. 1-Oxy-2-bromo-5-methyl-4-nitropyridine. _HNO3 (15 mL) and sulfuric acid (20 mL) were placed in a round-bottom flask. Compound 349.1 (11.0 g, 52.7 mmol, 1.00 equivalent, 90%) was added in several batches at room temperature. The resulting mixture was stirred overnight at 100 °C, then cooled to ambient temperature and quenched with 50 mL of ice water. The pH was slowly adjusted to 2–3 with sodium hydroxide (aqueous solution, 2 M), and the mixture was extracted with 3 × 50 mL of dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:2) as eluent to give 3.00 g (23%) of the title compound as a yellow solid.

Compound 349.3. Methyl 4-amino-5-methylpyridinecarboxylate. A solution of 1-oxy-2-bromo-5-methyl-4-nitropyridine (compound 349.2, 3.00 g, 12.9 mmol, 1.00 equivalent) in methanol (120 mL) was placed in a 250-mL autoclave (30 atm, note: after explosion-proof shielding) purged and maintained under an inert nitrogen atmosphere. Triethylamine (2.60 g, 25.7 mmol, 2.00 equivalent) and Pd(dppf) _Cl₂ (600 mg, 0.82 mmol, 0.06 equivalent) were added to the reaction mixture. The autoclave was purged and the mixture was then stirred overnight at 90 °C under 30 atm CO (gas). After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate:methanol (20:1) as the eluent to give 1.50 g (67%) of methyl 4-amino-5-methylpyridine-2-carboxylic acid as a yellow solid.

Compound 349.4. 4-Amino-5-methylpyridinecarboxylic acid. A solution of methyl 4-amino-5-methylpyridinecarboxylic acid (compound 349.3, 1.50 g, 8.12 mmol, 1.00 equivalent, 90%) and 5N sodium hydroxide (aqueous solution, 15 mL) in methanol (15 mL) was stirred overnight at room temperature, followed by concentration under reduced pressure. The residue was diluted with 20 mL _H₂O and the pH was adjusted to 3–4 with 2 M aqueous hydrogen chloride solution. The precipitate was collected by filtration and dried to give 0.8 g (58%) of the title compound as a yellow solid.

Compound 349.N-(2-(4-(4-cyanophenyl)piperidin-1-carbonyl)-5-methylpyridin-4-yl)-6-(isopropylamino)nicotinamide. The title compound was prepared using a similar procedure to that used to prepare compound 43, with compounds 349.4 and 1.5 replacing 5-amino-2,4-dimethylbenzoic acid and compound 11.2, respectively. m/z(ES+)483(M+H) ⁺ .

Compound 350.1. 1-Oxy-2-bromo-3-methylpyridine. The title compound (8.00 g, 85%) was prepared using a similar procedure to that used to prepare compound 349.1, but with 2-bromo-3-methylpyridine (8.60 g) instead of 2-bromo-5-methylpyridine.

Compound 350.2. 6-Bromo-5-methyl-2-cyanopyridine. Triethylamine (6.10 g, 60.3 mmol, 2.00 equivalent) and TMSCN (8.90 g, 3.00 equivalent) were added to a solution of 1-oxy-2-bromo-3-methylpyridine (compound 350.1, 5.65 g, 30.1 mmol, 1.00 equivalent) in acetonitrile (50 mL). The resulting solution was heated to reflux in an oil bath and stirred overnight, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:5) as eluent to give 2.00 g (34%) of the title compound as a yellow solid.

Compound 350.3. 6-Bromo-5-methyl-2-pyridine carboxamide. A solution of 6-bromo-5-methyl-2-cyanopyridine (compound 350.2, 900 mg, 4.57 mmol, 1.00 equivalent) in 40 mL of methanol was placed in a 50 mL sealed tube. _NH3 (gas) was bubbled through the solution, and the resulting solution was stirred overnight in an oil bath at 95 °C after being shielded from explosion. After cooling to ambient temperature, the mixture was concentrated under reduced pressure to give 800 mg (82%) of the title compound as a light brown solid.

Compound 350.4. 6-Amino-5-methyl-2-pyridinecarboxamide. A solution of 6-bromo-5-methyl-2-pyridinecarboxamide (compound 350.3, 800 mg, 3.74 mmol, 1.00 equivalent) and _CuSO₄ (80 mg) in NH₃· _H₂O (40 mL) was placed in a ₅₀ mL sealed tube. The resulting mixture was stirred overnight at 80 °C after being shielded from explosion. After cooling to ambient temperature, the mixture was extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 750 mg (crude) of the title compound as a brown solid.

Compound 350.5. 6-Amino-5-methylpyridinecarboxylate. A solution of 6-amino-5-methyl-2-pyridinecarboxamide (compound 350.4, 500 mg, 3.31 mmol, 1.00 equivalent) in concentrated hydrogen chloride (15 mL) was placed in a round-bottom flask. The resulting solution was heated to reflux overnight in an oil bath, and then concentrated under reduced pressure to give 600 mg (crude) of the title compound as a pale yellow solid.

Compound 350.N-(6-(4-(4-cyanophenyl)piperidin-1-carbonyl)-3-methylpyridin-2-yl)-6-(isopropylamino)nicotinamide. The title compound was prepared using a similar procedure to that used to prepare compound 43, with compounds 350.5 and 1.5 replacing 5-amino-2,4-dimethylbenzoic acid and compound 11.2, respectively. m/z(ES+)483(M+H) ⁺ .

Compound 351.1. Methyl 5-nitro-1H-pyrazole-3-carboxylic acid. A solution of 5-nitro-1H-pyrazole-3-carboxylic acid (5.00 g, 31.9 mmol, 1.00 equivalent) in methanol (150 mL) was placed in a round-bottom flask purged and maintained under an inert nitrogen atmosphere. Thionyl chloride (5.60 g, 47.8 mmol, 1.50 equivalent) was added dropwise at 0 °C. The resulting solution was stirred in an oil bath at 30 °C for 18 hours, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:30–1:10) as eluent to give 5.00 g (78%) of the title compound as a brown solid.

Compounds 351.2 and 351.3. Methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate and methyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate. A solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (3.00 g, 17.5 mmol, 1.00 equivalent) in N,N-dimethylformamide (30 mL) was placed in a round-bottom flask purged and maintained under an inert nitrogen atmosphere. Potassium carbonate (4.84 g, 35.0 mmol, 2.00 equivalent) and _CH3I (2.98 g, 21.0 mmol, 1.20 equivalent) were added at 0 °C. The resulting solution was stirred in an oil bath at 40 °C for 2 hours. After cooling to ambient temperature, the solid was removed by filtration, followed by the addition of 120 mL of ice water. The mixture was extracted with 3 × 100 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by recrystallization from diethyl ether. This yielded 1.10 g (34%) of methyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylic acid as a white solid. m/z (ES+) 186 (M+H) ⁺ . ^¹H -NMR, (300 MHz, DMSO- _d6 , ppm): δ 7.57 (s, 1H), 4.22 (s, 3H), 3.91 (s, 3H). The filtrate was concentrated under vacuum and the crude product (2 g) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (10% _CH3CN increased to 56.5% within 10 min); detector, UV 254 nm. The fractions containing the pure compound were combined and concentrated to give 470 mg (15%) of methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylic acid ester as a white solid. m/z (ES+) 186 (M+H) ⁺ . ^1H -NMR, (300 MHz, DMSO- _d6 , ppm): δ 7.64 (1H, s), 4.24 (3H, s), 3.87 (3H, s).

Compound 351.4. Methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate. Palladium on carbon (10%, 0.25 g) was added to a solution of methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate (351.2, 0.48 g, 2.60 mmol) in MeOH (15 mL) under nitrogen. The flask was further degassed with nitrogen and filled with _H₂ via a gasket. The mixture was stirred at room temperature for 1.5 h. After purging the system with nitrogen, the reaction mixture was filtered through a diatomaceous earth cake and concentrated to give 363 mg (90%) of white solid. m/z (ES+) 156 (M+H) ^⁺ .

Compound 351.5. Methyl 5-(3-isobutylureo)-1-methyl-1H-pyrazole-3-carboxylate. Triphosgene (0.084 g, 0.28 mmol) and DIEA (0.2 ml, 1.14 mmol) were added sequentially to a solution of methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate (compound 351.4, 0.088 g, 0.57 mmol) in THF (5 ml ₎ . After stirring the mixture at room temperature for 2 hours, isobutylamine (0.225 ml, 2.28 mmol) was added. The resulting mixture was stirred overnight at room temperature. The mixture was then partitioned between water and EtOAc. The EtOAc layer was washed sequentially with 1 _{M NaH₂PO₄ aqueous solution and brine, dried over Na₂SO₄ , and} concentrated to give 120 mg (83%) of a pale yellow solid. m/z(ES⁺) 255(M+H) ^⁺ .

Compound 351.6. 5-(3-isobutylureo)-1-methyl-1H-pyrazole-3-carboxylic acid. A solution of methyl 5-(3-isobutylureo)-1-methyl-1H-pyrazole-3-carboxylic acid (compound 351.5, 0.12 g, 0.47 mmol) in MeOH (5 mL) was mixed with 1 M LiOH in _H₂O (1.42 mL, 1.42 mmol). The mixture was stirred at room temperature for 5 hours. TLC showed the reaction was complete. The mixture was acidified to pH 3–4 at 0 °C and subsequently extracted with EcOAc (2 × 50 mL). The combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated to give 110 mg (100%) of a clear oil. _m /z(ES+) 241(M+H) ^⁺ .

Compound 351. 1-(3-(4-(4-cyanophenyl)piperidin-1-carbonyl)-1-methyl-1H-pyrazole-5-yl)-3-isobutylurea. A solution of 5-(3-isobutylureo)-1-methyl-1H-pyrazole-3-carboxylic acid (compound 351.6, 0.11 g, 0.46 mmol), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 0.097 g, 0.46 mmol), EDCI (0.090 g, 0.51 mmol), HOBT (0.065 g, 0.51 mmol, containing 20% _H₂O ) and DIEA (0.22 mL, 1.38 mmol) in DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with 50 mL of ethyl acetate and washed with 2 × 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC and developed with pure ethyl acetate to give 25 mg of the title compound as a grayish-white solid. m/z (ES+) 409 (M+H) ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.46 (s, 1H), 7.76 (d, 2H), 7.49 (d, 2H), 6.48 (t, 1H), 6.37 (s, 1H), 4.84 (d, 1H), 4.63 (d, 1H), 3.65 (s, 3H), 3.14 (m, 1H), 2.92 (t, 3H), 2.79 (m, 2H), 1.85 (m, 1H), 1.67 (m, 1H), 1.57 (m, 2H), 0.87 (d, 6H).

The compounds in the table below shall be prepared using standard chemical operations, readily available starting materials, and procedures similar to those used to prepare compounds 346, 347, 348, 349, 350, and 351:

Compound 392.1. 4-Cyclobutyl-5-formyl-2-methylbenzoic acid. A solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 230.1, 5.00 g, 12.7 mmol, 1.00 equivalent, 80%) in a solvent mixture of tetrahydrofuran and _Et₂O (50/50 mL) was placed in a three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Butyllithium (15 mL, 2.50 equivalent, 95%) was then added dropwise at -78 °C with stirring. N,N-dimethylformamide (2.50 g, 32.5 mmol, 2.00 equivalent) was added. The resulting solution was stirred at -78 °C for 1 hour and then carefully quenched by the slow addition of 50 mL of _NH₄Cl (aqueous solution). The pH was adjusted to 1–2 with hydrogen chloride (6 M). The resulting solution was diluted with 100 mL of ethyl acetate and then washed with 4 × 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:1) as the eluent to give 1.62 g (41%) of 4-cyclobutyl-5-formyl-2-methylbenzoic acid as a white solid.

Compound 392.2. 4-(1-(4-cyclobutyl-5-formyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound 392.1, 490 mg, 1.57 mmol, 1.00 equivalent, 70%) in N,N-dimethylformamide (8 mL) was placed in a round-bottom flask. Compound 1.5 (500 mg, 1.57 mmol, 1.00 equivalent), EDC·HCl (860 mg, 4.26 mmol, 2.00 equivalent, 95%), and 4-dimethylaminopyridine (550 mg, 4.28 mmol, 2.00 equivalent, 95%) were added to the reaction mixture. The resulting solution was stirred overnight at room temperature and then diluted with 30 mL of ethyl acetate. The resulting mixture was washed with 4 × 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:2) as the eluent to give 560 mg (74%) of the title compound as a white solid.

Compound 392. 4-(1-(4-cyclobutyl-5-formyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-[1-[(4-cyclobutyl-5-formyl-2-methylphenyl)carbonyl]piperidin-4-yl]benzonitrile (392.2, 300 mg, 0.74 mmol, 1.00 equivalent, 95%) in N,N-dimethylformamide (10 mL) was placed in a round-bottom flask. 3-Bromodihydro-2H-pyran-4(3H)-one (compound 1.10.1, 210 mg, 1.17 mmol, 1.00 equivalent), ammonia (82 mg, 0.59 mmol, 3.00 equivalent, 25% aqueous solution), and _NH₄OAc (270 mg, 2.81 mmol, 4.50 equivalent, 80%) were added, and the resulting mixture was stirred overnight at 130 °C under nitrogen. After cooling to room temperature, the mixture was diluted with 50 mL of ethyl acetate, washed with 4 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate as the eluent. The crude product (approximately 80 mg) was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN ( _CH3CN increased from 26% to 41% within 7 min, to 100% within 3 min, and decreased to 26% within 2 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 24.6 mg (7%) of the title compound as a white solid. m/z (ES+) 481 (M+H) ⁺ . ^¹H NMR (300 MHz, _CD₃ OD): δ 7.67 (d, J = 7.8 Hz, 2H), 4.47 (d, J = 8.1 Hz, 2H), 7.33 (br s, 1H), 7.26 and 7.15 (two singlets, amide rotational isomer, Ar-H, 1H), approximately 4.9 (1H, partially obscured by water peak), 4.68 (s, 2H), 4.06–3.88 (m, 3H), 3.73–3.58 (m, 1H), 3.33–3.18 (m, 1H), 3.07–2.92 (m, 2H), 2.83–2.73 (m, 2H), 2.44 and 2.34 (two singlets, amide rotational isomer, Ar-CH₃ ₎ , 3H), 2.25-1.91(m, 6H), 1.91-1.50(m, 4H). ¹ H NMR (400MHz, CDCl ₃ ): δ7.64(m, 2H), 7.34(m, 2H), 7.13-6.93(m, 2H), 4.99(m, 1H), 4.75(s, 2H), 3.98(m, 2H), 3 .73 (m, 1H), 3.53 (m, 1H), 3.31-2.83 (m, 5H), 2.41 (m, 1H), 2.37-1.61 (m, 11H), 1.44 (m, 1H).

Compound 393. 4-(1-(2-ethyl-4-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compounds 1 and 2, but with compound 211.2 used instead of compound 2.2. m/z(ES+)455(M+H) ⁺ .

Compound 394. 4-(1-(4-ethyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 393, but with compound 152.1 instead of methyl 2-bromo-4-methylbenzoate. m/z(ES+)455(M+H) ⁺ .

Compound 395. 4-(1-(4-ethyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 394, but with compound 11.2 hydrochloride instead of compound 1.5. m/z(ES+)473(M+H) ⁺ .

Compound 396. 4-(1-(2,4-diethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compounds 1 and 2, but with compounds 2.2 and 1.5 replaced by compounds 204.3 and 11.2, respectively. m/z(ES+)487(M+H) ⁺ .

Compound 397. 4-(1-(5-(5-acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and similar procedures to those used to prepare compounds 1 and 2, but with compound 204.3 instead of compound 2.2. m/z(ES+)510(M+H) ⁺ .

Compound 398. 4-(1-(5-(5-acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-ethyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compounds 1, 2, and 394. m/z(ES+)496(M+H) ⁺ .

Compound 399. 4-(1-(5-(5-acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-ethyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compounds 1, 2, and 394, but using compound 11.2 hydrochloride instead of compound 1.5. m/z(ES+)514(M+H) ⁺ .

Compound 400.1. 3-Methyldihydro-2H-pyran-4(3H)-one. A solution of LDA (2M THF, 132 mL, 1.20 equivalence) in tetrahydrofuran (300 mL) was added under a nitrogen atmosphere. The mixture was cooled to -78 °C, and then a solution of dihydro-2H-pyran-4(3H)-one (22.0 g, 220 mmol, 1.00 equivalence) in hexamethylphosphoramide (40 mL, 230 mmol, 1.05 equivalence) was added dropwise, followed by the dropwise addition of methyl iodine (34 mL, 550 mmol, 2.5 equivalence) at -78 °C. The resulting solution was stirred at -78 °C for 5 min, followed by stirring at 25 °C for 5 min. The reaction was carefully quenched with saturated _NH4Cl aqueous solution (80 mL) and extracted with diethyl ether (2 × 100 mL). The combined organic matter was dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using PE/ _Et₂O (5:1) as the eluent to give the title compound (6.00 _g , 24%) as a yellow oil.

Compound 400.2. 3-Bromo-5-methyldihydro-2H-pyran-4(3H)-one. A 250 mL three-necked round-bottom flask was purged and maintained under a nitrogen atmosphere. LDA (2.0 M in THF) (6 mL, 12 mmol, 1.20 equivalent) and tetrahydrofuran (30 mL) were added. The solution was cooled to -78 °C and then TMSCl (7 mL, 55 mmol) was added dropwise while stirring at -78 °C for 5 min. A solution of 3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1, 1.14 g, 9.99 mmol, 1.00 equivalent) in tetrahydrofuran (20 mL) was added dropwise and the resulting mixture was stirred at -78 °C for 10 min. The mixture was carefully quenched with a mixture of triethylamine (15 mL) and saturated _NaHCO3 aqueous solution (100 mL). The aqueous phase was extracted with diethyl ether (2 × 50 mL), and the combined organic matter was washed with citric acid aqueous solution ( ₃ × 100 mL), dried ( _K₂CO₃ ), filtered, and concentrated under vacuum to obtain a colorless oily intermediate, enol silyl ether. The enol silyl ether was dissolved in tetrahydrofuran (20 mL) and the system was purged with nitrogen. The mixture was cooled to 0 °C, and then N-bromosuccinimide (1.95 g, 11.0 mmol, 1.10 equivalent) was added fractionally. The resulting mixture was stirred at 25 °C for 1 hour, followed by quenching with saturated _NaHCO₃ aqueous solution (30 mL). The aqueous phase was extracted with diethyl ether (2 × 30 _mL ), and the combined organic matter was dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using PE/ _Et₂O (5:1) as the eluent to obtain the title compound (1.00 g, 52%), a colorless oily substance.

Compound 400.3. 2-Ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid. A solution of 3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2, 800 mg, 4.14 mmol, 1.6 equivalents) in N,N-dimethylformamide (5 mL) was placed in a round-bottom flask. Ammonium hydroxide (containing 25% _NH₃ in _H₂O ) (530 mg, 7.8 mmol, 3.0 equivalents), _NH₄OAc (904 mg, 11.7 mmol, 4.50 equivalents), and 2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4, 500 mg, 2.60 mmol, 1.00 equivalents) were added to the flask. The resulting mixture was stirred at 130 °C for 2 hours, followed by concentration under vacuum. The residue was purified by silica gel chromatography using dichloromethane/methanol (70/1) as the eluent to give the title compound (30.0 mg, 2%) as a white solid.

Compound 400. 4-(1-(2-ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. A solution of 2-ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid (compound 400.3, 30 mg, 0.10 mmol, 1.0 equivalent) in DMF/DCM (5/5 mL) was placed in a round-bottom flask. 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 50 mg, 0.22 mmol, 2.2 equivalent), EDC (40 mg, 2.0 equivalent), and 4-dimethylaminopyridine (28 mg, 2.0 equivalent) were added. The resulting solution was stirred overnight at 25°C, followed by quenching with water (10 mL). The mixture was extracted with ethyl acetate (3 × 5 _mL ), and the combined organic layers were dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (2:1) as the eluent to give the title compound (3.2 mg, 7%) as a pale yellow solid. m/z (ES+) 469 (M+H) ⁺ .

Compound 401. 4-(1-(4-cyclopropyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 392, but with compound 142.2 instead of compound 152.3. m/z(ES+)467(M+H) ⁺ .

Compound 402. 4-(1-(4-cyclopropyl-2-ethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 392, but with compound 226.5 instead of compound 230.1. m/z(ES+)481(M+H) ⁺ .

Compound 403. 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclopropyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid methyl ester. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compounds 1 and 2, but with compounds 142.2 and dimethyl dicarbonate/DIEA used instead of compounds 2.2 and acetic anhydride, respectively. m/z(ES+)524(M+H) ⁺ .

Compound 404. 4-(1-(5-(5-acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclopropyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and similar procedures to those used to prepare compounds 1 and 2, but with compound 142.2 substituted for compound 2.2. m/z(ES+)508(M+H) ⁺ .

Compound 405. 4-(1-(4-cyclobutyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 392, but with compound 11.2 hydrochloride instead of compound 1.5. m/z(ES+)499(M+H) ⁺ . ^1H NMR (300MHz, _CD3 OD) δ 7.97 (m, 2H), 7.97 (m, 2H), 7.67–7.53 (m, 2H), 4.80 (s, 2H), 4.10 (m, 2H), 3.75 (m, 1H), 3.55 (m, 2H), 3.27 (m, 1H), 2.90 (m, 2H), 2.53 and 2.43 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.38–1.80 (m, 10H).

