RU2779069C2 - Heterocyclic lipid synthesis modulators - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to heterocyclic compounds of formulas (III), (IIIb), (II), (I), (VI), where radicals R²¹, R²², R²⁴, R²⁵, L, Ar, L³, n, m, R³ have values specified in the claims. The invention also relates to a pharmaceutical composition based on the specified compounds.

EFFECT: new heterocyclic compounds are obtained, useful as modulators of synthesis of lipids having improved antiviral and anticancer activities.

16 cl, 26 tbl, 2 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. paragraph 119(e) of U.S. Provisional Application No. 61/667,894 filed July 3, 2012, U.S. Provisional Application No. 61/698511 filed September 7, 2012 , U.S. Provisional Application No. 61/699819, filed September 11, 2012, and U.S. Provisional Application 61/785933, filed March 14, 2013. The above applications are incorporated into this application in its entirety by reference.

FIELD OF TECHNOLOGY

In General, the present invention relates to heterocyclic lipid synthesis modulators and methods of their use. The heterocyclic lipid synthesis modulators of the present invention can be used to treat diseases characterized by dysregulation of fatty acid synthase function in a subject by modulating the fatty acid synthase pathway and/or fatty acid synthase function.

BACKGROUND OF THE INVENTION

Viral diseases are a serious public health problem that threatens a large part of the world's population. Some of the features of a viral infection that are of concern to health professionals include its high contagiousness (eg HIV, SARS (SARS), etc.) and its high mutability. Some viruses are also oncogenic (such as HPV, EBV, and HBV). Despite the fact that viruses are structurally the simplest organisms, they are among the most difficult to control and represent a challenge for research in the field of antiviral drugs.

To date, several antiviral drugs are widely used in the treatment of patients, such as Amantadine (Amantadine) and Oseltamivir (Oseltamivir) for the treatment of influenza, Acyclovir (Acyclovir) for the treatment of infections associated with HSV, Ganciclovir (Ganciclovir) for CMV infection, and numerous agents including combination drugs (Efavirenz, emtricitabine and tenofovir disoproxil fumarate) for the treatment of AIDS. These drugs have a number of undesirable neurological, metabolic and immunological side effects. Consequently, the development of new antiviral therapies has become a major challenge in medical and pharmaceutical research and development.

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

The current standard treatment regimen for HCV infection involves combination therapy with interferon alpha and ribavirin, often with the addition of a direct-acting protease inhibitor (telaprevir or boceprevir). Treatment is difficult and often causes disabling and severe side effects. For this reason, many patients are not treated at an early stage of the disease. In addition, in some groups of patients, treatment does not cause a long-term therapeutic response. There is an urgent need for new and effective treatments for HCV infection.

The main therapeutic approaches used to treat cancer include surgical removal of primary tumors, tumor irradiation, and parenteral administration of antimitotic cytotoxic agents. Unfortunately, only a relatively small subset of cancer patients have tumors that are pathway-bound (metabolic) and thus can be treated with newer targeting agents. The continued dominance of these conventional therapies is reflected in the lack of improvement in survival rates for most cancers. Classical therapies have low clinical success as well as devastating side effects. Therapies based on radiation and cytotoxicity lead to the destruction of rapidly dividing hematopoietic and intestinal epithelial cells, leading to impaired immune function, anemia, and impaired nutrient absorption. Surgery often results in the release of tumor cells into the circulatory or lymphatic systems, resulting in the formation of metastatic tumors. There is a need for improved methods of treating cancer.

BRIEF DESCRIPTION OF THE INVENTION

The present application aims to address the gap in antiviral and anticancer treatments by providing novel heterocyclic lipid synthesis modulators having improved antiviral and anticancer activities.

In various aspects, this application provides compounds of structure I:

or their pharmaceutically acceptable salts, in which:

L ³ is -CH ₂ -, -CHR ⁵⁰ -, -O-, -NR ⁵⁰ -, -NC(O)R ⁵⁰ - or -NC(O)OR ⁵⁰ -, where R ⁵⁰ is C ₁ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

n is 1, 2 or 3;

m is 1 or 2, provided that n+m≥3;

,

или

;L-Ar represents

,

or

;

,

,

,

или

, при условии что когда L-Ar представляет собой

, Ar не является

;Ar represents

,

,

,

or

, provided that when L-Ar is

, Ar is not

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle; and

R ²² is H, halogen or C ₁ -C ₂ alkyl.

In various aspects, this application provides compounds of structure II:

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

, при условии что когда L-Ar представляет собой

, Ar не является

;Ar represents

,

,

,

or

, provided that when L-Ar is

, Ar is not

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl; and

R ²⁴ is H, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl)-OH, -(C ₁ -C ₄ alkyl) _t -N(R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl) _t -O _t -(C ₃ -C ₅ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _t -(4-6 membered heterocycle) or -(C ₁ -C ₄ alkyl) _t - O-(C ₁ -C ₄ alkyl), where:

each t is independently 0 or 1; and

each R ²⁴¹ is independently H or C ₁ -C ₂ alkyl.

In various aspects, this application provides compounds of structure III:

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl;

R ²⁴ is H, -CN, -(C ₁ -C ₄ alkyl)-CN, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl)-OH, -(C ₁ -C ₄ alkyl)- N(R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl) _t -O _u -(C ₃ -C ₆ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _u -(4-6-membered heterocycle) or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl), where:

t is 0 or 1;

u is 0 or 1;

provided that when u is 1, t is 1; and

each R ²⁴¹ is independently H or C ₁ -C ₂ alkyl; and

R ²⁵ is halogen, -CN, -(C ₁ -C ₄ alkyl)-CN, C ₁ -C ₂ alkyl or cyclopropyl.

In various aspects, this application provides compounds of structure IIIb:

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl; and

each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -(C ₁ -C ₄ alkyl) -CN, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl) -OH, -(C ₁ -C ₄ alicl) -N(R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl) _t -O _u -(C ₃ -C ₅ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _u -(4-6-membered heterocycle) or -(C ₁ -C ₄ alkyl) _t -O-(C ₁ -C ₄ alkyl), where:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R ²⁴¹ is independently H or C ₁ -C ₂ alkyl, and the compound is not:

.

.

In various aspects, this application provides compounds of structure IIIc:

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl; and

each of R ²⁴ and R ²⁵ independently represents H, -C ₁ -C ₄ alkyl or halogen.

In various aspects, this application provides compounds of structure IV:

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

Ar represents

,

,

,

or

, при условии что когда L-Ar представляет собой

, Ar не является

;

, provided that when L-Ar is

, Ar is not

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl; and

R ²⁴ is H, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl)-OH, -(C ₁ -C ₄ alkyl)-N(R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl ) _t -O _u -(C ₃ -C ₅ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _u -(4-6 membered heterocycle) or -(C ₁ -C ₄ alkyl)-O- (C ₁ -C ₄ alkyl), where:

t is 0 or 1;

u is 0 or 1;

provided that when u is 1, t is 1; and

R ²⁴¹ is H or C ₁ -C ₂ alkyl.

In various aspects, this application provides compounds of structure V:

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

, при условии что когда L-Ar представляет собой

, Ar не является

;Ar represents

,

,

,

or

, provided that when L-Ar is

, Ar is not

;

L ² is -NHR ³⁵ or -C(O)NHR ³⁵¹ where R ³⁵¹ is C ₁ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl, 4-6 membered heterocycle, aryl or heteroaryl;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle), -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ or S(O) ₂ R ³⁵¹ , where R ³⁵¹ is C ₁ -C ₆ alkyl, C ₃ - C ₅ cycloalkyl, 4-6 membered heterocycle, aryl or heteroaryl.

In various aspects, this application provides compounds of structure VI:

or their pharmaceutically acceptable salts, in which:

each W, X, Y and Z is independently -N- or -CR ²⁶ - provided that no more than 2 of W, X, Y and Z are -N-;

each R ²⁶ is independently H, C ₁ -C ₄ alkyl, -O-(C ₁ -C ₄ alkyl), -N(R ²⁷ ) ₂ , -S(O) ₂ -(C ₁ -C ₄ alkyl) or -C(O)-(C ₁ -C ₄ alkyl);

each R ²⁷ is independently H or C ₁ -C ₄ alkyl or both R ²⁷ are C ₁ -C ₄ alkyl and combine to form a 3-6 membered ring together with the N atom to which they are attached, and where the ring is possible contains one oxygen atom as one of the ring members;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle), -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle; and

R ²² is H, halogen or C ₁ -C ₂ alkyl.

In various aspects, this application provides pharmaceutical compositions comprising any of the compounds of structures I, II, III, IIIb, IIIc, IV, V and VI and a pharmaceutically acceptable carrier, excipient or diluent.

In various aspects, provided herein are methods of treating a condition characterized by dysregulation of fatty acid synthase function in a subject, said method comprising administering to a subject in need of such treatment an effective amount of a compound of any of structures I, II, III, IIIb, IIIc , IV, V and VI. In various aspects, said disease characterized by dysregulation of the fatty acid synthase pathway is a viral infection or a cancer. In various aspects, said viral infection is treated with a compound of any of structures I, II, III, IIIb, IIIc, IV, V, and VI in combination with one or more additional antiviral treatments. In various aspects, a cancer is treated with a compound of any of structures I, II, III, IIIb, IIIc, IV, V, and VI in combination with one or more additional cancer treatments. In various aspects, said viral infection is hepatitis C. In various aspects, said cancer is breast cancer. In various aspects, said cancer is pancreatic cancer. In various aspects, said cancer is colon cancer.

DETAILED DESCRIPTION OF THE INVENTION

The present application addresses the disadvantages of treating conditions that are characterized by impaired FASN function in a subject, such as viral infection, cancer, or metabolic disorders, by providing novel heterocyclic lipid synthesis modulators.

According to various aspects, the present application provides compositions and methods for the treatment of viral infections. In general, compositions and methods for treating viral infections aim to modulate the fatty acid synthesis pathway. The fatty acid synthesis pathway is involved in virus replication in host cells. The present invention provides methods for treating viral infections that interact with the fatty acid synthesis pathway, such as hepatitis C.

According to various aspects, the present application provides compositions and methods for the treatment of cancer. Fatty acid synthase is responsible for converting malonyl-CoA to long-chain fatty acids, which is an early step in fatty acid biosynthesis. Many cancer cells overexpress fatty acid synthase. Without wishing to be bound by a particular theory, the present inventors speculate that inhibition of fatty acid synthase expression or selectivity of fatty acid synthase activity suppresses proliferation and results in cell death of cancer cells, while exerting only a small toxic effect on normal cells.

In addition, the present application provides compounds and methods for modulating host cells that are targets for viruses. Such modulation of target cells of the host may include activation or inhibition of target cells of the host. Accordingly, compounds that modulate components of the fatty acid synthesis pathway, such as the activity of a non-viral protein, such as a host cell protein, can be used as antiviral pharmaceutical agents.

Definitions

Chemical groups referred to as monovalent chemical groups (eg, alkyl, aryl, etc.) also include structurally acceptable polyvalent groups, as will be apparent to those skilled in the art. For example, while an "alkyl" group generally refers to a monovalent radical (e.g., CH ₃ CH ₂ -), in appropriate circumstances an "alkyl" group can also refer to a divalent radical (e.g., -CH ₂ CH ₂ -, which is equivalent to an "alkylene" group). Similarly, in circumstances where a divalent group is desired, it will be apparent to one of ordinary skill in the art that the term "alkyl" refers to the corresponding divalent arylene group.

All atoms are assumed to have their normal bonding valencies (eg, 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the atom). In some cases, the group may be defined as, for example, (A) _a B, where a is 0 or 1. In such cases, when a is 0, the group is B, and when a is 1, the group is AB.

In cases where a substituent may have differences in the number of atoms or groups of the same type (for example, alkyl groups may be C ₁ , C ₂ , C ₃ , etc.), the number of repeating atoms or groups may be represented set (eg, C ₁ -C ₆ alkyl), which includes all numbers in the set and all subsets. For example, C ₁ -C ₃ alkyl includes C ₁ , C ₂ , C ₃ , C _1-2 , C _1-3 and C _2-3 alkyl.

"Alkanoyl" refers to a carbonyl group containing a lower alkyl group as a substituent.

"Alkylamino" refers to an amino group substituted with an alkyl group.

"Alkoxy" refers to an O atom substituted with an alkyl group as defined herein, eg methoxy [-OCH ₃ , C ₁ alkoxy]. The term "C _1-6 alkoxy" embraces C ₁ alkoxy, C ₂ alkoxy, C ₃ alkoxy, C ₄ alkoxy, C ₅ alkoxy, C ₆ alkoxy, and any subset thereof.

"Alkoxycarbonyl" refers to a carbonyl group containing an alkoxy group as a substituent.

"Alkylcarbonyloxy" refers to the group -O-(C=O)-alkyl.

"Alkyl," "alkenyl" and "alkynyl" refer to optionally substituted straight or branched chain aliphatic groups containing 1-30 carbon atoms, or preferably 1-15 carbon atoms, or more preferably 1-6 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, vinyl, allyl, isobutenyl, ethynyl, and propynyl. The term "heteroalkyl" in the context of this application means alkyl containing one or more heteroatoms. The term "haloalkyl" in the context of this application means alkyl containing one to three halogen substituents.

"Alkylene" refers to an optionally substituted bivalent radical which is a branched or unbranched hydrocarbon moiety containing a specified number of carbon atoms and having two attachment sites. An example is propylene [-CH ₂ CH ₂ CH ₂ - and C ₃ alkylene].

"Amino" refers to the -NH ₂ group.

"Aryl" refers to optionally substituted aromatic groups that contain at least one ring containing a conjugated pi electron system and includes carbocyclic aryl and biaryl groups, all of which may be optionally substituted. Phenyl and naphthyl groups are the preferred carbocyclic aryl groups.

"Aralkyl" or "arylalkyl" refers to alkyl-substituted aryl groups. Examples of aralkyl groups include butylphenyl, propylphenyl, ethylphenyl, methylphenyl, 3,5-dimethylphenyl, t-butylphenyl.

, где R^N выбран из группы, состоящей из водорода, -OH, C₁-C₁₂ алкила, C₁-C₁₂ гетероалкила, алкенила, алкинила, циклоалкила, гетероцикла, арила, гетероарила, аралкила, алкокси, алкоксикарбонила, алканоила, карбамоила, сульфонила, сульфоната и сульфонамида."Carbamoyl" in the context of this application means a group of structure

where R ^N is selected from the group consisting of hydrogen, -OH, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl , sulfonyl, sulfonate and sulfonamide.

."Carbonyl" refers to the structure group

.

"Cycloalkyl" refers to an optionally substituted ring, which may be saturated or unsaturated and monocyclic, bicyclic or tricyclic, entirely formed by carbon atoms. An example of a cycloalkyl group is a cyclopentenyl group (C ₅ H ₇ -), which is an unsaturated cycloalkyl group consisting of five carbon atoms (C ₅ ).

"Heterocycle" refers to a possibly substituted 5-7 membered cycloalkyl ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, O or S, and optionally containing one double bond. "Heterocycle" also refers to a possibly substituted 4-8 membered cycloalkyl ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, O or S, and optionally containing one double bond.

"Halogen" refers to a radical - a chlorine, bromine, fluorine or iodine atom. The term "halogen" also implies the term "halide".

"Heteroatom" refers to an atom other than carbon, where boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms for compounds according to the present description.

"Heteroaryl" refers to optionally substituted aryl groups containing 1-9 carbon atoms in which the remaining atoms are heteroatoms, and includes the heterocyclic systems described in the Handbook of Chemistry and Physics, 49th edition , 1968, R.C. Weast, editor; The Chemical Rubber Co., Cleveland, Ohio). See in particular Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryls include thienyl, pyrryl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl, pyridazinyl, triazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl , benzothiazolyl, tetrazolopyridazinyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, thiadiazolyl, benzothiazolyl, benzothiadiazolyl and the like.

The "Optionally substituted" moiety may be substituted with 1-4, or preferably 1-3, or more preferably 1 or 2, non-hydrogen substituents. Unless otherwise indicated, when the substituent is on a carbon atom, it is selected from the group consisting of -OH, -CN, -NO ₂ , halogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate, sulfonamide and amino, none of which is further substituted. Unless otherwise indicated, when the substituent is on a carbon atom, it may also be selected from the group consisting of oxo. Unless otherwise indicated, when the substituent is on a carbon atom, it may also be selected from the group consisting of alkylcarbonyloxy, which in turn is unsubstituted. Unless otherwise indicated, when the substituent is on a carbon atom, it may also be selected from the group consisting of alkylamino, which in turn is unsubstituted. Unless otherwise indicated, when the substituent is on a carbon atom, it may also be selected from the group consisting of C ₁ -C ₁₂ alkenyl and C ₁ -C ₁₂ alkynyl, neither of which is further substituted. Unless otherwise indicated, when the substituent is on the nitrogen atom, it may also be selected from the group consisting of C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy , alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamide, none of which is further substituted. Unless otherwise indicated, when the substituent is on the nitrogen atom, it may also be selected from the group consisting of C ₁ -C ₁₂ alkenyl and C ₁ -C ₁₂ alkynyl, neither of which is further substituted.

"Oxo" refers to the =O substituent.

, где R^N выбран из группы, состоящей из водорода, -OH, C₁-C₁₂ алкила, C₁-C₁₂ гетероалкила, алкенила, алкинила, циклоалкила, гетероцикла, арила, гетероарила, аралкила, алкокси, алкоксикарбонила, алканоила, карбамоила, сульфонила, сульфоната и сульфонамида.The term "sulfonamide" in the context of this application means a group having the structure

where R ^N is selected from the group consisting of hydrogen, -OH, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl , sulfonyl, sulfonate and sulfonamide.

, где R^S выбран из группы, состоящей из водорода, C₁-C₁₀ алкила, C₂-C₁₀ алкенила, C₂-C₁₀ алкинила, C₁-C₁₀ алканоила или C₁-C₁₀ алкоксикарбонила.The term "sulfonate" in the context of this application means a group having the structure

where R ^{S is} selected from the group consisting of hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ alkanoyl, or C ₁ -C ₁₀ alkoxycarbonyl.

, где R^M выбран из группы, состоящей из водорода, C₁-C₁₂ алкила, C₁-C₁₂ гетероалкила, алкенила, алкинила, циклоалкила, гетероцикла, арила, гетероарила, аралкила и алкокси."Sulfonyl" in the context of this application, alone or as part of another group, refers to the group SO ₂ . The SO ₂ fragment is possibly substituted. In particular, "sulfonyl" in the context of the present application means a group having the structure

where R ^M is selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, and alkoxy.

Compounds according to the present application may exist in the form of stereoisomers in which asymmetric or chiral centers are present. Stereoisomers are designated as (R) or (S) depending on the configuration of the substituents around the chiral carbon atom. The terms (R) and (S) in this specification are the configurations defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45: 13- 30), incorporated herein by reference. This application discusses various stereoisomers and mixtures thereof, which are specifically included in the scope of this application. Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers. The individual stereoisomers of the compounds of the present application may be prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers, or by preparation of racemic mixtures followed by resolution well known to those of ordinary skill in the art. These separation methods are represented by (1) adding a mixture of enantiomers to a chiral auxiliary element, separating the resulting mixture of diastereomers by recrystallization or chromatography and releasing the optically pure product from the auxiliary element, or (2) direct separation of a mixture of optical enantiomers on chiral chromatographic columns.

Also described in this application, groups that exist in a variety of tautomeric forms include all such forms covered by a given tautomeric structure.

Individual atoms in the described compounds can be any isotope of the specified element. For example, hydrogen may be in the form of deuterium.

"Pharmaceutical acceptable" means approved or likely to be approved by the Federal or State Office of Control or contained in the USP or other generally accepted pharmacopeia for use in animals, and more particularly in humans. This may be a substance that is not biologically or otherwise undesirable, ie. the substance can be administered to the subject without causing any undesirable biological effects or without entering into harmful effects with any of the components of the composition in which it is included.

The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that has the desired pharmacological activity of the parent compound. Such salts include, for example, acid addition salts and base addition salts.

The "acid addition salts" of the present application are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentane propionic 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, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[ 2.2.2]oct-2-en-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert- butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

"Base addition salts" according to the present application are formed when the acid proton in the parent compound or is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Suitable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like.

It is to be understood that reference to a pharmaceutically acceptable salt includes solvent addition forms or crystalline forms thereof, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are often formed during the crystallization process. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include various forms of crystalline formations of the same elemental composition of the compound. Polymorphs typically have differing X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability, and solubility. Various factors such as solvent recrystallization, crystallization rate, and storage temperature can lead to the predominance of one crystal form.

The term "treatment" includes the administration of the compounds or agents of the present invention to a subject to prevent or slow down, alleviate a condition, or stop or inhibit the development of symptoms or conditions associated with diseases associated with fatty acid synthase.

A "therapeutically effective amount" or "pharmaceutically effective amount" means an amount that, when administered to a subject, produces the effects for which it is administered. For example, a "therapeutically effective amount" when administered to a subject to inhibit fatty acid synthase activity is sufficient to inhibit fatty acid synthase activity. A "therapeutically effective amount" when administered to a subject for the treatment of a disease is sufficient to produce a curative effect on said disease.

Unless otherwise indicated, the terms "subject" or "patient" are used interchangeably and refer to mammals such as humans or non-human primates, as well as experimental animals such as rabbits, rats and mice, and other animals. . Accordingly, the term "subject" or "patient" in the context of the present application refers to any mammalian patient or subject to which compounds according to the present invention can be administered. According to an illustrative aspect of the present invention, in order to identify patient subjects for treatment according to the methods of the present invention, accepted 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 a subject. These screening methods include, for example, conventional studies aimed at identifying risk factors that are associated with a target or suspected disease or condition. These and other conventional methods allow the clinician to select patients in need of therapy using the methods and compositions of the present invention.

The chemical names of the compounds according to the present application were generated using ChemDraw Ultra software version 12.0 (CambridgeSoft Corp., Cambridge Mass).

FASN signaling pathway modulators

One aspect of the present application includes a method for inhibiting a viral infection or treating a cancer by contacting a cell with an agent that modulates the fatty acid synthesis pathway. Said method for inhibiting a viral infection or treating a cancer can be applied in vitro by contacting virus-infected/cancer cells with an agent that modulates the fatty acid synthesis pathway, or in vivo by administering an agent that modulates the fatty acid synthesis pathway to a subject infected with a virus/having cancer disease. In one aspect, the agent may be an inhibitor of the fatty acid synthesis pathway.

Examples of inhibitors of the fatty acid synthesis pathway suitable for use in the methods and compositions of the present application are described below.

In various aspects, this application provides compounds of structure I:

or their pharmaceutically acceptable salts, in which:

L ³ is -CH ₂ -, -CHR ⁵⁰ -, -O-, -NR ⁵⁰ -, -NC(O)R ⁵⁰ - or -NC(O)OR ⁵⁰ - where R ⁵⁰ is C ₁ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

n is 1, 2 or 3;

m is 1 or 2, provided that n+m≥3;

,

или

;L-Ar represents

,

or

;

,

,

,

или

, при условии что когда L-Ar представляет собой

, Ar не является

;Ar represents

,

,

,

or

, provided that when L-Ar is

, Ar is not

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle; and

R ²² is H, halogen or C ₁ -C ₂ alkyl.

As indicated above, each of the indicated fragments is C ₁ -C ₂ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl, 4-6-membered heterocycle and 5-6-membered heteroaryl - may possibly be substituted. Accordingly, this application provides compounds of structure I, in which:

L ³ is -CH ₂ -, CHR ⁵⁰ , -O-, -NR ⁵⁰ -, -NC(O)R ⁵⁰ - or -NC(O)OR ⁵⁰ -, where R ⁵⁰ is a possibly substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl or optionally substituted 4-6 membered heterocycle;

n is 1, 2 or 3;

m is 1 or 2, provided that n+m≥3;

,

или

;L-Ar represents

,

or

;

,

,

,Ar represents

,

,

,

или

or

, при условии что когда L-Ar представляет собой

, Ar не является

;

, provided that when L-Ar is

, Ar is not

;

Het is a possibly substituted 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, optionally substituted C ₁ -C ₄ alkyl, -O- (optionally substituted C ₃ -C ₅ cycloalkyl), -O- (optionally substituted 4-6 membered heterocycle), or -O -(possibly substituted C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or optionally substituted C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halo, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl, or optionally substituted 4-6 membered heterocycle; and

R ²² is H, halogen or optionally substituted C ₁ -C ₂ alkyl.

или

и Ar представляет собой

,

,

,

или

.In some embodiments of the present application, compounds of structure I are provided wherein L-Ar is

or

and Ar is

,

,

,

or

.

и Ar представляет собой

,

,

,

или

.In some embodiments of the present application, compounds of structure I are provided wherein L-Ar is

and Ar is

,

,

,

or

.

In some embodiments of the present application, compounds of structure I are provided wherein R ¹ is H, -CN, -C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6- membered heterocycle) or -O-(C ₁ -C ₄ alkyl), wherein when R ¹ is not H or -CN, R ¹ is optionally substituted with one or more halogens.

In some embodiments of the present application, compounds of structure I are provided wherein R ¹ is halogen, -CN, or C ₁ -C ₂ haloalkyl.

In some embodiments of the present application, compounds of structure I are provided wherein R ¹ is -CN or C ₁ -C ₂ haloalkyl.

In some embodiments of the present application, compounds of structure I are provided wherein R ¹ is -CN.

In some embodiments of the present application, compounds of structure I are provided wherein R ¹ is -Cl.

In some embodiments of the present application, compounds of structure I are provided wherein R ² is H.

In some embodiments of the present application, compounds of structure I are provided wherein R ²¹ is halo, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, or a 4-6 membered heterocycle.

In some embodiments of the present application, compounds of structure I are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl.

In some embodiments of the present application, compounds of structure I are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl.

In some embodiments of the present application, compounds of structure I are provided wherein R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure I are provided wherein R ²² is H.

In some embodiments of the present application, compounds of structure I are provided wherein R ²² is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure I are provided wherein R ²² is -CH ₃ .

In some embodiments of the present application, compounds of structure I are provided wherein L ³ is -N(CH ₃ )-.

In some embodiments of the present application, compounds of structure I are provided in which n is 2 and m is 2.

In some embodiments of the present application, compounds of structure I are provided in which n is 1 or 2.

In some embodiments of the present application, compounds of structure I are provided in which n is 1 and m is 2.

In some embodiments of the present application, compounds of structure I are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl and R ²² is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure I are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl and R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure I are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl and R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure I are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl and R ²² is H or -CH ₃ .

In various aspects, this application provides compounds of structure II:

II

II

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

, при условии что когда L-Ar представляет собой

, Ar не является

;Ar represents

,

,

,

or

, provided that when L-Ar is

, Ar is not

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl; and

R ²⁴ is H, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl)-OH, -(C ₁ -C ₄ alkyl) _t -N(R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl) _t -O _t -(C ₃ -C ₅ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _t -(4-6 membered heterocycle) or -(C ₁ -C ₄ alkyl) _t - O-(C ₁ -C ₄ alkyl), where:

each t is independently 0 or 1; and

each R ²⁴¹ is independently H or C ₁ -C ₂ alkyl.

As indicated above, each of said C ₁ -C ₂ alkyl, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, 4-6 membered heterocycle, and 5-6 membered heteroaryl groups may optionally be substituted. Accordingly, this application provides compounds of structure II, in which:

,

или

;L-Ar represents

,

or

;

,

,

или

, при условии что когда L-Ar представляет собой

, Ar не является

;Ar represents

,

,

or

, provided that when L-Ar is

, Ar is not

;

Het is a possibly substituted 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, optionally substituted C ₁ -C ₄ alkyl, -O- (optionally substituted C ₃ -C ₅ cycloalkyl), -O- (optionally substituted 4-6 membered heterocycle), or -O -(possibly substituted C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or optionally substituted C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halo, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl, or optionally substituted 4-6 membered heterocycle;

R ²² is H, halogen or optionally substituted C ₁ -C ₂ alkyl; and

R ²⁴ is H, optionally substituted C ₁ -C ₄ alkyl, -(optionally substituted C ₁ -C ₄ alkyl)-OH, -(optionally substituted C ₁ -C ₄ alkyl) _t -N(R ²⁴¹ ) ₂ , - (possibly substituted C ₁ -C ₄ alkyl) _t -O _t - (possibly substituted C ₃ -C ₅ cycloalkyl), - (possibly substituted C ₁ -C ₄ alkyl) _t -O _t - (possibly substituted 4-6 membered heterocycle) or -(possibly substituted C ₁ -C ₄ alkyl) _t -O-(possibly substituted C ₁ -C ₄ alkyl), where:

t is 0 or 1; and

R ²⁴¹ is H or optionally substituted C ₁ -C ₂ alkyl.

или

и Ar представляет собой

,

,

,

или

.In some embodiments of the present application, compounds of structure II are provided wherein L-Ar is

or

and Ar is

,

,

,

or

.

и Ar представляет собой

,

,

,

или

.In some embodiments of the present application, compounds of structure II are provided wherein L-Ar is

and Ar is

,

,

,

or

.

.In some embodiments of the present application, compounds of structure II are provided wherein Ar is

.

In some embodiments of the present application, compounds of structure II are provided wherein R ¹ is halogen, -CN, or C ₁ -C ₂ haloalkyl.

In some embodiments of the present application, compounds of structure II are provided wherein R ¹ is -CN.

In some embodiments of the present application, compounds of structure II are provided wherein R ² is H.

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, or a 4-6 membered heterocycle.

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is H, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, or a 4-6 membered heterocycle.

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl.

In some embodiments of the present application, compounds of structure II are provided in which R ²¹ is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure II are provided in which R ²¹ is C ₃ -C ₅ cycloalkyl.

In some embodiments of the present application, compounds of structure II are provided wherein R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure II are provided wherein R ²² is H.

In some embodiments of the present application, compounds of structure II are provided wherein R ²² is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure II are provided wherein R ²² is -CH ₃ .

In some embodiments of the present application proposed compounds of structure II, in which R ²⁴ represents C ₁ -C ₄ alkyl or -(C ₁ -C ₄ alkyl) _t -O-(C ₁ -C ₄ alkyl).

In some embodiments of the present application, compounds of structure II are provided wherein R ²⁴ is -(C ₁ -C ₂ alkyl) _t -O-(C ₁ -C ₂ alkyl).

In some embodiments of the present application, compounds of structure II are provided wherein R ²⁴ is C ₁ -C ₄ alkyl or -(C ₁ -C ₄ alkyl) _t -O-(C ₁ -C ₄ alkyl) where t is 0 or 1.

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl and R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl and R ²² is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl and R ²² is -CH ₃ .

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl and R ²² is H.

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl and R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl and R ²² is H or -CH ₃ .

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl and R ²² is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl and R ²² is -CH ₃ .

In some embodiments of the present application, compounds of structure II are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl and R ²² is H.

In some embodiments of the present application, compounds of structure II are provided wherein R ²⁴ is -(C ₁ -C ₂ alkyl) _t -O-(C ₁ -C ₂ alkyl) and where t is 0 or 1.

In some embodiments of the present application, compounds of structure II are provided wherein R ¹ is -CN and R ² is H.

In various aspects, this application provides compounds of structure III:

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl;

R ²⁴ is H, -CN, -(C ₁ -C ₄ alkyl)-CN, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl)-OH, -(C ₁ -C ₄ alkyl)- N(R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl) _t -O _u -(C ₃ -C ₆ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _u -(4-6-membered heterocycle) or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl), where:

t is 0 or 1;

u is 0 or 1;

provided that when u is 1, t is 1; and

each R ²⁴¹ is independently H or C ₁ -C ₂ alkyl; and

R ²⁵ is halogen, -CN, -(C ₁ -C ₄ alkyl)-CN, C ₁ -C ₂ alkyl or cyclopropyl.

As indicated above, each of said C ₁ -C ₂ alkyl (i.e., methyl and ethyl), cyclopropyl, C ₁ -C ₂ alkyl, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocycle and 5-6 membered heteroaryl may optionally be substituted.

Accordingly, this application provides compounds of structure III, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a possibly substituted 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, optionally substituted C ₁ -C ₄ alkyl, -O- (optionally substituted C ₃ -C ₅ cycloalkyl), -O- (optionally substituted 4-6 membered heterocycle), or -O -(possibly substituted C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or optionally substituted C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halo, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl, or optionally substituted 4-6 membered heterocycle;

R ²² is H, halogen or optionally substituted C ₁ -C ₂ alkyl;

R ²⁴ is H, -CN, -(possibly substituted C ₁ -C ₄ alkyl) -CN, optionally substituted C ₁ -C ₄ alkyl, -(possibly substituted C ₁ -C ₄ alkyl) -OH, -(possibly substituted C ₁ -C ₄ alkyl)-N(R ²⁴¹ ) ₂ , -(possibly substituted C ₁ -C ₄ alkyl) _t -O _u -(possibly substituted C ₃ -C ₆ cycloalkyl), -(possibly substituted C ₁ -C ₄ alkyl) _t -O _u -(possibly substituted 4-6 membered heterocycle) or -(possibly substituted C ₁ -C ₄ alkyl)-O-(possibly substituted C ₁ -C ₄ alkyl), where:

t is 0 or 1;

u is 0 or 1;

provided that when u is 1, t is 1; and

R ²⁴¹ is H or optionally substituted C ₁ -C ₂ alkyl; and

R ²⁵ is halo, -CN, -(optionally substituted C ₁ -C ₄ alkyl)-CN, optionally substituted methyl, optionally substituted ethyl, or optionally substituted cyclopropyl.

, Ar не является

.In some embodiments of the present application, compounds of structure III are provided wherein when L-Ar is

, Ar is not

.

или

и Ar представляет собой

,

,

,

или

.In some embodiments of the present application, compounds of structure III are provided wherein L-Ar is

or

and Ar is

,

,

,

or

.

и Ar представляет собой

,

,

,

или

.In some embodiments of the present application, compounds of structure III are provided wherein L-Ar is

and Ar is

,

,

,

or

.

.In some embodiments of the present application, compounds of structure III are provided wherein Ar is

.

In some embodiments of the present application, compounds of structure III are provided in which R ¹ is halogen, -CN, or C ₁ -C ₂ haloalkyl.

In some embodiments of the present application, compounds of structure III are provided in which R ¹ is -CN.

In some embodiments of the present application, compounds of structure III are provided wherein R ² is H.

In some embodiments of the present application proposed compounds of structure III, in which R ²¹ represents halogen, C ₁ -C ₄ alkyl or C ₃ -C ₅ cycloalkyl.

In some embodiments of the present application proposed compounds of structure III, in which R ²¹ represents C ₁ -C ₄ alkyl or C ₃ -C ₅ cycloalkyl.

In some embodiments of the present application proposed compounds of structure III, in which R ²¹ represents C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl.

In some embodiments of the present application, compounds of structure III are provided wherein R ²¹ is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure III are provided in which R ²¹ is -CH ₃ .

In some embodiments of the present application, compounds of structure III are provided wherein R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure III are provided in which R ²² is H or -CH ₃ .

In some embodiments of the present application, compounds of structure III are provided in which R ²² is -CH ₃ .

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁴ is H, -CN, -(C ₁ -C ₄ alkyl) -CN, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl) -OH, -(C ₁ -C ₄ alkyl) -N(R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl) _t -O _u -(C ₃ -C ₆ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _u -(4-6-membered heterocycle) or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl).

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁴ is H, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl)-OH, -(C ₁ -C ₄ alkyl)-N( R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl) _t -O _u -(C ₃ -C ₆ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _u -(4-6-membered heterocycle) or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl).

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁴ is C ₁ -C ₄ alkyl or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl).

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁴ is -(C ₁ -C ₂ alkyl)-O-(C ₁ -C ₂ alkyl).

In some embodiments of the present application, compounds of structure III are provided in which R ²⁴ is -CH ₂ -O-CH ₃ .

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁴ is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁴ is -CH ₃ .

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁴ is C ₃ -C ₆ cycloalkyl.

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁴ is C ₃ -C ₅ cycloalkyl.

In some embodiments of the present application, compounds of structure III are provided in which R ²⁴ is -CN or -(C ₁ -C ₂ alkyl)-CN.

In some embodiments of the present application, compounds of structure III are provided in which R ²⁴ is -CN.

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁴ is -(C ₁ -C ₂ alkyl)-CN.

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁴ is H, -CH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OH, -(CH ₂ ) ₂ OCH ₃ or -(CH ₂ ) ₂ N(CH ₃ ) ₂ .

In some embodiments of the present application proposed compounds of structure III, in which R ²⁴ represents methyl, isopropyl, cyclopropyl, -CN or -(C ₁ -C ₂ alkyl)-CN.

In some embodiments of the present application, compounds of structure III are provided in which R ²⁴ is substituted with one or more substituents selected from C ₁ -C ₂ alkyl, oxo, -CN, halogen, alkanoyl, alkoxycarbonyl, -OH and C ₁ -C ₂ alkoxy .

In some embodiments of the present application, compounds of structure III are provided in which R ²⁴ is substituted with one or more substituents selected from methyl, -F, methoxy, -C(=O)CH ₃ and -C(=O)-OCH ₃ .

In some embodiments of the present application, compounds of structure III are provided in which R ²⁴ is substituted with two substituents that are the same or different.

In some embodiments of the present application, compounds of structure III are provided in which R ²⁴ is substituted with three substituents that are the same or different.

In some embodiments of the present application, compounds of structure III are provided in which R ²⁵ is halogen, -CN, C ₁ -C ₂ alkyl, or cyclopropyl.

In some embodiments of the present application proposed compounds of structure III, in which R ²⁵ represents halogen, C ₁ -C ₂ alkyl or cyclopropyl.

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁵ is -CN, -Cl, or -CH ₃ .

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁵ is -Cl.

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁵ is -CH ₃ .

In some embodiments of the present application, compounds of structure III are provided in which R ²⁵ is substituted with one or more substituents selected from -OH, halogen, C ₁ -C ₂ alkyl, and alkylcarbonyloxy.

In some embodiments of the present application, compounds of structure III are provided in which R ²⁵ is substituted with one or more substituents selected from -F, methyl, and -OC(=O)-CH ₃ .

In some embodiments of the present application, compounds of structure III are provided in which R ²⁵ is substituted with two substituents that are the same or different.

In some embodiments of the present application, compounds of structure III are provided in which R ²⁵ is substituted with three substituents that are the same or different.

In some embodiments of the present application proposed compounds of structure III, in which R ²⁴ represents C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl)-CN or -(C ₃ -C ₆ cycloalkyl).

In some embodiments of the present application proposed compounds of structure III, in which R ²⁴ represents -CN, -(C ₁ -C ₂ alkyl)-CN, -(C ₃ -C ₆ cycloalkyl) or methyl.

In some embodiments of the present application proposed compounds of structure III, in which R ²⁵ represents halogen, methyl, ethyl or cyclopropyl.

In some embodiments of the present application, compounds of structure III are provided wherein R ²⁵ is halogen, -CN, methyl, ethyl, or cyclopropyl.

In some embodiments of the present application, compounds of structure III are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₆ cycloalkyl and R ²² is H or -CH ₃ .

In some embodiments of the present application, compounds of structure III are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₆ cycloalkyl, R ²² is H or -CH ₃ , R ²⁴ is -CH ₂ -O -CH ₃ and R ²⁵ is -CH ₃ .

In some embodiments of the present application, compounds of structure III are provided wherein R ²¹ is -CH ₃ and R ²² is H.

In some embodiments of the present application, compounds of structure III are provided wherein R ¹ is -CN and R ² is H.

In some embodiments of the present application, compounds of structure III are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₆ cycloalkyl and R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure III are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₆ cycloalkyl, R ²² is H or C ₁ -C ₂ alkyl, R ²⁴ is -CH ₂ -O-CH ₃ and R ²⁵ is -CH ₃ .

In some embodiments of the present application, compounds of structure III are provided wherein R ²¹ is C ₁ -C ₂ alkyl and R ²² is H.

In various aspects, this application provides compounds of structure IIIb:

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl; and

each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -(C ₁ -C ₄ alkyl) -CN, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl) -OH, -(C ₁ -C ₄ alkyl) -N(R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl) _t -O _u -(C ₃ -C ₅ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _u -(4-6-membered heterocycle) or -(C ₁ -C ₄ alkyl) _t -O-(C ₁ -C ₄ alkyl), where:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R ²⁴¹ is independently H or C ₁ -C ₂ alkyl, where the compound is not:

.

.