Compound 406.1. 5-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclobutyl-2-methylbenzoic acid. A solution of 4-cyclobutyl-5-carboxylic acid (compound 392.1, 2.00 g, 9.16 mmol, 1.00 equivalent) in N,N-dimethylformamide (15 mL) was mixed with tert-butyl 3-bromo-4-oxopiperidin-1-carboxylic acid (9.00 g, 16.2 mmol, 2.00 equivalent), ammonium hydroxide (3.84 g, 27.4 mmol, 3.00 equivalent, 25%), and _NH₄OAc (3.18 g, 41.3 mmol, 4.50 equivalent). The resulting mixture was stirred overnight at 130 °C under nitrogen. After cooling to ambient temperature, the mixture was diluted with 50 mL of ethyl acetate, washed with 3 × 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (20:1) as the eluent to give 2.00 g (27%) of the title compound as a brown solid.

Compound 406.2. 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid tert-butyl ester. A solution of 5-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclobutyl-2-methylbenzoic acid (compound 406.1, 1.00 g, 1.22 mmol, 1.00 equivalent, 50%) in N,N-dimethylformamide (5 mL) was mixed with 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 270 mg, 1.21 mmol, 1.00 equivalent), EDC·HCl (460 mg, 2.40 mmol, 2.00 equivalent), and 4-dimethylaminopyridine (296 mg, 2.42 mmol, 2.00 equivalent). The resulting mixture was stirred overnight at 25 °C. The mixture was then diluted with 30 mL of ethyl acetate, washed with 3 × 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 890 mg (63%) of the title compound as a brown solid.

Compound 406.3. 4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. A solution of 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-carboxylic acid tert-butyl ester (406.2, 600 mg, 0.620 mmol, 1.00 equivalent, 60%) in dichloromethane (3 mL) and trifluoroacetic acid (1.5 mL) was stirred at 25 °C for 3 hours, and then diluted with 5 mL of hydrochloric acid (3 mol/L) and 10 mL of water. The resulting mixture was washed with 3 × 20 mL of ethyl acetate and then the pH was adjusted to approximately 9 with sodium hydroxide (aqueous solution, 3 M). The mixture was extracted with 4 × 20 mL of dichloromethane. The combined organic layers were _dried ( _Na₂SO₄ ) and concentrated under reduced pressure to give 140 mg (37%) of the title compound as a brown solid.

Compound 406. 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. NaBH(OAc)3 (252 mg, 1.13 mmol, 3.00 equivalent, 95%) and HCHO (37%) (2.2 mL, 2.00 equivalent) were added to a solution of 4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin- ₄ -yl)benzonitrile (406.3, 190 mg, 0.30 mmol, 1.00 equivalent, 75%) in tetrahydrofuran (10 mL). The resulting mixture was stirred in an oil bath at 40°C for 2 hours and then concentrated under reduced pressure. The residue was diluted with dichloromethane and washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried ( _Na₂SO₄ ) and concentrated. The crude product ₍ approximately 80 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, Xbridge Prep C18, 5 μm, 19 × 150 mm; mobile phase, water containing 0.03% _NH₃H₂O and _CH₃CN ( _CH₃CN increased from 36% to 48% within 8 min, to 100% within 1 min, and decreased to 36% within 1.5 min); detector, Waters 2489254 and 220 _nm . The fractions containing the purified compound were combined and lyophilized to give 23.4 mg (16%) of the title compound as a white solid. m/z (ES+) 494 (M+H) ^⁺ . ^¹H NMR (300 MHz, _CD₃ OD): δ 7.69 (d, J = 6.0 Hz, 2H), 7.48 (d, J = 6.0 Hz, 2H), 7.37–7.31 (m, 1H), 7.26 and 7.15 (two singlets, amide rotational isomer, Ar-H, 1H), approximately 4.9 (1H, partially obscured by water peak), 4.02–3.90 (m, 1H), 3.73–3.57 (m, 1H), 3.57 (s, 2H), 3.34–3.21 (m, 1H), 3.06–2.94 (m, 2H), 2.90–2.77 (m, 4H), 2.54 (s, 3H), 2.45 and 2.34 (two singlets, amide rotational isomer, ArCH₃ ₎ , 3H), 2.11-1.86(m, 6H), 1.86-1.54(m, 4H).

Compound 407. 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 406, but with compound 11.2 hydrochloride instead of compound 1.5. m/z(ES+)512(M+H) ⁺ .

Compound 408. 4-(1-(4-methyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 406, but with 3-iodo-4-methylbenzoic acid instead of compound 230.1. m/z(ES+)440(M+H) ⁺ .

Compound 409. 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (406.3, 180 mg, 0.300 mmol, 1.00 equivalent, 80%) in N,N-dimethylformamide (5 mL) was prepared by adding dimethyl dicarbonate (176 mg, 1.31 mmol, 5.00 equivalent) and DIEA (169 mg, 1.31 mmol, 5.00 equivalent). The resulting solution was stirred overnight at 25°C and then quenched with 20 mL of methanol. The resulting mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19×150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (28% _CH3CN increased to 43% within 8 min, to 100% within 3 min, and decreased to 28% within 2 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 29.9 mg (19%) of the title compound as a white solid. m/z (ES+) 538 (M+H) ⁺ . ^1H NMR (400MHz, _CD3 OD): δ 7.70 (m, 2H), 7.50–7.35 (m, 4H), 4.90 (m, 1H), 4.70 (s, 2H), 4.00 (m, 2H), 3.80 (m, 4H), 3.60 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.50 and 2.40 (two singlets, amide rotational isomer, _ArCH3 , 3H), 2.16–2.00 (m, 6H), 1.86–1.64 (m, 4H).

Compound 410. Methyl 2-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 409, but with compound 11.2 instead of compound 1.5. m/z(ES+)556(M+H) ⁺ . ^¹H NMR (400 MHz, _CD₃OD ) δ 7.78 (m, 2H), 7.67 (m, 2H), 7.35–7.20 (m, 2H), 4.80 (m, 1H), 4.55 (s, 2H), 4.00 (m, 1H), 4.84 (m, 2H), 3.77 (s, 3H), 3.60 (m, 1H), 3.28 (m, 1H), 2.80 (s, 2H), 2.47 and 2.36 (two singlets, amide rotational isomer, _ArCH₃ , 3H), 2.30–1.80 (m, 9H), 1.62 (m, 1H), 1.32 (m, 1H).

Compound 411. Methyl 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclopropyl-4-ethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 409, but with compound 226.5 instead of compound 230.1. m/z(ES+)538(M+H) ⁺ .

Compound 412. 4-(1-(4-cyclopropyl-2-ethyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 406, but with compound 226.5 instead of compound 230.1. m/z(ES+) 494(M+H) ⁺ .

Compound 413.1. 4-Cyclobutyl-3-iodobenzoic acid. A solution of compound 168.2 (11.0 g, 34.8 mmol, 1.00 equivalent) and sodium hydroxide (4.00 g, 100 mmol, 3.00 equivalent) in methanol (about 100 mL) was stirred overnight at 50 °C. After cooling to ambient temperature, the mixture was concentrated to dryness. The residue was dissolved in water (50 mL) and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 3–4 with 6 M aqueous hydrogen chloride solution. The precipitate was collected by filtration and dried to give 8.60 g (82%) of the title compound as a white solid.

Compound 413. 4-(1-(4-cyclobutyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 392, but with compound 413.1 instead of compound 230.1. m/z(ES+)477(M+H) ⁺ . ¹ H NMR (300MHz, CD ₃ OD) δ7.76-7.65(m, 5H), 7.48(m, 2H), 5.00(m, 1H), 4.80(s, 2H), 4.10(m, 2H), 3.80(m , 2H), 3.45(m, 1H), 3.04(m, 2H), 2.90(m, 2H), 2.18-1.95(m, 6H), 1.85-1.77(m, 4H).

Compound 414. 4-(1-(4-cyclobutyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 413, but with compound 11.2 hydrochloride instead of compound 1.5. m/z(ES+)485(M+H) ⁺ . ¹ H NMR (300MHz, CD ₃ OD) δ7.82-7.77 (m, 3H), 7.68-7.65 (m, 4H), 4.80 (m, 3H), 4.90 (m, 2H), 3.83-3.46 (m, 3H), 2.90 (m, 2H), 2.29 (m, 1H), 2.18-1.83 (m, 10H).

Compound 415. 4-(1-(4-cyclobutyl-3-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 414, but with 3-methyldihydro-2H-pyran-4(3H)-one instead of dihydro-2H-pyran-4(3H)-one. m/z(ES+) 499(M+H) ⁺ .

Compound 416. 4-(1-(4-cyclopropyl-3-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 413, but with bromo(cyclopropyl)magnesium and 3-methyldihydro-2H-pyran-4(3H)-one used instead of bromo(cyclobutyl)magnesium and dihydro-2H-pyran-4(3H)-one, respectively. m/z(ES+)467(M+H) ⁺ .

Compound 417. 4-(1-(4-cyclobutyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 406, but with compound 413.1 instead of compound 230.1. m/z(ES+) 480(M+H) ⁺ . ¹ H NMR (300MHz, CD ₃ OD) δ7.72-7.63 (m, 4H), 7.56 (s, 1H), 7.49 (m, 2H), 4.82 (m, 1H), 4.56 (s, 2H), 3.89 (m, 2H), 3.80 (m, 2H), 3.08 (m, 2H), 3.04 (s, 3H), 2.99 (m, 2H), 2.18-1.66 (m, 11H).

Compound 418. 4-(1-(4-cyclobutyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 417, but with compound 11.2 hydrochloride instead of compound 1.5. m/z(ES+)498(M+H) ⁺ . ¹ H NMR (300MHz, CD ₃ OD) δ7.79 (m, 2H), 7.74-7.59 (m, 5H), 4.73 (br s, 1H), 4.54 (br s, 2H), 3.94 (m, 2H), 3.76 (br s, 2H), 3.61 (br s, 1H), 3.20 (br s, 2H), 3.16 (s, 3H), 2.39-1.96 (m, 10H), 1.79 (m, 1H).

Compound 419. Methyl 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 409, but with compound 413.1 instead of compound 230.1. m/z(ES+) 524(M+H).

Compound 420. 2-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-cyclobutylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid methyl ester. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 409, but with compounds 413.1 and 11.2 replacing compounds 230.1 and 1.5, respectively. m/z(ES+)542(M+H).

Compound 421. Ethyl 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclobutylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 409, but with compounds 413.1 and diethyl dicarbonate used instead of compounds 230.1 and dimethyl dicarbonate, respectively. m/z(ES+) 538(M+H).

Compound 422. Methyl 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2-cyclopropylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 421, but with magnesium bromo(cyclopropyl) and dimethyl diethyl dicarbonate used instead of magnesium bromo(cyclobutyl) and diethyl dicarbonate, respectively. m/z(ES+)510(M+H).

Compound 423. 4-(1-(2,4-dimethyl-5-(5-(oxecyclobutane-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. A mixture of 4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 2.9, 62 mg), oxecyclobutane-3-one (18 μl), sodium cyanoborate (18 mg), and acetic acid (80 μl) in MeOH/THF (1:1 v/v) was stirred for 16 hours. The reaction mixture was then diluted with dichloromethane and washed successively with saturated sodium bicarbonate solution and brine. The organic layer was dried ( _MgSO₄ ) and concentrated. The residue was purified by preparative TLC in DCM with 8% MeOH to give 42 mg of white solid (60%). m/z (ES+) 496 (M+H) ⁺ . ^¹H NMR (400 MHz, chloroform-d) δ 7.63 (d, 2H), 7.32 (d, 2H), 7.27 and 7.20 (two singlets, amide rotational isomer, 1H), 7.02 (s, 1H), 4.96 (s, 1H), 4.74 (m, 4H), 3.88–3.77 (m, 1H), 3.63 (d, 1H), 3.49 (d, 2H), 3.08 (t, 1H), 2.97–2.62 (m, 6H), 2.45 (d, 3H), 2.31 and 2.22 (two singlets, amide rotational isomer, 3H), 2.11–1.40 (m, 4H).

Compound 424. 4-(1-(5-(5-cyclopropyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 423. m/z(ES+)480(M+H) ⁺ . ^¹H NMR (400 MHz, chloroform-d) δ 10.58, 7.61 (d, 2H), 7.33 (d, 2H), 7.23 and 7.15 (two singlets, amide rotational isomer, 1H), 6.97 (s, 1H), 4.93 (s, 1H), 3.80–3.66 (m, 2H), 3.64–3.49 (m, 1H), 3.02 (m, 3H), 2.91–2.64 (m, 4H), 2.41 (d, 3H), 2.28 and 2.18 (two singlets, amide rotational isomer, 3H), 2.07–1.86 (m, 2H), 1.84–1.37 (m, 2H), 0.66–0.40 (m, 4H).

Compound 425. 4-(1-(2,4-dimethyl-5-(5-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 406, but with compound 2.9 instead of compound 406.3. m/z(ES+)454(M+H) ⁺ .

Compound 426. 4-(1-(5-(5-ethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 423. m/z(ES+)468(M+H) ⁺ . ^¹H NMR (400 MHz, chloroform-d) δ 7.63 (d, 2H), 7.40–7.19 (m, 3H), 7.04 (s, 1H), 4.95 (s, 1H), 3.75–3.51 (m, 3H), 3.09 (m, 1H), 2.95–2.77 (m, 6H), 2.71 (m, 2H), 2.46 (s, 3H), 2.30 and 2.21 (two singlets, amide rotational isomer, 3H), 2.12–1.89 (m, 1H), 1.85–1.43 (m, 3H), 1.22 (m, 3H).

Compound 427. 4-(1-(5-(5-(2-fluoroethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. A mixture of 4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 2.9, 88 mg), 1-bromo-2-fluoroethane (150 μl), potassium iodide (50 mg), and triethylamine (140 μl) in DMF (2 mL) was stirred for 48 hours. The reaction mixture was then diluted with dichloromethane and washed with brine. The organic layer was dried ( _MgSO4 ) and concentrated. The residue was purified by preparative TLC using 8% MeOH in DCM to give 51 mg of white solid (52%). m/z(ES+)486(M+H) ⁺ . ^¹H NMR (400 MHz, chloroform-d) 7.63 (d, 2H), 7.32 (d, 2H), 7.28 and 7.20 (two singlets, amide rotational isomer, 1H), 7.00 (s, 1H), 4.93 (m, 1H), 4.67 (dt, _J1 = 47.6 Hz, _J2 = 4.9 Hz, 2H), 3.71 (d, 2H), 3.62 (d, 1H), 3.03–2.71 (m, 8H), 2.43 (d, 3H), 2.29 and 2.19 (two singlets, amide rotational isomer, 3H), 2.08–1.89 (m, 2H), 1.85–1.49 (m, 2H), 3.18–3.05 (m, 1H).

Compound 428. 4-(4-fluoro-1-(5-(5-(2-fluoroethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 427, but with compound 11.2 hydrochloride instead of compound 1.5. m/z(ES+)504(M+H) ⁺ . ^¹H NMR (400 MHz, chloroform-d) δ 7.70 (d, 2H), 7.50 (d, 2H), 7.28 and 7.21 (two singlets, amide rotational isomer, 1H), 7.00 (s, 1H), 4.92–4.77 (m, 1H), 4.66 (dt, _J1 = 47.7 Hz, _J2 = 4.8 Hz, 2H), 3.68 (d, 2H), 3.58–3.35 (m, 2H), 3.33–3.11 (m, 1H), 2.95 (dt, 4H), 2.76 (d, 2H), 2.42 (s, 3H), 2.28 and 2.20 (two singlets, amide rotational isomer, 3H), 2.16–1.72 (m, 4H).

Compound 429.1. 5-Oxalide heptane-1,4-dicarboxylic acid 1-tert-butyl-4-ethyl ester. A solution of _BF3 · _Et2O (16.0 mL, 1.30 equivalent) in ether (20 mL) was added dropwise to a solution of 4-oxopiperidin-1-carboxylic acid tert-butyl ester (20.0 g, 100 mmol, 1.00 equivalent) in diethyl ether (60 mL) at -30 °C. After stirring at -30 °C for 30 min, ethyl 2-diazoacetic acid (16.0 g, 140 mmol, 1.30 equivalent) in diethyl ether (20 mL) was added dropwise to the reaction mixture at -30 °C. The resulting solution was stirred at -30 °C for 1 h, followed by heating to 25 °C and stirring for 2 h. The reaction was then quenched with 100 mL of 30% potassium carbonate aqueous solution. The mixture was extracted with 2 × 250 mL of ethyl acetate, and the combined organic layers were washed with 2 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1/10) as the eluent to give 19.0 g (66%) of the title compound as a pale yellow oil.

Compound 429.2. 4-oxazolidinyl heptane-1-carboxylic acid tert-butyl ester. A solution of 1-tert-butyl-4-ethyl 5-oxazolidinyl heptane-1,4-dicarboxylic acid tert-butyl-4-ethyl ester (429.1, 19.0 g, 66.6 mmol, 1.00 equivalent) in 1,4-dioxane (190 mL) was added dropwise to a solution of sodium hydroxide (4.00 g, 100 mmol, 1.50 equivalent) in 100 mL of water. The resulting mixture was stirred overnight at room temperature. The pH was then adjusted to 4–5 with hydrogen chloride (aqueous solution, 3 M), and the solution was extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were washed with 2 × 10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:3) as eluent to give 11.0 g (77%) of the title compound as a yellow oil.

Compound 429.3. 4-Bromo-5-oxazacycloheptan-1-carboxylic acid tert-butyl ester. A solution of 4-oxazacycloheptan-1-carboxylic acid tert-butyl ester (429.2, 11.0 g, 51.6 mmol, 1.00 equivalent) in chloroform (220 mL) at 0 °C was added dropwise to a solution of _4- oxazacycloheptan-1-carboxylic acid tert-butyl ester (429.2, 11.0 g, 51.6 mmol, 1.00 equivalent) in chloroform (110 mL). The resulting mixture was stirred overnight at room temperature. The solid formed was collected by filtration and dissolved in 200 mL of dichloromethane. _Et3N (12.2 g) and (Boc) _2O (8.70 g, 40.3 mmol, 1.00 equivalent) were added to the mixture at 0 °C. The resulting solution was stirred at room temperature for 3 hours, followed by concentration under pressure. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:10) as the eluent to give 4.00 g (27%) of the title compound as a yellow oil.

Compound 429.4, 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]acoxane-6(1H)-carboxylic acid tert-butyl ester. Compound 16.4 (500 mg, 1.44 mmol, 1.00 equivalent), NH₄OH (606 mg, 4.33 mmol, 3.00 equivalent, 25%), and NH₄OAc (500 mg, 6.49 mmol, 4.50 equivalent) were added to a solution of 4-bromo-5-oxazacycloheptan- _1- carboxylic acid tert-butyl ester (429.3, 844 mg, 2.89 mmol, 2.00 equivalent) in N, _N -dimethylformamide (5 mL). The resulting mixture was stirred overnight at 130 °C under nitrogen. After cooling to ambient temperature, 30 mL of ethyl acetate was added. The resulting mixture was washed with 3 × 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate as the eluent to give 343 mg (43%) of the title compound as a brown solid.

Compound 429.5. 4-(1-(5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]acopenein-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile trifluoroacetate. Trifluoroacetic acid (1.3 mL) was added to a solution of compound 429.4 (550 mg, 0.990 mmol, 1.00 equivalent) in DCM (3 mL). After stirring at 25 °C for 4 hours, the mixture was concentrated under reduced pressure and dried to give 400 mg (71%) of the title compound as a brown solid.

Compound 429. 4-(1-(5-(6-acetyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]acopentam-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 2, but with compound 429.5 instead of compound 2.9. m/z(ES+)496(M+H) ⁺ . ¹ HNMR (300MHz, CD ₃ OD) δ7.65 (d, J=8.1Hz, 2H), 7.44-7.32 (m, 4H), 4.90 (m, 1H), 3.86 (m, 2H), 3.60 (m, 1H), 3.20(m, 2H), 3.00(m, 6H), 2.40-2.31(m, 6H), 2.20(s, 3H), 2.00-1.60(m, 5H).

Compound 430. Methyl 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]acoxane-6(1H)-carboxylic acid. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 409, but with compound 429.5 instead of compound 406.3. m/z(ES+)496(M+H) ⁺ .

Compound 431. 4-(1-(5-(6-isopropyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]acoxane-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-(5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]acoxane-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile trifluoroacetate (429.5, 80.0 mg, 0.140 mmol, 1.00 equivalent) in N,N-dimethylformamide (5 mL) was prepared by adding 2-iodopropane (270 mg, 1.59 mmol, 9.00 equivalent) and DIEA (205 mg, 1.59 mmol, 9.00 equivalent). The resulting solution was stirred overnight in an oil bath at 80°C. After cooling to ambient temperature, the mixture was diluted with 50 mL of ethyl acetate, washed with 3 × 20 _mL of brine, dried ( _Na₂SO₄ ), and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:10) as the eluent. The product (50 mg) was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(S HIMADZU)): column, Xbridge Prep C18, 5 _{μm, 19 × 150 mm; mobile phase, water containing 0.03% NH₃H₂O and CH₃CN (CH₃CN increased from 38.0} % to 51.0% within 8 min, to 100.0% within 2 min, and decreased to 38.0% within 1 min); detector, Waters 2489254 and 220 nm. The fractions containing the pure compound were combined and lyophilized to give 15.0 mg (21%) of the title compound as a white solid. m/z(ES+) 496(M+H) ⁺ . ^1H NMR (400MHz, _CD3OD ) δ 7.69 (d, J = 8.0Hz, 2H), 7.49 (m, 2H), 7.33–7.23 (m, 2H), 4.86 (m, 1H), 3.65 (m, 1H), 3.30 (m, 1H), 3.15 (m, 1H), 2.99 (m, 6H), 2.80 (m, 4H), 2.45 (s, 3H), 2.40 and 2.29 (two singlets, amide rotational isomer, 3H), 2.10 (m, 1H), 1.70 (m, 3H), 1.15 (d, J = 6.8Hz, 6H).

Compound 432. 4-(1-(5-(5-ethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 431, but with compound 2.9 instead of compound 429.5. m/z(ES+)482(M+H) ⁺ .