As indicated above, each of said C ₁ -C ₂ alkyl, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, 4-6 membered heterocycle, and 5-6 membered heteroaryl moieties may optionally be substituted. Accordingly, this application provides compounds of structure IIIb, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a possibly substituted 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, optionally substituted C ₁ -C ₄ alkyl, -O- (optionally substituted C ₃ -C ₅ cycloalkyl), -O- (optionally substituted 4-6 membered heterocycle), or -O -(possibly substituted C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or optionally substituted C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halo, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl, or optionally substituted 4-6 membered heterocycle;

R ²² is H, halogen or optionally substituted C ₁ -C ₂ alkyl; and

each R ²⁴ and R ²⁵ is independently H, halogen, -CN, -(possibly substituted C ₁ -C ₄ alkyl) -CN, optionally substituted C ₁ -C ₄ alkyl, -(possibly substituted C ₁ -C ₄ alkyl) -OH, (possibly substituted C ₁ -C ₄ alkyl) -N(R ²⁴¹ ) ₂ , -(possibly substituted C ₁ -C ₄ alkyl) _t -O _u -(possibly substituted C ₃ -C ₅ cycloalkyl), -( optionally substituted C ₁ -C ₄ alkyl) _t -O _u - (optionally substituted 4-6 membered heterocycle) or - (optionally substituted C ₁ -C ₄ alkyl) _t -O- (optionally substituted C ₁ -C ₄ alkyl) , in which:

t is 0 or 1;

u is 0 or 1; and

R ²⁴¹ is H or optionally substituted C ₁ -C ₂ alkyl,

where the connection is not:

.

.

, Ar не является

.In some embodiments of the present application, compounds of structure IIIb are provided wherein when L-Ar is

, Ar is not

.

или

и Ar представляет собой

,

,

,

или

.In some embodiments of the present application, compounds of structure IIIb are provided wherein L-Ar is

or

and Ar is

,

,

,

or

.

и Ar представляет собой

,

,

,

или

.In some embodiments of the present application, compounds of structure IIIb are provided wherein L-Ar is

and Ar is

,

,

,

or

.

.In some embodiments of the present application, compounds of structure IIIb are provided wherein Ar is

.

In some embodiments of the present application, compounds of structure IIIb are provided in which R ¹ is halogen, -CN, or C ₁ -C ₂ haloalkyl.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ¹ is -CN.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ² is H.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is halo, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, or a 4-6 membered heterocycle.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, or a 4-6 membered heterocycle.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is -CH ₃ .

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application proposed compounds of structure IIIb, in which R ²² represents H or-CH ₃ .

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²² is -CH ₃ .

In some embodiments of the present application, compounds of structure IIIb are provided wherein each R ²⁴ and R ²⁵ is independently H, -CN, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl)-OH, (C ₁ - C ₄ alkyl)-N(R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl) _t -O _u -(C ₃ -C ₅ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _u -( 4-6-membered heterocycle) or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl).

In some embodiments of the present application, compounds of structure IIIb are provided wherein each R ²⁴ and R ²⁵ is independently H, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl) _t -O _u -(4-6- membered heterocycle) or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl).

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁴ is H, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl)-OH, -(C ₁ -C ₄ alkyl)-N( R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl) _t -O _u -(C ₃ -C ₅ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _u -(4-6-membered heterocycle) or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl).

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁴ is -CN, -Cl, C ₁ -C ₄ alkyl, or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl) .

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁴ is C ₁ -C ₄ alkyl or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl).

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁴ is -(C ₁ -C ₂ alkyl)-O-(C ₁ -C ₂ alkyl).

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁴ is C ₁ -C ₄ alkyl.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁴ is -CH ₃ .

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁴ is hydrogen.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁴ is substituted with one or more substituents selected from halo, C ₃ -C ₅ cycloalkyl, and C ₁ -C ₂ alkoxy.

In some embodiments of the present application, compounds of structure IIIb are provided in which R ²⁴ is substituted with one or more substituents selected from -F, cyclopropyl, and -OCH ₃ .

In some embodiments of the present application, compounds of structure IIIb are provided in which R ²⁴ is substituted with two substituents that are the same or different.

In some embodiments of the present application, compounds of structure IIIb are provided in which R ²⁴ is substituted with three substituents that are the same or different.

In some embodiments of the present application proposed compounds of structure IIIb, in which R ²⁵ represents halogen, methyl, ethyl or cyclopropyl.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁵ is -CN, -Cl, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl) _t -O-(C ₃ -C ₅ cycloalkyl ) or -(C ₁ -C ₄ alkyl) _t -O-(C ₁ -C ₄ alkyl).

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁵ is -CN, -Cl, -CH ₃ , -O-(C ₃ -C ₅ cycloalkyl), or -O-(C ₁ -C ₂ alkyl) .

In some embodiments of the present application proposed compounds of structure IIIb, in which R ²⁵ represents -CN, -Cl or C ₁ -C ₄ alkyl.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁵ is -CH ₃ .

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁵ is -Cl.

In some embodiments of the present application, compounds of structure IIIb are provided in which R ²⁵ is substituted with one or more halo.

In some embodiments of the present application, compounds of structure IIIb are provided in which R ²⁵ is substituted with one or more -F.

In some embodiments of the present application, compounds of structure IIIb are provided in which R ²⁵ is substituted with two substituents.

In some embodiments of the present application, compounds of structure IIIb are provided in which R ²⁵ is substituted with three substituents.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is -CH ₃ and R ²² is H or methyl.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl and R ²² is H or -CH ₃ .

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is -CH ₃ and R ²² is H.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²⁴ is H or -CH ₃ and R ²⁵ is -Cl.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ¹ is -CN and R ² is H.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl and R ²² is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl and R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is C ₁ -C ₂ alkyl and R ²² is H or -CH ₃ .

In some embodiments of the present application, compounds of structure IIIb are provided wherein R ²¹ is C ₁ -C ₂ alkyl and R ²² is H.

In various aspects, this application provides compounds of structure IIIc:

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl; and

each of R ²⁴ and R ²⁵ independently represents H, -C ₁ -C ₄ alkyl or halogen.

As indicated above, each of said C ₁ -C ₂ alkyl, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, 4-6 membered heterocycle, and 5-6 membered heteroaryl moieties may optionally be substituted. Accordingly, this application provides compounds of structure IIIc in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a possibly substituted 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, optionally substituted C ₁ -C ₄ alkyl, -O- (optionally substituted C ₃ -C ₅ cycloalkyl), -O- (optionally substituted 4-6 membered heterocycle), or -O -(possibly substituted C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or optionally substituted C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halo, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl, or optionally substituted 4-6 membered heterocycle;

R ²² is H, halogen or optionally substituted C ₁ -C ₂ alkyl; and

each of R ²⁴ and R ²⁵ independently represents H, optionally substituted with C ₁ -C ₄ alkyl or halogen.

, Ar не является

.In some embodiments of the present application, compounds of structure IIIc are provided wherein L-Ar is

, Ar is not

.

или

и Ar представляет собой

,

,

,

или

.In some embodiments of the present application, compounds of structure IIIc are provided wherein L-Ar is

or

and Ar is

,

,

,

or

.

и Ar представляет собой

,

,

,

или

.In some embodiments of the present application, compounds of structure IIIc are provided wherein L-Ar is

and Ar is

,

,

,

or

.

In some embodiments of the present application, compounds of structure IIIc are provided in which R ¹ is halogen, -CN, or C ₁ -C ₂ haloalkyl.

In some embodiments of the present application, compounds of structure IIIc are provided wherein R ²¹ is halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, or a 4-6 membered heterocycle.

In some embodiments of the present application, compounds of structure IIIc are provided wherein R ²¹ is -CH ₃ .

In some embodiments of the present application, compounds of structure IIIc are provided wherein R ²² is H.

.In some embodiments of the present application, compounds of structure IIIc are provided wherein R ²¹ is methyl, R ²² is H, and L-Ar is

.

In various aspects, this application provides compounds of structure IV:

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

Ar represents

,

,

,

or

, при условии что когда L-Ar представляет собой

, Ar не является

;

, provided that when L-Ar is

, Ar is not

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle) or -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ represents H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl; and

R ²⁴ is H, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl)-OH, -(C ₁ -C ₄ alkyl)-N(R ²⁴¹ ) ₂ , -(C ₁ -C ₄ alkyl ) _t -O _u -(C ₃ -C ₅ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _u -(4-6 membered heterocycle) or -(C ₁ -C ₄ alkyl)-O- (C ₁ -C ₄ alkyl), where:

t is 0 or 1;

u is 0 or 1;

provided that when u is 1, t is 1; and

R ²⁴¹ is H or C ₁ -C ₂ alkyl.

As indicated above, each of these C ₁ -C ₂ alkyl, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, 4-6 membered heterocycle, and 5-6 membered heteroaryl moieties may optionally be substituted. Accordingly, this application provides compounds of structure IV, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

, при условии что когда L-Ar представляет собой

, Ar не является

;Ar represents

,

,

,

or

, provided that when L-Ar is

, Ar is not

;

Het is a possibly substituted 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, optionally substituted C ₁ -C ₄ alkyl, -O- (optionally substituted C ₃ -C ₅ cycloalkyl), -O- (optionally substituted 4-6 membered heterocycle), or -O -(possibly substituted C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or optionally substituted C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halo, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl, or optionally substituted 4-6 membered heterocycle;

R ²² is H, halogen or optionally substituted C ₁ -C ₂ alkyl;

R ²⁴ is H, optionally substituted C ₁ -C ₄ alkyl, -(optionally substituted C ₁ -C ₄ alkyl)-OH, -(optionally substituted C ₁ -C ₄ alkyl)-N(R ²⁴¹ ) ₂ , -( optionally substituted C ₁ -C ₄ alkyl) _t -O _u - (optionally substituted C ₃ -C ₅ cycloalkyl), - (optionally substituted C ₁ -C ₄ alkyl) _t -O _u - (optionally substituted 4-6 membered heterocycle ) or -(possibly substituted C ₁ -C ₄ alkyl)-O-(possibly substituted C ₁ -C ₄ alkyl), where:

t is 0 or 1;

u is 0 or 1;

provided that when u is 1, t is 1; and

R ²⁴¹ is H or optionally substituted C ₁ -C ₂ alkyl.

или

и Ar представляет собой

,

,

,

или

.In some embodiments of the present application, compounds of structure IV are provided wherein L-Ar is

or

and Ar is

,

,

,

or

.

In some embodiments of the present application, compounds of structure IV are provided wherein R ¹ is halogen, -CN, or C ₁ -C ₂ haloalkyl.

In some embodiments of the present application, compounds of structure IV are provided wherein R ¹ is -CN.

In some embodiments of the present application, compounds of structure IV are provided wherein R ² is H.

In some embodiments of the present application, compounds of structure IV are provided wherein R ²¹ is halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, or a 4-6 membered heterocycle.

In some embodiments of the present application, compounds of structure IV are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl.

In some embodiments of the present application, compounds of structure IV are provided wherein R ²¹ is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure IV are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl.

In some embodiments of the present application, compounds of structure IV are provided wherein R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure IV are provided wherein R ²² is H.

In some embodiments of the present application, compounds of structure IV are provided wherein R ²² is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure IV are provided wherein R ²² is -CH ₃ .

In some embodiments of the present application, compounds of structure IV are provided wherein R ²⁴ is C ₁ -C ₄ alkyl or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl).

In some embodiments of the present application, compounds of structure IV are provided wherein R ²⁴ is -(C ₁ -C ₂ alkyl)-O-(C ₁ -C ₂ alkyl).

In some embodiments of the present application, compounds of structure IV are provided wherein R ²¹ is C ₁ -C ₂ alkyl or C ₃ -C ₅ cycloalkyl and R ²² is C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure IV are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl and R ²² is H or C ₁ -C ₂ alkyl.

In some embodiments of the present application, compounds of structure IV are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl and R ²² is H or -CH ₃ .

In some embodiments of the present application, compounds of structure IV are provided wherein R ²¹ is C ₃ -C ₅ cycloalkyl and R ²² is H or -CH ₃ .

In some embodiments of the present application, compounds of structure IV are provided wherein R ¹ is -CN and R ² is H.

In various aspects, this application provides compounds of structure V:

or their pharmaceutically acceptable salts, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

, при условии что когда L-Ar представляет собой

, Ar не является

;Ar represents

,

,

,

or

, provided that when L-Ar is

, Ar is not

;

L ² is -NHR ³⁵ or -C(O)NHR ³⁵¹ where R ³⁵¹ is C ₁ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl, 4-6 membered heterocycle, aryl or heteroaryl;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle), -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle;

R ²² is H, halogen or C ₁ -C ₂ alkyl; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , C(O)OR ³⁵¹ or S(O) ₂ R ³⁵¹ , where R ³⁵¹ is C ₁ -C ₆ alkyl, C ₃ - C ₅ cycloalkyl, 4-6 membered heterocycle, aryl or heteroaryl.

As indicated above, each of the indicated fragments is C ₁ -C ₂ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl, 4-6-membered heterocycle, 5-6-membered heteroaryl , aryl and heteroaryl - may optionally be substituted. Accordingly, this application provides compounds of structure V, in which:

,

или

;L-Ar represents

,

or

;

,

,

,

или

, при условии что когда L-Ar представляет собой

, Ar не является

;Ar represents

,

,

,

or

, provided that when L-Ar is

, Ar is not

;

L ² is -NHR ³⁵ or -C(O)NHR ³⁵¹ where R ³⁵¹ is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl, optionally substituted 4-6 membered heterocycle, optionally substituted aryl or optionally substituted heteroaryl;

Het is a possibly substituted 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, optionally substituted C ₁ -C ₄ alkyl, -O- (optionally substituted C ₃ -C ₅ cycloalkyl), -O- (optionally substituted 4-6 membered heterocycle), or -O -(possibly substituted C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or optionally substituted C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halo, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl, or optionally substituted 4-6 membered heterocycle;

R ²² is H, halogen or optionally substituted C ₁ -C ₂ alkyl; and

R ³⁵ is -C(O)R ³⁵¹ , -C(O)NHR ³⁵¹ , -C(O)OR ³⁵¹ or -S(O) ₂ R ³⁵¹ , where R ³⁵¹ is a possibly substituted C ₁ -C ₆ alkyl , optionally substituted C ₃ -C ₅ cycloalkyl, optionally substituted 4-6 membered heterocycle, optionally substituted aryl, or optionally substituted heteroaryl.

, Ar не является

.In some embodiments of the present application, compounds of structure V are provided wherein when L-Ar is

, Ar is not

.

In some embodiments of the present application, compounds of structure V are provided wherein L ² is -NHR ³⁵ .

In some embodiments of the present application proposed compounds of structure V, in which L ² represents-C(O)NHR ³⁵¹ .

In various aspects, this application provides compounds of structure VI:

, или их фармацевтически приемлемые соли, в которых:

, or their pharmaceutically acceptable salts, in which:

each W, X, Y and Z is independently -N- or -CR ²⁶ - provided that no more than 2 of W, X, Y and Z are -N-;

each R ²⁶ is independently H, C ₁ -C ₄ alkyl, -O-(C ₁ -C ₄ alkyl), -N(R ²⁷ ) ₂ , -S(O) ₂ -(C ₁ -C ₄ alkyl) or -C(O)-(C ₁ -C ₄ alkyl);

each R ²⁷ is independently H or C ₁ -C ₄ alkyl or both R ²⁷ are C ₁ -C ₄ alkyl and combine to form a 3-6 membered ring together with the N atom to which they are attached, and where the ring is possible contains one oxygen atom as one of the ring members;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, C ₁ -C ₄ alkyl, -O-(C ₃ -C ₅ cycloalkyl), -O-(4-6 membered heterocycle), -O-(C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl or 4-6 membered heterocycle; and

R ²² is H, halogen or C ₁ -C ₂ alkyl.

As indicated above, each of said C ₁ -C ₂ alkyl, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, 4-6 membered heterocycle, and 5-6 membered heteroaryl moieties may optionally be substituted. Accordingly, this application provides compounds of structure VI, in which:

each W, X, Y and Z is independently -N- or -CR ²⁶ - provided that no more than 2 of W, X, Y and Z are -N-;

R ²⁶ is H, optionally substituted C ₁ -C ₄ alkyl, -O-(optionally substituted C ₁ -C ₄ alkyl), -N(R ²⁷ ) ₂ , -S(O) ₂ -(optionally substituted C ₁ - C ₄ alkyl) or -C(O)-(possibly substituted C ₁ -C ₄ alkyl);

each R ²⁷ is independently H or optionally substituted C ₁ -C ₄ alkyl or both R ²⁷ are optionally substituted C ₁ -C ₄ alkyl and combine to form a possibly substituted 3-6 membered ring together with the N atom to which they attached, and where the ring optionally contains one oxygen atom as one of the members of the ring;

,

,

,

или

;Ar represents

,

,

,

or

;

Het is a possibly substituted 5-6 membered heteroaryl;

R ¹ is H, -CN, halogen, optionally substituted C ₁ -C ₄ alkyl, -O- (optionally substituted C ₃ -C ₅ cycloalkyl), -O- (optionally substituted 4-6 membered heterocycle), or -O -(possibly substituted C ₁ -C ₄ alkyl) wherein when R ¹ is not H, -CN or halogen, R ¹ is optionally substituted with one or more halogens;

each R ² is independently hydrogen, halogen, or optionally substituted C ₁ -C ₄ alkyl;

R ³ is H or F;

R ¹¹ is H or -CH ₃ ;

R ²¹ is H, halo, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl, or an optionally substituted 4-6 membered heterocycle; and

R ²² is H, halogen or optionally substituted C ₁ -C ₂ alkyl.

.In some embodiments of the present application, compounds of structure VI are provided wherein Ar is

.

In some embodiments of the present application, compounds of structure VI are provided wherein Y is -CR ²⁶ -, where R ²⁶ is -N(R ²⁷ ) ₂ .

In some embodiments of the present application, compounds of structure VI are provided wherein X is -N-.

Synthesis of compounds

Also described in the present invention are methods for synthesizing compounds according to the present application. Compounds according to the present application can be synthesized according to the synthesis schemes below.

Scheme 1 shows methods suitable for synthesizing fragment L of structures I-IV. In Scheme 1, m' and n' are each independently 1 or 2. Ar is defined on structures I-V.

Scheme 1

в каждой из структур I-IV.Scheme 2 suggests methods suitable for obtaining a fragment

in each of structures I-IV.

Scheme 2

Schemes 3-5 provide methods suitable for the preparation of compounds of structure III.

Scheme 3

Scheme 4

Scheme 5

Schemes 6-7 provide methods suitable for the preparation of compounds of structure II.

Scheme 6

Scheme 7

Scheme 8 provides methods suitable for the preparation of compounds of structure IIIb.

Scheme 8

Scheme 9 provides methods suitable for the preparation of compounds of structure I.

Scheme 9

Additional methods for obtaining specific compounds according to this application are given in the examples. It will be apparent to a person skilled in the art that other compounds of the structures may be prepared by modifying the specific schemes shown using methods known to those skilled in the art. Additional examples are shown in Table 26.

Many such methods are well known in the art. However, many known methods are specified in Compendium of Organic Synthetic Methods (Vol. 1, 1971; Vol. 2, 1974; Vol. 3, 1977; Vol. 4, 1980; Vol. 5, 1984; and Vol. 6 March in Advanced Organic Chemistry (1985) Comprehensive Organic Synthesis Selectivity, Strategy & Efficiency in Modern Organic Chemistry In 9 Volumes (1993) Advanced Organic Chemistry Part B: Reactions and Synthesis, Second Edition (1983) Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, Second Edition (1977); Protecting Groups in Organic Synthesis, Second Edition; and Comprehensive Organic Transformations (1999).

Methods of antiviral treatment

In various aspects, provided herein are methods of treating a viral infection in a subject, said method comprising administering to a subject in need of such treatment an effective amount of a compound of structures I, II, III, IIIb, IIIc, IV, V, and VI or those described in Table 26 .

In various aspects, the present application provides methods for treating a viral infection, said method comprising administering compounds of the present application to a subject in need of treatment with an agent.

In various aspects, this application provides methods for treating hepatitis C infection by administering to a subject one or more of the compounds described herein.

In certain aspects, the compounds of the present application may be used in combination with other antiviral treatments to treat a viral infection.

In various aspects, the compounds of the present application may be used to treat an infection in an animal subject, such as a human.

Anticancer activity

In various aspects, the present application provides methods for treating a cancer in a subject, said method comprising administering to a subject in need of such treatment an effective amount of a compound of structures I, II, III, IIIb, IIIc, IV, V, and VI or those described in Table 26 In further aspects, compounds having structures I, II, III, IIIb, IIIc, IV, V and VI, or described in Table 26, can be used in the preparation of a medicament for the treatment of cancer.

In specific aspects, the present application provides a method for inhibiting tumor cell growth in a subject, said method comprising administering to a subject in need of such treatment an effective amount of a compound of structure I, II, III, IIIb, IIIc, IV, V, and VI, or as described in Table 26. According to further aspects, the tumor can be obtained from tissue of the breast, lung, thyroid, lymph node, kidney, ureter, bladder, ovary, testicle, prostate, bone, skeletal muscle, bone marrow, stomach, esophagus, small intestine , colon, rectum, pancreas, liver, smooth muscle, brain, spinal cord, nerves, ear, eye, nasopharynx, oropharynx, salivary gland, or heart. In certain aspects, the compounds of the present invention may be administered concomitantly with one or more additional anti-cancer treatments.

In specific aspects, the present application provides a method of treating pancreatic cancer in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound of structure I, II, III, IIIb, IIIc, IV, V, and VI, or as described in Table 26.

In specific aspects, the present application provides a method for treating colon cancer in a subject, said method comprising administering to a subject in need of such treatment an effective amount of a compound of structure I, II, III, IIIb, IIIc, IV, V, and VI, or as described in Table 26.

Rapidly proliferating cancer cells activate the fatty acid synthesis pathway to maintain high lipid levels necessary for membrane assembly and oxidative metabolism. (Flavin, R. et al. (2010) Future Oncology. 6(4):551-562). Fatty acid synthesis inhibitors have shown activity in vivo 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 the formation of new blood vessels, and inhibitors of this pathway have activity in in vitro models of angiogenesis. (Browne, C.D., et al. (2006) The FASEB Journal, 20(12):2027-2035).

Application for metabolic disorders

In various aspects, the compounds of the present application are suitable for the treatment of metabolic disorders. FASN has been shown to be involved in the regulation of glucose, lipid and cholesterol metabolism. Mice with liver-specific FASN inactivation have normal physiology, except when they are kept on a fat-free diet, in which they develop hypoglycemia and fatty liver, which are reversible with the introduction of fat into the diet. (Chakravarthy, M.V., et al. (2005) Cell Metabolism 1:309-322). Db/+ mice maintained on a high fructose diet show a decrease in hepatic triglyceride levels and increased insulin sensitivity when exposed to platensimycin, a covalent inhibitor of FASN, for 28 days. (Wu, M. et al. (2011) PNAS 108(13):5378-5383). Normal glucose levels also decrease in db/db mice after treatment with platensimycin. These results provide evidence that FASN inhibition can lead to therapeutically applicable beneficial effects in animal models of diabetes and related metabolic disorders. Thus, the FASN inhibitors disclosed herein are suitable for the treatment of diseases characterized by dysregulation in these systems. Without limitation, examples include obesity and diabetes.

Pharmaceutical Compositions, Formulations, Routes of Administration and Effective Doses

Also provided herein are pharmaceutical compositions containing compounds according to the present application.

In various aspects, this application provides pharmaceutical compositions comprising any of the compounds of structures I, II, III, IIIb, IIIc, IV, V and VI and a pharmaceutically acceptable carrier, excipient or diluent.

According to certain aspects of the present application proposed pharmaceutical compositions containing any of the compounds from table 26 and a pharmaceutically acceptable carrier, excipient or diluent.

According to another aspect, the present invention relates to compositions, routes of administration and effective doses of pharmaceutical compositions containing an agent or combination of agents according to the present invention. Such pharmaceutical compositions are suitable for the treatment of viral infections as described above.

The compounds of the present invention may be administered as pharmaceutical formulations, including formulations suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal patch, pulmonary, vaginal, suppository, or parenteral administration (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) or in a form suitable for administration by aerosol, inhalation or insufflation. 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).

According to various aspects, the pharmaceutical composition contains carriers and excipients (including, without limitation, buffers, carbohydrates, mannitol, proteins, polypeptides, or amino acids such as glycine, antioxidants, bacteriostats, chelating agents, suspending agents, thickening agents, and/or preservatives), water, oils, including petroleum jelly, animal, vegetable or synthetic oils such as peanut oil, soybean oil, mineral oil, sesame oil and the like, saline solutions, aqueous dextrose and glycerin solutions, flavoring agents, colorants, viscosity reducing agents, and others acceptable additives, adjuvants or binders, other pharmaceutically acceptable adjuvants required to approximate physiological conditions such as pH buffering agents, tonicity regulators, emulsifiers, wetting agents and the like. Examples of excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene, glycol, water, ethanol, and the like. In another aspect, the pharmaceutical composition is substantially free of preservatives. According to another aspect, the pharmaceutical composition may contain at least one preservative. For a general methodology for pharmaceutical dosage forms, see Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins, Baltimore Md. (1999)). It should be understood that while any suitable carrier known to one of ordinary skill in the art may be used to administer the compositions of the present invention, the type of carrier will vary depending on the route of administration.

Also, the compounds can be enclosed in liposomes using well known technology. Biodegradable microspheres can also be used as carriers for pharmaceutical compositions according to the present invention. Suitable biodegradable microspheres are described in, for example, US Pat. Nos. 4,897,268; 5075109; 5928647; 5811128; 5820883; 5853763; 5814344 and 5942252.

The compound of the present invention can be administered in liposomes or microspheres (or microparticles). Methods for making liposomes and microspheres for administration to a patient are well known to those of ordinary skill in the art. In US patent No. 4789734, the contents of which are incorporated into the present description by reference, describes methods of enclosing biological materials in liposomes. Essentially, the substance is dissolved in an aqueous solution, suitable phospholipids and lipids are added, as well as surfactants if necessary, and the substance is subjected to dialysis or sonication as necessary. For a review of known methods, see G. Gregoriadis, Chapter 14, "Liposomes," Drug Carriers in Biology and Medicine, pp. 2 sup. 87-341 (Academic Press, 1979).

Microspheres composed of polymers or proteins are well known to those skilled in the art and can be adapted to pass through the gastrointestinal tract directly into the bloodstream. Alternatively, the compound of the present invention may be enclosed in microspheres or a complex of microspheres implanted for sustained release over a period of days to months. See, for example, US Pat.

The concentration of the drug can be changed, the pH of the solution is buffered and the isotonicity is changed to achieve compatibility with intravenous injection, as is well known in the art.

The compounds of the present invention may be formulated as a sterile solution or suspension in suitable carriers well known in the art. Pharmaceutical compositions may be sterilized using conventional well known sterilization techniques or may be subjected to sterile filtration. The resulting aqueous solutions may be packaged for use as is or lyophilized, the lyophilized formulation being combined with a sterile solution prior to administration. Suitable formulations and additional carriers are described in The Science and Practice of Pharmacy (20th ^Ed ., Lippincott Williams & Wilkins, Baltimore MD), the contents of which are incorporated herein by reference in their entirety.

Representative salts are salts of inorganic ions such as, for example, sodium, potassium, magnesium ions and the like. Such salts include salts 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. In addition, if the agent(s) contains a carboxy group or other acidic group, it can be converted into a pharmaceutically acceptable addition salt with inorganic or organic bases. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonium, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine and the like.

The agent(s) or pharmaceutically acceptable salts may be administered alone or in the form of a pharmaceutical composition in which the active agent(s) is in admixture with one or more pharmaceutically acceptable carriers.

EXAMPLES

EXAMPLE 1

Synthesis of compounds according to the present application

General: All described reactions and operations were carried out in well ventilated fume hoods. Operations and reactions carried out at elevated or reduced pressure were carried out behind explosion-proof screens. Abbreviations: ACN, acetonitrile; AcOH, acetic acid; AIBN, azobisisobutyronitrile; BF ₃ -Et ₂ O, boron trifluoride diethyl etherate; (Boc) ₂ O, di-tert-butyl dicarbonate; 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; DMA, N,N-dimethylacetamide; DMAP, 4-dimethylaminopyridine; DME, 1,2-dimethoxyethane; DMEDA - N,N'-dimethylethylenediamine; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; DPPP, 1,3-bis(diphenylphosphino)propane; EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; EtOAc, ethyl acetate; EtOH, Ethanol; HATU, 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HBTU, O-Benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate or 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate; HMPA, hexamethylphosphoramide; HOAc, acetic acid; HOBT, 1-Hydroxybenzotriazole; LDA, lithium diisopropylamine; m-CPBA, 3-chloroperbenzoic acid; MeOH, methanol; MsCl, methanesulfonyl chloride; MsOH, methanesulfonic acid; NaHMDS, sodium hexamethyldisilazane, NBS, N-bromosuccinimide; NCS, N-chlorosuccinimide; NIS, N-iodosuccinimide; Pd(dppf)Cl ₂ , [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); PE, petroleum ether; PPA, polyphosphoric acid; PTAT, phenyltrimethylammonium tribromide; PTSA, p-toluenesulfonic acid; Py, pyridine; Pyr, pyridine; TBAF, tetrabutylammonium fluoride; TEA, triethylamine; TFA, trifluoroacetic acid; TFUA, trifluoroacetic anhydride; THF, tetrahydrofuran; TMSCl, chlorotrimethylsilane; TMSCN, trimethylsilyl cyanide; TsOH, p-toluenesulfonic acid.

Compound 1.1. tert-Butyl 4-(4-cyanophenyl)piperidine-1-carboxylate. Into a 500 ml three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a suspension of Zn (21.6 g, 330 mmol) in DMA (53 ml). 7:5 v/v a mixture of TMSCl/1,2-dibromoethane (5.8 ml) was added dropwise to the mixture at a rate sufficient to keep the temperature below 65°C. The mixture was stirred for another 10 minutes, then a solution of tert-butyl-4-iodopiperidine-1-carboxylate (68.7 g, 220 mmol) in DMA (122 ml) was added dropwise at 40-45°C and the mixture was stirred at the same temperature for 30 minutes. The mixture was cooled to room temperature and stirring was stopped so that the zinc powder settled. In another 500 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a mixture of 4-bromobenzonitrile (20 g, 110 mmol), CuI (2.1 g, 11 mmol), Pd(dppf)Cl ₂ (4, 51 g, 5.5 mmol) and DMA (100 ml). The freshly prepared zinc reagent solution was poured into an addition funnel and added dropwise to the mixture at room temperature. The resulting mixture was stirred at 85° C. for 4 h, then cooled to 20° C. and diluted with methyl tert-butyl ether (500 ml) and carefully quenched with 1 M ammonium chloride (500 ml). The mixture was stirred at room temperature for 30 minutes and then filtered to remove solids. The organic layer was washed with saturated aqueous ammonium chloride (100 ml), then brine (3×100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to give the title compound as a brown oil (20 g, imp.) and used in the next step without further purification.

Compound 1.2. 4-(Piperidin-4-yl)benzonitrile hydrochloride. A solution of tert-butyl 4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1, 20 g, crude) in ethyl acetate (200 ml) was placed in a 500 ml three-necked round bottom flask. Hydrogen chloride (gas) was introduced into the solution, and the resulting mixture was stirred for 30 minutes at room temperature. The solids were collected by filtration, then washed with ethyl acetate (100 ml) and ether (100 ml) to give the title compound as a white solid (14 g, 57% after two steps).

Compound 1.3. 5-Iodine-2,4-dimethylbenzoic acid. A solution of 2,4-dimethylbenzoic acid (20.0 g, 133 mmol), sodium iodate (14.27 g, 66.72 mmol), iodine (37.25 g, 146.8 mmol) and sulfuric acid (1.96 g, 20.0 mmol) in acetic acid (150 ml) was stirred at 110°C for 6 h. The mixture was left to cool to ambient temperature, then carefully diluted in water (1.2 l). Saturated aqueous Na ₂ S ₂ O ₃ (800 ml) was carefully added to this mixture. The resulting solids were collected by filtration, then dissolved in ethyl acetate (1.2 L) and washed with saturated aqueous Na ₂ S ₂ O ₃ (300 ml) and then brine (400 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was recrystallized from ethanol:H ₂ O (2:1) to give the title compound as a white solid (30 g, 82%).

Connection 1.4. 2,4-Dimethyl-5-propionylbenzoic acid. A solution of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3, 2.00 g, 7.24 mmol) in ethylene glycol dimethyl ether (20 ml) was placed in an autoclave with a capacity of 100 ml (30 atm). Triphenylphosphine (190 mg, 0.73 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (500 mg, 0.71 mmol) and diethylaluminum chloride (2 M, 10.8 ml, 21.6 mmol) were added to the reaction mixture. The resulting mixture was stirred under pressure with carbon monoxide (gas, 30 atm) at 80°C for 15 hours (Caution: Highly toxic gas under high pressure. All necessary precautions were taken). After cooling to room temperature, the mixture was gently purged, then quenched with 20 ml of water. Aqueous HCl (2 M) was added carefully to reach pH 5-6 and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with brine (2×100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:40-1:20) as eluent to give the title compound as a light yellow solid (1.2 g, 80%).

Compound 1.5. Methyl 2,4-dimethyl-5-propionyl benzoate. To a 100 ml round bottom flask were carefully added 2,4-dimethyl-5-propionylbenzoic acid (compound 1.4, 1.2 g, 5.8 mmol), sulfuric acid (1.0 ml, 19 mmol) and methanol (30 ml) . The resulting solution was stirred at 70°C for 5 hours, then concentrated under reduced pressure. The precipitate was carefully diluted with H ₂ O (50 ml) and was extracted with ethyl acetate (100 ml). The organic layer was washed with H ₂ O (2×100 ml) and brine (100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100) as eluent to give the title compound as a light yellow solid (0.90 g, 70%).

Compound 1.6. Methyl 5-(2-bromopropanoyl)-2,4-dimethylbenzoate. In a 100 ml round bottom flask was placed a solution of methyl 2,4-dimethyl-5-propionylbenzoate (compound 1.5, 600 mg, 2.72 mmol) in chloroform (20 ml). Bromine (154 µl, 3.00 mmol) was added and the resulting solution was stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure to give the title compound as a yellow oil (1.0 g, imp. ), which was used in the next step without further purification.

Compound 1.7. Methyl 5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate. A solution of methyl 5-(2-bromopropanoyl)-2,4-dimethylbenzoate (compound 1.6, 400 mg, 1.34 mmol) in acetonitrile (30 ml) was placed in a round bottom flask. Acetimidamide hydrochloride (260 mg, 2.75 mmol) and potassium carbonate (550 mg, 3.99 mmol) were added and the resulting mixture was stirred at 80° C. for 15 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the precipitate was diluted with ethyl acetate (50 ml) and washed with brine (2×25 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) in ethyl acetate as eluent to give the title compound as a yellow oil (0.20 g, 58%).

Compound 1.8. 5-(2,4-Dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid. Methyl 5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 1.7, 300 mg, 1.16 mmol) and sodium hydroxide (465 mg , 11.6 mmol) in methanol (20 ml) and H ₂ O (5 ml). The resulting solution was stirred at 55°C for 4 h, then, after cooling to room temperature, aqueous HCl (2 M) was added to reach a pH value of 5. The resulting mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (5 ml). Solids were removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (280 mg, imp.) which was used in the next step without further purification.

Compound 1 4-(1-(5-(2,4-Dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. 5-(2,4-Dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid mixture (compound 1.8, 280 mg, 1.15 mmol), EDC⋅HCl (330 mg, 1.72 mmol) , 4-dimethylaminopyridine (420 mg, 3.44 mmol) and HOBT (180 mg, 1.33 mmol) in N,N-dimethylformamide (6 ml) were stirred at room temperature. After 5 minutes, 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 230 mg, 1.03 mmol) was added and the resulting solution was stirred at room temperature for 15 hours, then quenched with ice water (20 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organics were washed with brine (2×50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.05% TFA and CH ₃ CN (22% CH ₃ CN to 37% in 7 minutes, to 100% in 2 minutes, to 22% in 1 minute); Detector, Waters 2489, 254 & 220 nm. Fractions containing the pure compound were combined and lyophilized to give the title compound as a white solid (214 mg, 50%). m/z (ES+) 413 (M+H) ⁺ . ¹ H NMR (300 MHz, CD ₃ OD): δ 7.68 (d, J=7.8 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.36 (br s, 1H), 7.27 & 7.16 (2 singlets, rotamers, Ar-H, 1H), ~4.9-4.82 (m, 1H partially covered by water peak), 3.72-3.55 (m, 1H), ~3.35-3.20 (m, 1H partially overlapped by methanol solvent peak), 3.08-2.92 (m, 2H), 2.65 (s, 3H), 2.44 & 2.34 (2 singlets, rotamers, Ar-CH ₃ , 3H), 2.29 (s, 3H), 2.22 (s, 3H), 2.10-1.96 (m, 1H), 1 .93-1.53 (m, 3H).

Compounds 2.1 and 2.2. Methyl 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate and methyl 5-(2-(methoxymethyl)-4-methyloxazol-5-yl)- 2,4-dimethylbenzoate. A mixture of methyl 5-(2-bromopropanoyl)-2,4-dimethylbenzoate (compound 1.6, 600 mg, 2.01 mmol), 2-methoxyethanimidamide hydrochloride (510 mg, 4.09 mmol), potassium carbonate (840 mg, 6.08 mmol) and acetonitrile (30 ml). The resulting mixture was stirred at 80°C overnight, then cooled to room temperature and concentrated under reduced pressure. The precipitate was diluted with H ₂ O (50 ml) and was extracted with ethyl acetate (100 ml). The organics were washed with brine (2×50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as eluent to give methyl 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4- dimethylbenzoate (compound 2.1) (0.11 g, 19%) and methyl 5-(2-(methoxymethyl)-4-methyloxazol-5-yl)-2,4-dimethylbenzoate (compound 2.2) (0.30 g, 52%), both as yellow oils.

Compound 2.3. 5-(2-(Methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid. A solution of methyl 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 2.1, 150 mg, 0.52 mmol) in methanol (15 ml) and H ₂ O (5 ml). Sodium hydroxide (280 mg, 7.00 mmol) was added and the resulting solution was stirred at 40° C. for 15 h. concentrated under reduced pressure. The precipitate was dissolved in methanol (5 ml) and the solids were filtered off. The filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (140 mg, imp.) which was used in the next step without further purification.

Compound 2 4-(1-(5-(2-(Methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid mixture (compound 2.3, 140 mg, 0.51 mmol), EDC⋅HCl (150 mg, 0 .78 mmol), 4-dimethylaminopyridine (190 mg, 1.56 mmol) and HOBT (80 mg, 0.59 mmol) in N,N-dimethylformamide (6 ml). The mixture was stirred at room temperature, then 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 100 mg, 0.45 mmol) was added after 15 min. The resulting solution was stirred for 15 h at room temperature, then quenched with 20 ml H ₂ O. The aqueous layer was extracted with ethyl acetate (40 ml) and the combined organics washed with brine (2×30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.05% TFA and CH ₃ CN (23% CH ₃ CN to 38% in 7 minutes, to 100% in 2 minutes, to 23% in 1 minute); Detector, Waters 2489, 254 & 220 nm. Fractions containing the pure compound were combined and lyophilized to give the title compound as a white solid (70.4 mg, 35%).

Compound 3 4-(1-(5-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. Into a 50 ml three-neck round-bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a mixture of 4-(1-(5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4 -dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 2, 30 mg, 0.068 mmol), NaI (20 mg, 0.13 mmol), 15-cron-5 (30 mg, 0.14 mmol) and dichloromethane (10 ml). The mixture was cooled to -30° C. and boron tribromide (70 mg, 0.28 mmol) was added. The resulting mixture was allowed to warm to room temperature and stirred for 15 hours. The reaction mixture was carefully quenched by adding saturated aqueous sodium bicarbonate (10 ml) and the resulting mixture was extracted with dichloromethane (2×20 ml). The combined organics were washed with saturated aqueous Na ₂ S ₂ O ₃ (2×20 ml), then dried (Na ₂ SO ₄ ), filtered 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 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.05% TFA and CH ₃ CN (21% CH ₃ CN to 35% in 8 min, to 100% in 2 min, to 21% in 1 min); Detector, Waters 2489, 254 & 220 nm. Fractions containing the pure compound were combined and lyophilized to give the title compound as a white solid (5.0 mg, 17%). m/z (ES+) 429 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.74-7.65 (m, 2), 7.48 (d, J=8.0 Hz, 2H), 7.38 (d, J= 5.6 Hz, 1H), 7.29 & 7.16 (2 singlets, rotamers, Ar-H, 1H), ~4.9 (1H closed by water peak), 3.64 (app t, J=15, 0 Hz, 1H), ~3.35-3.21 (m, 1H partially overlapped by methanol solvent peak), 3.09-2.93 (m, 1H), 2.45 & 2.34 (2 singlets, rotamers , Ar-CH ₃ , 3H), 2.29 (s, 3H), 2.24 (s, 3H), 2.09-1.97 (m, 1H), 1.92-1.71 (m, 2H), 1.70-1.55 (m, 1H).