Compound 433. 4-(1-(4-cyclopropyl-5-(5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 431, but with compounds 142.2 and 3-bromo-4-oxopiperidin-1-carboxylic acid tert-butyl ester instead of compounds 152.3 and 5-oxozyracycloheptane-1,4-dicarboxylic acid tert-butyl 4-ethyl ester (429.2), respectively. m/z(ES+)508(M+H) ⁺ .

Compounds 434 and 435. 4-(1-(2,4-dimethyl-5-(4,5,7,8-tetrahydro-1H-oxaconzo[4,5-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile and 4-(1-(2,4-dimethyl-5-(4,6,7,8-tetrahydro-1H-oxaconzo[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compounds were prepared as a separable mixture using standard chemical operations and a procedure similar to that used to prepare compound 429, but with oxepane-4-one instead of compound 4-oxozhepane-1-carboxylic acid tert-butyl ester (429.2). 434: m/z(ES+)455(M+H) ⁺ . 435: m/z(ES+)455(M+H) ⁺ .

Compound 436. 4-(1-(5-(6-(2-fluoroethyl)-1,4,5,6,7,8-hexahydroimidazo[4,5-d]acopentam-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compound 427, but with compound 429.5 substituted for compound 2.9. m/z(ES+)500(M+H) ⁺ . ^1H NMR (400MHz, CD ₃ OD) δ 7.64 (d, J = 8.1Hz, 2H), 7.43 (m, 2H), 7.28–7.20 (m, 2H), 4.86 (m, 1H), 4.60 (dt, J ₁ = 47.7Hz, J ₂ = 4.8Hz, 2H), 3.60 (m, 1H), 3.20 (m, 1H), 3.00 (m, 8H), 2.80 (m, 4H), 2.40 (s, 3H), 2.35 and 2.24 (two singlets, amide rotational isomer, 3H), 1.99 (m, 1H), 1.70 (m, 3H).

Compound 437. 4-(1-(4-cyclobutyl-3-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]acopentenyl-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 418, but with compound 429.3 substituted for tert-butyl 3-bromo-4-oxopiperidin-1-carboxylate. m/z(ES+)512(M+H) ⁺ .

Compound 438. 4-(1-(4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]acopentenyl-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 407, but with compound 429.3 substituted for compound tert-butyl 3-bromo-4-oxopiperidin-1-carboxylate. m/z(ES+)526(M+H) ⁺ .

Compound 439. 4-(1-(4-cyclobutyl-3-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]acoxane-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 417, but with compound 429.3 substituted for tert-butyl 3-bromo-4-oxopiperidin-1-carboxylate. m/z(ES+)494(M+H) ⁺ .

Compound 440. 4-(1-(4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]acopentenyl-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 406, but with compound 429.3 substituted for tert-butyl 3-bromo-4-oxopiperidin-1-carboxylate. m/z(ES+)508(M+H) ⁺ .

Compound 441.(R)-1-(2-chloro-5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-4-ethylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea. The title compound was prepared using readily available reagents and a similar procedure to that used to prepare compound 67, with compound 178.2 replacing compound 48.1. m/z(ES+)513(M+H) ⁺ .

Compound 442.(R)-1-(2-chloro-4-ethyl-5-(4-fluoro-4-(4-fluorophenyl)piperidin-1-carbonyl)phenyl)-3-((tetrahydrofuran-2-yl)methyl)urea. The title compound was prepared using readily available reagents and a similar procedure to that used to prepare compound 67, with compound 178.2 replacing compound 48.1. m/z(ES+)506(M+H) ⁺ .

Compound 443.1. Methyl 4-cyclobutyl-3-nitrobenzene. Fuming _HNO3 (5 mL, 97%) was added dropwise to a solution of methyl 4-cyclobutylbenzoe (compound 168.1, 3.80 g, 20.0 mmol, 1.00 equivalent) in acetic anhydride (12 mL) at 0 °C. The mixture was stirred in an oil bath at 30 °C. After 2 hours, 30 mL of water was carefully added and the mixture was extracted with 2 × 30 mL of ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of _NaHCO3 (note: gas escape), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:25) as eluent to give 3.00 g (64%) of the title compound as a pale yellow oil.

Compound 443.2. Methyl 3-amino-4-cyclobutylbenzoate. A flask containing a solution of methyl 4-cyclobutyl-3-nitrobenzene (compound 443.1, 2.50 g, 10.6 mmol, 1.00 equivalent) in methanol (30 mL) was purged with nitrogen. Palladium on carbon (10%, 60% water, 1.2 g) was added and the flask was carefully purged with nitrogen again. The atmosphere was then changed to hydrogen and the mixture was stirred overnight at 20 °C. After purging the system with nitrogen, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:5) as eluent to give 1.60 g (73%) of the title compound as a white solid.

Compound 443.3. 3-Amino-4-cyclobutylbenzoic acid. A solution of methyl 3-amino-4-cyclobutylbenzoate (1.00 g, 4.87 mmol, 1.00 equivalent) and sodium hydroxide (compound 443.2, 800 mg, 20.0 mmol, 4.00 equivalent) in a solvent mixture of methanol and _H₂O (20/10 mL) was placed in a round-bottom flask. The resulting solution was stirred at 20 °C for 8 hours. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The pH of the remaining aqueous layer was adjusted to approximately 4–5 with HCl (aqueous solution, 1 M). The resulting precipitate was then collected by filtration and dried to give 500 mg (54%) of the title compound as a white solid.

Compound 443.4. 4-(1-(3-amino-4-cyclobutylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using a similar procedure to that used to prepare compound 42.2, but with compound 443.3 instead of compound 42.1.

Compound 443.(R)-1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-cyclobutylphenyl)-3-(tetrahydrofuran-3-yl)urea. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 64, replacing compounds 42.2 and (R)-(tetrahydrofuran-2-yl)methylamine with compounds 443.4 and (R)-tetrahydrofuran-3-amine, respectively. m/z(ES+)491(M+H) ⁺ .

Compound 444. (S)-1-(5-(4-(4-cyanophenyl)-4-fluoropiperidin-1-carbonyl)-2-cyclobutylphenyl)-3-(tetrahydrofuran-3-yl)urea. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 443, with (S)-tetrahydrofuran-3-amine instead of (R)-tetrahydrofuran-3-amine. m/z(ES+)491(M+H) ⁺ . ^1H NMR (300MHz, _CD3OD ): δ 7.83–7.77 (m, 3H), 7.69 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.1 Hz, 1H), 7.22 (dd, J = 7.8 Hz, J = 1.5 Hz, 1H), 4.80–4.62 (m, 1H), 4.39–4.31 (m, 1H), 4.02–3.78 (m, 4H), 3.72–3.49 (m, 3H), approximately 3.3 (1H, partially obscured by methanol solvent peak), 2.50–2.37 (m, 2H), 2.37–1.78 (m, 10H).

Compound 445.1. Methyl 4-cyclobutyl-2-methyl-5-(3-oxopentanoyl)benzoate. LiHMDS (680 mg, 4.06 mmol, 2.00 equivalent) in tetrahydrofuran (5 mL) was added dropwise to a solution of methyl 5-acetyl-4-cyclobutyl-2-methylbenzoate (compound 238.1, 500 mg, 2.03 mmol, 1.00 equivalent) in tetrahydrofuran (15 mL) at 0 °C. After stirring at 0 °C for 30 min, propionyl chloride (280 mg, 3.03 mmol, 1.50 equivalent) in tetrahydrofuran (5 mL) was added dropwise. The resulting mixture was stirred at 15 °C for 31 min and then concentrated under reduced pressure. The residue was diluted with 40 mL of ethyl acetate, washed with brine (3 × 40 _mL ), dried ( _Na₂SO₄ ), and concentrated under reduced pressure. This produces 500 mg (crude) of the title compound, which is brown and oily.

Compound 445.2. Methyl 4-cyclobutyl-5-(5-ethyl-1H-pyrazole-3-yl)-2-methylbenzoate _{. NH₂NH₂} · _H₂O was added to a solution of methyl 4-cyclobutyl-2-methyl-5-(3-oxopentanoyl)benzoate (compound 445.1, 300 mg, 0.990 mmol, 1.00 equivalent) in methanol (15 mL). The resulting solution was stirred in an oil bath at 80 °C for 1.5 h and then concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate, washed with 3 × 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:5) as eluent to give 188 mg (64%) of the title compound as a yellow oil.

Compound 445.3. 4-Cyclobutyl-5-(5-ethyl-1H-pyrazole-3-yl)-2-methylbenzoic acid. An aqueous solution of sodium hydroxide (76.0 mg, 1.90 mmol, 3.00 equivalent in 3 mL of water) was added to a solution of methyl 4-cyclobutyl-5-(5-ethyl-1H-pyrazole-3-yl)-2-methylbenzoate (compound 445.2, 188 mg, 0.630 mmol, 1.00 equivalent) in methanol (6 mL). The resulting solution was stirred in an oil bath at 70 °C for 2 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was diluted with 20 mL of _H₂O . The pH of the mixture was adjusted to approximately 4 with an aqueous solution of HCl (2 M) _. The mixture was then extracted with 3 × 20 mL of ethyl acetate. The combined organic layers were washed with 3 × 20 mL of brine, dried ( _Na₂SO₄ ), and concentrated under reduced pressure. This produces 0.180 g (crude) of the title compound, which is a yellow, oily substance.

Compound 445. 4-(1-(4-cyclobutyl-5-(5-ethyl-1H-pyrazole-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-cyclobutyl-5-(5-ethyl-1H-pyrazole-3-yl)-2-methylbenzoic acid (compound 445.3, 130 mg, 0.460 mmol, 1.00 equivalent) in N,N-dimethylformamide (5 mL) was supplemented with 4-(piperidin-4-yl)benzonitrile hydrochloride (1.5, 102 mg, 0.460 mmol, 1.00 equivalent), EDCI (176 mg, 0.920 mmol, 2.00 equivalent), and 4-dimethylaminopyridine (112 mg, 0.920 mmol, 2.00 equivalent). The resulting solution was stirred at 30 °C for 2 hours and then diluted with 40 mL of ethyl acetate. The mixture was washed with 3 × 40 mL of brine, _dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH₃CN ( _CH₃CN increased from 59.0% to 73.0% within 6 min, to 100.0% within 7 min, and decreased to 59.0% within 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 150 mg (72%) of the title compound as a white solid. m/z (ES+) 453 (M+H) ⁺ .

Compound 446.1 methyl 4-cyclobutyl-2-methyl-5-((trimethylsilyl)ethynyl)benzoate. A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 152.3, 1.32 _{g, 4 mmol), trimethylsilyl ethynylene (663 μl, 4.8 mmol), Pd(PPh3)2Cl2 ( 85} mg, 0.12 mmol), and copper iodide (CuI, 46 mg, 0.24 mmol) in THF (8 mL) and triethylamine (2 mL) was degassed and then heated to 80 °C for 1.5 h under nitrogen. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth and concentrated. The residue was dissolved in ethyl acetate (EtOAc), washed with brine, dried over _MgSO4 , and concentrated. The residue was purified by rapid chromatography ( _SiO₂ ; hexane containing 3% EtOAc) to give 1.17 g (97%) of the title compound in liquid form. ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.01 (s, 1H), 7.15 (s, 1H), 4.01–3.75 (m, 4H), 2.63 (s, 3H), 2.54–2.31 (m, 2H), 2.27–2.12 (m, 2H), 2.12–1.98 (m, 1H), 1.94–1.80 (m, 1H), 0.28 (s, 9H).

Compound 446.2. Methyl 4-cyclobutyl-5-ethynyl-2-methylbenzoate. 4.1 mL of TBAF (1.0 M in THF) was added to a solution of compound 446.1 (1.17 g, 3.9 mmol) in 6 mL of THF at -20 °C. The mixture was stirred at this temperature for 30 min and then diluted with water (15 mL) and extracted twice with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO₄ ), and concentrated. The residue was purified by rapid chromatography ( _SiO₂ ; hexane containing 2% EtOAc) to give 816 mg (91%) of the title compound in liquid form. m/z (ES-) 227 (MH) ⁺ . ¹ H NMR (400MHz, CDCl ₃ )δ8.05(s, 1H), 7.20(s, 1H), 4.02-3.80(m, 4H), 3.25(s, 1H), 2.64(s, 3H), 2 .52-2.38(m, 2H), 2.29-2.13(m, 2H), 2.12-1.98(m, 1H), 1.93-1.79(m, 1H).

Compound 446.3. Methyl 4-cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoate. Methyl 4-cyclobutyl-5-ethynyl-2-methylbenzoate (compound 446.2, 180 mg, 0.69 mmol) was dissolved in TMSN ₃ (1 ml) in a sealed tube. The reaction was heated to 170 °C for 24 hours after explosion-proof shielding, followed by cooling to 0 °C. EtOAc (10 ml) and water (20 ml) were added. The resulting mixture was stirred at room temperature for 1 hour. The organic phase was then washed with brine, dried ( _MgSO4 ), and concentrated. The residue was purified by rapid chromatography ( _SiO2 ; hexane containing 0-30% EtOAc) to give 92 mg (49%) of the title compound in liquid form. m/z (ES+)(272)(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ )δ8.04(s, 1H), 7.83(s, 1H), 7.35(s, 1H), 3.90(s, 4H), 2.69(s, 3H), 2.2 7-2.15 (m, 2H), 2.13-2.03 (m, 2H), 1.99-1.90 (m, 1H), 1.86-1.76 (m, 1H).

Compound 446.4. 4-Cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoic acid. A solution of methyl 4-cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoate (compound 446.3, 92 mg, 0.34 M) in 2N NaOH (1.5 mL) and methanol (MeOH) (4 mL) was heated at 50 °C for 16 hours. After cooling to room temperature, the methanol was removed under reduced pressure. The residue was neutralized to pH 3-4 with 2N HCl and extracted with EtOAc. The organic phase was then washed with brine, dried ( _MgSO₄ ), and concentrated to give 83 mg of a white solid, which was used without further purification. m/z (ES-) 256 (MH) ⁺ .

Compound 446. 4-(1-(4-cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoyl)piperidin-4-yl)benzonitrile. A mixture of the above acid (compound 446.4, 44 mg, 0.17 mmol), compound 1.5 (42 mg, 0.19 M), EDCI (49 mg, 0.26 mmol), HOBt (33 mg, 0.19 mmol), and DIEA (120 μl, 0.68 mmol) in DMF (1 mL) was stirred at room temperature for 2.5 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over _MgSO4 , and concentrated. The residue was purified by rapid chromatography ( _SiO2 ; dichloromethane in 8% methanol) to give 46 mg of the title compound (70%) in foamy form. m/z (ES+) 426 (M+H) ⁺ . ^¹H NMR (400 MHz, _CDCl₃ ) δ 12.20 (s, 1H), 7.70 (d, 1H), 7.66–7.49 (m, 2H), 7.44–7.21 (m, 4H), 5.01 (d, 1H), 3.83 (p, 1H), 3.72 (d, 1H), 3.27–3.06 (m, 1H), 2.91 (m, 2H), 2.46 (two singlets, amide rotational isomer, 3H), 2.27–1.89 (m, 3H), 1.86–1.43 (m, 7H).

Compound 447. 4-(1-(4-cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using a similar procedure to that used to prepare compound 446, but with compound 11.2 hydrochloride substituted for compound 1.5. m/z(ES+)(444)(M+H) ⁺ . ^¹H NMR (400 MHz, _CDCl₃ ) δ 12.00 (s, 1H), 7.77 (s, 1H), 7.67 (m, 2H), 7.49 (d, 2H), 7.37 (m, 2H), 4.92 (d, 1H), 3.85 (t, 1H), 3.61 (m, 1H), 3.52 (m, 1H), 3.25 (m, 1H), 2.45 (two singlets, amide rotational isomer, 3H), 2.28–1.89 (m, 8H), 1.85 (m, 2H).

Compound 448.1. Methyl 5-(6,7-dihydro-4H-pyrano[4,3-d]thiazolyl-2-yl)-2,4-dimethylbenzoate. Sodium bicarbonate (396 mg, 4.71 mmol, 1.00 equivalent) and 3-bromodihydro-2H-pyrano-4(3H)-one (compound 1.10.1, 186 mg, 1.04 mmol, 1.00 equivalent) were added to a solution of methyl 5-thiocarbamoyl-2,4-dimethylbenzoate (compound 130.1, 500 mg, 2.24 mmol, 1.00 equivalent) in ethanol (5 mL) to be added. The resulting solution was stirred overnight at 80 °C under nitrogen. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in 10 mL of water and ethyl acetate. The aqueous phase was extracted with 2 × 20 mL of ethyl acetate, and the combined organic layers were dried ( _MgSO₄ ) and concentrated under reduced pressure to give 400 mg (56%) of the title compound as a yellow solid.

Compound 448.2. 5-(6,7-dihydro-4H-pyrano[4,3-d]thiazolyl-2-yl)-2,4-dimethylbenzoic acid. A solution of compound 448.1 (304 mg, 1.00 mmol) and sodium hydroxide (aqueous solution, 280 mg, 7.00 mmol in 3 mL of water) in methanol (5 mL) was stirred in an oil bath at 56 °C for 1 hour. After cooling to ambient temperature, the methanol was removed under reduced pressure. The pH of the remaining aqueous layer was adjusted to 3–4 with hydrogen chloride (aqueous solution, 2 M). The precipitate was collected by filtration and dried in an oven under reduced pressure to give 230 mg (79%) of the title compound as a yellow solid.

Compound 448. 4-(1-(5-(6,7-dihydro-4H-pyrano[4,3-d]thiazolyl-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. A solution of compound 448.2 (100 mg, 0.35 mmol, 1.00 equivalent) in N,N-dimethylformamide (3 mL), DIEA (140 mg, 1.08 mmol, 3.00 equivalent), and HBTU (197 mg, 0.52 mmol, 1.50 equivalent) was stirred at 25 °C for 0.5 h. A solution of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 92.2 mg, 0.41 mmol, 1.10 equivalent) in DIEA (1 mL) was added dropwise. The resulting solution was stirred at 25 °C for 0.5 h, followed by quenching with 10 mL of water. The aqueous phase was extracted with 2 × 20 mL of ethyl acetate, and the combined organic layers were washed with 1 × 20 mL of water and 1 × 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:1) as the eluent. The product was further purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19 × 150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN (25% _CH3CN rising to 80% within 7 min, to 100% within 1 min, and decreasing to 25% within 1 min); detector, Waters 2489254 and 220 nm. The fractions containing the purified compound were combined and lyophilized to give 134.9 mg (85%) of the title compound as a white solid. m/z (ES+) 458 (M+H) ⁺ .

Compounds 449.1 and 400.1. 3,3-Dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1) and 3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1). Under argon atmosphere, at -78°C, 50 mL of THF (4.612 g, 46 mmol) of dihydro-2H-pyran-4(3H)-one was added dropwise to an LDA solution (2.0 M, in heptane/THF/ethylbenzene) (28 mL, 55 mmol). The mixture was stirred at -78°C for 5 minutes, followed by the addition of 500 mL of THF (14 mL, 225 mmol) of iodomethane. The resulting mixture was then heated to 0°C and stirred at 0°C for 2 hours. The reactants were heated to room temperature for 5 minutes, then cooled to 0°C and quenched with saturated ammonium chloride (30 mL). The mixture was then extracted with diethyl ether (2 × 50 mL). The combined organic compounds were washed with brine (50 mL), dried ( _MgSO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane in 15% ethyl acetate) to give an oily 3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1) (694 mg, 13%) and an oily 3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1) (860 mg, 16%).

Compound 449.2. 5-Bromo-3,3-dimethyldihydro-2H-pyran-4(3H)-one. A solution of lithium diisopropylamine (2.0 M, in heptane/THF/ethylbenzene) diluted with THF (10 mL) (2.5 mL, 5.1 mmol) was cooled to -78 °C under argon. Trichlorosilane (2.5 mL, 19.5 mmol) was added, followed by a THF (5 mL) solution of 3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1, 500 mg, 3.9 mmol) and triethylamine (8.0 mL, 57 mmol). The resulting mixture was stirred at -78 °C for 5 min and then quenched with saturated _NaHCO3 (20 mL). The mixture was extracted with diethyl ether (30 mL) and the organic matter was washed with 1 M citric acid (50 _mL ), dried ( _K₂CO₃ ), filtered, and concentrated under vacuum. The residue was dissolved in THF (5 mL) and cooled to 0 °C. N-bromosuccinimide (694 mg, 3.9 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours and then quenched with saturated _NaHCO₃ (10 mL). The mixture was extracted with diethyl ether (2 × 20 mL) and the organic matter was washed with brine, dried ( _MgSO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane in 8% ethyl acetate) to give the title compound (150 mg, 18%) as an oil.

Compound 449.3. Methyl 5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoate. A mixture of 5-bromo-3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.2, 150 mg, 0.72 mmol), methyl 5-formamidinyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 135 mg, 0.55 mmol), and potassium carbonate (228 mg, 1.65 mmol) in acetonitrile (8 mL) was heated at 100 °C for 48 hours. The mixture was concentrated under vacuum, and the residue was dissolved in ethyl acetate (10 mL) and washed with brine (20 mL), dried ( _MgSO4 ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane in 50% ethyl acetate) to give the title compound (27 mg, 15%) as a white solid.

Compound 449.4. 5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoic acid. 2M lithium hydroxide (430 μl, 0.86 mmol) was added to 3 mL of THF containing methyl 5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoate (compound 449.3, 27 mg, 0.086 mmol), and the mixture was heated at 50 °C for 16 h. The volatile solvent was removed under vacuum, and the resulting residue was neutralized to pH 3 with 2M HCl and concentrated under vacuum to give a white solid, which was used in the next reaction without further purification. m/z (ES-) 299 (MH) ^- .