Connection 4.1. 3-Formyl-4-methylbenzoic acid. n-BuLi (10 ml, 2.5 M in THF, 25 mmol). The mixture was stirred for 1 h at a temperature below -70°C, then slowly added DMF (5 ml). The resulting solution was slowly warmed to room temperature, stirred for 1 h, then carefully quenched by slow addition of water (50 ml). The pH was adjusted to ~3-4 with aqueous HCl (6 M) and the resulting mixture was extracted with ethyl acetate (2×50 ml). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow solid (1.6 g, 98%).

Connection 4.2. 3-(1-Hydroxybut-3-en-1-yl)-4-methylbenzoic acid. Into a 100 ml three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 3-formyl-4-methylbenzoic acid (compound 4.1, 2.00 g, 12.2 mmol) in tetrahydrofuran (50 ml). The mixture was cooled to -10 to 0° C., then allylmagnesium bromide (1 M in Et ₂ O, 24.4 ml, 24.4 mmol) was added dropwise. The resulting mixture was stirred for 1 h at -10-0°C, then carefully extinguished with saturated aqueous NH ₄ Cl (50 ml) and diluted with ethyl acetate (200 ml). The organic layer was washed with saturated aqueous NH ₄ Cl (80 ml) and brine (2×80 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a light red solid material (2.4 g, crude), which was used in the next step without further purification.

Compound 4.3. Methyl 3-(1-hydroxybut-3-en-1-yl)-4-methylbenzoate. A solution of 3-(1-hydroxybut-3-en-1-yl)-4-methylbenzoic acid (compound 4.2, 1.4 g, 6.79 mmol) in N,N-dimethylformamide was added to a 100 ml round bottom flask. (20 ml). Sodium bicarbonate (1.14 g, 13.6 mmol) and methyl iodide (0.847 ml, 13.6 mmol) were added and the resulting mixture was stirred overnight at 25°C. The reaction mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ (50 ml) and diluted with EtOAc (150 ml). The organic layer was washed with brine (3×50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) as eluent to give the title compound as a light yellow oil (800 mg, 53%).

Compound 4.4. Methyl 3-(2-cyclopropyl-1-hydroxyethyl)-4-methylbenzoate. Into a 100 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of methyl 3-(1-hydroxybut-3-en-1-yl)-4-methylbenzoate (compound 4.3, 50 mg, 0.23 mmol). Diethylzinc (1 M in toluene) (3.45 ml, 3.45 mmol) in toluene (10 ml) was added and the mixture was cooled to 0-5°C, then diiodomethane (924 mg, 3.45 mmol) was added dropwise . The resulting mixture was stirred for 2 h at room temperature, then carefully quenched with 1 M aqueous HCl (50 ml) and diluted with MTBE (50 ml). The aqueous phase was extracted with MTBE (3×20 ml) and the combined organics were washed with saturated sodium bicarbonate (2×20 ml), brine (2×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) as eluent to give the title compound as a yellow oil (40 mg, 74%).

Compound 4.5. Methyl 3-(2-cyclopropylacetyl)-4-methylbenzoate. A solution of methyl 3-(2-cyclopropyl-1-hydroxyethyl)-4-methylbenzoate (compound 4.4, 200 mg, 0.85 mmol) in dichloromethane (30 ml) was placed in a 100 ml round bottom flask. Dess-Martin periodinan (721 mg, 1.70 mmol) was then added portionwise at room temperature. The resulting solution was stirred for 1 h at room temperature, then extinguished with saturated aqueous Na ₂ S ₂ O ₃ (30 ml). The resulting mixture was extracted with DCM (3×20 ml) and the combined organics washed with brine (2×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:5) as eluent to give the title compound as a yellow oil (150 mg, 75%).

Compound 4.6. Methyl 3-(2-bromo-2-cyclopropylacetyl)-4-methylbenzoate. A solution of methyl 3-(2-cyclopropylacetyl)-4-methylbenzoate (compound 4.5, 150 mg, 0.65 mmol) in chloroform (15 ml) was placed in a 100 ml round bottom flask. Bromine (40 μl, 0.78 mmol) in chloroform (2 ml) was added dropwise to the reaction mixture. The resulting solution was stirred for 2 hours at room temperature, then concentrated under reduced pressure to give the title compound as a yellow oil (200 mg, imp.), which was used in the next step without further purification.

Connection 4.7. 2-Methoxyacetimidamide hydrochloride. A 250 ml round bottom flask was charged with a solution of 2-methoxyacetonitrile (6.00 g, 84.4 mmol) in methanol (60 ml). Sodium methoxide (860 mg, 15.9 mmol) was added and the mixture was stirred at room temperature for 40 h. Ammonium chloride (4.52 g, 84.5 mmol) was then added and the mixture was stirred at 40° C. for 12 h, then concentrated under reduced pressure. The precipitate was diluted with H ₂ O (20 ml) and washed with ethyl acetate (2×20 ml). The aqueous layer was concentrated under reduced pressure to give the title compound as a yellow solid (5 g, imp.) which was used in the next step without further purification.

Connection 4.8 and connection 4.9. Methyl 3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate and methyl 3-(4-cyclopropyl-2-(methoxymethyl)oxazol-5-yl)-4 -methyl benzoate. Methyl 3-(2-bromo-2-cyclopropylacetyl)-4-methylbenzoate (compound 4.6, 150 mg, 0.48 mmol), 2-methoxy hydrochloride acetimidamide (compound 4.7, 90 mg, 0.72 mmol), potassium carbonate (200 mg, 1.44 mmol) and N,N-dimethylformamide (15 ml). The resulting mixture was stirred at 80°C for 3 h, then diluted with ethyl acetate (100 ml). The mixture was washed with brine (3×30 ml) and water (3×30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as eluent to give methyl 3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate ( compound 4.8) (30 mg, 21%) and methyl 3-(4-cyclopropyl-2-(methoxymethyl)oxazol-5-yl)-4-methylbenzoate (compound 4.9) (60 mg, 41%), both as yellow oils.

Compound 4.10. 3-(4-Cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid. A solution of methyl 3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 4.8, 35 mg, 0.12 mmol) in methanol (5 ml) was placed in a round bottom flask , and a solution of sodium hydroxide (9.6 mg, 0.24 mmol) in water (0.3 ml) was added to the reaction mixture. The resulting solution was stirred for 2 h at room temperature, then diluted with water (5 ml). Aqueous HCl (6 M) was added carefully to adjust the pH to 1-2 and the mixture was extracted with dichloromethane (4×10 ml). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow oil (30 mg, crude) which was used in the next step without further purification.

Compound 4 4-(1-(3-(4-Cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 4.10, 30 mg, 0.10 mmol) in dichloromethane (5 ml) was placed in a round bottom flask. HBTU (76 mg, 0.20 mmol), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 35 mg, 0.15 mmol, 1.50 eq.) and triethylamine (28 μl, 0.20 eq) were added. mmol) and the mixture was stirred overnight at room temperature. The mixture was diluted with DCM (30 ml) and washed with water (3×15 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD, 5 µm 19*150 mm; mobile phase, water with 0.05% TFA and CH ₃ CN (25.0% CH ₃ CN to 38.0% in 7 min, to 100.0% in 4 min, to 25.0% in 1 min); Detector, Waters 2489, 254 & 220 nm. Fractions containing the pure compound were combined and lyophilized to give the title compound as a white solid (5.9 mg, 12%). m/z (ES+) 455 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.69 (d, J=8.0 Hz, 2H), 7.59-7.53 (m, 2H), 7.53-7.47 (m , 3H), ~4.9-4.75 (m, 1H partially covered by water peak), 4.72 (s, 2H), 3.99-3.85 (m, 1H), 3.52 (s, 3H), ~3.3 (m, 1H overlapped by methanol solvent peak), 3.08-2.93 (m, 2H), 2.37 (s, 3H), 2.08-1.93 (m, 1H ), 1.93-1.65 (m, 4H), 1.02-0.94 (m, 2H), 0.74-0.68 (m, 2H).

Compound 5.1. tert-Butyl-3-(4-cyanophenyl)azetidine-1-carboxylate. Used modified relative to that described in Org. Lett. 2008, 10, 3259 as described below. To a 20 ml vial was added (4-cyanophenyl)boronic acid (1.01 g, 6.87 mmol), trans-2-aminocyclohexanol hydrochloride (32 mg, 0.21 mmol), nickel(II) iodide (66 mg, 0.21 mmol) and sodium hexamethyldisilazane (1.29 g, 7.06 mmol). The system was purged with nitrogen and isopropyl alcohol (7 ml) was placed in it. The mixture was stirred at room temperature for 10 minutes, then sonicated for 1 minute. tert-Butyl-3-iodazetidine-1-carboxylate (1.00 g, 3.53 mmol) was added with stirring and the syringe was flushed with isopropyl alcohol (2×500 µl). The suspension was stirred at 80°C for 1 hour, then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes to 25% ethyl acetate) to give the title compound as a pale yellow oil which solidified after some time (0.832 g, 46%). m/z (ES+) 203 (MC ₄ H ₈ +H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.65 (d fine structure, J=8.4 Hz, 2H), 7.43 (d fine structure, J=8.4 Hz, 2H), 4.37 (app t, J=8.8 Hz, 2H), 3.98-3.91 (m, 2H), 3.81-7.73 (m, 1H).

Compound 5.2. 4-(azetidin-3-yl)benzonitrile hydrochloride. tert-Butyl 3-(4-cyanophenyl)azetidine-1-carboxylate (compound 5.1, 100 mg, 0.387 mmol) was placed in a 4 ml vial. HCl in dioxane (4 M, 500 μl, 2 mmol) was added and the unsealed mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in DCM and concentrated under reduced pressure. This action with DCM was repeated twice to drive off any excess HCl to give the title compound as a white powder (80 mg, more than expected in theory), m/z (ES+) 159 (M+H ) ⁺ .

Compound 5.3. Methyl 3-iodine-4-methylbenzoate. To a solution of 3-iodo-4-methylbenzoic acid (28.0 g, 0.107 mol) in MeOH (300 ml) at 0°C was added carefully concentrated H ₂ SO ₄ (30 ml). The mixture was heated at 60°C overnight, then cooled, and the solvent was removed under reduced pressure. The precipitate was carefully poured into ice water (200 ml) and the mixture was extracted with EtOAc (500 ml). The organics were washed with water (100 ml), saturated NaHCO ₃ (100 ml), brine (100 ml), dried (MgSO ₄ ), filtered and concentrated to give the title compound as a brown oil (29.0 g , 98%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (d, J=1.7 Hz, 1H), 7.90 (dd, J=7.9 Hz, 1.7 Hz, 1H), 7, 29 (d, J=7.9 Hz, 1H), 3.90 (s, 2H), 2.48 (s, 3H).

Connection 5.4. Methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. Methyl 3-iodo-4-methylbenzoate mixture (compound 5.3, 5.00 g, 18.1 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2 '-bi(1,3,2-dioxaborolane) (5.20 g, 20.5 mmol), KOAc (5.33 g, 54.3 mmol) and PdCl ₂ (dppf)⋅CH ₂ Cl ₂ (0, 74 g, 0.91 mmol) in DMSO (50 ml) was degassed with argon. The mixture was then heated at 80° C. under argon overnight. The mixture was left to cool, then partitioned between EtOAc (400 ml) and water (80 ml). The organic phase was washed with water (80 ml), saturated aqueous NaHCO ₃ (80 ml), brine (80 ml), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes: EtOAc 20:1) to give the title compound as a white crystalline solid (3.56 g, 71%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 (d, J=1.9 Hz, 1H), 7.97 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7, 23 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 2.58 (s, 3H), 1.35 (s, 12H).

Connection 5.5. 5-iodine-2,4-dimethyl-1H-imidazole. NIS (14.0 g, 62.4 mmol) was added portionwise to a solution of 2,4-dimethyl-1H-imidazole (5.00 g, 52.0 mmol) in acetonitrile (100 ml). The mixture was heated at 80°C for 16 hours, then cooled to room temperature. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (300 ml) and water (80 ml). The organic layer was washed with saturated sodium thiosulfate (50 ml), brine (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 1:1 to 10% MeOH in EtOAc) to give the title compound as a light yellow solid (8.56 g, 74%). m/z (ES+) 223 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.69 (br s, 1H), 2.38 (s, 3H), 2.19 (s, 3H).

Compound 5.6. Methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate. Methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 3.56 g, 12.9 mmol), 5-iodine -2,4-dimethyl-1H-imidazole (compound 5.5, 3.43 g, 15.4 mmol), K ₂ CO ₃ (5.33 g, 38.6 mmol) and PdCl ₂ (dppf)⋅CH ₂ Cl ₂ (1.05 g, 1.29 mmol) was added to a round bottom flask. The flask was purged with argon, then dioxane (70 ml) and water (20 ml) were added and the mixture was heated at 90° C. for 16 hours. The mixture was cooled, then additional K ₂ CO ₃ (1 M, 25 ml, 25.0 mmol) and PdCl ₂ (dppf)⋅CH ₂ Cl ₂ catalyst (1.0 g, 1.2 mmol) were added. The mixture was heated at 90°C for another 10 hours, then cooled to room temperature and filtered through Celite (Celite®). The solvent was removed under reduced pressure and the precipitate was cooled to 0°C and oxidized to pH 3-4 with aqueous HCl (2M). The acidic mixture was washed with EtOAc (150 ml), and then the aqueous solution of the substance was adjusted to pH 10-11 with aqueous sodium hydroxide (2 M) and was extracted with EtOAc (5×200 ml). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM to 5% MeOH in DCM) to give the title compound as a thick brown oil (2.42 g, 77%). m/z (ES+) 245 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89-7.87 (m, 2H), 7.31 (d fine structure, J=8.6 Hz, 1H), 3.89 (s, 3H ), 2.38 (s, 3H), 2.31 (s, 3H), 2.11 (s, 3H).

Connection 5.7. 3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid hydrochloride. Aqueous NaOH (2 M, 4.8 ml, 9.6 mmol). The mixture was stirred at room temperature for 3 hours, then the organic solvent was removed under reduced pressure. The aqueous precipitate was cooled to 0° C. and acidified to pH 3-4 with aqueous HCl (1 M). The mixture was concentrated to dryness and 5% methanol in DCM (20 ml) was added to the precipitate. The mixture was stirred at room temperature for 5 minutes and solids (inorganic salts) were filtered from the solution. The filtrate was concentrated to give the title compound as a brown foam (0.484 g, 67%). m/z (ES+) 231 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.22 (br s, 1H), 14.16 (br s, 1H), 13.11 (br s, 1H), 7.97 (dd, J =8.0 Hz, 1.8 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 2.58 (s, 3H), 2.31(s, 3H), 2.15(s, 3H).

Compound 5 4-(1-(3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. To a mixture of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7, 0.484 g, 2.10 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 0.41 g, 2.10 mmol), HOBT (0.085 g, 7.40 mmol) and EDCI (0.603 g, 3.15 mmol) in DMF (8 ml) was added DIEA (1.09 ml, 6. 3 mmol). The mixture was stirred at room temperature for 16 hours, then partitioned between EtOAc (300 ml) and water (30 ml). The organic layer was washed with brine (3×30 ml) and the combined aqueous phases were back-extracted with EtOAc (2×50 ml). All organic extracts were combined, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc to 5% MeOH in EtOAc) to give the title compound as a white solid (0.35 g, 45%). m/z (ES+) 371 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (d fine structure, J=8.4 Hz, 2H), 7.54-7.48 (m, 2H), 7.44 (d fine structure, J=8.2 Hz, 2H), 7.30 (d, J=7.9 Hz, 1H), 4.77-4.56 (m, 2H), 4.35-4.18 (m , 2H), 3.97-3.87 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H), 2.10 (s, 3H).

Connection 6.1. Methyl 4-bromo-2-methyl benzoate. To a solution of 4-bromo-2-methylbenzoic acid (5.11 g, 23.8 mmol, 1.0 eq.) in methanol (25 ml) was added sulfuric acid (2.0 ml) dropwise over about 3 minutes ( slightly exothermic reaction). The resulting mixture was heated under reflux for 4 hours. After cooling to room temperature, the reaction mixture was carefully quenched in saturated aqueous NaHCO ₃ (100 ml) (attention - significant gas evolution) and was extracted with dichloromethane (200 ml × 1, then 50 ml × 1). The combined organic phases were washed with brine/saturated NaHCO ₃ (9:1) (50 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to give the title compound as a colorless oil (5.28 g, 97%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.78 (d, J=8.0 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.38 (dd, J=1.6 Hz, 1H), 3.89 (s, 3H), 2.58 (s, 3H).

Compound 6.2. Methyl 4-cyclobutyl-2-methylbenzoate. Cyclobutylzinc (II) bromide (50 ml, 0.5 M in THF, 25.0 mmol) was added to a mixture of methyl 4-bromo-2-methylbenzoate (compound 6.1, 5.2 g, 22.7 mmol) and PdCl ₂ (dppf)⋅CH ₂ Cl ₂ (1.85 g, 2.27 mmol). The mixture was degassed and the flask was filled with argon through a balloon. The mixture was heated at 65° C. under argon for 24 hours, then cooled to 0° C. and carefully quenched with water (10 ml). The mixture was diluted with EtOAc (200 ml) and washed with water, then brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 30:1 to 20:1) to give the title compound as a clear oil (4.1 g, 89%). ¹ H NMR (400 MHz, CDCl ₃ ) 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 6.3. Methyl 4-cyclobutyl-5-iodo-2-methylbenzoate. N-iodosuccinimide (3.52 g, 15.6 mmol) was added portionwise to a solution of methyl 4-cyclobutyl-2-methylbenzoate (compound 6.2, 3.2 g, 15.6 mmol) in concentrated sulfuric acid (25 ml) at 0°C. The mixture was stirred at 0°C for 30 minutes and at RT for 2 hours, after which the mixture became very thick. The mixture was again cooled to 0° C. and MeOH (30 ml) was added slowly with care. The mixture was heated at 60°C for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the precipitate was poured into ice water (100 ml). The mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, then aqueous 1 M NaHCO ₃ (note - significant gas evolution), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes: EtOAc 30:1 to 20:1) to give the title compound as a light yellow oil (4.17 g, 81%). ¹ H NMR (400 MHz, CDCl ₃ ) 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 6.4. Methyl 5-cyano-4-cyclobutyl-2-methylbenzoate. A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 6.3, 4.17 g, 12.6 mmol), Zn(CN) ₂ (2.96 g, 25.2 mmol) and Pd(PPh ₃ ) ₄ (0.73 g, 0.63 mmol) in DMF (30 mL) was degassed and the flask was filled with argon. The mixture was heated at 100° C. under argon overnight. After cooling to air temperature, the mixture was quenched with saturated water. FeSO ₄ (20 ml) and diluted with EtOAc (200 ml). The greenish solid was removed by filtration through Celite® and the filtrate was partitioned between water and EtOAc. The organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 30:1 to 20:1) to give the title compound as a white solid (2.55 g, 88%). ¹ H NMR (400 MHz, CDCl ₃ ) 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 6.5. 5-Carbamoyl-4-cyclobutyl-2-methylbenzoic acid. Methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (compound 6.4, 12.00 g, 52.3 mmol) was added to a 1 L round bottom flask and dissolved in DMSO (100 ml). Aqueous sodium hydroxide (1 M, 260 ml, 260 mmol) was carefully added with stirring and the mixture was purged with nitrogen. The mixture was stirred at 95°C for 13 hours and then cooled to room temperature. The solution was washed with diethyl ether (100 ml) and the basic aqueous solution was acidified to pH~2 by slowly adding an aqueous HCl solution (1 M), and then an aqueous solution of H ₃ PO ₄ (1 M). The precipitated solids were filtered and washed with water (2 x 100 mL), then dried to constant weight to give the title compound as a white powder (11.68 g, 96%). m/z (ES-) 232 (M-H) ^- . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.75 (br s, 1H), 7.75 (s, 1H), 7.74 (br s, 1H), 7.34 (br s, 1H), 7.28 (s, 1H), 3.90 (app p, J=9.0 Hz, 1H), 2.56 (s, 3H), 2.32-2.20 (m, 2H) , 2.16-2.02(m, 2H), 2.00-1.87(m, 1H), 1.82-1.71(m, 1H).