Compound 449. 4-(1-(5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. Crude 5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoic acid (compound 449.4, 0.086 mmol) was dissolved in DMF (1 mL). 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 19 mg, 0.086 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylurea (HBTU) (65 mg, 0.17 mmol), and DIEA (45 μl, 0.26 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was then diluted with ethyl acetate (10 mL) and washed with brine (10 mL), dried ( _MgSO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (ethyl acetate) to give the title compound (15 mg, 30%) as a solid foam. m/z (ES+) 469 (M+H) ⁺ .

Compound 450. 4-(1-(2,4-dimethyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare compound 449, but with 3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1) instead of 3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z(ES+)455(M+H) ⁺ .

Compounds 451.1 and 451.2: tert-butyl 3-methyl-4-oxopiperidin-1-carboxylate and tert-butyl 3,3-dimethyl-4-oxopiperidin-1-carboxylate. Sodium hydride (60%, in mineral oil) (1.27 g, 31.8 mmol) was suspended in THF (80 mL) under a nitrogen atmosphere. Tert-butyl 4-oxopiperidin-1-carboxylate (6.0 g, 30 mmol) was added fractionally at room temperature. The mixture was stirred at room temperature for 1.5 h, followed by the addition of methyl iodine (3.8 mL, 6.1 mmol). The mixture was stirred overnight at room temperature and then cooled to 0 °C and carefully quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL), dried ( _Na₂SO₄ ), _filtered , and concentrated under vacuum. The crude product was purified by silica gel chromatography (10:1 hexane/ethyl acetate) to obtain compound 451.1 (1.7 g, 27%) as a transparent oil and compound 451.2 (963 mg, 14%) as a crystalline solid.

Compound 451.3. 5-Bromo-3,3-dimethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester. 3,3-Dimethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (0.963 g, 4.24 mmol) was dissolved in THF (10 mL) and then phenyltrimethylammonium tribromide (PTAT) (1.59 g, 4.24 mmol) was added. The mixture was stirred at room temperature for 2 hours, followed by the addition of water (20 mL) and extraction with ethyl acetate ( ₁₀₀ mL). The organic matter was dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (10:1 hexane/ethyl acetate) to give compound 451.3 (0.94 g, 73%) as a white crystalline solid.

Compound 451. 4-(4-(5-(5-acetyl-7,7-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)cyclohexyl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 2, but with 5-bromo-3,3-dimethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (compound 451.3) instead of 3-bromo-4-oxopiperidin-1-carboxylic acid tert-butyl ester. m/z(ES+)510(M+H) ⁺ .

Compound 452. 4-(1-(5-(5-isopropyl-7,7-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. 4-(1-(5-(7,7-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (0.12 g, 0.26 mmol) (an intermediate prepared in the synthesis of compound 451), DMF (4 mL), acetic acid (69 μL, 1.21 mmol), sodium triacetoxyborohydride (0.11 g, 0.52 mmol), and acetone (0.50 mL, 6.8 mmol) were mixed and stirred at room temperature for 2 hours. The reaction was carefully quenched with water (10 mL) and the mixture was extracted with ethyl acetate ( ₆₀ mL). The organic matter was dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The crude product was purified sequentially by preparative TLC (DCM/10% MeOH) and a second preparative TLC (ethyl acetate/5% MeOH) to give the title compound (4.1 mg, 8.1%) as a white powder. m/z (ES+) 510 (M+H) ⁺ .

Compound 454.1. 4-Methoxy-2-methylpyridine-1(2H)-carboxylic acid phenyl ester. A solution of 4-methoxypyridine (30.0 g, 275 mmol, 1.00 equivalent) in tetrahydrofuran (1.2 L) was added under a nitrogen atmosphere purged and maintained. The mixture was cooled to -40 °C and phenyl chloroformate (45.0 g, 287 mmol, 1.05 equivalent) was added dropwise. The resulting solution was stirred at -40 °C for 1 hour, followed by the addition of methylmagnesium bromide (3 M, 110 mL, 1.20 equivalent) to the reaction mixture while maintaining the temperature at -40 °C. The resulting solution was slowly heated to 5–10 °C and stirred for 2 hours, followed by careful quenching with ice water (100 mL). The mixture was extracted with ethyl acetate (2 × 1 L) and the combined organic matter was washed with brine (1 × 300 _mL ), dried ( _Na₂SO₄ ), filtered and concentrated under vacuum to give the title compound (71.0 g, > theoretical value), which is a light brown oil.

Compound 454.2. 2-Methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester. A solution of 4-methoxy-2-methylpyridine-1(2H)-carboxylic acid phenyl ester (454.1, 70.0 g, 285 mmol, 1.00 equivalent) in tetrahydrofuran (1.2 L) was added under a nitrogen atmosphere. The solution was cooled to -78 °C, and then potassium tert-butoxide (128 g, 1.14 mol, 4.00 equivalent) was added fractionally. The resulting mixture was stirred at 10–15 °C for 20 h, and then concentrated under vacuum. The residue was dissolved in EtOAc (1.5 L) and then carefully quenched with ice water (200 mL). The layers were separated and the aqueous phase was extracted with additional ethyl acetate (100 mL). The combined organic compounds were washed with aqueous sodium hydroxide solution (1.5 M, 3 × 100 mL), aqueous hydrochloric acid solution (1 M, 2 × 100 mL), and brine (200 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:200–1:20) as the eluent to give the title compound (31.0 g, 51%) as a pale yellow oil.

Compounds 453.1 and 454.3. 6-Methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (453.1) and 2-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (454.3). A solution of 2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (compound 454.2, 10.5 g, 49.5 mmol, 1.00 equivalent) in tetrahydrofuran (300 mL) was added while purging and maintaining a nitrogen atmosphere in a 500 mL three-necked round-bottom flask. The solution was cooled to -78 °C and trisec-butylborohydride (1 M in THF, 60 mL, 1.20 equivalent) was added dropwise. The resulting solution was stirred at -78°C for 2 hours, followed by dropwise addition of chlorotrimethylsilane (6.96 g, 64.1 mmol, 1.30 equivalents) with stirring. The resulting solution was stirred at 10–15°C for 16 hours and then concentrated under vacuum. The residue was diluted with n-hexane (500 mL) and the solid was filtered off. The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:100–1:20) as the eluent to give a mixture of the title compounds (10.0 g, 71%) as a pale yellow solid.

Compounds 453.2 and 454.4. 5-Bromo-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (453.2) and 3-bromo-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (454.4). A mixture of 6-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and 2-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (compounds 453.1 and 454.2, 4.00 g, 12.5 mmol, 1.00 equivalent, 89% composite purity) in tetrahydrofuran (250 mL) was placed in a round-bottom flask. The mixture was cooled to 0–5 °C and N-bromosuccinimide (4.97 g, 27.9 mmol, 2.2 equivalents) was added to the reaction mixture in portions. The resulting mixture was stirred at 25 °C for 2 hours, followed by concentration under vacuum. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:100–1:10) as the eluent to give a mixture of the title compounds (2.50 g, 69%) as a yellow oil.

Compounds 453.3 and 454.5. 5-(5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoic acid (453.3) and 5-(5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoic acid (454.5). A mixture of tert-butyl 5-bromo-2-methyl-4-oxopiridine-1-carboxylate and tert-butyl 3-bromo-2-methyl-4-oxopiridine-1-carboxylate (compounds 453.2 and 454.4, 1.60 g, 5.48 mmol, 1.00 equivalent) in N,N-dimethylformamide (10 mL) was added. 5-Formyl-2,4-dimethylbenzoic acid (compound 16.3, 978 mg, 5.49 mmol, 1.00 equivalent), ammonium acetate (1.90 g, 24.7 mmol, 4.50 equivalent), and ammonium hydroxide (2.88 g, 16.4 mmol, 3.00 equivalent, 20%) were added, and the resulting mixture was stirred at 130 °C for 2 hours. The mixture was cooled to 10–15 °C and then quenched with ice water (50 mL). The resulting solution was extracted with ethyl acetate (2 × 50 mL), and the organic matter was combined. The pH of the aqueous phase was adjusted to 6 with hydrogen chloride (2 M), and the solution was extracted with ethyl acetate ( ₂ × 150 mL). All organic extracts were combined, dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:4–2:1) as the eluent to give a mixture of the title compounds (480 mg, 23%) as a pale yellow oil.

Compounds 453.4 and 454.6. 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (compound 453.4) and 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (compound 454.6). A solution of 5-(5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoic acid and 5-(5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoic acid (compounds 453.3 and 454.5, 480 mg, 1.25 mmol, 1.00 equivalent) in N,N-dimethylformamide (10 mL) was placed in a round-bottom flask. DIEA (643 mg, 4.98 mmol, 4.00 equivalent), EDC (476 mg, 2.48 mmol, 2.00 equivalent), and 1-hydroxybenzotriazole (337 mg, 2.50 mmol, 2.00 equivalent) were added, and the resulting solution was stirred at 25 °C for 20 min. Subsequently, 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 276 mg, 1.24 mmol, 1.00 equivalent) was added in portions at 0 °C. The resulting solution was stirred at 25 °C for 16 h, and then quenched with ice water (40 mL). The resulting solid was collected by filtration and subsequently dissolved in ethyl acetate (100 mL). The resulting organic matter was washed with brine (2 × 30 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum to give a mixture of the title compounds (440 mg, 64%) as a pale yellow oil.

Compounds 453.5 and 454.7. 4-(1-(2,4-dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile 2,2,2-trifluoroacetate (compound 453.5) and 4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile 2,2,2-trifluoroacetate (compound 454.7). A solution of 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid tert-butyl ester and 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (compounds 453.4 and 454.6, 440 mg, 0.790 mmol, 1.00 equivalent) in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was placed in a round-bottom flask. The resulting solution was stirred at 25°C for 20 hours and then concentrated under vacuum to obtain a mixture of the title compound (450 mg, 99%) in a yellow oily form.

Compounds 453 and 454. Methyl 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound 453) and methyl 2-(5-(4-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound 454). Place a solution of 4-(1-(2,4-dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile 2,2,2-trifluoroacetate and 4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile 2,2,2-trifluoroacetate in dichloromethane (6 mL) into an 8-mL sealed tube. Add DIEA (114 mg, 0.880 mmol, 5.00 equivalent) and cool the mixture to 0°C. Dimethyl dicarbonate (29.6 mg, 0.220 mmol, 1.25 equivalents) was added dropwise at 0 °C with stirring, and the resulting solution was subsequently stirred at 0–5 °C for 2.5 h. The resulting mixture was concentrated under vacuum and the residue was purified by preparative HPLC (1#-Pre-HPLC-001(SHIMADZU)): column, Xbridge Prep C18, 5 μm, 19 × 150 mm; mobile phase, water containing 0.03% _NH₃H₂O and _{CH₃CN (CH₃CN increased} from 39.0% to 52.0% within 7 min, to 100.0% within 1 min, and decreased to 39.0% within 1 min); detector, Waters 2489 254 and 220 nm. The title compound (30 mg) was obtained as a mixture of isomers by preparative HPLC. Purification of the isomer mixture by chiral preparative HPLC (2#-Gilson Gx 281(HPLC-09)): column, Chiralpak IA, 2×25em, 5um; mobile phase, hexane (0.1% DEA) and ethanol (0.2% TEA) (maintained at 50.0% ethanol (0.2% TEA) for 10 min); detector, UV 220/254nm. The chiral preparative HPLC fractions containing the pure, separated products were appropriately combined and lyophilized to obtain methyl 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid (compound 453) (14.2 mg, 13%) and methyl 2-(5-(4-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylic acid (compound 454) (11.8 mg, 10%), both in white solid form. Compound 453: m/z(ES+)512(M+H) ⁺ . Compound 454: m/z(ES+)512(M+H) ⁺ .

Compounds 455 and 456. 4-(1-(5-(5,6-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 455) and 4-(1-(5-(4,5-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 456). Place a solution of 4-(1-(2,4-dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile trifluoroacetate and 4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile trifluoroacetate in tetrahydrofuran (5 mL) into a 10-mL sealed tube. Formaldehyde (1 mL, 37 wt%) and sodium triacetoxyborohydride (162 mg, 0.760 mmol, 3.5 equivalences) were added to the mixture and stirred at 40 °C for 2.5 h. The mixture was concentrated under vacuum and the residue was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, Xbridge Prep C18, 5 μm, 19 × 150 mm; mobile phase, water containing 0.03% NH3H2O and CH3CN (CH3CN increased from 32% to 42% in 8 min, to 100% in 2 min, and decreased to 32% in 1 min); detector, Waters 2489 254 nm and 220 nm. The title compound (50 mg) was obtained as a mixture of isomers by preparative HPLC. Purification of the isomer mixture by chiral preparative HPLC under the following conditions (2#-Gilson Gx 281(HPLC-09)): column, Chiralpak IC, 2×25cm, 5µm; mobile phase, hexane (0.2% TEA) and ethanol (0.2% TEA) (maintained at 50.0% ethanol (0.2% TEA) for 27 min); detector, UV 220/254nm. The chiral preparative HPLC fractions containing the pure, separated products were appropriately combined and lyophilized to obtain 4-(1-(5-(5,6-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 455) (13.5 mg, 13%) and 4-(1-(5-(4,5-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 456) (6.8 mg, 7%), both in white solid form. Compound 455: m/z (ES+) 468 (M+H) ⁺ . Compound 456: m/z(ES+)468(M+H) ⁺ .

Compounds 457.1 and 457.2. 3-Bromo-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (Compound 457.1) and 5-bromo-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (Compound 457.2). A solution of 2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (5.00 g, 23.4 mmol, 1.00 equivalent) in diethyl ether (700 mL) was placed in a 1-L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Ammonium acetate (904 mg, 11.7 mmol, 0.50 equivalent) and azobisisobutyronitrile (AIBN) (192 mg, 1.17 mmol, 0.05 equivalent) were added. The mixture was cooled to 0 °C, and then N-bromosuccinimide (4.15 g, 23.5 mmol, 1.00 equivalent) was added in portions. The resulting mixture was stirred at 25°C for 4 hours, followed by concentration under vacuum. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:100–1:10) as the eluent to obtain a mixture of the title compounds (4.10 g, 60%) that was a pale yellow oil.

Compound 457. 4-(1-(5-(5-acetyl-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare compounds 400 and 2, but using a mixture of 3-bromo-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester (compound 457.1) and 5-bromo-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester (compound 457.2) instead of 3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2). The product contains approximately 10% of another methyl regioisomer, 4-(1-(5-(5-acetyl-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. m/z(ES+)496(M+H) ⁺ .

Compound 458. 4-(1-(5-(5′-acetyl-3′,4′,5′,6′-tetrahydrospiro[cyclopropane-1,7′-imidazo[4,5-c]pyridin]-2′-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compounds 449 and 2, but with tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylic acid (Remen, L. et al., Bioorg. and Med. Chem. Lett., 2009, 32, 351-357) instead of 3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z(ES+)508(M+H) ⁺ . ^1H -NMR (300MHz, _CD3 OD): δ 7.71 (d, J = 8.1Hz, 2H), 7.47 (d, J = 7.8Hz, 2H), 7.37–7.20 (m, 2H), 4.77 and 4.71 (two singlets, acetyl amide rotational isomer, _CH2 , 2H), 3.77 and 3.72 (two singlets, acetyl amide rotational isomer, _CH2 , 2H), 3.71–3.67 (m, 1H), 3.30–3.18 (m, 1H), 2.99 (t, J = 11.6Hz, 2H), 2.48–2.27 (m, 6H), 2.24 and 2.21 (two singlets, acetyl amide rotational isomer, acetyl _CH3 , 3H), 2.10-1.95 (m, 1H), 1.92-1.52 (m, 3H), 1.18-0.96 (m, 4H).

Compound 459. 4-(1-(5-(6-methoxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare compound 449, but with 4-methoxycyclohexanone (Kaiho, T. et al., J. Med. Chem., 1989, 32, 351-357) instead of 3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z(ES+)469(M+H) ⁺ . ^1H -NMR (300MHz, _CD3OD ): δ7.69 (d, J = 8.1Hz, 2H), 7.53–7.44 (m, 2H), 7.37–7.21 (m, 2H), estimated to be one proton in methanol (1H), 3.84–3.75 (m, 1H), 3.73–3.57 (m, 1H), 3.45 (s, 3H), 3.27–3.19 (m, 1H), 3.05–2.91 (m, 3H), 2.79–2.58 (m, 3H), 2.46 (s, 3H), 2.40 and 2.29 (two singlets, amide rotational isomer, 3H), 2.17–1.92 (m, 3H), 1.92–1.67 (m, 3H).

Compound 460. 4-(1-(5-(6-hydroxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-(5-(6-methoxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 459, 80 mg, 0.17 mmol, 1.0 equivalent) in a solvent mixture (10/10 mL) of acetonitrile and dichloromethane was placed in a round-bottom flask. Tetrachlorosilane (32 mg, 0.19 mmol, 1.1 equivalent) and sodium iodide (28 mg, 0.19 mmol, 1.1 equivalent) were added to the reaction mixture, and the resulting mixture was stirred overnight at 20 °C. The reaction was quenched with an aqueous sodium bicarbonate solution (10 _mL ) and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic matter was dried ( _Na₂SO₄ ), filtered, concentrated under vacuum, and the residue was purified by silica gel chromatography using ethyl acetate as the eluent to give the title compound (7.1 mg, 9%) as a yellow solid. m/z(ES+) 455(M+H) ⁺ .

Compound 461.1. 4-Methoxyhept-1,6-diene. A solution of hept-1,6-dien-4-ol (2.00 g, 17.8 mmol, 1.00 equivalent) and methyl iodoform (5.00 g, 35.2 mmol, 2.00 equivalent) in tetrahydrofuran (30 mL) was placed in a round-bottom flask. The solution was cooled to 0 °C and sodium hydride (1.00 g, 25.0 mmol, 1.50 equivalent, 60% in mineral oil) was added to the reactants in portions. The resulting mixture was stirred overnight at room temperature, then carefully quenched with water (5 mL) and diluted with diethyl ether (30 mL). The organic matter was washed with brine (2 × 20 mL), dried ( _{Na₂SO₄ )} , filtered, and concentrated under vacuum to give the title compound (2.00 g, 84%) as a colorless oil.

Compound 461.2. 4-Methoxycyclopent-1-ene. A solution of 4-methoxyhept-1,6-diene (compound 461.1, 200 mg, 1.43 mmol, 1.00 equivalent, 90%) in dichloromethane (25 mL) was placed in a round-bottom flask purged and maintained under an inert nitrogen atmosphere. Grubbs II catalyst (55 mg, 0.06 mmol, 0.04 equivalent) was added, and the resulting solution was stirred overnight at room temperature. The mixture was concentrated under vacuum to give the title compound (100 mg, 57%) as a colorless oil.

Compound 461.3. 2-Bromo-4-methoxycyclopentanol. A solution of 4-methoxycyclopent-1-ene (compound 461.2, 1.00 g, 8.66 mmol, 1.00 equivalent, 85%) in dichloromethane (100 mL) and a solution of N-bromosuccinimide (2.00 g, 11.3 mmol, 1.00 equivalent) in water (20 mL) were added to a round-bottom flask. The reaction mixture was stirred at room temperature for 3 hours, and the resulting mixture was then washed with water (20 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum to give the title compound (1.00 g, 36%) as a colorless oil.

Compound 461.4. 2-Bromo-4-methoxycyclopentanone. A solution of 2-bromo-4-methoxycyclopentanone (compound 461.3, 1.00 g, 3.08 mmol, 1.00 equivalent, 60%) in dichloromethane (100 mL) was placed in a round-bottom flask. Dess-Martin periodinane (2.00 g, 4.72 mmol, 1.10 equivalent) was added in portions, and the mixture was stirred overnight at room temperature. The mixture was then diluted with water (20 mL) and quenched with _{Na₂S₂O₄} ( ₄ g). The aqueous phase was extracted with dichloromethane (100 mL) _, and the combined organic matter was washed with brine (30 mL ₎ , dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum to give the title compound (800 mg, 81%) as a brown oil.

Compound 461.5. Methyl 5-(3a-hydroxy-5-methoxy-1,3a,4,5,6,6a-hexahydrocyclopentadien[d]imidazol-2-yl)-2,4-dimethylbenzoate. A solution of 2-bromo-4-methoxycyclopentanone (compound 461.4, 600 mg, 1.86 mmol, 60%) in ACN (15 mL) was placed in a round-bottom flask. Methyl 5-formamidinyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 320 mg) and potassium carbonate (430 mg, 3.11 mmol) were added, and the mixture was stirred overnight at 80 °C. The mixture was concentrated under vacuum, and the residue was diluted with ethyl acetate (50 mL) and then washed with brine (2 × 20 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using dichloromethane/methanol (10:1) as the eluent to obtain the title compound (200 mg, 27%), which was a brown oil.

Compound 461.6. Methyl 5-(5-methoxy-1,4,5,6-tetrahydrocyclopentadien[d]imidazol-2-yl)-2,4-dimethylbenzoate. A solution of methyl 5-(3a-hydroxy-5-methoxy-1,3a,4,5,6,6a-hexahydrocyclopentadien[d]imidazol-2-yl)-2,4-dimethylbenzoate (compound 461.5, 200 mg, 0.38 mmol, 1.00 equivalent, 60%) in N,N-dimethylformamide (mL) was placed in a round-bottom flask. p-Toluenesulfonic acid (20 mg, 0.12 mmol, 0.18 equivalent) was added, and the resulting solution was stirred overnight at 80 °C, followed by concentration under vacuum. The residue was purified by silica gel chromatography using dichloromethane/methanol (10:1) as the eluent to obtain the title compound (100 mg, 66%), which was a brown oil.

Compound 461.7. 5-(5-methoxy-1,4,5,6-tetrahydrocyclopentadien[d]imidazol-2-yl)-2,4-dimethylbenzoic acid. A solution of methyl 5-(5-methoxy-1,4,5,6-tetrahydrocyclopentadien[d]imidazol-2-yl)-2,4-dimethylbenzoate (compound 461.6, 100 mg, 0.270 mmol, 1.00 equivalent, 80%) in methanol (3 mL) was placed in a round-bottom flask. A solution of sodium hydroxide (67.0 mg, 1.68 mmol, 5.00 equivalent) in water (3 mL) was added, and the resulting mixture was stirred overnight at 70 °C, followed by concentration under vacuum. The residue was diluted with water (3 mL), and the pH of the solution was adjusted to 2–3 with an aqueous solution of hydrogen chloride (12 M). The mixture was extracted with ethyl acetate (3 × 10 mL) and the combined organic matter was concentrated under vacuum to give the title compound (80 mg, 84%) as a brown solid.

Compound 461. 4-(1-(5-(5-methoxy-1,4,5,6-tetrahydrocyclopentadienzimidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 5-(5-methoxy-1,4,5,6-tetrahydrocyclopentadienzimidazol-2-yl)-2,4-dimethylbenzoic acid (compound 461.7, 60 mg, 0.17 mmol, 1.00 equivalent, 80%) in N,N-dimethylformamide (4 mL) was placed in a round-bottom flask. 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 46 mg, 0.20 mmol, 1.00 equivalent), 4-dimethylaminopyridine (52 mg, 0.43 mmol, 2.00 equivalent), and EDC·HCl (80 mg, 0.42 mmol, 2.00 equivalent) were added, and the mixture was stirred overnight at room temperature. The resulting solution was diluted with ethyl acetate (30 mL), washed with brine (3 × 10 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The residue (40 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, SunFire Prep C18, 19×150 mm 5 μm; mobile phase, water containing 0.05% TFA and _CH3CN ( _CH3CN increased from 15.0% to 55.0% in 7 min, to 100.0% in 1 min, and decreased to 15.0% in 1 min); detector, Waters 2489 254 and 220 nm. The fractions containing the purified product were combined and lyophilized to give the title compound (8.9 mg, 11%) as a white solid. m/z (ES+) 455 (M+H) ⁺ .

Compound 462.1. 5-Bromo-2,2-dimethyldihydro-2H-pyran-4(3H)-one. A solution of 2,2-dimethyloxane-4-one (1.00 g, 7.80 mmol, 1.00 equivalent) in diethyl ether (20 mL) was placed in a round-bottom flask. N-bromosuccinimide (1.50 g, 25.5 mmol, 3.26 equivalent) was added in portions, followed by ammonium acetate (60.0 mg, 0.78 mmol, 0.10 equivalent). The resulting mixture was stirred overnight at 25 °C and then diluted with ethyl acetate (20 mL). The resulting mixture was washed with brine (2 × ₄₀ mL), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:30) as the eluent to give the title compound (508 mg, 31%) as a yellow oil.

Compound 462. 4-(1-(5-(6,6-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d][imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare compound 461, but with 5-bromo-2,2-dimethyldihydro-2H-pyran-4(3H)-one (compound 462.1) instead of 2-bromo-4-methoxycyclopentanone (compound 461.4). m/z(ES+)469(M+H) ⁺ .

Compound 463.1. Trimethyl((4-(trimethylsilyl)but-3-yn-1-yl)oxy)silane. A solution of but-3-yn-1-ol (20.0 g, 285 mmol, 1.00 equivalent) in tetrahydrofuran (300 mL) was placed in a 1-L three-necked round-bottom flask and the mixture was purged with nitrogen. The mixture was cooled to -78 °C, and then n-butyllithium (2.5 M in THF) (270 mL, 2.40 equivalent) was added dropwise, followed by trimethylchlorosilane (67.9 g, 625 mmol, 2.20 equivalent). The resulting mixture was then stirred at 25 °C for 1 hour, followed by careful quenching with an aqueous solution of sodium bicarbonate (250 mL). The aqueous phase was extracted with diethyl ether (3 × 100 mL), and the combined organic compounds were dried ( _Na₂SO₄ ), _filtered , and concentrated under vacuum. The residue was purified by silica gel chromatography using diethyl ether/petroleum ether (1:10-1:1) as the eluent to obtain the title compound (10.0 g, 16%) as a colorless oil.

Compound 463.2. Trimethyl((4-(trimethylsilyl)but-3-en-1-yl)oxy)silane. A solution of compound 463.1 (2.00 g, 7.46 mmol, 1.00 equivalent, 80%) in hexane (30 mL) was placed in a round-bottom flask. The system was purged with nitrogen. Quinoline (0.1 mL, 0.10 equivalent) and Lindlar reagent (poisoned with Pb) (0.2 g, 0.10 equivalent, 5%) were added to the mixture. The resulting mixture was hydrogenated overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, the system was purged with nitrogen and the solid was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography using hexane/diethyl ether (20:1) as the eluent to give the title compound (1.50 g, 74%) as a colorless oil.

Compound 463.3. 6-Methyl-3,6-dihydro-2H-pyran. A mixture of trimethyl((4-(trimethylsilyl)but-3-en-1-yl)oxy)silane (compound 463.2, 1.50 g, 6.93 mmol, 1.00 equivalent), acetaldehyde (900 mg, 20.4 mmol, 3.00 equivalent), and indium(III) chloride (1.50 g, 1.00 equivalent) in dichloromethane (15 mL) was placed in a round-bottom flask. The resulting mixture was stirred overnight at 25 °C, and then diluted with DCM (50 mL). The organic matter was washed with brine (3 × 20 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum to give the title compound (0.600 g, 88%) as a brown oil.

Compounds 463.4 and 463.5. 4-Bromo-2-methyldihydro-2H-pyran-3(4H)-one (compound 463.4) and 3-bromo-2-methyldihydro-2H-pyran-4(3H)-one (compound 463.5). A solution of o-iodobenzoic acid (IBX) (3.42 g, 6.11 mmol, 2.00 equivalent) in DMSO (12 mL) was placed in a round-bottom flask. The mixture was stirred at 25 °C for 30 min, followed by dropwise addition of a solution of 6-methyl-3,6-dihydro-2H-pyran (compound 463.3, 600 mg, 4.28 mmol, 1.00 equivalent, 70%) in dichloromethane (30 mL). The mixture was cooled to 0–5 °C, followed by fractional addition of N-bromosuccinimide (1.20 g, 6.74 mmol, 1.10 equivalent). The resulting mixture was stirred overnight at 25° _C , and the solids were removed by filtration. The filtrate was diluted with dichloromethane (50 mL) and washed with brine (3 × 20 mL). The mixture was dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:20) as the eluent to give a mixture of the title compounds (600 mg, 73%) as a brown oil.

Compound 463. 4-(1-(2,4-dimethyl-5-(4-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare compound 461, but using a mixture of 4-bromo-2-methyldihydro-2H-pyran-3(4H)-one (compound 463.4) and 3-bromo-2-methyldihydro-2H-pyran-4(3H)-one (compound 463.5) instead of 2-bromo-4-methoxycyclopentanone (compound 461.4). m/z(ES+)455(M+H) ⁺ .

Compound 464.1. 4-(allyloxy)pent-1-ene. A 500-mL four-necked round-bottom flask was purged and maintained under an inert nitrogen atmosphere, followed by the addition of a suspension of sodium hydride (14.0 g, 350 mmol, 2.01 equivalents, 60%) in N,N-dimethylformamide (100 mL). The mixture was cooled to 0 °C, and then a solution of pent-4-en-2-ol (15.0 g, 174 mmol, 1.00 equivalents) was added dropwise to N,N-dimethylformamide (100 mL), while the mixture was stirred at 0 °C for 20 min. The mixture was cooled to -20 °C, and a solution of 3-bromoprop-1-ene (20.9 g, 172 mmol, 0.99 equivalents) was added to N,N-dimethylformamide (100 mL). The resulting mixture was warmed to room temperature and stirred overnight, followed by careful quenching with _H₂O (500 mL). The aqueous phase was extracted with ethyl acetate (4 × 100 mL), and the combined organic matter was washed with brine (2 × 200 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum to give the title compound (13.3 g, 61%) as a yellow oil.

Compound 464.2. 2-Methyl-3,6-dihydro-2H-pyran. A 500-mL three-necked round-bottom flask was purged and maintained under an inert nitrogen atmosphere, followed by the addition of a solution of 4-(allyloxy)pent-1-ene (compound 464.1, 3.00 g, 23.8 mmol, 1.00 equivalent) to a DCE (200 mL). Grubb catalyst (810 mg, 0.950 mmol, 0.04 equivalent) was added, and the mixture was stirred at 60 °C for 4 h. The mixture was then concentrated under vacuum at 20 °C to give the title compound (2.00 g, 86%) as a colorless oil.

Compounds 464.3 and 464.4: 4-bromo-6-methyltetrahydro-2H-pyran-3-ol and 5-bromo-2-methyltetrahydro-2H-pyran-4-ol. A solution of methyl-3,6-dihydro-2H-pyran (compound 464.2, 2.00 g, 20.4 mmol, 1.00 equivalent) in a mixture of tetrahydrofuran and _H₂O (20/20 mL) was placed in a round-bottom flask. N-bromosuccinimide (3.60 g, 20.3 mmol, 1.00 equivalent) was added, and the resulting mixture was stirred overnight at room temperature. The mixture was extracted with dichloromethane (2 × 20 mL), and the combined organic matter was washed with brine (2 × 20 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum to give a mixture of the title compounds (1.10 g, crude matter) as a yellow oil.

Compounds 464.5 and 464.6. 4-Bromo-6-methyldihydro-2H-pyran-3(4H)-one and 5-bromo-2-methyldihydro-2H-pyran-4(3H)-one. A solution (1.10 g, 5.64 mmol, 1.00 equivalent) of a mixture of 4-bromo-6-methyltetrahydro-2H-pyran-3-ol (compound 464.3) and 5-bromo-2-methyltetrahydro-2H-pyran-4-ol (compound 464.4) in dichloromethane (30 mL) was placed in a round-bottom flask. Dysmartin periodine (2.90 g, 6.84 mmol, 1.21 equivalent) was added and the resulting solution was stirred overnight at room temperature, followed by quenching with water (20 mL). The aqueous phase was extracted with dichloromethane (2 × 20 mL), and the combined organic matter was washed with brine (2 × 50 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum to obtain a mixture (0.7 g) of the title compound in a yellow oily form.

Compound 464.7. Methyl 2,4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate. A solution of a mixture (700 mg, 3.63 mmol) of 4-bromo-6-methyldihydro-2H-pyran-3(4H)-one (compound 464.5) and 5-bromo-2-methyldihydro-2H-pyran-4(3H)-one (compound 464.6) in acetonitrile (20 mL) was placed in a round-bottom flask. Methyl 5-formamidinyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 750 mg) and potassium carbonate (1.00 g, 7.25 mmol) were added, and the mixture was stirred overnight at 75 °C under nitrogen. The mixture was cooled and the solids were removed by filtration. The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:1) as the eluent to obtain the title compound (100 mg, 9%) as a yellow solid.

Compound 464.8.2, 4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid. A solution of methyl 2,4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate (compound 464.7, 100 mg, 0.330 mmol, 1.00 equivalent) in methanol (10 mL) was placed in a round-bottom flask. A solution of lithium hydroxide (76 mg, 3.17 mmol, 10.0 equivalent) in water (10 mL) was added, and the resulting solution was stirred at room temperature for 4 hours. The mixture was concentrated under vacuum, and then aqueous HCl was added until the pH reached 5–6. The mixture was adjusted to pH 5–6 with aqueous HCl, and then concentrated under vacuum. MeOH (5 mL) was added to the residue, and the solids were removed by filtration. The filtrate was concentrated under vacuum to obtain the title compound (60 mg, 63%) as a yellow solid.

Compound 464. 4-(1-(2,4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. A solution of 2,4-dimethyl-5-[6-methyl-3H,4H,6H,7H-pyrano[3,4-d]imidazol-2-yl]benzoic acid (50 mg, 0.17 mmol, 1.00 equivalent) in N,N-dimethylformamide (10 mL) was placed in a round-bottom flask. EDC·HCl (67 mg, 0.35 mmol, 2.00 equivalents), 4-dimethylaminopyridine (64 mg, 0.52 mmol, 3.00 equivalents), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 39 mg, 0.18 mmol, 1.00 equivalents) were added, and the solution was stirred at room temperature for 2 hours. The reaction was quenched with water (20 mL), and the aqueous phase was extracted with ethyl acetate (2 × 20 _mL ). The combined organic matter was dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:1) as the eluent. The crude product (20 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, Xbridge Prep Phenyl, 5 μm, 19 × 150 mm; mobile phase, water containing _0.03 % _NH₃H₂O and _CH₃CN ( _CH₃CN increased from 30% to 60% within 9 min, to 100% within 1 min, and decreased to 30% within 1 min); detector, Waters 2489 254 nm and 220 nm. The fractions containing the purified product were combined and lyophilized to give the title compound (8.0 mg, 10%) as a white solid. m/z (ES+) 455 (M+H) ^⁺ .

Compound 465. 2-(5-(4-(4-cyanophenyl)piperidin-1-carbonyl)-2,4-dimethylphenyl)-1,4,5,6-tetrahydrocyclopentadien[d]imidazolium-5-carboxynitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 461, but with cyclopent-3-enecarboxynitrile (Johnson, CR et al., J. Org. Chem., 1969, 34, 860-864) instead of 4-methoxycyclopent-1-ene (compound 461.2). m/z(ES+) 450(M+H) ⁺ .

Compound 466.1. Tetrahydrofuran-3,4-dimethyldimethanesulfonate. A solution of tetrahydrofuran-3,4-diol (500 mg, 4.80 mmol, 1.00 equivalent) and triethylamine (1.45 g, 14.3 mmol, 3.00 equivalent) in dichloromethane (8 mL) was placed in a round-bottom flask. The mixture was cooled to 0–5 °C and a solution of methanesulfonyl chloride (1.40 g, 12.2 mmol, 2.50 equivalent) in dichloromethane (2 mL) was added dropwise. The solution was stirred at room temperature for 2 hours and then diluted with dichloromethane (100 mL). The solution was washed successively with aqueous _NH₄Cl (2 × 30 mL) and brine (30 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum to give the title compound (1.00 g, 72%) as a brown solid.

Compound 466.2.3, 4-diazidotetrahydrofuran. A mixture of tetrahydrofuran-3,4-dimethyldimethanesulfonate (compound 466.1, 2.00 g, 7.30 mmol, 1.00 equivalent, 95%) and sodium azide (4.00 g, 61.5 mmol, 8.00 equivalent) in N,N-dimethylformamide (20 mL) was placed in a round-bottom flask. The resulting mixture was stirred overnight at 100 °C after being shielded from explosion, then cooled and diluted with diethyl ether (100 mL). The mixture was washed with brine (5 × 20 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum to give the title compound (1.00 g, 80%) as a colorless oil.

Compound 466.3. Tetrahydrofuran-3,4-diamine. A solution of 3,4-diazidotetrahydrofuran (compound 466.2, 900 mg, 5.26 mmol, 1.00 equivalent, 90%) in ethanol (10 mL) was placed in a round-bottom flask. The system was purged with nitrogen and palladium on carbon (10 wt% Pd) (900 mg) was added. After further purging with nitrogen, the atmosphere was changed to hydrogen and the resulting suspension was stirred overnight at room temperature under a hydrogen atmosphere. After purging with nitrogen, the solids were removed by filtration and the filtrate was concentrated under vacuum to obtain the title compound (600 mg, 98%) as a colorless oil.

Compound 466.4. Methyl 5-(imino(methoxy)methyl)-2,4-dimethylbenzoate hydrochloride. A solution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 900 mg, 4.28 mmol, 1.00 equivalent, 90%) in methanol (20 mL) was placed in a 50 mL three-necked round-bottom flask. Hydrogen chloride gas was introduced by bubbling the solution for 0.5 h. The reaction mixture was then transferred to a 30 mL sealed tube and stirred overnight at room temperature. The mixture was concentrated under vacuum, and the residue was diluted with ethyl acetate (30 mL) and extracted with water (10 mL). The aqueous phase was concentrated under vacuum to give the title compound (200 mg, 15%) as a white solid.

Compound 466.5.2, methyl 4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furano[3,4-d]imidazol-2-yl)benzoate. A solution of tetrahydrofuran-3,4-diamine (compound 466.3, 140 mg, 1.17 mmol, 1.00 equivalent, 85%) in ethanol (6 mL) was placed in a round-bottom flask. Methyl 5-(imino(methoxy)methyl)-2,4-dimethylbenzoate hydrochloride (compound 466.4, 300 mg, 0.930 mmol, 1.00 equivalent) and triethylamine (140 mg, 1.38 mmol, 1.00 equivalent) were added, and the resulting solution was stirred overnight at 80 °C, followed by concentration under vacuum. The residue was purified by silica gel chromatography using dichloromethane/methanol (10:1) as the eluent to obtain the title compound (120 mg, 34%), which was a brown oil.

Compound 466.5. 2,4-Dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furano[3,4-d]imidazol-2-yl)benzoic acid. A solution of methyl 2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furano[3,4-d]imidazol-2-yl)benzoate (compound 466.5, 100 mg, 0.330 mmol, 1.00 equivalent, 90%) and sodium hydroxide (73 mg, 1.82 mmol, 5.00 equivalent) in methanol/ _H₂O (3/3 mL) was placed in a round-bottom flask. The resulting solution was stirred overnight at 70 °C, and then concentrated under vacuum. The residue was diluted with _H₂O (5 mL) and the pH of the solution was adjusted to 2–3 with hydrogen chloride (12N), followed by extraction with ethyl acetate (3 × 10 mL). The combined organic compounds were concentrated in a vacuum to obtain the title compound (80.0 mg, 84%) as a yellow solid.

Compound 466.4-(1-(2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. A solution of 2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furano[3,4-d]imidazol-2-yl)benzoic acid (compound 466.5, 80.0 mg, 0.250 mmol, 1.00 equivalent, 80%) in N,N-dimethylformamide (4 mL) was placed in a round-bottom flask. 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 82.0 mg, 0.350 mmol, 1.20 equivalent), 4-dimethylaminopyridine (76.0 mg, 0.620 mmol, 2.00 equivalent), and EDC·HCl (116 mg, 0.610 mmol, 2.00 equivalent) were added, and the resulting solution was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (30 mL), washed with brine (3 × 15 _mL ), dried ( _Na₂SO₄ ), filtered, and concentrated under vacuum. The crude product (50 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): column, Xbridge Prep C18, 5 μm, 19 × 150 mm; mobile phase, water containing 0.05% TFA and _CH3CN (15% _CH3CN increased to 50% within 9 min, to 100% within 1 min, and decreased to 15% within 1 min); detector, Waters 2489 254 nm and 220 nm. The fractions containing the purified product were combined and lyophilized to give the title compound (13 mg, 12%) as a white solid. m/z (ES+) 429 (M+H) ⁺ . ^1H -NMR (300MHz, _CD3OD ): δ7.70 (d, 2H), 7.53–7.36 (m, 4H), 5.09 (s, 2H), 4.17 (d, J = 10.8 Hz, 2H), 3.77 (d, J = 10.5 Hz, 2H), 3.60–3.44 (m, 1H), approximately 3.3 (m, partially overlapping with water, 1H), 3.10–2.92 (m, 2H), 2.48 (s, 3H), 2.45 and 2.35 (two singlets, amide rotational isomer, Ar- _CH3 , 3H), 2.10–1.97 (m, 1H), 1.92–1.52 (m, 3H).

Compound 467. 4-(1-(4-fluoro-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compounds 1 and 2, but with 4-fluoro-2-methylbenzoic acid instead of 2,4-dimethylbenzoic acid. m/z(ES+)445(M+H) ⁺ .

Compound 468. 4-(1-(5-(5-acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-chloro-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 2, but with 4-chloro-2-methylbenzoic acid instead of 2,4-dimethylbenzoic acid. m/z(ES+)502(M+H) ⁺ .

Compound 469. 1-(2-(2-chloro-5-(4-(4-fluorophenyl)piperidin-1-carbonyl)-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)acetone. The title compound was prepared using standard chemical procedures and a similar procedure to that used to prepare compounds 2 and 468. m/z(ES+) 495(M+H) ⁺ .

Compound 470.1. Methyl 2-bromo-4-fluorobenzoate. A solution of 2-bromo-4-fluorobenzoic acid (21.8 g, 99.5 mmol, 1.00 equivalent) in a solvent mixture of sulfuric acid (20 mL) and methanol (20 mL) was placed in a round-bottom flask. The resulting solution was stirred at 85 °C for 5 hours, then cooled and concentrated under vacuum. The residue was diluted with ethyl acetate (200 mL) and washed successively with brine (200 mL) and aqueous solution of _NaHCO3 (100 _mL ; note: gas escaped), dried ( _Na2SO4 ), filtered, and concentrated under vacuum to give the title compound (22.0 g, 95%) as a pale yellow oil.

Compound 470.1. Methyl 2-ethyl-4-fluorobenzoate. The title compound (colorless oil, 14.5 g, 93%) was prepared using a similar procedure to that used to prepare compound 48.1, but with methyl 2-bromo-4-fluorobenzoate (compound 470.1, 20.0 g) instead of methyl 2-bromo-4-methylbenzoate.

Compound 470. 4-(1-(2-ethyl-4-fluoro-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compounds 1 and 2, but with methyl 2-ethyl-4-fluorobenzoate (compound 470.1) instead of 2,4-dimethylbenzoic acid and with 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5). m/z(ES+)477(M+H) ⁺ .

Compound 471.1. 4-Chloro-5-iodo-2-methylbenzoic acid. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 2.1, but with 4-chloro-2-methylbenzoic acid instead of 2,4-dimethylbenzoic acid.

Compound 471.2. 4-Chloro-5-formyl-2-methylbenzoic acid. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 392.2, but with 4-chloro-5-iodo-2-methylbenzoic acid (compound 471.1) instead of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 392.1).

Compound 471. 4-(1-(4-chloro-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare compound 400, but with 4-chloro-5-formyl-2-methylbenzoic acid (compound 471.2) instead of 2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4), 3-bromodihydro-2H-pyran-4(3H)-one instead of 3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2), and 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5). m/z(ES+)479(M+H) ⁺ .