Compound 6 5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-cyclobutyl-4-methylbenzamide. To a 4 ml vial was added 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 27 mg, ~90% pure, 0.13 mmol), HOBt (20 wt% H ₂ O) (22 mg, 0 .13 mmol), EDC (27 mg, 0.14 mmol). A solution of 5-carbamoyl-4-cyclobutyl-2-methylbenzoic acid (compound 6.5, 28 mg, 0.12 mmol) in DMF (500 µl) was added, followed by DIEA (83 µl, 0.48 mmol). The mixture was sealed and stirred at room temperature for 18 hours. Additional amine (3 mg, ~0.015 mmol) and EDC (5 mg, ~0.026 mmol) were added and the mixture was stirred at room temperature for an additional 27 hours. The mixture was diluted with ethyl acetate (5 ml) and washed with brine (8 ml). The aqueous layer was extracted with ethyl acetate (2 ml) and the combined organics washed with brine, 1M NaH ₂ PO ₄ , saturated NaHCO ₃ and brine (7 ml each). The product started to precipitate out of solution after the last brine wash, so the organics were diluted with DCM (3 ml) and MeOH (~200 µl). The organics were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was triturated with Et ₂ O (1.5 ml), filtered and washed with Et ₂ O (0.5 ml) to give the title compound as an off-white powder (41.4 mg, 92% ). m/z (ES+) 374 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.67 (d fine structure, J=8.4 Hz, 2H), 7.40 (d fine structure, J=8.4 Hz, 2H), 7.32 (s, 1H), 7.25 (s, 1H), 5.79 (br s, 1H), 5.70 (br s, 1H), 4.67-4.57 (m, 1H) , 4.39-4.30(m, 1H), 4.28-4.18(m, 1H), 4.00-3.86(m, 3H), 2.46(s, 3H), 2 .42-2.31 (m, 2H), 2.19-1.96 (m, 3H), 1.88-1.77 (m, 1H).

Compound 7.1. Methyl 4-methyl-3-(2-methyl-1H-imidazol-5-yl)benzoate. To a solution of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 600 mg, 2.17 mmol) in dioxane (20 ml) was added 2-methyl-4-bromoimidazole (419 mg, 2.6 mmol), Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ (180 mg, 0.22 mmol). The mixture was degassed with argon and stirred for 10 minutes, then aqueous potassium carbonate (1 M, 10 ml, 10 mmol) was added and the mixture was stirred at 90°C for 18 hours. After cooling to air temperature, the reaction mixture was diluted with EtOAc and filtered through Celite®. The organic phase was washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% MeOH in EtOAc) to give the title compound as a foam (324 mg, 65%). m/z (ES+) 231 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (br s, 1H), 7.86 (dd, J=7.9, 1.9 Hz, 1H), 7.32 (d, J=7 .9 Hz, 1H), 7.08 (s, 1H), 3.92 (s, 3H), 2.53 (s, 3H), 2.51 (s, 3H).

Compound 7.2. Methyl 3-(5-chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoate. To a solution of methyl 4-methyl-3-(2-methyl-1H-imidazol-5-yl)benzoate (compound 7.1, 317 mg, 1.38 mmol) in carbon tetrachloride (30 ml) was added NCS (184 mg, .38 mmol). The mixture was stirred at 50°C for 16 hours, then cooled to room temperature and washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to give the title compound as a solid (300 mg, 82%). m/z (ES+) 265 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.55 (br s, 1H), 8.01-7.87 (m, 2H), 7.37 (d, J=7.8 Hz, 1H), 3.91 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H).

Compound 7.3. 3-(5-Chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoic acid. A mixture of methyl 3-(5-chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoate (compound 7.2, 10 mg, 0.038 mmol) in methanol (2 ml) and aqueous NaOH (2 M, 0 .2 ml, 0.4 mmol) was stirred at 50° C. for 16 h. The organic solvent was removed under reduced pressure, and aqueous HCl (2 M) was added to the precipitate until a pH~3-4 was reached. Solvents were removed under reduced pressure to give a white solid, which was a mixture of the title compound and salts, which was used in the next step without further purification. m/z (ES-) 249 (M-H) ^- .

Compound 7 4-(1-(3-(4-Chloro-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. Mixture of 3-(5-chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoic acid (compound 7.3, ~0.038 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 8 .6 mg, 0.044 mmol), EDCI (12 mg, 0.063 mmol), HOBt (8 mg, 0.044 mmol) and DIEA (28 μl, 0.16 mmol) in DMF (1 ml) were stirred at room temperature for 16 hours . The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine (as much), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by preparative TLC on silica gel (8% MeOH in DCM) to give the title compound as a foam (2.8 mg, 19% over 2 steps). m/z (ES+) 391 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.54-7.40 (m, 3H), 7, 37 (d, J=1.9 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 4.80-4.58 (m, 2H), 4.41-4.19 (m, 2H), 4.03-3.92 (m, 1H), 2.49 (s, 3H), 2.32 (s, 3H).

Compound 8 4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)azetidin-3-yl)benzonitrile. To a 4 ml vial was added 5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-cyclobutyl-4-methylbenzamide (compound 6, 39 mg, 0.104 mmol), dioxane (200 μl) and 1.1 -dimethoxy-N,N-dimethylethanamine (76 µl, 0.52 mmol). The mixture was heated at 90°C for 3 hours, then cooled to room temperature. Acetic acid (42 μl, 0.73 mmol) and hydrazine hydrate (30 μl, 0.62 mmol) were added and the mixture was stirred at 90° C. for 1 hour. The mixture was diluted with DCM (5 ml) and washed with aqueous NaH ₂ PO ₄ (1 M, 5 ml) then saturated aqueous NaHCO ₃ (5 ml). The organics were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (DCM/8% MeOH) to give the title compound as a white powder (18.7 mg, 43%). m/z (ES+) 412 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.65 (d fine structure, J=8.4 Hz, 2H), 7.57 (s, 1H), 7.39 (d fine structure, J=8.4 Hz, 2H), 7.29(s, 1H), 4.61(app t, J=9.6 Hz, 1H), 4.39(app t, J=8.8 Hz, 1H), 4.27-4.18 (m, 1H), 4.17-4.07 (m, 1H), 4.02-3.94 (m, 1H), 3.94-3.84 ( m, 1H), 2.50 (s, 3H), 2.48 (s, 3H), 2.25-2.11 (m, 2H), 2.11-1.88 (m, 3H), 1 .82-1.71 (m, 1H).

Connection 9.1. Methyl 4-cyclobutyl benzoate. To a stirred mixture of ZnBr ₂ (83.0 g, 369 mmol) in THF (500 ml) under nitrogen at 0°C was added dropwise a solution of bromine(cyclobutyl)magnesium (242 ml, 363 mmol, 1.5 M in THF) within 20 minutes. The resulting mixture was cooled to -40°C and added Pd(dppf)Cl ₂ (2.00 g, 2.73 mmol) and methyl-4-bromobenzoate (20.0 g, 93.0 mmol). The resulting mixture was stirred at -40°C for 1 h under nitrogen atmosphere, and then carefully extinguished with saturated aqueous NH ₄ Cl (500 ml). The mixture was extracted with ethyl acetate (3×500 ml) and the combined organic layers were washed with brine (3×500 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as light yellow oil (18.0 g, crude).

Compound 9.2. Methyl 4-cyclobutyl-3-iodobenzoate. To a solution of methyl 4-cyclobutyl benzoate (compound 9.1, 2.00 g, 10.5 mmol) in acetic acid (30 ml) was carefully added sodium iodate (1.00 g, 4.68 mmol), iodine (3, 00 g, 11.8 mmol) and sulfuric acid (0.15 g). The resulting mixture was stirred overnight at 100°C. After cooling to room temperature, the reaction mixture was carefully quenched with saturated aqueous Na ₂ S ₂ O ₃ (30 ml) and the resulting mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (3×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow oil (1.50 g, 45%).

Connection 9.3. 4-Cyclobutyl-3-iodobenzoic acid. A solution of methyl 4-cyclobutyl-3-iodobenzoate (compound 9.2, 11.0 g, 34.8 mmol) and sodium hydroxide (4.00 g, 100 mmol) in methanol (100 ml) and water (50 ml) was stirred at 50°C during the night. After cooling to ambient temperature, the volatile solvent was removed under reduced pressure. The aqueous residue was washed with ethyl acetate (20 ml). The pH of the aqueous layer was then adjusted to 3-4 with aqueous hydrogen chloride (6M). The resulting precipitate was collected by filtration and dried to give the title compound as a white solid (8.60 g, 82%).

Compound 9 4-(1-(4-Cyclobutyl-3-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1, except for the use of 4-cyclobutyl-3-iodobenzoic acid (compound 9.3) instead of 5-iodo-2,4-dimethylbenzoic acid ( compound 1.3) and 2-methoxyacetimidamide hydrochloride (compound 4.7) instead of acetimidamide hydrochloride. m/z (ES+) 469 (M+H) ⁺ .

Connection 10.1. Methyl 4-cyclopropyl benzoate. Into a 1 L three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of a mixture of ZnBr ₂ (41.5 g, 184 mmol) and tetrahydrofuran (500 ml). The mixture was cooled to 0° C., then cyclopropyl magnesium bromide (2 M in THF) (92 ml, 184 mmol) was added dropwise with stirring over 30 minutes. The mixture was then cooled to -40° C. and Pd(dppf)Cl ₂ (3.00 g, 4.1 mmol) was added portionwise over 1 minute. Methyl 4-bromobenzoate (10.0 g, 46.50 mmol) in THF (50 ml) was added dropwise over 30 minutes at -40°C. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then carefully quenched by adding aqueous NH ₄ Cl (sat., 500 ml). The mixture was extracted with ethyl acetate (3×300 ml) and the combined organic layers were washed with brine (3×300 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as eluent to give 8.87 g (impure) of the title compound as a yellow oil.

Compound 10.2. Methyl 3-bromo-4-cyclopropyl benzoate. A mixture of methyl 4-cyclopropyl benzoate (compound 10.1, 500 mg, 2.84 mmol), N-bromosuccinimide (500 mg, 2.81 mmol) and trifluoroacetic acid (20 ml) was placed in a 50 ml round bottom flask. The mixture was stirred overnight at 50° C., then cooled and carefully quenched with water (10 ml). The mixture was extracted with ethyl acetate (3×30 ml) and the combined organic layers were washed with brine (3×30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as eluent to give 0.5 g (69%) of the title compound as a yellow oil.

Compound 10.3. 3-Bromo-4-cyclopropylbenzoic acid. A solution of methyl 3-bromo-4-cyclopropyl benzoate (compound 10.2, 500 mg, 1.96 mmol) in methanol (10 ml) and a solution of sodium hydroxide (500 mg, 12.5 mmol) in water were placed in a 50 ml round bottom flask. (5 ml). The resulting solution was stirred overnight at 50°C, then the volatiles were removed under reduced pressure. The pH of the residual solution was adjusted to 6-7 with aqueous HCl (6M). The resulting solids were collected by filtration to give 0.3 g (63%) of the title compound as a white solid.

Compound 10.4. 4-Cyclopropyl-3-formylbenzoic acid. Into a 100 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 3-bromo-4-cyclopropylbenzoic acid (compound 10.3, 500 mg, 2.07 mmol) in tetrahydrofuran/Et ₂ O (1:1, 20 ml). The solution was cooled to -78° C., then n-BuLi (2.5 M in THF) (1.8 ml, 4.5 mmol) was added dropwise with stirring. The resulting solution was stirred for another 30 minutes at -78°C, then N,N-dimethylformamide (0.49 ml, 6.3 mmol) was added dropwise over 10 minutes. The mixture was stirred for 2 h at -78°C, then extinguished with water (100 ml). The pH of the solution was adjusted to 3-4 with aqueous HCl (6 M), then extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (3×30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as eluent to give 0.3 g (76%) of the title compound as a white solid.

Compound 10.5. 4-Cyclopropyl-3-(1-hydroxypropyl)benzoic acid. Into a 250 ml three neck round bottom flask which was purged and kept under an inert nitrogen atmosphere and which contained THF (60 ml) was charged a solution of ethylmagnesium bromide (3 M in diethyl ether) (24.6 ml, 73.8 mmol). A solution of 4-cyclopropyl-3-formylbenzoic acid (compound 10.4, 3.5 g, 18.4 mmol) in THF (40 ml) was added dropwise at room temperature over 45 minutes. The resulting mixture was stirred for 1.5 h at room temperature, then carefully quenched with water/ice (50 ml). The mixture was diluted with EtOAc (100 ml) and the organic layer was washed with aqueous NH ₄ Cl (sat., 2×100 ml) and the organic layers were combined. The pH of the aqueous phase was adjusted to 3-4 with aqueous hydrogen chloride (2 M) and was extracted with ethyl acetate (2×150 ml). The combined organic extracts were washed with brine (30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate:PE (1:10-2:1) as eluent to give 3.4 g (84%) of the title compound as a white solid.

Connection 10.6. 4-Cyclopropyl-3-propionylbenzoic acid. In a 500 ml round bottom flask, was placed a mixture of 4-cyclopropyl-3-(1-hydroxypropyl)benzoic acid (compound 10.5, 3.4 g, 15.44 mmol) in 1,2-dichloroethane (300 ml) and Dess-periodinane. Martin (7.2 g, 16.9 mmol). The mixture was stirred for 1.5 hours at room temperature and then the solids were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with ethyl acetate:PE (1:9) to methanol/ethyl acetate (20:1) as eluent to give 2.3 g (68%) of the compound indicated in name, as a light yellow solid.

Connection 10.7. Methyl 4-cyclopropyl-3-propionyl benzoate. A solution of 4-cyclopropyl-3-propanoylbenzoic acid (compound 10.6, 500 mg, 2.29 mmol) in N,N-dimethylformamide (20 ml) and potassium carbonate (633 mg, 4.55 mmol) were placed in a 50 ml round bottom flask. . The mixture was cooled to 0-5°C, then iodomethane (157 μl, 2.52 mmol) was added dropwise. The resulting mixture was stirred for 1 h at 5-10° C., then quenched with water/ice (80 ml). The aqueous phase was extracted with ethyl acetate (2×150 ml) and the combined organic layers were washed with brine (20 ml), sodium carbonate (sat., 20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. 400 mg (75%) of the title compound were obtained as a light brown oil.

Compound 10 4-(1-(4-Cyclopropyl-3-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1, except for the use of methyl 4-cyclopropyl-3-propionyl benzoate (compound 10.7) instead of methyl-2,4-dimethyl-5- propionyl benzoate (compound 1.5) and 2-methoxyacetimidamide hydrochloride (compound 4.7) instead of acetimidamide hydrochloride. m/z (ES+) 455 (M+H) ⁺ .

Compound 11.1. 4-Methyl-3-propionylbenzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 10.6, except for the use of 3-bromo-4-methylbenzoic acid instead of 3-bromo-4-cyclopropylbenzoic acid (compound 10.3).

Compound 11 4-(1-(3-(2-(Methoxymethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1, except for the use of 4-methyl-3-propionylbenzoic acid (compound 11.1) instead of 2,4-dimethyl-5-propionylbenzoic acid ( compound 1.4) and 2-methoxyacetimidamide hydrochloride (compound 4.7) instead of acetimidamide hydrochloride. m/z (ES+) 429 (M+H) ⁺ .

Compound 12 4-(1-(3-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 3, except for the use of 4-(1-(3-(2-(methoxymethyl)-4-methyl-1H-imidazole-5 -yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 11) instead of 4-(1-(5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2, 4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 2). m/z (ES+) 415 (M+H) ⁺ .

Connection 13.1. tert-Butyl-4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate. A solution of butyllithium (150 ml, 2.43 M in THF) in within 30 minutes. The resulting solution was stirred for 2 hours at -78°C. Then, a solution of tert-butyl-4-oxo-piperidine-1-carboxylate (60 g, 301 mmol) in tetrahydrofuran (800 ml) was added dropwise with stirring at -78° C. for 30 minutes. The mixture was stirred for 1 h at -78°C, then the reaction mixture was carefully quenched with water (350 ml). The resulting mixture was extracted with ethyl acetate (2×400 ml), and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:200-1:10) as eluent to give 91 g (85%) of the title compound as a yellow oil.

Connection 13.2. tert-Butyl-4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate. Mixture of tert-butyl 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (compound 13.1, 36 g, 101 mmol), Pd(PPh ₃ ) ₄ (11.7 g, 10.1 mmol) and Zn (CN) ₂ (17.9 g, 152.4 mmol) in DMF (400 ml) under nitrogen was stirred overnight at 80°C. The mixture was cooled to air temperature, then the reaction mixture was quenched by adding 600 ml of FeSO ₄ (aq., sat.) and diluted with ethyl acetate. The resulting mixture was thoroughly stirred, then filtered through Celite (Celite®) and washed with 1 M FeSO ₄ , water and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with potassium carbonate (aq., sat., 200 ml), then brine (200 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:200-1:5) as eluent to give 23 g (75%) of the title compound as a white solid.

Connection 13.3. tert-Butyl 4-(4-cyanophenyl)-4-fluoropiperidine-1-carboxylate. Deoxofluoro (Deoxo-Fluor®) (4.4 g, 19.9 mmol ). The resulting mixture was stirred for 1 hour at -78°C. The reaction mixture was then carefully quenched with sodium bicarbonate (aq., sat., 50 ml) and extracted with dichloromethane (3×100 ml). The combined organic layers were washed with brine (150 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:30) as eluent to give 2.5 g (35%) of the title compound as a white solid.

Connection 13.4. 4-(4-Fluoropiperidin-4-yl)benzonitrile hydrochloride. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 1.2, except that compound 13.3 was used instead of compound 1.1. m/z (ES+) 205 (M+H) ⁺ . ¹ H NMR (300 MHz, CD ₃ OD): 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).

Connection 14.1. 4-Methyl-2-(trifluoromethyl)-1H-imidazole. Into a 250 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, were placed 2-oxopropanal (5 g, 27.8 mmol), acetic acid (150 ml), 1-ethoxy-2,2,2-trifluoroethanol (13 .3 g, 83.2 mmol) and ammonium acetate (17.1 g, 222 mmol). The mixture was stirred for 18 h at 110°C, then cooled to room temperature and concentrated under reduced pressure. The precipitate was quenched with a mixture of water and ice (30 ml) and the aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (30 ml) and concentrated under reduced pressure. The precipitate was dissolved in aqueous hydrogen chloride (5 M, 20 ml) and washed with ethyl acetate (2×50 ml). The pH of the aqueous layer was adjusted to 8-9 with sodium carbonate, then extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with ethyl acetate:PE (1:5) as eluent to give 1.2 g (29%) of the title compound as a brown oil.

Connection 14.2. 4-Methyl-1H-imidazole-2-carbonitrile. Into a 250 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, were placed 4-methyl-2-(trifluoromethyl)-1H-imidazole (compound 14.1, 800 mg, 5.33 mmol) and 5% aqueous ammonium hydroxide (50 ml). The resulting solution was stirred for 40 hours at 25-30°C, then the pH of the solution was adjusted to 5-6 with acetic acid. The aqueous phase was extracted with ethyl acetate (3×150 ml) and the combined organic extracts were washed with brine (2×50 ml) and aqueous Na ₂ CO ₃ (sat., 2×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate:PE (1:20-1:10) as eluent to give 350 mg (61%) of the title compound as a white solid.

Compound 14.3. 5-Iodo-4-methyl-1H-imidazole-2-carbonitrile. In a 25 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a mixture of 4-methyl-1H-imidazole-2-carbonitrile (compound 14.2, 350 mg, 3.27 mmol) and aqueous sodium hydroxide (2 M, 5 ml) and stirred for 15 minutes at room temperature. A solution of iodine (1.25 g, 4.92 mmol) in dichloromethane (5 ml) was then added dropwise. The resulting mixture was stirred for 24 h at room temperature, then diluted with a mixture of water and ice (10 ml). The aqueous layer was washed with DCM (10 ml) and then acidified to pH 5-6 with acetic acid. The aqueous phase was extracted with EtOAc (5×50 ml) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 500 mg (66%) of the title compound as a brown solid.