Compound 472.1. Methyl 4-chloro-2-ethyl-5-iodobenzoate. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 211.2, but with methyl 4-chloro-2-ethylbenzoate (compound 178.2) instead of methyl 2-ethyl-4-methylbenzoate (compound 48.1).

Compound 472.2. 4-Chloro-2-ethyl-5-iodobenzoic acid. The title compound was prepared using standard chemical procedures and a similar process to that used to prepare compound 211.3, but with methyl 4-chloro-2-ethyl-5-iodobenzoate (compound 472.1) instead of 2-ethyl-5-iodo-4-methylbenzoate (compound 211.2).

Compound 472. 4-(1-(4-chloro-2-ethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical operations and a procedure similar to that used to prepare compound 400, but with 4-chloro-2-ethyl-5-iodobenzoic acid (compound 472.2) instead of 2-ethyl-5-carboxyloyl-4-methylbenzoic acid (compound 211.4), with 3-bromodihydro-2H-pyran-4(3H)-one instead of 3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2), and with 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5). m/z(ES+)493(M+H) ⁺ .

Compound 473. 4-(1-(5-(5-acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-chloro-2-ethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and a procedure similar to that used to prepare compound 2, but with methyl 4-chloro-2-ethyl-5-iodobenzoate (compound 472.1) instead of methyl 5-iodo-2,4-dimethylbenzoate (compound 2.2). m/z(ES+)516(M+H) ⁺ . ^1H -NMR (300MHz, _CD3OD ): δ7.73-7.54 (m, 4H), 7.53-7.42 (m, 2H), 4.75 and 4.70 (two singlets, acetyl amide rotational isomer, _CH2 , 2H), 4.02-3.88 (m, 2H), 3.68-3.52 (m, 1H), 3.32-3.20 (m, 1H), 3.07-2.88 (m, 3H), 2.88-2.58 (m, 3H), 2.25 and 2.22 (two singlets, acetyl amide rotational isomer, acetyl _CH3 , 3H), 2.11-1.98 (m, 1H), 1.93-1.53 (m, 3H), 1.39-1.22 (m, 3H).

Other example compounds are listed in Table 1.

Example 1 - FASN inhibition of the disclosed compound

Assessing FASN biochemical activity: The FASN enzyme was isolated from SKBr3 cells. SKBr3 is a human breast cancer cell line with high FASN expression levels. FASN is expected to comprise approximately 25% of the cytosolic proteins in this cell line. SKBr3 cells were homogenized in a Dounce homogenizer and then centrifuged at 4°C for 15 min to remove particulate matter. The protein content of the supernatant was then analyzed, diluted to an appropriate concentration, and used to measure FASN activity. The presence of FASN was confirmed by Western blotting. A similar method for isolating FASN from SKBr3 cells is described in Teresa, P. et al. (Clin. Cancer Res. 2009; 15(24), 7608-7615).

The FASN activity of SKBr3 cell extracts was determined by measuring the amount of thiol-containing coenzyme A (CoA) released during NADPH oxidation or fatty acid synthase reactions. The dye CPM (7-diethylamino-3-(4′-cis-butenylimino-phenyl)-4-methylcoumarin) contains a thiol reactive group that increases its fluorescence emission upon reaction with the hydrogen sulfide group of CoA. The biochemical activities shown in Table 1 were determined using fluorescence measurements of CoA release via the procedure described in Chung C.C. et al. (Assay and Drug Development Technologies, 2008, 6(3), 361-374).

Example 2 - Antiviral Activity

The antiviral activity of the structure (I-Z) was evaluated using the HCV 1b replication subsystem:

The replicons were constructed using the ET (luc-ubi-neo/ET) cell line, which is an HCV replicons containing a stable luciferase (Luc) reporter and three cell culture adaptive mutations in the Huh7 human hepatocellular carcinoma cell line (Pietschmann et al., (2002) J.Virol. 76: 4008-4021). Antiviral evaluation analysis of the HCV replicons investigated the effects of the compounds at six half-log concentrations. Human interferon α-2b was included as a positive control in all procedures. Near-confluence cultures of the ET line were plated out in 96-well plates specifically designed for analyzing cell number (cytotoxicity) or antiviral activity, and the drugs were added to the appropriate wells the following day. Cells were treated 72 hours later while still near confluence. _EC50 (concentrations that inhibited replicones by 50% and 90%, respectively), _IC50 (concentrations that reduced cell viability by 50%), and SI (selectivity index: _IC50 / _EC50 ) values were determined. HCV RNA replicon content was assessed by TaqMan RT-PCR using either HCV RNA replicon-derived Luc activity or HCV RNA. Cell counts (cytotoxicity) were estimated using both methods. When using the Luc analysis system, cell number was estimated using the colorimetric CytoTox-1 cell proliferation assay (Promega), while in RNA-based analyses, ribosomal RNA (rRNA) levels measured by TaqMan RT-PCR were used as an indicator of cell number. The results are summarized in Table 2 below.

Table 2

Example 3 - FASN inhibition is related to HCV inhibition

The antiviral activity of 15 compounds disclosed herein was measured using the HCV replicon system (the number is related to the compounds in Table 1). Following published methods (Lohmann et al., (1999) Science 285(5424): 110-113; Lohmann et al., (2001) J.Virol 75(3): 1437-1449; and Qi et al., (2009) Antiviral Res. 81(2): 166-173), the replicon cell line 1b (HCV 1b/Luc-Neo replicon (1b Con1 integrated with firefly genes)) was established using Huh7 via G418 selection. The replicon was assembled using synthetic gene fragments. The GT1b line possessed PV-EKT and three adaptive mutations: E1202G (NS3), T1280I (NS3), and K1846T (NS4B), and its backbone was Con1. The culture medium was:

DMEM supplemented with 10% FBS, G418 (250 μg/ml), streptomycin (100 μg/ml)/penicillin (100 U/ml), L-glutamine (100×), and NEAA (100×).

The culture medium is prepared as follows:

500ml DMEM culture medium (Gibco, catalog number 11960-077)

57ml fetal bovine serum (Gibco, catalog number 16140-071)

5.7ml penicillin-streptomycin (Gibco, catalog number 15140-122)

5.7ml MEM Non-essential Amino Acids (Gibco, Catalog No. 111140-050)

5.7ml L-Glutamine (Gibco, catalog number 125030-081)

574.1 ml culture medium + 2.87 ml 50 mg/ml G418 [final 0.25 mg/ml] (Gibco, catalog number 10131-027)

Dissolve the compound in DMSO to provide a 10 mM stock solution or use from the stock DMSO solution. Dilute the compound to produce 10 half-log (3.16-fold) serial dilutions for analysis in duplicate in DMSO on 384-well plates (Echo qualified 384-well PP (Labcyte catalog number P-05525)). Repeat this experiment three times on different three days.

Cells were collected when confluence reached 90%-100%. The cell concentration was adjusted to 8 × ^10⁴ cells/ml and added to 384-well white analytical microplates (tissue culture treated, Greiner catalog number 781080) to achieve a final cell density of 2,000 cells/well. The plates were incubated at 5% _CO₂ and 37°C for 72 hours.

After 72 hours of incubation, Bright-Glo luciferase reagent (Promega, catalog number E2650) and CellTiter Flo (Promega, catalog number G6080/1/2) were prepared and stored in the dark while equilibrating to room temperature. The treated cells were also equilibrated to room temperature. 10 μL of CellTiter Flo was added to each well of the compound-treated cells and incubated in a microtiter plate for approximately 0.5 hours. Cell viability was measured using an Envision reader (from Perkin Elmer) to estimate cytotoxicity. 30 μL of firefly luciferase substrate was added to each well, and chemiluminescence was measured as an indicator of HCV replication.

Calculate the anti-replicon activity (inhibition %) using the following equation:

Calculate cytotoxicity using the following equation:

As illustrated in Table 3 and Figure 1 below, a correlation was established between FASN inhibitory efficacy and antiviral activity. It is noted that none of these compounds caused significant cytotoxicity.

Table 3

Example 4 - FASH inhibitors maintain their effectiveness against HCV mutations (which confuse resistance to direct-acting antiviral agents). active

A major challenge in treating hepatitis C is the rapid emergence of resistance in response to direct-acting antiviral agents. Resistance typically arises when the virus produces point mutants that support basic viral function but prevent antiviral binding. The ability of three FASN inhibitors (compounds 55, 20, and 70) to inhibit HCV mutants conferring resistance to representative antiviral agents was tested. These mutants were introduced into GT1b constructs based on the Con1 backbone containing the PVIRES-luciferase Ubi-Neo gene and one adaptive mutation (S2204I). (Lohmann et al., (1999) Science 285(5424): 110-113; Lohmann et al., (2001) J.Virol 75(3): 1437-1449; and Qi et al., (2009) Antiviral Res. 81(2): 166-173). Antiviral activity was measured using the method described in Example 3.

The mutations studied are shown in Table 4 below.

Table 4. Mutations studied

The known NS4B allosteric inhibitor (compound A), the known NS5A inhibitor (compound B), the known non-nucleoside NS5B inhibitor (compound C), the known NS3/NS4A protease inhibitor (compound D), and the known nucleoside NS5B inhibitor (compound E) were tested in parallel with the FASN inhibitor of this disclosure to determine the expression of resistance mutations.

The following shows the antiviral _EC50 of various compounds against the mutant group, as well as the relative changes in _EC50 relative to the GT1b wild-type replicon. Normal analytical changes are ±3-4 fold. _EC50 changes outside this range suggest resistance and are indicated in bold. The three FASN inhibitors remained active against the entire mutant group, while the direct-acting antiviral agents showed resistance against mutations at their individual binding sites.

Table 5 Antiviral EC ₅₀

Table 6. Change in EC50 ratio relative to wild type

Example 5 - FASN Inhibitors in Combination Therapy

This example describes the in vitro antiviral activity and cytotoxicity of compounds with structure (V-K) in combination with IFN-α, ribavirin, compounds B, C, D, and E against the HCV GT1b replicon cell line.

Material:

Virus: The GT1b replicon plasmid was assembled using a synthetic gene fragment. The replicon genome contains the PVIRES-luciferase Ubi-Neo gene segment and has one adaptive mutation (S22041) and a Con1 backbone. The replicon GT1b cell line was established using the following disclosed method.

Culture media and reagents: Table 7 below provides details about the culture media and reagents used in this example.

Table 7 List of Culture Media and Reagents

Analytical Instruments: The following analytical instruments were used for the analysis in this embodiment:

POD-810

Topcount(PE)

Envision (PE)

Multidrop (Thermo)

method:

Preparation of compound plates for single-compound assays: The compounds were provided in dry powder form and reconstituted in DMSO to produce stock solutions. A POD-810 system was used to generate 10-point half-log (3.16-fold) serial dilutions for analysis in 96-well plates. The maximum test concentrations for each compound are detailed in Table 8.

Analytical protocol (single compound): Ten concentrations of each compound, serially diluted 3.16-fold (semi-logarithmic), were analyzed in duplicate with DMSO. HCV replicon GT1b cells were collected and adjusted to a cell concentration of 8E+04 cells/ml. The membranes were then coated in 100 μL/well using Multidrop in 96 analytical microplates to achieve a final cell density of 8,000 cells/well. The plates were incubated at 37°C for 72 hours in 5% _CO2 .

At the end of the 72-hour incubation period, antiviral activity and cytotoxicity were measured. Bright-Glo luciferase reagent and Cell Titer Flo were prepared and stored in the dark while equilibrating to room temperature. The cell plate was also equilibrated to room temperature. 20 μL of Cell Titer Flo was added to each well using Multidrop to add cells treated with the compound and cells without the compound. The plate was incubated for 1 hour, and cell viability was measured using an Envision reader to calculate cytotoxicity. 50 μL of firefly luciferase substrate was added to each well, incubated for 2 minutes, and chemiluminescence was measured to calculate _EC50 .

Calculate the anti-replicon activity (% inhibition) using the following equation:

% Inhibition = [1 - ((compound - background)/(DMSO - background)) × 100].

Test compounds and analytical setup for the two-compound combination study: The DMSO stock solutions of the compounds used in the single-compound tests were also used in this analysis. A combined dilution matrix was generated in a 96-well microplate using a POD-810 system. Seven-point, two-fold serial dilutions were generated in matrix form using the POD-810 system. The maximum concentrations tested for each compound are detailed below.

Table 8 Expected activities and highest concentrations of compounds tested in single-agent and combination studies

Compounds with the structure (V-K) were tested individually and in combination with compounds detailed in Table 9. Each compound was also tested individually as a single agent.

Table 9. Combinations of compounds evaluated in vitro

plan combination 1 (V-K)+ compound D 2 (V-K)+ compound C 3 (V-K)+ compound B 5 (V-K)+ compound E 6 (V-K)+IFN-α 7 (V-K)+RBV

Analytical setup (dual-drug combination): Seven concentrations of each compound were analyzed in a matrix format at 2-fold serial dilutions, plus each drug individually. HCV replicon GT1b cells were collected and adjusted to a cell concentration of 8E+04 cells/mL. 100 μL was spread into 96 analytical microplates using Multidrop to achieve a final cell density of 8,000 cells/well. The plates were incubated at 37°C for 72 hours in 5% _CO2 .

At the end of the 72-hour incubation period, antiviral activity and cytotoxicity were measured. Bright-Glo luciferase reagent and Cell Titer Flo were prepared and stored in the dark while equilibrating to room temperature. The cell plate was also equilibrated to room temperature. 20 μL of Cell Titer Flo was added to each well containing both compound-treated and compound-free cells using Multidrop. The plate was incubated for 1 hour, and cell viability was measured using an Envision analyzer to calculate cytotoxicity. The liquid was then removed from the plate, and 50 μL of PBS and 50 μL of firefly luciferase substrate solution were added to each well. After a 2-minute incubation period, chemiluminescence was measured (to calculate HCV replication). Data were analyzed using a MacSynergy ^™ II.

Analysis results:

The activity and cytotoxicity of the compounds. EC ₅₀ and CC ₅₀ values are summarized in Table 10 below.

Table 10 EC ₅₀ and CC ₅₀ for each tested compound

Combination effects. The combination effects of compound pairs were calculated using MacSynergy ^™ II, and the results are summarized in Table 11 below.

Table 11 Overview of the combinatorial effects of compound pairs

*No combination resulted in cytotoxicity.

in conclusion

The Z-factor indicator analysis of the compound pairs summarized in Table 12 is of better quality than the QC standard.

Table 12 Summary of Z-factors for drug pairs

The EC ₅₀ values of individual compounds in the combination matrix (summarized in Table 13) are consistent with the EC ₅₀ data obtained from single compound inhibition in Table 10.

Table 13 Summary of _EC50 for single doses in compound combinations

Compounds with the (V-K) structure exhibited addition antiviral activity when combined with agents providing multiple mechanisms of action, without enhanced cytotoxicity. These results are summarized in Table 14 below.

Table 14 Summary of antiviral mechanisms of addition with structural (V-K) compounds; the term "direct-acting antiviral activity" ("DAA") refers to compounds that bind to viral proteins and inhibit those proteins rather than host proteins.

molecular mechanism category IFN-α Cellular defense Host RBV Multiple Host Compound D HCV protease DAA Compound B NS5A inhibitors DAA Compound C NS5B inhibitors DAA Compound E NS5B inhibitors DAA

IFN-α and RBV represent current standard-of-care treatments for hepatitis C infection, and HCV protease inhibitors telaprevir and boceprivir have recently been approved. The addition antiviral activity and lack of cytotoxic enhancement when combined with IFN-α and RBV further indicate that the compounds of this invention do not interfere with key host processes such as cellular defense (IFN-α) or guanidine nucleotide biosynthesis (RBV). If the compounds of this invention (such as those with structure (V-K)) are administered in combination with current standard treatment regimens, they should therefore be therapeutically effective. Furthermore, the addition antiviral activity observed in compounds B, C, and E indicates that the molecules of this invention (such as those with structure (V-K)) can be effectively combined with currently developed agents targeting newer mechanisms (e.g., NS5A and NS5B inhibitors).

Example 6 - Antitumor Activity - Multivariate Cytotoxicity Analysis

Cells were grown at 37°C in a humid atmosphere with 5% _CO2 in RPMI 1640, 10% FBS, 2 mM L-alanyl-L-glutamine, 1 mM sodium pyruvate, or a special medium. Cells were seeded in 384-well plates and incubated at 37°C in a humid atmosphere with 5% _CO2 . The compound was added 24 hours after seeding. Simultaneously, zero-time untreated cell plates were generated.

After a 72-hour incubation period, cells were fixed and stained with fluorescently labeled antibodies and nuclear dyes to allow direct observation of the nucleus, apoptotic cells, and mitotic cells. Apoptotic cells were detected using an anti-active caspase-3 antibody. Mitotic cells were detected using an anti-phospho-histone-3 antibody.

Compounds were serially diluted in semi-logarithmic (3.16-fold) increments and analyzed at 10 concentrations, with the final analytical concentration of 0.1% DMSO taken from the highest test concentration specified in the Sample Information section. Automated fluorescence microscopy was performed using a GE Healthcare IN Cell Analyzer 1000, with images acquired using a 4× objective.

12-bit TIFF images were acquired using an InCell analyzer 10003.2 and analyzed using Developer Toolbox 1.6 software. Nonlinear regression was used to fit the data to an S-shaped 4-point, 4-parameter one-site dose-response model to calculate _EC50 and _IC50 values, where: y(fit) = A + [(BA)/(1 + ((C/x) ^Λ D))]. Curve fitting, EC50/IC50 calculation, and report generation were performed using software (AIM) based on the custom data reduction engine MathIQ.

Multivariate cytotoxicity assays utilize cell imaging-based techniques, where cells are fixed and stained with fluorescently labeled antibodies and nuclear dyes for direct observation of the nucleus, apoptotic cells, and mitotic cells. Apoptotic cells are detected using an anti-active caspase-3 antibody. Mitotic cells are detected using an anti-phospho-histone-3 antibody.

Cell proliferation is measured by the signal intensity of the incorporated nuclear dye. The output of the cell proliferation analysis is called the relative cell count. To determine the cell proliferation endpoint, the cell proliferation data output is converted into a percentage of control (POC) using the following formula:

POC = Relative cell count (compound pores) / Relative cell count (media pores) × 100

The doubling during the 72-hour analysis period was determined using a zero-time untreated plate: Doubling during 72 hours = LN[cell count (72-hour endpoint) × cell count (zero time)] / LN (2). The output of each biomarker was multiplied based on the media background normalized to the relative cell count in each well.

Caspase-3 activation markers were used to label cells undergoing early to late apoptosis. Output showed apoptotic cells based on a fold increase in mediator background normalized to the relative cell count in each well. The concentration of the test compound that induced a 5-fold induction of caspase-3 signaling indicated significant apoptosis induction. Wells with concentrations higher than the _IC95 relative cell count were excluded from the caspase-3 induction assay.

Phospho-histone-3 markers were used to label mitotic cells. The output is shown as the fold increase in mitotic cell signaling based on the mediator background normalized to the relative cell count in each well. When the fold increase in mitotic cell signaling based on the background was approximately 1, there was “no effect” on the cell cycle. A two-fold or greater increase in phosphate-histone-3 signaling based on the mediator background indicated that the test compound significantly induced mitotic arrest.

A two-fold or greater reduction in phosphate-histone-3 signaling only indicates G1/S phase inhibition when the cytotoxicity level is below the _IC95 of the measured relative cell count. When a two-fold or greater reduction in phosphate-histone- ₃ signaling is observed at concentrations above the IC95 of the relative cell count, the decrease in mitotic cell count is most likely attributable to a more general cytotoxic effect rather than true G1/S phase inhibition. Wells with concentrations above the _IC95 of the relative cell count were excluded from the phosphate-histone-3 analysis.

The criteria for a positive reaction are cell proliferation measured by relative cell count.

Apoptosis:

An increase of more than 5-fold in activated caspase-3 signaling indicates an apoptotic response.

Mitosis:

An increase of more than 2-fold in phosphate-histone-3 indicates mitotic arrest.

A decrease of <2-fold in phosphate-histone-3 indicates G1/S blockade.

Table 15 Results

Example 7 - Effect of FASN inhibitors on fatty liver disease in mice

The effect of the FASN inhibitor of this application on steatosis was determined in C57BL/6 male mice on a high-fat diet (HFD).

This example describes the function of compound 364A.

Five male C57BL/6NCrSim mice from two groups were used for the treatment with the vector and the FASN inhibitor, at the start of administration. Mice were allowed unrestricted access to a high-fat diet (Research Diets Catalogue No. D09100301: 40 kcal partially hydrogenated vegetable shortening and 20% fructose and 2% cholesterol by weight). In addition, all animals received an oral dose of the vector or the FASN inhibitor (10 mg/kg mouse body weight) once daily for 57 consecutive days. At sacrifice, the right lobe of the liver was placed in a preservative (10% neutral buffered formalin), and liver samples were prepared for microscopic evaluation by an authorized pathologist. Liver samples were stained with Oil Red O for fat or with Masson's trichrome for collagen.

Slides were prepared from the right lobe of the liver, and oil red O staining was used for fat and massen trichrome staining was used for collagen. Histopathological findings for Study 1, using both oil red O and trichrome staining, are summarized in Table 16, and representative images of the staining are shown in Figure 2. Animals receiving the mediator for 57 days while maintaining HFD developed severe intracellular fat deposits. As shown by oil red O staining, hepatocytes were enlarged and filled with small lipid vesicles. No obvious inflammation or collagen accumulation was observed. Animals receiving 10 mg/kg compound 364A for 57 days while maintaining HFD showed no evidence of intracellular fat deposits and appeared normal. These results are illustrated by representative images in Figure 2, where the lipid deposits and hepatocyte enlargement present in the mediator control were completely absent in the seemingly normal livers of animals treated with 10 mg/kg compound 364A. These results indicate that prophylactic once-daily administration of 10 mg/kg compound 364A inhibited the development of steatosis in this model. These results support the efficacy of FASN inhibitors in the treatment of NAFLD, NASH, and metabolic syndrome.