Compound 14 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazole-2-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-iodo-4-methyl-1H-imidazole-2-carbonitrile (compound 14.3) instead of 5-iodo- 2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 382 (M+H) ⁺ .

Compound 15 5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazole-2-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-iodo-4-methyl-1H-imidazole-2-carbonitrile (compound 14.3) instead of 5-iodo- 2,4-dimethyl-1H-imidazole (compound 5.5) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 410 (M+H) ⁺ .

Compound 16.1. 3,3,3-Trifluoro-2-oxopropanal. A mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (10.37 g, 38.43 mmol) and sodium acetate (12.61 g, 153.7 mmol in water (50 ml) The resulting solution was stirred overnight at 100°C, then cooled to room temperature and was extracted with ethyl acetate (3×20 ml) The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure with obtaining 1.52 g (31%) of the title compound as a light yellow oil.

Compound 16.2. 2-Methyl-4-(trifluoromethyl)-1H-imidazole. A solution of acetaldehyde (296 μl, 5.29 mmol), 3,3,3-trifluoro-2-oxopropanal (compound 16.1, 1.0 g, 7.9 mmol) and 25% ammonium hydroxide ( 0.8 ml) in methanol (5 ml). The solution was stirred for 3 h at 0°C, then stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure, and then the residue was diluted with water (50 ml). The aqueous phase was extracted with ethyl acetate (3×20 ml) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by chromatography to give 430 mg (54%) of the title compound as a light yellow solid.

Compound 16.3. 2-Methyl-1H-imidazole-4-carbonitrile. A solution of 2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2, 300 mg, 2.00 mmol) in 5% ammonium hydroxide (35 ml) was placed in a 100 ml round bottom flask. The resulting solution was stirred for 4 days at room temperature, then the pH of the solution was adjusted to 7 with acetic acid. The aqueous phase was extracted with ethyl acetate (3×10 ml) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 170 mg (79%) of the title compound as a light yellow solid .

Compound 16.4. 5-Iodo-2-methyl-1H-imidazole-4-carbonitrile. A mixture of 2-methyl-1H-imidazole-4-carbonitrile (compound 16.3, 50 mg, 0.47 mmol), N-iodosuccinimide (116 mg, 0.52 mmol) in ACN (5 ml) was placed in a 25 ml round bottom flask. . The resulting solution was heated at reflux overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/2) to give 60 mg (55%) of the title compound as a light yellow solid.

Compound 16 5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-2-methyl-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-iodo-2-methyl-1H-imidazole-4-carbonitrile (compound 16.4) instead of 5-iodo- 2,4-dimethyl-1H-imidazole (compound 5.5) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 410 (M+H) ⁺ .

Compound 17.1. 3-Butyryl-4-methylbenzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 10.6, except for the use of 3-bromo-4-methylbenzoic acid instead of 3-bromo-4-cyclopropylbenzoic acid (compound 10.3) and propyl magnesium bromide instead of ethylmagnesium bromide.

Compound 17 4-(1-(3-(4-Ethyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 1, except for the use of 3-butyryl-4-methylbenzoic acid (compound 17.1) instead of 2,4-dimethyl-5-propionylbenzoic acid ( compound 1.4) and 2-methoxyacetimidamide hydrochloride (compound 4.7) instead of acetimidamide hydrochloride. m/z (ES+) 443 (M+H) ⁺ .

Compound 18.1. 2-Methyl-5-propionylbenzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 10.6, except for the use of 5-bromo-2-methylbenzoic acid instead of 3-bromo-4-cyclopropylbenzoic acid (compound 10.3).

Compound 18 4-(1-(5-(2,4-Dimethyl-1H-imidazol-5-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1, except for the use of 2-methyl-5-propionylbenzoic acid (compound 18.1) instead of 2,4-dimethyl-5-propionylbenzoic acid ( connection 1.4). m/z (ES+) 399 (M+H) ⁺ .

Compound 19 4-(1-(4-Ethyl-3-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 1, except for the use of 4-ethylbenzoic acid in place of 2,4-dimethylbenzoic acid and 2-methoxyacetimidamide hydrochloride (compound 4.7) in place of acetimidamide hydrochloride. m/z (ES+) 443 (M+H) ⁺ .

Compound 20.1. Methyl 4-(bromomethyl)-3-iodobenzoate. A mixture of methyl 3-iodo-4-methylbenzoate (compound 5.3, 3.00 g, 10.9 mmol) in CCl ₄ (50 ml), NBS (2.9 g, 16.3 mmol) was placed in a 100 ml round bottom flask. ), azobisisobutyronitrile (360 mg, 2.19 mmol) and potassium carbonate (1.65 g, 11.9 mmol). The resulting mixture was stirred overnight at 70°C, then cooled to room temperature and concentrated under reduced pressure. The precipitate was diluted with EtOAc (100 ml) and the mixture was washed with brine (2×50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20) as eluent to give 3.0 g (78%) of the title compound as a yellow solid.

Compound 20.2. Methyl 3-iodine-4-(methoxymethyl)benzoate. A mixture of methyl 4-(bromomethyl)-3-iodobenzoate (compound 20.1, 3.0 g, 8.5 mmol) and sodium methoxide (1.8 g, 33 mmol) in methanol (100 ml ). The resulting solution was stirred for 2 hours at 50°C, then cooled to room temperature and concentrated under reduced pressure. The precipitate was diluted with ethyl acetate (50 ml) and the solids were filtered off. The filtrate was concentrated under reduced pressure to give 2.0 g (77%) of the title compound as a yellow solid.

Compound 20 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-(methoxymethyl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of methyl 3-iodo-4-(methoxymethyl)benzoate (compound 20.2) instead of methyl-3-iodo-4 -methylbenzoate (compound 5.3) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 429 (M+H) ⁺ .

Compound 21.1. 2,5-Diiodine-4-methyl-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5.5, except for the use of 4-methyl-1H-imidazole (2.0 g, 24.4 mmol) instead of 2,4-dimethyl -1H-imidazole and 2 equivalents of NIS to give 4.0 g (49%) of the title compound as a white solid.

Compound 21.2. 5-iodine-4-methyl-1H-imidazole. 2,5-diiodo-4-methyl-1H-imidazole (compound 21.1, 1.0 g, 3.0 mmol), Na ₂ SO ₃ (3.0 g, 25.4 mmol) and ethanol/water (20/40 ml). The resulting mixture was stirred overnight at reflux, then cooled and concentrated under reduced pressure. The precipitate was dissolved in water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 0.60 g (96%) of the title compound as a white solid.

Compound 21 4-(1-(4-methyl-3-(4-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-iodo-4-methyl-1H-imidazole (compound 21.2) instead of 5-iodo-2,4- dimethyl-1H-imidazole (compound 5.5) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 385 (M+H) ⁺ .

Compound 22 4-(1-(3-(2,4-Dimethyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 1, except for the use of 3-iodobenzoic acid instead of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3). m/z (ES+) 385 (M+H) ⁺ .

Compound 23.1. Methyl 3-hydroxypropanimidate hydrochloride. A solution of 3-hydroxypropanenitrile (2.00 g, 28.1 mmol) in ether (10 ml) and methanol (5 ml) was placed in a 50 ml three-necked round bottom flask. Gaseous HCl was introduced into the solution by blowing. The resulting solution was stirred for 2 hours at room temperature, then the resulting mixture was carefully concentrated under reduced pressure. The precipitate was washed with ether (2 x 20 ml) and the solids were collected by filtration to give 1.3 g (33%) of the title compound as a white solid.

Compound 23.2. 3-Hydroxypropanimidamide hydrochloride. A solution of methyl 3-hydroxypropanecarboximidate hydrochloride (compound 23.1, 2.00 g, 14.3 mmol) in methanol (5 ml) was placed in a 50 ml three-necked round bottom flask. The solution was cooled to 0° C. and ammonium (gas) was introduced over 20 minutes. The resulting solution was stirred for 2 hours at room temperature, then concentrated under reduced pressure. The precipitate was washed with petroleum ether (2 x 20 ml) and EtOAc (2 x 20 ml) and the solids were collected by filtration to give 1.6 g (imp.) of the title compound as a white solid.

Compound 23 4-(1-(3-(2-(2-Hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1, except for the use of 4-methyl-3-propionylbenzoic acid (compound 11.1) instead of 2,4-dimethyl-5-propionylbenzoic acid ( compound 1.4) and 3-hydroxypropanimidamide hydrochloride (compound 23.2) instead of acetimidamide hydrochloride. m/z (ES+) 429 (M+H) ⁺ .

Compound 24.1. 4-(1-(3-(2-(2-Chloroethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-(3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile ( compound 23, 75 mg, 0.18 mmol) in dichloromethane (5 ml). Thionyl chloride (25 μl, 0.35 mmol) was added and the resulting solution was stirred for 3 hours at room temperature. The solvents were carefully removed under reduced pressure to give 50 mg (impure) of the title compound as a yellow solid.

Compound 24 4-(1-(3-(2-(2-(Dimethylamino)ethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-(3-(2-(2-chloroethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 24.1 , 26 mg, 0.06 mmol, 1.00 eq.) in EtOH (10 mL). Dimethylamine (1 M in THF, 0.3 ml, 0.3 mmol) was added and the mixture was sealed under a nitrogen balloon. The resulting solution was stirred overnight with a 100° C. oil bath. After cooling to room temperature, 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, XBridge Shield RP18 OBD, 5 µm, 19*150 mm; mobile phase, Water with 0.03% NH ₃ H ₂ O and CH ₃ CN (31% CH ₃ CN to 43% in 7 minutes, to 100% in 0.5 minutes, to 31% in 3.5 minutes); Detector, Waters 2489, 254 & 220 nm. Fractions containing pure compound were combined and lyophilized to give 6.3 mg (24%) of the title compound as a white solid. m/z (ES+) 456 (M+H) ⁺ .

Compound 25.1. 4-(1-(3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 1, except for the use of 4-fluorobenzoic acid instead of 2,4-dimethylbenzoic acid.

Compound 25 4-(1-(4-(Azetidin-1-yl)-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. A solution of 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile (compound 25.1, 200 mg, 0.50 mmol) in 1,4-dioxane (4 ml). Azetidine hydrochloride (50 mg, 0.53 mmol) and cesium carbonate (500 mg, 1.53 mmol) were added and the mixture was stirred for 48 hours at 120° C. behind a shock shield. The mixture was cooled and the solids were removed by filtration. The filtrate 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 OBD, 5 µm, 19*150 mm; mobile phase, water with 50 mmol NH ₄ HCO ₃ and CH ₃ CN (33.0% CH ₃ CN to 46.0% in 10 min, to 100.0% in 3 min, to 33.0% in 1 min) ; Detector, Waters 2489, 254 & 220 nm. Fractions containing pure compound were combined and lyophilized to give 59.6 mg (27%) of the title compound as a white solid. m/z (ES+) 440 (M+H) ⁺ .

Compound 26.1. 4-Methyl-3-(2-methyl-1H-imidazol-4-yl)benzoic acid. Methyl 4-methyl-3-(2-methyl-1H-imidazol-5-yl)benzoate (compound 7.1, 219 mg, 0.95 mmol) was dissolved in a mixture of methanol (20 ml) and aqueous sodium hydroxide (5 ml, 2 M). The resulting solution was heated at 50°C for 16 h, then the reaction mixture was cooled to room temperature, and the organic solvent was removed under reduced pressure. The resulting aqueous precipitate was acidified to pH 3-4 with aqueous HCl (2 M). The resulting solids were collected and dried to give 128 mg (62%) of the title compound as a white solid, m/z (ES-) 215 (MH) ^- .

Compound 26 4-(1-(4-Methyl-3-(2-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 4-methyl-3-(2-methyl-1H-imidazol-4-yl)benzoic acid (compound 26.1 , 65 mg, 0.30 mmol) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 74 mg, 0.33 mmol) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). 79 mg (68%) of the title compound were obtained as a white solid, m/z (ES+) 385 (M+H) ⁺ .

Compound 27.1. Methyl 3-acetyl-4-methylbenzoate. Into a 250 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a mixture of methyl 3-iodo-4-methylbenzoate (compound 5.3, 4.50 g, 16.3 mmol), 1-(vinyloxy)butane (4 .21 ml, 32.6 mmol), TEA (4.53 ml, 32.5 mmol), 1,3-bis(diphenylphosphino)propane (672 mg, 1.63 mmol) and Pd(OAc) ₂ (349 mg , 1.55 mmol) in DMSO (50 ml). The mixture was stirred for 12 hours at 120°C, then cooled to room temperature. The pH was adjusted to 1-2 with aqueous hydrogen chloride (2 M) and stirred for 1 hour. The aqueous phase was extracted with ethyl acetate (3×200 ml) and the combined organic layers were washed with water (100 ml) then brine (3×100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:50) as eluent to give 1.45 g (46%) of the title compound as a yellow solid.

Compound 27.2. Methyl 3-(2-bromoacetyl)-4-methylbenzoate. In a 50 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of methyl 3-acetyl-4-methylbenzoate (compound 27.1, 200 mg, 1.04 mmol) in chloroform (4 ml). Bromine (53 μl, 1.04 mmol) was added dropwise and the solution was stirred for 2 hours at room temperature, then concentrated under reduced pressure. 300 mg (impure) of the title compound was obtained as a brown solid.

Compound 27.3. Methyl 3-(2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate. Into a 50 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of methyl 3-(2-bromoacetyl)-4-methylbenzoate (compound 27.2, 281 mg, 1.04 mmol) in ACN (5 ml). 2-methoxyacetimidamide (compound 4.7, 194 mg, 1.56 mmol) and potassium carbonate (434 mg, 3.14 mmol) were added and the resulting mixture was stirred for 12 hours at 80° C., then concentrated under reduced pressure. The precipitate was diluted with water (50 ml) and was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (3×50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) as eluent to give 50 mg (19%) of the title compound as a brown solid.

Compound 27.4. Methyl 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate. In a 50 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of methyl 3-(2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.3, 40 mg, 0. 15 mmol) and NCS (24.6 mg, 0.18 mmol) in CCl ₄ (20 ml). The resulting mixture was stirred for 2 h at 50° C., then cooled to room temperature and quenched with water (100 ml). The aqueous phase was extracted with ethyl acetate (100 ml) and the combined organic layers were washed with brine (3×30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 30 mg (imp.) of the title compound , as a yellow solid.

Compound 27.5. 3-(4-Chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid. Methyl 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.4, 50 mg , 0.19 mmol) and sodium hydroxide (31 mg, 0.76 mmol) in methanol/water (3 ml/3 ml). The resulting solution was stirred for 12 hours at room temperature. The pH of the solution was adjusted to 1-2 with hydrogen chloride (6 M), then concentrated under reduced pressure to give 150 mg (impure) of the title compound as the HCl salt as a white solid.

Compound 27 4-(1-(3-(4-Chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. In a 50 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5, 20 mg , 0.07 mmol) in N,N-dimethylformamide (3 ml). 4-dimethylaminopyridine (17.4 mg, 0.14 mmol), EDC⋅HCl (27 mg, 0.14 mmol), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 15.5 mg, 0 .07 mmol, 1.00 eq.), and the resulting solution was stirred for 12 hours at room temperature. The reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.05% TFA and CH ₃ CN (35% CH ₃ CN to 50% in 7 minutes, to 100% in 3 minutes, to 35% in 1 minute); Detector, Waters 2489, 254&220 nm. Fractions containing pure compound were combined and lyophilized to give 15 mg (47%) of the title compound as a white solid, m/z (ES+) 449 (M+H) ⁺ .

Compound 28.1. 3-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid. A solution of methyl 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.4, 380 mg, 1.29 mmol, 1.00 eq.) in HBr (40% in AcOH) (10 ml). The solution was stirred overnight at 80°C, then cooled and concentrated under reduced pressure. The crude precipitate was purified by preparative HPLC (Water with 0.05% TFA and CH ₃ CN (0% CH ₃ CN in 3 min, then to 100% in 5 min, to 0% in 1 min); Detector, 254&220 nm. Fractions containing pure product were combined and lyophilized to give 171 mg (50%) of the title compound as a crude yellow oil.

Compound 28 4-(1-(3-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 27, except for the use of 3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4- methylbenzoic acid (compound 28.1) instead of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5) and 4-(azetidin-3-yl)benzonitrile hydrochloride ( compound 5.2) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 407 (M+H) ⁺ .

Compound 29 4-(1-(3-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 27, except for the use of 3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4- methylbenzoic acid (compound 28.1) instead of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5). m/z (ES+) 435 (M+H) ⁺ .

Compound 30 4-(1-(3-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 27, except for the use of 3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4- methylbenzoic acid (compound 28.1) instead of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5) and 4-(3-fluoroazetidin-3-yl) hydrochloride benzonitrile (compound 43.4) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 425 (M+H) ⁺ .

Compound 31.1. Methyl 5-iodine-2,4-dimethylbenzoate. A solution of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3, 10.0 g, 32.6 mmol, 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 ethyl acetate (200 ml). The resulting mixture was washed with water (3 x 50 ml), sodium bicarbonate (aq. sat., 2 x 50 ml, caution: gas evolution), then brine (2 x 50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 9.2 g (88%) of the title compound as a yellow oil.

Compound 31 4-(1-(5-(4-Chloro-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 27, except for the use of methyl 5-iodo-2,4-dimethylbenzoate (compound 31.1) instead of methyl-3-iodo-4- methyl benzoate (compound 5.3), acetimidamide hydrochloride instead of 2-methoxyacetimidamide (compound 4.7) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 405 (M+H) ⁺ .

Compound 32 4-(1-(5-(4-Chloro-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 27, except for the use of methyl 5-iodo-2,4-dimethylbenzoate (compound 31.1) instead of methyl-3-iodo-4- methyl benzoate (compound 5.3) and acetimidamide hydrochloride instead of 2-methoxyacetimidamide (compound 4.7). m/z (ES+) 433 (M+H) ⁺ .

Compound 33 4-(1-(3-(4-Chloro-2-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 27, except for the use of methyl 3-iodobenzoate instead of methyl 3-iodo-4-methylbenzoate (compound 5.3) and acetimidamide hydrochloride instead of 2 -methoxyacetimidamide (compound 4.7). m/z (ES+) 405 (M+H) ⁺ .

Compound 34 4-(1-(3-(4-Chloro-2-methyl-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 27, except for the use of methyl 3-iodobenzoate instead of methyl 3-iodo-4-methylbenzoate (compound 5.3), acetimidamide hydrochloride instead of 2 -methoxyacetimidamide (compound 4.7) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 377 (M+H) ⁺ .

Compound 35 The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 3-(4-chlorophenyl)pyrrolidine instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) . m/z (ES+) 394 (M+H) ⁺ .

Compound 36.1. tert-Butyl-4-([1,2,4]triazolo[4,3- a ]pyridin-6-yl)piperidine-1-carboxylate. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1.1, except for the use of 6-bromo-[1,2,4]triazolo[4,3- a ]pyridine instead of 4-bromobenzonitrile . m/z (ES+) 303 (M+H) ⁺ .

Compound 36.2. 6-(Piperidin-4-yl)-[1,2,4]triazolo[4,3- a ]pyridine. To a solution of tert-butyl 4-([1,2,4]triazolo[4,3- a ]pyridin-6-yl)piperidine-1-carboxylate (compound 36.1, 0.05 g, 0.165 mmol) in dichloromethane ( 2 ml) TFA (0.2 ml) was added. The mixture was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure. The precipitate was purified by preparative TLC (10% MeOH in dichloromethane + ~0.5% NH ₄ OH) to give 0.25 g (76%) of the title compound as a light brown oil, m/z (ES+ ) 203 (M+H) ⁺ .