Table 16: Histopathological evaluation of liver stained sections and grading of the severity of hepatic steatosis in Study 1

The second study used three groups of five male C57BL/6J mice (carrier administered for 28 days, carrier administered for 57 days, and carrier administered for 28 days followed by treatment with the FASN inhibitor compound of this application for 29 days), at the start of administration, at a age of 4 to 5 weeks. Mice were allowed unrestricted access to a high-fat diet (Research Diets catalog number D09100301: 40 kcal partially hydrogenated vegetable shortening and 20% fructose and 2% cholesterol by weight). At sacrifice, the right lobe of the liver was placed in a preservative (10% neutral buffered formalin), and liver samples were prepared for microscopic evaluation by an authorized pathologist. Liver samples were stained with Oil Red O for fat or with Masson's trichrome for collagen.

Histopathological findings from tissue staining are summarized in Table 17, and representative hematoxylin-eosin staining images from Study 2 are shown in Figure 3. Animals administered the mediator for 57 days while maintaining HFD developed severe fatty deposits in hepatocytes. Much less and smaller fatty deposits were observed in the livers of animals administered the mediator for 28 days followed by compound 364A for 29 days, despite these animals having received HFD for a total of 57 days. These results indicate that therapeutic administration of 10 mg/kg compound 364A once daily inhibited the progression of hepatic steatosis in this model.

Table 17: Histopathological assessment of liver stained sections and grading of the severity of hepatic steatosis in Study 2

As described in Tables 1 and 2 above, the scoring system for hepatic steatosis is as follows: 0 = Normal - Tissue considered normal under the study conditions and taking into account the age, sex, and strain of the animal. Variations that would otherwise be considered abnormal may exist. 1 = Minimal - Variations that are barely within the normal range. 2 = Mild - Lesions are generally easy to identify, but their severity is limited. No functional impairment may occur. 3 = Moderate - Lesions are significant, but the likelihood of increased severity is high. Limited tissue or organ dysfunction may be present. 4 = Severe - The severity is either entirely considered likely or large enough to predict significant tissue or organ dysfunction.

Example 8 - Effects of FASN inhibitors on IL-1β levels in vivo and in vitro

The effects of the FASN inhibitors of this application on IL-1β levels were evaluated in vivo and in vitro. The effects of compounds 364A, 6B, and 242A are described in this example.

Fasting-feeding study in rats

Female SD rats were fasted for 12 hours, and then both groups were orally administered 60 mg/kg body weight or 100 mg/kg of the FASN inhibitor of this application. A separate control group was given the formulation carrier material. One hour later, the animals were allowed to eat for 6 hours, followed by a 5-hour fast, and then a 10-hour feeding period. Blood samples were collected at each time point to determine IL-1β levels.

High-fat studies in mice

Two groups of male C57BL/6J mice were orally administered 3 mg/kg or 10 mg/kg of the FASN inhibitor of this application once daily. A separate control group was administered the formulation carrier material. Blood samples were collected at various time points to determine IL-1β levels.

Human IL-1b research

Blood from healthy donors was treated with an anticoagulant, and peripheral blood mononuclear cells (PBMCs) were isolated. Attached mononuclear cells from the PBMCs were selected by attaching the cells to tissue culture dishes.

The FASN inhibitor of this application reduced serum IL-1β levels, which occurred in fasted rats after food intake or in mice fed a high-fat diet. Treatment with the FASN inhibitor also reduced the release of IL-1β from freshly isolated human blood cells. These results support the efficacy of the FASN inhibitor in treating inflammatory conditions present in NAFLD, NASH, metabolic syndrome, and other inflammatory diseases.

In untreated or mediated rats, serum IL-1β levels gradually increased between 2 and 22 hours as a response to fasting followed by feeding (Figure 4). Treatment with compound 6B prior to feeding reduced the IL-1β response throughout this timeframe, and by more than 5-fold by 22 hours (Figure 5).

Serum IL-1β levels were measured in mice after maintaining a high-fat diet for 14 and 37 days. Compared with mice receiving the agonist (Fig. 6A and Fig. 6B), mice treated with compound 364A had reduced IL-1β levels at both the time of food reintroduction (Fig. 6A and Fig. 6B) and the time of feeding (1-hour data in Fig. 6A and Fig. 6B) for 14 and 37 days.

Human PBMCs and monocytes in cell cultures were stimulated with the Toll 4 receptor agonist lipopolysaccharide (LPS) or the Toll 2 receptor agonist lipoteichoic acid (LTA). As shown in Figures 7A and 7B, neither cell culture secreted IL-1β into the cell culture supernatant without stimulation. Stimulation with LPS or LTA plus DMSO (the solvent for compound 242A) induced IL-1β secretion. Treatment of PBMCs (a mixed monocyte population including lymphocytes and monocytes) with compound 242A reduced IL-1β levels induced by LPS or LTA stimulation. For monocytes, treatment with compound 242A reduced IL-1β levels induced by LTA stimulation, while only slightly reducing them after LPS stimulation.

Example 9 - Effect of FASN Inhibitor on T Cell Differentiation

The effects of FASN inhibitors on the differentiation of naïve CD4+ T cells isolated from mouse or human blood into pro-inflammatory _Th17 cells and anti-inflammatory T _reg cells were examined. The effects of compounds 364A and 152 are described in this example.

Primary T cell isolation procedure

Primary CD4+ T cells were isolated from whole blood collected in sodium citrate tubes and enriched using the Dynabeads ^™ Untouched Mouse (catalog number 11415D) or Human (catalog number 11346D) CD4+ T Cell Isolation Kit (ThermoFisher). Primary mouse CD4+ T cells were seeded into 48-well tissue culture plates (Costar) coated with beads containing 1 μg/mL anti-CD3 and anti-CD28 antibodies. Primitive mouse CD4+ T cells were induced to differentiate for 4 days using a culture medium containing the following additives to produce mouse _Th17 cell cultures: anti-IL-2 (30 ng/mL) (R&D Systems); recombinant mouse IL-6 (Peprotech) (10 ng/mL); recombinant human TGFβ (1 ng/mL) (Peprotech); recombinant mouse IL-1β (10 ng/mL) (Peprotech); recombinant mouse IL-23 (10 ng/mL) (R&D Systems); anti-IL-4 antibody (20 ng/mL) (Biocell); and anti-IFNγ antibody (50 ng/mL) (Biocell). _Th17 cells were cultured in IMDM GlutaMAX medium (Life Technologies) supplemented with 10% heat-inactivated FCS (Biochrom) and 500 U penicillin-streptomycin (Life Technologies).

Differentiation process - human T cells

Primitive human CD4+ T cells were seeded into 48-well tissue culture plates (Costar) coated with beads containing 1 μg/mL anti-CD3 and anti-CD28 antibodies. See Endo et al., 2015, Cell Reports 12: 1042-1055. Primitive human CD4+ T cells were induced to differentiate for 4 days to produce human _Th17 cultures using a culture medium containing the following additives: anti-IL-2 (30 ng/mL) (R&D Systems); recombinant human IL-6 (10 ng/mL) (BD Biosciences); recombinant human TGFβ (1 ng/mL) (BD Biosciences); recombinant human IL-1β (10 ng/mL) (BD Biosciences); recombinant human IL-23 (10 ng/mL) (BD Biosciences); anti-IL-4 antibody (20 ng/mL) (R&D Systems); and anti-IFNγ antibody (50 ng/mL) (R&D Systems). Th ₁₇ cells were cultured in IMDM GlutaMAX medium (Life Technologies) supplemented with 10% heat-inactivated FCS (Biochrom) and 500U penicillin-streptomycin (Life Technologies).

Flow cytometry

For mouse cells, monoclonal antibodies specific to the following antigens (and labeled with the indicated fluorescent markers) were used: CD4 PerCP (GKl.5; 1:800) (Affymetrix/eBioscience); Foxp3 Alexa488 (FJK-16s; 1:400) (Affymetrix/eBioscience); and IL-17A PE and IL-17A PE (eBio17B7; 1:400 and 1:200) (Affymetrix/eBioscience).

For human cells, monoclonal antibodies specific to the following antigens (and labeled with the indicated fluorescent markers) were used: Foxp3FITC (236A/E7; 1:100) (Affymetrix/eBioscience); IL-17A PE-Cy7 (eBio64DEC17; 1:100) (Affymetrix/eBioscience); and CD4PerCP (SK3; 1:200) (BDBiosciences).

To analyze surface markers, cells were stained in PBS containing 0.25% BSA and 0.02% azide. Dead cells were excluded using the LIVE/DEAD fixed dead cell staining kit (Life Technologies).

For intracellular cytokine staining, cells were treated with brefidobacterium A (5 mg/mL) for 2 hours and stained using a fixation/permeation kit (BD Biosciences) according to the manufacturer’s instructions.

The quantification and intensity of fluorescent cells were obtained on FACSCalibur (BD Biosciences), and the data were analyzed using CELLQuest software.

FASN inhibition (50 nM compound 364A) on mouse CD4+ primordial T cells under 4-day Th ₁₇ differentiation conditions inhibited Th ₁₇ cell differentiation and stimulated T _reg differentiation. Under compound 364A treatment, the percentage of IL-17+ Th17 cells decreased from 41.2% to 3.9% of the CD4+ population, while the percentage of FoxP3+ Treg cells increased from 0.04% to 23.8% of the CD4+ population (Figures 8A and 8B).

FASN inhibition (50 nM compound 364A) on human CD4+ primordial T cells from two different donors under 4-day Th ₁₇ differentiation conditions inhibited Th ₁₇ cell differentiation and stimulated T _reg differentiation. Under compound 364A treatment, IL-17+ Th 17 cells decreased from 31% to 1.7% of the CD4+ population (donor 1) and from 37.2% to 1.6% (donor 2), while FoxP3+ Treg cells increased from 0.05% to 24.2% of the CD4+ population (donor 1) and from 1.1% to 30.2% (donor 2) (Figures 9A to 9D).

FASN inhibition (100 nM compound 152) on human CD4+ primordial T cells from two different donors under 4-day Th17 differentiation conditions inhibited _Th17 cell differentiation and stimulated Treg differentiation. Under compound 364A treatment, IL-17+ Th17 cells decreased from 30% to 10.3% of the CD4+ population (donor 1) and from 30.2% to 6.4% (donor 2), while FoxP3+ Treg cells increased from 0.06% to 26.1% of the CD4+ population (donor 1) and from 0.04% to 20.4% (donor 2) (Figures 10A to 10D).

The data clearly demonstrate that FASN is required when primordial CD4+ T cells are stimulated to differentiate into _Th17 inflammatory cells under pro-inflammatory conditions. Inhibition of FASN with small molecule inhibitors such as compound 364A or compound 152 prevents this pro-inflammatory differentiation and redirects it to the production of anti-inflammatory T _reg cells. These results support the efficacy of FASN inhibitors in treating inflammatory conditions present in NAFLD, NASH, metabolic syndrome, and other inflammatory diseases.

While preferred aspects of the invention have been shown and described herein, those skilled in the art will recognize that these aspects are provided by way of example only. Numerous modifications, variations, and alternatives will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the aspects of the invention described herein can be used to practice the invention. The scope of the invention, as well as the methods and structures and their equivalents covered by the following claims, is intended to be defined by the following claims.

Example 10 - Compound 364A reversed multiple components of NASH in mice.

The ability of compound 364A to reverse symptoms of deterministic diet-induced nonalcoholic steatohepatitis in mice was investigated.

C57BL/6J mice were fed a high-fat/fructose/cholesterol diet (HFFCD) for 44 weeks. For the next 8 weeks, the animals continued on the HFFCD and received once-daily oral treatment with compound 364A, anti-fibrotic pirfenidone, compound 364A with pirfenidone, or a mediator control. At the end of the study, analyses included histological evaluation (NAFLD activity score (NAS) and fibrosis stage), gene expression (liver), total triglyceride and cholesterol levels (liver and plasma), plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and serum cytokine levels.

method

Diet-induced animal model (DIO-NASH mouse model): DIO-NASH mice were male C57BL/6J mice that were fed a diet high in 60% trans fat containing fructose and cholesterol for 44 weeks prior to the experiment. Figure 11 shows a schematic diagram of the study design and dosage groups for the FASN inhibitor 364A and pirfenidone.

Liver biopsy: Mice were anesthetized in the atmosphere with isoflurane (2-3%). A midline incision was made in the lower abdomen, exposing the left lobe of the liver. A cone-shaped wedge-shaped section of liver tissue (approximately 50 mg) was excised from the distal portion of this lobe and fixed in 10% neutral buffered formalin (4% formaldehyde) for histological analysis. The cut surface of the liver was immediately electrocoagulated using a bipolar coagulation device (ERBE VIO 100 electrosurgical unit). The liver was returned to the abdominal cavity, the abdominal wall was sutured, and the skin was closed with a stapler. For postoperative recovery, mice received subcutaneous administration of carbofol (5 mg/kg) on the day of OP and on days 1 and 2 post-OP.

Blood collection: During isoflurane anesthesia, open the abdominal cavity and draw cardiac blood into an EDTA tube using a standard syringe or a vacuum blood collection tube coated with heparin/EDTA. Store the blood at 4°C.

Plasma preparation: Centrifuge blood at 2000g for 10 minutes. Transfer the plasma supernatant to a new tube, immediately freeze in liquid nitrogen, and store at -80°C.

Blood and plasma measurements (triglycerides (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST)): Blood samples were collected in heparinized tubes, plasma was separated and stored at -80°C until analysis. TG, TC, ALT, and AST were measured on a Cobas ^™ C-501 automated analyzer using a commercially available kit (Roche Diagnostics, Germany) according to the manufacturer's instructions.

NAFLD Activity Score (NAS) and Fibrosis Stage: Liver samples were fixed in formalin, embedded in paraffin, and stained with hematoxylin and eosin (H&E) and Sirius Red. The NAS and fibrosis stage (summarized below) of the samples were scored using the clinical criteria outlined by Kleiner et al., 2005. The total NAS score represents the sum of scores for steatosis, inflammation, and ballooning, and is within the range of 0-8.

Table 18: Guidance for NAS and Fibrosis Stage Assessment

Liver tissue assay: Hydroxyproline is a major component of collagen, and the total collagen content in the liver was determined by colorimetric detection of hydroxyproline using QZBhypro and Quickzyme hydroxyproline assays. Homogenized liver tissue was hydrolyzed with hydrochloric acid, and the supernatant was transferred to a 96-well plate. Oxidized hydroxyproline was reacted with 4-(dimethylamino)benzaldehyde (DMAB) to obtain a colorimetric product proportional to the amount of hydroxyproline present. The absorbance was measured at 560 nm.

The triglyceride content in the liver was determined using a Cobas ^™ C-111 automated analyzer with a triglyceride reagent (catalog number 22-045-795, Roche Diagnostics, Germany). Homogenized liver tissue was heated to 80–100°C twice, centrifuged in a microcentrifuge, and the triglyceride content in the supernatant was measured.

Cholesterol levels in the liver were determined using a cholesterol reagent (catalog number 22-045-780, Roche Diagnostics, Germany) on a Cobas ^™ C-111 automated analyzer. Homogenized liver tissue was heated to 80–100°C twice, centrifuged in a microcentrifuge, and the cholesterol content in the supernatant was measured.

Histological staining procedure: In short, slides with paraffin-embedded sections are dewaxed in xylene and rehydrated in a series of gradient ethanol.

Hematoxylin and eosin (H&E) staining: The slide was incubated in Mayer's hematoxylin (Dako), washed in tap water, stained in eosin Y solution (Sigma-Aldrich), hydrated, fixed with Pertex, dried, and then scanned.

Sirius Red Staining: The slide was incubated in Weigert's Sigma-Aldrich iron hematoxylin, washed in tap water, stained with Sirius Red (Sigma-Aldrich), and washed twice in acidified water. Excess water was removed by shaking the slide, which was then hydrated in 100% ethanol (replaced three times), clarified in xylene, fixed with Pertex, dried, and subsequently scanned.

Type I collagen IHC staining: Type I collagen IHC was performed using a standard procedure (Southern Biotech, catalog number 1310-01). In short, after antigen retrieval and inhibition of endogenous peroxidase activity, the slides were incubated with the primary antibody. The primary antibody was detected using a polymerized HRP-linker antibody conjugate. Next, DAB was used as the chromogen to visualize the primary antibody. Finally, the sections were counterstained with hematoxylin and covered with coverslips.

Galactolectin-3 IHC staining: Galactolectin-3 (Biolegend, catalog number 125402) IHC was performed using a standard procedure. In short, after antigen retrieval and inhibition of endogenous peroxidase activity, the slides were incubated with the primary antibody. The primary antibody was detected using a adapter secondary antibody, followed by amplification using a polymerized HRP-adaptor antibody conjugate. Next, DAB was used as the chromogen to visualize the primary antibody. Finally, the sections were counterstained with hematoxylin and covered with coverslips.

Quantification of IHC and fatty degeneration: IHC-positive staining was quantified using image analysis with Visiomorph software (Visiopharm, Denmark). The Visiomorph protocol is designed for two-step analysis of a virtual slide. The first step involves a coarse examination of the tissue at low magnification (1x objective). Liver cysts were excluded. The second step involves detecting IHC-positive staining at high magnification (10x objective). The quantitative estimate of IHC-positive staining was calculated as an area fraction (AF) according to Equation 1:

Quantitative evaluation of fatty degeneration: Fatty degeneration was quantified on H&E-stained slides using image analysis with Visiomorph software (Visiopharm, Denmark). The Visiomorph protocol involves a two-step analysis of the virtual slide. The first step is a coarse tissue examination at low magnification (1x objective). The second step is the examination of fatty degeneration at high magnification (20x objective). The quantitative estimate of fatty degeneration is calculated as an area fraction according to Equation 2:

result

In this diet-induced biopsy-confirmed NASH mouse model, FASN inhibition with compound 364A alleviated hepatocyte ballooning, liver inflammation, and steatosis, reduced plasma ALT and AST levels, decreased hepatic triglycerides and cholesterol, and identified markers consistent with fibrosis regression, including decreased expression of collagen, α-SMA, and TIMP1, and increased expression of MMP9. Co-administration of pirfenidone further alleviated liver fibrosis while maintaining the beneficial effects specific to FASN inhibition.

As shown in Figures 12 and 13, FASN inhibition by compound 364A, alone or in combination with the antifibrotic pirfenidone, improved liver function. Figure 12 shows the assessment of liver function in DIO-NASH mice after treatment with compound 364A and pirfenidone, using plasma liver biomarkers alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total cholesterol (TC). Figure 13 shows the assessment of liver function in DIO-NASH mice after treatment with compound 364A and pirfenidone, using liver sample biomarkers liver triglycerides and liver cholesterol.

As shown in Figures 14 to 18, FASN inhibition by compound 364A, alone or in combination with an antifibrotic agent, reduced adverse liver symptoms. Changes in Figures 14 to 18 were rated as increased severity (I), no change (N), or decreased severity (D). Figure 14 shows the changes in hepatic steatosis obtained by liver biopsy histological analysis after treatment of DIO-NASH mice with compound 364A and pirfenidone. Figure 15 shows the changes in hepatic inflammation obtained by liver biopsy histological analysis after treatment of DIO-NASH mice with compound 364A and pirfenidone. Figure 16 shows the changes in hepatic ballooning obtained by liver biopsy histological analysis after treatment of DIO-NASH mice with compound 364A and pirfenidone. Figure 17 shows the changes in hepatic fibrosis obtained by liver biopsy histological analysis after treatment of DIO-NASH mice with compound 364A and pirfenidone. Figure 18 shows the changes in overall liver health and NAFLD severity, summarized by NAFLD activity score (NAS) obtained from liver biopsy histological analysis after DIO-NASH mice were treated with compound 364A and pirfenidone.

As shown in Figures 19 and 20, FASN inhibition, alone or in combination with antifibrotic agents, reduced the expression of genes responsible for fibrosis. Figure 19 shows the changes in liver collagen gene expression obtained by liver biopsy gene analysis after treatment of DIO-NASH mice with compound 364A and pirfenidone. Figure 20 is a 2-D graph showing the changes in collagen gene expression obtained by liver biopsy gene analysis after treatment of DIO-NASH mice with compound 364A and pirfenidone.

These results provide evidence that FASN inhibition, alone or in combination with antifibrotic agents, can reverse steatohepatitis in a diet-induced and biopsy-confirmed NASH mouse model.

Example 11 - Compound 364A reduced collagen accumulation in bleomycin-induced dermal fibrosis in mice.

The ability of compound 364A to reduce collagen inflammation in mice with bleomycin-induced dermatofibrosis was investigated. Bleomycin-induced dermatofibrosis was established in C57/BL6 mice by daily subcutaneous injection of bleomycin for 4 weeks. Oral treatment with compound 364A once daily was initiated concurrently with bleomycin injection or 2 weeks after bleomycin injection. At the end of the study, collagen content at the bleomycin injection site was determined biochemically. Regardless of whether treatment was initiated concurrently with bleomycin injection or 2 weeks after bleomycin injection, FASN inhibition reduced skin collagen content.

method

Skin fibrosis protocol: Six-week-old female C57BL/6J mice free of specific pathogens were obtained. On day 0, skin fibrosis was induced in 50 mice by subcutaneous administration of bleomycin sulfate (BLM) in saline solution at a dose of 50 μg/mouse every other day (days 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26). On day 0, skin fibrosis was induced in 10 mice by subcutaneous administration of BLM in saline solution at a dose of 50 μg/mouse every other day (days 0, 2, 4, 6, 8, 10, and 12). Control mice were given saline solution instead of BLM subcutaneously.

Figure 21 shows a schematic diagram of the study design and dosage groups.

Based on their body weight the day before treatment began, mice with the BLM-induced skin fibrosis model were randomly divided into 6 groups of 10 mice each. Individual body weight was measured daily during the experiment. Clinical signs and behaviors of the mice were monitored daily. If an animal showed a weight loss of >30% compared to day 0, and/or if it showed signs of impending death such as a prone position, the animal was euthanized before the end of the study, and blood and skin samples were collected according to protocol.

Groups: Group 1 (Control): Ten normal mice were kept untreated until day 28. Group 2 (Mediator): Ten BLM-induced dermatofibrosis model mice were orally administered mediator [30% PEG400 aqueous solution] once daily from day 0 to day 28 at a volume of 5 mL/kg. Group 3 (Low Compound 364A): Ten BLM-induced dermatofibrosis model mice were orally administered mediator supplemented with compound 364A once daily from day 0 to day 28 at a dose of 1 mg/kg. Group 4 (Medium Compound 364A): Ten BLM-induced dermatofibrosis model mice were orally administered mediator supplemented with compound 364A once daily from day 0 to day 28 at a dose of 3 mg/kg. Group 5 (High Compound 364A): Ten BLM-induced dermatofibrosis model mice were orally administered mediator supplemented with compound 364A once daily from day 0 to day 28 at a dose of 10 mg/kg. Group 6 (Compound 364A treatment): Ten BLM-induced dermatofibrosis model mice were orally administered the carboxylic acid at a dose of 5 mL/kg once daily from day 0 to day 13, and supplemented with carboxylic acid containing compound 364A once daily from day 14 to day 28 at a dose of 10 mg/kg. Group 7 (baseline): Ten BLM-induced dermatofibrosis model mice were orally administered the carboxylic acid at a dose of 5 mL/kg once daily from day 0 to day 14. Mice in groups 1 through 6 were terminated 1 hour after the last dose on day 28, and mice in group 7 were terminated 1 hour after the last dose on day 14 for the following assays.

Biochemical analysis: Skin collagen was quantified using the Sircol Collagen Assay Kit.

Histological analysis of skin sections: For HE staining, sections were cut from paraffin blocks of skin tissue pre-fixed in 10% neutral buffered formalin and stained with Lillie-Mayer's hematoxylin and eosin solution. For quantitative analysis of dermal thickness, bright-field images of HE-stained sections were captured at 100x magnification using a digital camera, and dermal thickness was measured at 5 fields/section using ImageJ software (National Institute of Health, USA).

Sample collection: For serum samples, blood was collected via direct cardiac puncture into serum separation tubes without anticoagulants, and then centrifuged at 15,000 × g for 2 minutes at 4°C. The supernatant was collected and stored at -80°C. Skin samples were rapidly frozen in liquid nitrogen and stored at -80°C.

Statistical testing: The Bonferroni Multiple Comparison Test was used for statistical testing. A p-value < 0.05 was considered statistically significant. A trend or tendency was assumed when a one-tailed t-test returned a p-value < 0.1. Results are expressed as mean ± standard deviation.

result

In a bleomycin-induced skin fibrosis model, FASN inhibition with compound 364A reduced skin collagen content in a dose-dependent manner, regardless of whether the treatment was administered concurrently with or two weeks after bleomycin injection. Figure 22 shows the variation of mouse skin collagen content with the dose of compound 364A, obtained through histological analysis of skin sections.

Example 12 - Compound 364A affects gene expression in hepatic stellate cells.

The relative mRNA expression of fibrosis genes in immortalized human hepatic stellate cells (LX-2 cells) treated with compound 364A or sorafenib was investigated.

method

Cell lines: Primary human hepatic stellate cells (phHSC) and immortalized human hepatic stellate cells (LX-2) were used.

Compound 364A and small molecule sorafenib: Compound 364A was dissolved in DMSO at stock solutions of 1, 3, 10, and 30 μM, and then dissolved in DMEM cell culture medium supplemented with 0.1% BSA but without antibiotics at a series of working concentrations of 5, 15, 50, and 150 nM. For the positive control, cells were treated in parallel with the kinase inhibitor sorafenib dissolved in DMSO at a concentration of 7.5 μM.

Experimental protocol: At the start of each experiment, astrocytes were serum starved overnight in DMEM (antibiotic-free) medium supplied with 0.1% BSA to synchronize cellular metabolic activity. Cells were then exposed to different working concentrations of compound 364A or sorafenib for 24, 48, and 72 hours.

Cellular and genetic analysis: Cell proliferation and apoptosis were evaluated using dyes. Fibrogene gene expression was assessed by real-time PCR for the following genes: (i) α-smooth muscle actin; (ii) collagen I; (iii) β-PDGF receptor; (iv) MMP2; (v) TIMP1; and (vi) TIMP2.

Cytotoxicity assay: 5,000 LX-2 cells or 10,000 phHSCs were seeded per well in 96-well plates. Cells were starved overnight in DMEM (antibiotic-free) supplemented with 0.1% BSA to synchronize cellular metabolic activity. Cells were then incubated with different concentrations of compound 364A for a specified duration, and MTS assays were performed using the CellTiter 96 AQueous Single Solution Cell Proliferation Assay Kit according to the manufacturer's protocol.

Cell proliferation assay: Seed 5,000 LX-2 cells or 10,000 phHSCs per well in a 96-well plate. After overnight serum starvation in DMEM (antibiotic-free) supplemented with 0.1% BSA, expose cells to a specified concentration of compound 364A. At 24 and 48 hours of drug exposure, label cells with BrdU at 37°C for 2 hours (for LX-2 cells) or 16 hours (for phHSCs). Use the cell proliferation ELISA BrdU colorimetric kit according to the manufacturer's instructions.

Cell viability assay: 150,000 LX-2 cells or 200,000 phHSCs were seeded per well in a 6-well plate. Cells were starved overnight in DMEM (antibiotic-free) supplemented with 0.1% BSA to synchronize cellular metabolic activity. Cells were then incubated with compound 364A at the specified concentration and duration. Cells were collected and mixed with 0.4% trypan blue (1:1). Cell viability was immediately counted using a Countess automated cell counter.

Fibrogene gene expression in hepatic stellate cells was determined by RT-qPCR: The expression of the following fibrogene genes was quantified by RT-qPCR: (1) Collagen 1α1 (Col1α1); (2) α-smooth muscle actin (αSMA); (3) β-PDGF receptor (β-PDGFR); (4) Transforming growth factor-β receptor 1 (TGFβ-R1); (5) Tissue metalloproteinase inhibitor-1 (TIMP1); (6) Tissue metalloproteinase inhibitor-2 (TIMP2); and (7) Matrix metalloproteinase 2 (MMP2).

Sorafenib (7.5 μtM) was used as a positive control and run in parallel. 150,000 LX-2 cells or 200,000 phHSCs were seeded per well in 6-well plates. Cells were starved overnight in DMEM (antibiotic-free) supplemented with 0.1% BSA to synchronize cellular metabolic activity. Cells were then incubated with either compound 364A or sorafenib at the specified concentration and duration. Cells were collected and total RNA was extracted using the RNeasy Micro Kit. Reverse transcription was performed using 0.5 μg of total RNA with the RNA to cDNA EcoDry Premix (Double Primed) kit. Fibrogene gene expression was measured by qPCR using custom-designed primers and an iQ SYBR Green Supermix instrument on a LightCycler 480II instrument. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a housekeeping gene, and its expression (Ct value) remained constant with different doses of compound 364A and sorafenib. The fibroblast generation gene was standardized relative to GAPDH.

Experimental data analysis: Each experiment was repeated at least three times. Data analysis was performed using appropriate scientific and statistical software. Standard error (±SE) was calculated using Student's t-test. Unless otherwise stated, a p-value less than 0.05 was considered statistically significant.

result

In vitro, FASN inhibition with compound 364A reduced the expression of fibrosis genes in LX-2 hepatocytes in a dose-dependent manner (by real-time PCR). Figure 23 shows the relative mRNA expression of fibrosis genes Col 1a1, αSMA, βPDGFR, TGFbR1, TIMP1, TIMP2, and MMP2 in immortalized human hepatic stellate cells (LX-2 cells) treated with compound 364A or sorafenib for 48 hours, followed by drug removal and recovery for 48 hours.

The recovery of fibroblast gene expression 48 hours after compound withdrawal indicates that the gene downregulation was not a toxic effect of the compound.

All publications and patent applications cited in this specification are incorporated herein by reference as if a single publication or patent application were specifically and individually incorporated by reference.

Table 1 is given below:

Claims (10)

1. Use of a fatty acid synthase inhibitor in the preparation of a medicament for treating diseases or conditions with elevated interleukin-1β (IL1β) levels, elevated t helper ( _Th ) cell levels, or reduced or suppressed regulatory T cells ( _Tregs ), wherein said fatty acid synthase inhibitor has the following formula: (a) Equation (IX) Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: _C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: t is 0 or 1; The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; ^L1 is either ^CR23 or N; ^L2 is CH or N; At least one of ^L1 or ^L2 is N; and R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or (b) Equation (X): Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently hydrogen, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; ^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ; Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , or _C1 - _C4 straight-chain or branched alkyl, wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; n is 1, 2, or 3; m is 1 or 2; R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms; R ²² is H, halogen, or _C1 - _C2 alkyl; Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; s is 0, 1, or 2; Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or (c) Equation (VI-J) Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl; R ²² is H, halogen, or _C1 - _C2 alkyl; R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or (d) Formula (XII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently hydrogen, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein: t is 0 or 1; u is 0 or 1; The constraint is that when u is 1, t is 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or (e) Equation (XIII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently hydrogen, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein: Each t is independently 0 or 1; Each u is independently 0 or 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or (f) Equation (XIV): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently hydrogen, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein: Each t is independently 0 or 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or (g) Equation (XV): Or its pharmaceutically acceptable salt, wherein: ^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle; n is 1, 2, or 3; m can be 1 or 2, and the constraint is that n+m≥3; L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently hydrogen, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or (h) formula (XVI): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently hydrogen, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and ^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or (i) Equation (XVII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently hydrogen, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein: t is 0 or 1; u is 0 or 1; The constraint is that when u is 1, t is 1; and R ²⁴¹ is H or _C1 - _C2 alkyl; or (j) Equation (XVIII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is a condition when L-Ar is, and Ar is not ^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , where R ³⁵¹ is _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently hydrogen, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or (k) Equation (XIX): Or its pharmaceutically acceptable salt, wherein: Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-; Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl); Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring; Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently hydrogen, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or (l) Equation (XX): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently hydrogen, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or (m) Equation (XI): Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl). 2. Use of a fatty acid synthase inhibitor in the preparation of a medicament for treating acne, wherein the fatty acid synthase inhibitor has the following formula: (a) Equation (IX) Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: _C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: t is 0 or 1; The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; ^L1 is either ^CR23 or N; ^L2 is CH or N; At least one of ^L1 or ^L2 is N; and R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or (b) Equation (X): Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; ^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ; Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , or _C1 - _C4 straight-chain or branched alkyl, wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; n is 1, 2, or 3; m is 1 or 2; R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms; R ²² is H, halogen, or _C1 - _C2 alkyl; Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; s is 0, 1, or 2; Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or (c) Equation (VI-J) Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl; R ²² is H, halogen, or _C1 - _C2 alkyl; R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or (d) Formula (XII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein: t is 0 or 1; u is 0 or 1; The constraint is that when u is 1, t is 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or (e) Equation (XIII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein: Each t is independently 0 or 1; Each u is independently 0 or 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or (f) Equation (XIV): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein: Each t is independently 0 or 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or (g) Equation (XV): Or its pharmaceutically acceptable salt, wherein: ^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle; n is 1, 2, or 3; m can be 1 or 2, and the constraint is that n+m≥3; L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or (h) formula (XVI): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and ^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or (i) Equation (XVII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein: t is 0 or 1; u is 0 or 1; The constraint is that when u is 1, t is 1; and R ²⁴¹ is H or _C1 - _C2 alkyl; or (j) Equation (XVIII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is conditional if Ar is not true when L-Ar is true. ^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl, or heteroaryl; or (k) Equation (XIX): Or its pharmaceutically acceptable salt, wherein: Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-; Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl); Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring; Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or (l) Equation (XX): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or (m) Equation (XI): Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl). 3. Use of fatty acid synthase inhibitors in the preparation of medicaments for the treatment of pulmonary fibrosis, wherein said fatty acid synthase inhibitor has the following formula: (a) Equation (IX) Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: _C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: t is 0 or 1; The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; ^L1 is either ^CR23 or N; ^L2 is CH or N; At least one of ^L1 or ^L2 is N; and R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or (b) Equation (X): Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; ^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ; Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , or _C1 - _C4 straight-chain or branched alkyl, wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; n is 1, 2, or 3; m is 1 or 2; R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms; R ²² is H, halogen, or _C1 - _C2 alkyl; Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; s is 0, 1, or 2; Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or (c) Equation (VI-J) Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl; R ²² is H, halogen, or _C1 - _C2 alkyl; R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or (d) Formula (XII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein: t is 0 or 1; u is 0 or 1; The constraint is that when u is 1, t is 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or (e) Equation (XIII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein: Each t is independently 0 or 1; Each u is independently 0 or 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or (f) Equation (XIV): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein: Each t is independently 0 or 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or (g) Equation (XV): Or its pharmaceutically acceptable salt, wherein: ^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle; n is 1, 2, or 3; m can be 1 or 2, and the constraint is that n+m≥3; L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or (h) formula (XVI): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and ^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or (i) Equation (XVII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein: t is 0 or 1; u is 0 or 1; The constraint is that when u is 1, t is 1; and R ²⁴¹ is H or _C1 - _C2 alkyl; or (j) Equation (XVIII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is conditional if L-Ar is true, then Ar is not true. ^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or (k) Equation (XIX): Or its pharmaceutically acceptable salt, wherein: Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-; Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl); Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring; Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or (l) Equation (XX): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or (m) Equation (XI): Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl). 4. Use of fatty acid synthase inhibitors in the preparation of medicaments for the treatment of metabolic syndrome, wherein said fatty acid synthase inhibitor has the following formula: (a) Equation (IX) Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: _C3 - _C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is H, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t -OH, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: t is 0 or 1; The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; ^L1 is either ^CR23 or N; ^L2 is CH or N; At least one of ^L1 or ^L2 is N; and R ²³ is H or a _C1 - _C4 straight-chain or branched alkyl group; or (b) Equation (X): Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; ^L3 is C(R ⁶⁰ ) ₂ , O or NR ⁵⁰ ; Each R ⁶⁰ is independently H, -OH, -CN, _-Ot- ( _C3 - _C5 cycloalkyl), -O-( _C1 - _C4 straight-chain or branched alkyl), or -C(O)-N(R ⁶⁰¹ ) ₂ , wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; Each R ⁵⁰ is independently H, -C(O) _-Ot- ( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C3 - _C5 cyclic alkyl), _-C3 - _C5 cyclic alkyl optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R ⁵⁰¹ ) ₂ , or _C1 - _C4 straight-chain or branched alkyl, wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; n is 1, 2, or 3; m is 1 or 2; R ²¹ is H, halogen, _C1 - _C4 straight-chain or branched alkyl or _C3 - _C5 cycloalkyl, wherein the _C3 - _C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms; R ²² is H, halogen, or _C1 - _C2 alkyl; Each R ²⁶ is independently -OH, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 straight-chain or branched alkyl), -C(O) _-Ot- ( _C1 - _C4 alkyl), or -C(O)-N(R ⁵⁰¹ ) ₂ , wherein: t is 0 or 1; and The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; s is 0, 1, or 2; Each of R ⁶⁰¹ and R ⁵⁰¹ is independently an H or _C1 - _C4 straight-chain or branched alkyl group; and Two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be optionally joined to form a ring, wherein two of ^R26 , ^R60 , ^R50 , ^R501 , and ^R601 may be two ^R26 , two ^R60 , two ^R50 , two ^R501 , or two ^R601 ; or (c) Equation (VI-J) Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl; R ²² is H, halogen, or _C1 - _C2 alkyl; R ³⁵ is -C(O)-R ³⁵¹ , -C(O)-NHR ³⁵¹ , -C(O)-OR ³⁵¹ , or S(O) ₂ R ³⁵¹ ; and R ³⁵¹ is a _C1 - _C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or (d) Formula (XII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is H, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ou- ( _C3 - _C6 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ou- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein: t is 0 or 1; u is 0 or 1; The constraint is that when u is 1, t is 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; and R ²⁵ is a halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C2 alkyl, or cyclopropyl; or (e) Equation (XIII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and Each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -( _C1 - _C4 alkyl)-CN, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein: Each t is independently 0 or 1; Each u is independently 0 or 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or (f) Equation (XIV): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl) _t -N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t - _Ot- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t - _Ot- (4- to 6-membered heterocycle), or -( _C1 - _C4 alkyl) _t -O-( _C1 - _C4 alkyl), wherein: Each t is independently 0 or 1; and Each R ²⁴¹ is independently H or _C1 - _C2 alkyl; or (g) Equation (XV): Or its pharmaceutically acceptable salt, wherein: ^L3 is _-CH2- , -CHR50-, ^-O- , ^-NR50- , -NC(O) ^R50- or -NC(O) ^OR50- , where ^R50 is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl or a 4- to 6-membered heterocycle; n is 1, 2, or 3; m can be 1 or 2, and the constraint is that n+m≥3; L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or (h) formula (XVI): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and ^R24 and ^R25 are each independently H, _-C1 - _C4 alkyl, or halogen; or (i) Equation (XVII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is subject to the constraint that Ar is not equal when L-Ar is equal. Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ²⁴ is H, _C1 - _C4 alkyl, -( _C1 - _C4 alkyl)-OH, -( _C1 - _C4 alkyl)-N(R ²⁴¹ ) ₂ , -( _C1 - _C4 alkyl) _t -O _u- ( _C3 - _C5 cycloalkyl), -( _C1 - _C4 alkyl) _t -O _u- (4- to 6-membered heterocycle) or -( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), wherein: t is 0 or 1; u is 0 or 1; The constraint is that when u is 1, t is 1; and R ²⁴¹ is H or _C1 - _C2 alkyl; or (j) Equation (XVIII): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar is a condition when L-Ar is, and Ar is not ^L2 is -NHR ³⁵ or -C(O)NHR ³⁵¹ , where R ³⁵¹ is _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ , or S(O) _2R ³⁵¹ , wherein R ³⁵¹ is a _C1 - _C6 alkyl, _C3 - _C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl, or heteroaryl; or (k) Equation (XIX): Or its pharmaceutically acceptable salt, wherein: Each W, X, Y, and Z is independently -N- or -CR ²⁶ -, with the constraint that no more than two of W, X, Y, and Z are -N-; Each R ²⁶ is independently H, _C1 - _C4 alkyl, -O-( _C1 - _C4 alkyl), -N(R ²⁷ ) ₂ , -S(O) _2- ( _C1 - _C4 alkyl) or -C(O)-( _C1 - _C4 alkyl); Each R ²⁷ is independently H or _C1 - _C4 alkyl, or both R ²⁷ are _C1 - _C4 alkyl and are joined together to form a 3- to 6-membered ring with the N to which they are attached, and wherein the ring optionally includes an oxygen atom as one of the members of the ring; Ar for Het is a 5- to 6-membered heteroaryl group; ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ¹¹ is H or -CH ₃ ; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; and ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; or (l) Equation (XX): Or its pharmaceutically acceptable salt, wherein: L-Ar is Ar for ^R1 is H, -CN, halogen, _C1 - _C4 alkyl, -O-( _C3 - _C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-( _C1 - _C4 alkyl), wherein when ^R1 is not H, -CN or halogen, ^R1 is optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 alkyl; ^R3 is H or F; R ²¹ is H, halogen, _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, or a 4- to 6-membered heterocycle; R ²² is H, halogen, or _C1 - _C2 alkyl; R ²⁴ is -O-( _C1 - _C4 alkyl), -O-( _C1 - _C4 alkyl)-O-( _C1 - _C4 alkyl), -O-( _C3 - _C5 cycloalkyl), or -O-(4- to 6-membered heterocycle), wherein R ²⁴ is optionally substituted with one or more hydroxyl groups or halogens; and R ²⁵ is H, a halogen, a _C1 - _C4 alkyl or _C3 - _C5 cycloalkyl, wherein R ²⁵ is optionally substituted with one or more halogens; or (m) Equation (XI): Or its pharmaceutically acceptable salt, wherein: ^R1 is H, -CN, halogen, _C1 - _C4 straight-chain or branched alkyl, -O-( _C3 - _C5 cycloalkyl) or -O-( _C1 - _C4 straight-chain or branched alkyl), wherein: The _C3 - _C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; and When ^R1 is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each ^R2 is independently H, halogen, or _C1 - _C4 straight-chain or branched alkyl; ^R3 is H, -OH, or a halogen; R ²¹ is cyclobutyl, azacyclobutyl-1-yl, or cyclopropyl; ^R22 is H, a halogen, or a _C1 - _C2 alkyl group; and R ³⁵¹ is _C1 - _C2 alkyl or _C2 -O-( _C1 or _C2 alkyl). 5. The use according to claim 1, wherein the drug is used to treat diseases or conditions with elevated interleukin 1β (IL1β) levels. 6. The use according to claim 1, wherein the drug is used to treat diseases or conditions with elevated t helper ( _Th ) cell levels. 7. The use according to claim 1, wherein the drug is used to treat diseases or conditions in which regulatory T cells (T _reg ) are reduced or suppressed. 8. The use according to any one of claims 1-7, wherein the fatty acid synthase inhibitor has the formula (IX), (X), (XII), (XIV), (XV) or (XX), or a pharmaceutically acceptable salt thereof. 9. The use according to any one of claims 1-7, wherein the fatty acid synthase inhibitor has formula (IX) or a pharmaceutically acceptable salt thereof. 10. The use according to any one of claims 1-7, wherein the fatty acid synthase inhibitor has formula (X) or a pharmaceutically acceptable salt thereof.