Compound 36 yl)-4-methylphenyl)methanone. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 6-(piperidin-4-yl)-[1,2,4]triazolo[4,3- a ]pyridine (compound 36.2) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 415 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 9.12 (d, J=0.8 Hz, 1H), 8.41 (d, J=1.4 Hz, 1H), 7.73 (dt, J=9.6, 1.0, 1.0 Hz, 1H), 7.53 (dd, J=9.5, 1.6 Hz, 1H), 7.47-7.37 (m, 2H) , 7.33 (d, J=1.7 Hz, 1H), 4.84 (m, 1H), 4.00 (m, 1H), 3.00 (m, 2H), 2.42 (s, 3H), 2.32 (s, 3H), 2.14 (s, 3H), 2.10 (m, 1H), 1.96 (m, 1H), 1.77 (m, 3H).

Compound 37 4-(1-(3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-) hydrochloride. yl)benzonitrile (compound 5.2). m/z (ES+) 399 (M+H) ⁺ . ¹ H NMR (400 MHz, Methanol-d4) δ 7.65 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 1H), 7.34 (dd, J=7.20, 2.0 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H) 4.84-4 .71 (m, 1H), 4.02-3.89 (m, 1H), 3.03-2.91 (m, 2H), 2.36 (s, 3H), 2.29 (s, 3H ), 2.09 (s, 3H), 2.00-1.64 (m, 5H).

Compound 38 methanone. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 7-(piperidin-4-yl)imidazo[1,5- a ]pyridine hydrochloride (compound 39.5) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 399 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.25 (s, 1H), 8.18 (d, J=7.6 Hz, 1H), 7.43-7.34 (m, 3H), 7.31-7.27 (m, 2H), 6.68 (dd, J=7.6, 1.6 Hz, 1H), 4.85-4.76 (m, 1H), 4.04- 3.93 (m, 1H), 3.05-2.80 (m, 2H), 2.37 (s, 3H), 2.31 (s, 3H), 2.11 (s, 3H), 1 .95-1.58 (m, 5H).

Compound 39.1. (4-Bromopyridin-2-yl)methanamine. A solution of 4-bromopyridine-2-carbonitrile (10 g, 95%, 51.9 mmol; US Pat. No. 20090239876 A1, Example 2) in tetrahydrofuran (220 ml) was placed in a 1 L round bottom flask, followed by the addition of BH ₃ - THF (1 M) (330 ml) with stirring at room temperature. The resulting solution was stirred overnight at room temperature, then carefully quenched with formic acid (100 ml). The mixture was concentrated under reduced pressure to give the title compound as formic acid salt which was present as a light yellow solid and was used in the next step without further purification (8 g, imp.).

Compound 39.2. N-((4-Bromopyridin-2-yl)methyl)formamide. In a 500 ml round bottom flask were placed (4-bromopyridin-2-yl)methanamine (compound 39.1, 8.0 g, imp.) and formic acid (200 ml). The solution was stirred for 2 hours at 100° C., then cooled and the pH was adjusted to 7 by careful and slow addition of aqueous sodium carbonate (sat.). The aqueous phase was extracted with ethyl acetate (3×200 ml) and the combined organic layers were washed with brine (3×30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate as eluent to give the title compound as a yellow oil (8.0 g, 90% pure, 65% yield over 2 steps).

Compound 39.3. 7-bromimidazo[1,5- a ]pyridine. In a 100 ml round bottom flask was placed a solution of N-((4-bromopyridin-2-yl)methyl)formamide (compound 39.2, 3.0 g, 90%, 12.6 mmol) in dichloromethane (20 ml). The solution was cooled to 0-5° C., then trifluoroacetic anhydride (1.93 ml, 13.9 mmol) was added dropwise. The resulting solution was stirred for 1 hour at room temperature, then the pH was adjusted to 7 by careful and slow addition of aqueous sodium carbonate (sat.). The aqueous phase was extracted with dichloromethane (3×20 ml) and the combined organic layers were washed with brine (3×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/1) as eluent to give the title compound as a brown solid (1.0 g, 40%).

Compound 39.4. tert-Butyl 4-(imidazo[1,5- a ]pyridin-7-yl)piperidine-1-carboxylate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 1.1, except for the use of 7-bromoimidazo[1,5- a ]pyridine (compound 39.3) instead of 4-bromobenzonitrile.

Compound 39.5. 7-(Piperidin-4-yl)imidazo[1,5- a ]pyridine hydrochloride.

The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1.2, except for the use of tert-butyl-4-(imidazo[1,5- a ]pyridin-7-yl)piperidin-1 -carboxylate (compound 39.4) instead of tert-butyl-4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1).

Compound 39 2-Cyclobutyl-5-(4-(imidazo[1,5- a ]pyridin-7-yl)piperidine-1-carbonyl)-N,4-dimethylbenzamide. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 62, except for the use of 7-(piperidin-4-yl)imidazo[1,5- a ]pyridine hydrochloride (compound 39.5) instead of 5-(piperidin-4-yl)-1H-indazole (compound 62.5) to give the title compound as a white solid, m/z (ES+) 431 (M+H) ⁺ .

Compound 40.1. (E)-N'-((4-Bromopyridin-2-yl)methylene)-4-methylbenzenesulfonohydrazide. 4-Bromopicolinaldehyde (2.0 g, 10.8 mmol) and 4-methylbenzenesulfonohydrazide (2.0 g, 10.8 mmol) were mixed in MeOH (20 ml) and dichloromethane (20 ml). The mixture was stirred at room temperature for 1 hour. The solvents were removed under reduced pressure to give 3.80 g (theor.) of the title compound as a yellow solid, m/z ES+ 354, 356 (M+H) ⁺ .

Compound 40.2. 5-Bromo-[1,2,3]triazolo[1,5- a ]pyridine. A solution of (E)-N'-((4-bromopyridin-2-yl)methylene)-4-methylbenzenesulfonohydrazide (compound 40.1, 3.8 g, 10.7 mmol) in morpholine (12 ml) was heated at 130°C in within 3 hours. The reaction mixture was cooled to room temperature, then diluted with EtOAc (150 ml) and washed with water (2×30 ml). The organic layer was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 4:1) to give 2.10 g (99%) of the title compound as a light yellow solid, m/z (ES+) 198.200 ( M+H) ⁺ .

Compound 40.3. tert-Butyl-4-([1,2,3]triazolo[1,5- a ]pyridin-5-yl)piperidine-1-carboxylate. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1.1, except for the use of tert-butyl-4-([1,2,3]triazolo[1,5- a ]pyridine- 5-yl)piperidine-1-carboxylate (compound 40.2) instead of 4-bromobenzonitrile. m/z (ES+) 303 (M+H) ⁺ .

Compound 40.4. 5-(Piperidin-4-yl)-[1,2,3]triazolo[1,5- a ]pyridine. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 36.2, except for the use of tert-butyl-4-([1,2,3]triazolo[1,5- a ]pyridine- 5-yl)piperidine-1-carboxylate (compound 40.3) instead of tert-butyl-4-([1,2,4]triazolo[4,3- a ]pyridin-6-yl)piperidine-1-carboxylate (compound 36.1 ). m/z (ES+) 203 (M+H) ⁺ .

Compound 40 yl)-4-methylphenyl)methanone. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 5-(piperidin-4-yl)-[1,2,3]triazolo[1,5- a ]pyridine (compound 40.4) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 415 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.84 (d, J=7.2 Hz, 1H), 8.07 (d, J=0.8 Hz, 1H), 7.77 (t, J=0.8, 0.8 Hz, 1H), 7.44-7.34 (m, 2H), 7.32 (d, J=1.6 Hz, 1H), 7.18 (dd, J = 7.6, 2.0 Hz, 1H), 4.87-4.76 (m, 1H), 4.08-3.92 (m, 1H), 3.11-2.95 (m, 2H ), 2.37 (s, 3H), 2.31 (s, 3H), 2.11 (s, 3H), 2.00-1.67 (m, 5H).

Compound 41.1. 4-Bromo-2-hydrazinylpyridine. Hydrazine (5 ml, 159 mmol) was added to a solution of 4-bromo-2-fluoropyridine (2.0 g, 11.4 mmol) in pyridine (10 ml). The mixture was heated at 70°C for 2 hours, then cooled to room temperature. The volatile organics were removed under reduced pressure, then water (60 ml) was added to the precipitate and an off-white solid precipitated. The solid was filtered, washed with water, and dried under reduced pressure at 50° C. to give 1.77 g (84%) of the title compound as an off-white solid, m/z (ES+) 188, 190 ( M+H) ⁺ .

Compound 41.2. 7-Bromo-[1,2,4]triazolo[4,3- a ]pyridine. 4-Bromo-2-hydrazinylpyridine (compound 41.1) was suspended in formic acid (3 ml). The mixture was heated at 100°C for 1 hour, then after completion of the reaction, the mixture was cooled to room temperature. Volatile organic substances were removed under reduced pressure, then water (50 ml) was added to the precipitate. The resulting solids were filtered, washed with water and dried under reduced pressure at 50° C. to give 1.68 g (90%) of the title compound as an off-white solid, m/z (ES+) 198.200 ( M+H) ⁺ .

Compound 41.3. tert-Butyl-4-([1,2,4]triazolo[4,3- a ]pyridin-7-yl)piperidine-1-carboxylate. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1.1, except for the use of 7-bromo-[1,2,4]triazolo[4,3- a ]pyridine (compound 41.2) instead of 4-bromobenzonitrile. m/z (ES+) 303 (M+H) ⁺ .

Compound 41.4. 7-(Piperidin-4-yl)-[1,2,4]triazolo[4,3- a ]pyridine. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 36.2, except for the use of tert-butyl-4-([1,2,4]triazolo[4,3- a ]pyridine- 7-yl)piperidine-1-carboxylate (compound 41.3) instead of tert-butyl-4-([1,2,4]triazolo[4,3- a ]pyridin-6-yl)piperidine-1-carboxylate (compound 36.1 ) m/z (ES+) 203 (M+H) ⁺ .

Compound 41 yl)-4-methylphenyl)methanone. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 7-(piperidin-4-yl)-[1,2,4]triazolo[4,3- a ]pyridine (compound 41.4) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 415 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 9.13 (s, 1H), 8.45 (d, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.44- 7.36 (m, 2H), 7.33 (d, J=1.6 Hz, 1H), 7.07 (dd, J=7.2, 1.6 Hz, 1H), 4.87-4 .78 (m, 1H), 4.08-3.96 (m, 1H), 3.11-2.95 (m, 2H), 2.40 (s, 3H), 2.32 (s, 3H ), 2.13 (s, 3H), 2.10-1.73 (m, 5H).

Compound 42.1. tert-Butyl-4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate. Into a 1 L three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 1-chloro-4-iodobenzene (10.0 g, 41.9 mmol) in tetrahydrofuran (150 mL). The solution was cooled to -78°C, then n-BuLi (2.4 M) (16.6 ml, 39.8 mmol) was added dropwise and the resulting mixture was stirred for 0.5 h at -78°C. A solution of tert-butyl-4-oxo-piperidine-1-carboxylate (7.60 g, 38.1 mmol) in tetrahydrofuran (50 ml) was added dropwise and the resulting mixture was stirred for 1 h at -78°C. Then the reaction mixture was heated to 0°C, and carefully extinguished by the slow addition of water (150 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (150 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:50 to 1:3) to give the title compound as a light yellow solid (9.3 g, 78%).

Compound 42.2. tert-Butyl-4-(4-chlorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate. In a 250 ml round bottom flask was placed a solution of tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (compound 42.1, 9.00 g, 28.9 mmol) in pyridine (50 ml). Phosphoryl chloride (7.93 ml, 84.8 mmol) was added dropwise with stirring. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The precipitate was diluted with ethyl acetate (20 ml) and carefully quenched by slow addition of aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with aqueous sodium bicarbonate (2×30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100 to 1:10) to give the title compound as a colorless oil (6.1 g, 72%).

Compound 42.3. tert-Butyl-4-(4-chlorophenyl)piperidine-1-carboxylate. A mixture of Pt ₂ O (200 mg) and methanol (50 ml) was placed in a 250 ml round bottom flask. The mixture was purged with nitrogen, then hydrogen was introduced and the mixture was stirred for 15 minutes. A solution of tert-butyl 4-(4-chlorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (compound 42.2, 6.00 g, 20.4 mmol) in methanol (50 ml) was added and the resulting mixture stirred under hydrogen atmosphere overnight at room temperature. After purging with nitrogen, the solids were filtered off and the resulting solution was concentrated in vacuo to give the title compound as a light green oil (5.30 g, 88%).

Compound 42.4. 4-(4-Chlorophenyl)piperidine. A solution of tert-butyl 4-(4-chlorophenyl)piperidine-1-carboxylate (compound 42.3, 5.00 g, 16.9 mmol) in dichloromethane (100 ml), trifluoroacetic acid (9, 6 g, 84 mmol). The resulting solution was stirred overnight at room temperature and then concentrated under reduced pressure. The precipitate was carefully diluted with ethyl acetate (100 ml) and aqueous sodium bicarbonate was added until pH 8 was reached. The resulting mixture was washed with brine (100 ml) and the organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to obtain the compound, indicated in the title, in the form of a light yellow solid (2.30 g, 70%).

Compound 43.1. tert-Butyl-3-(4-bromophenyl)-3-hydroxyazetidine-1-carboxylate. Into a 1 L three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 1-bromo-4-iodobenzene (25.0 g, 88.4 mmol) in tetrahydrofuran/diethyl ether (400/200 mL). The solution was cooled to -78°C, then n-BuLi (2.5 M, 37.1 ml, 92.8 mmol) was added dropwise over 10 min. To the resulting mixture was added tert-butyl-3-oxoazetidine-1-carboxylate (16.6 g, 97.0 mmol) in THF (100 ml) dropwise at -78°C. The resulting mixture was stirred for 1.5 h at -78°C, then carefully quenched with water (300 ml). The aqueous phase was extracted with ethyl acetate (200 ml) and the combined organic layers were washed with brine (2×100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20-1:5) as eluent, followed by recrystallization from ethyl acetate:PE 1:100 to give 8.0 g (28%) of the title compound. in the title, as a white solid.

Compound 43.2. tert-Butyl-3-(4-cyanophenyl)-3-hydroxyazetidine-1-carboxylate. In a 500 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a mixture of tert-butyl 3-(4-bromophenyl)-3-hydroxyazetidine-1-carboxylate (compound 43.1, 16.3 g, 49.7 mmol ) in N,N-dimethylformamide (250 ml), zinc cyanide (8.7 g, 75 mmol) and Pd(PPh ₃ ) ₄ (5.77 g, 5.00 mmol). The resulting mixture was stirred for 15 h at 100°C, then cooled to room temperature. The reaction mixture was quenched with saturated aqueous FeSO ₄ (500 ml) and thoroughly mixed. The mixture was filtered through Celite® and layers were separated from the filtrate. The aqueous phase was extracted with ethyl acetate (300 ml) and the combined organic layers were washed with brine (2×100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/100-1/3) as eluent to give 14 g (imp.) of the title compound as a white solid.

Compound 43.3. tert-Butyl-3-(4-cyanophenyl)-3-fluoroazetidine-1-carboxylate. In a 250 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of tert-butyl 3-(4-cyanophenyl)-3-hydroxyazetidine-1-carboxylate (compound 43.2, 5.00 g, 18.2 mmol) in dichloromethane (120 ml). The solution was cooled to -78° C. and Deoxofluoro® (bim(2-methoxyethyl)aminosulfur trifluoride) (5.99 g, 27.1 mmol) was added dropwise. The resulting mixture was stirred for 1.5 h at -78°C, then carefully extinguished with sodium bicarbonate (50 ml, 1 M). The organic layer was further washed with brine (2×50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50-1/30) as eluent to give 3.2 g (64%) of the title compound as a colorless oil.

Compound 43.4. 4-(3-Fluoroazetidin-3-yl)benzonitrile hydrochloride. A solution of tert-butyl 3-(4-cyanophenyl)-3-fluoroazetidine-1-carboxylate (compound 43.3, 1.00 g, 3.62 mmol) in dioxane (10 ml) and HCl in dioxane (4 M in dioxane, 10 ml, 40 mmol). The resulting mixture was stirred for 1 hour at 60°C, then cooled and concentrated under reduced pressure. The precipitate was washed with EtOAc (20 ml) and the resulting solids were collected by filtration to give 522 mg (68%) of the title compound as a white solid, m/z (ES+) 177 (M+H) ⁺ . ¹ H NMR (300 MHz, CD3OD): δ 7.91 (d, J=7.8 Hz, 2H), 7.82 (d, J=8.1 Hz, 2H), 4.85-4.52 (m, 4H).

Compound 44.1. 2-Cyclopropyl-1H-imidazole. A solution of cyclopropanecarbaldehyde (500 mg, 7.13 mmol), oxaldehyde (455 mg, 7.84 mmol) in methanol (5 ml) was placed in a 25 ml round bottom flask. The solution was cooled to 0°C, then 25% ammonium hydroxide (1 ml) was added dropwise. The resulting solution was stirred for 3 hours at 0° C., then stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in brine (50 ml). The aqueous phase was extracted with ethyl acetate (3×10 ml) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 600 mg (78%) of the title compound as a light brown solid. .

Compound 44.2. 2-Cyclopropyl-4,5-diiodo-1H-imidazole. In a 100 ml round bottom flask was placed a solution of 2-cyclopropyl-1H-imidazole (compound 44.1, 1.8 g, 16.6 mmol) in sodium hydroxide (2 M, 40 ml). A solution of iodine (8.5 g, 33.5 mmol) in dichloromethane (40 ml) was added dropwise and the resulting mixture was stirred overnight at room temperature. The aqueous layer was separated and neutralized with acetic acid, and quenched by adding Na ₂ S ₂ O ₃ (sat. aq.). The solids were collected by filtration to give 3.8 g (63%) of the title compound as a brown solid.

Compound 44.3. 2-Cyclopropyl-4-iodo-1H-imidazole. A 100 ml round bottom flask was charged with a solution of sodium sulfite (11.3 g, 89.7 mmol) in H ₂ O/EtOH (30/15 ml). 2-Cyclopropyl-4,5-diiodo-1H-imidazole (compound 44.2, 3.8 g, 10.6 mmol) was added and the resulting solution was refluxed overnight. The reaction mixture was cooled and the volatiles removed under reduced pressure. The solids were collected by filtration to give 1.8 g (73%) of the title compound as a light brown solid.

Compound 45.1. 5-iodine-2-isopropyl-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 44.3, except for the use of 2-isopropyl-1H-imidazole instead of 2-cyclopropyl-1H-imidazole (compound 44.1).

The compounds listed in Table 1 were prepared using standard chemistry and procedures using readily available starting materials or starting reagents described herein. The procedures used were similar to those used to prepare compound 7 using the appropriate imidazoles (2-methyl-4-bromoimidazole, compound 44.3 or compound 45.1) and the corresponding amines (compound 1.2, compound 13.4, compound 42.4, compound 5.2 or compound 43.4).

Compound 50.1. Methyl 4-chloro-3-iodobenzoate. 4-Chloro-3-iodobenzoic acid (5.31 g, 18.8 mmol) was dissolved in methanol (50 ml) and concentrated sulfuric acid (3 ml) was added carefully. The solution was stirred at 80°C for 4 hours, then cooled to room temperature, and volatile organic substances were removed under reduced pressure. The precipitate was partitioned between EtOAc (50 ml) and water (50 ml) and the organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ ; 0-10% EtOAc in hexanes) to give 5.32 g (95%) of the title compound as an oil. ¹ H NMR (400 MHz, chloroform-d) δ 8.54 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.4, 2.0 Hz, 1H), 7, 53 (d, J=8.4 Hz, 1H), 3.94 (s, 3H).

Compound 50.2. Methyl 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. Mixture of methyl 4-chloro-3-iodo-benzoate (compound 50.1, 3.85 g, 13.0 mmol), bis(pinacolato)diboron (3.96 g, 15.6 mmol), Pd(dppf)Cl ₂ ⋅DHM (531 mg, 0.65 mmol) and potassium acetate (3.83 g, 39.0 mmol) in DMSO (40 ml) were degassed with argon and then heated to 80°C for 18 hours. The reaction mixture was cooled, then diluted with ethyl acetate (200 ml) and washed successively with water, aq. HCl (1 M), saturated aq. NaHCO ₃ and brine, then dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ ; 0-10% EtOAc in hexanes) to give 1.92 g (49%) of the title compound as a white solid. ¹ H NMR (400 MHz, chloroform-d) δ 8.36 (d, J=2.3 Hz, 1H), 8.01 (dd, J=8.4, 2.3 Hz, 1H), 7, 44 (d, J=8.4 Hz, 1H), 3.94 (s, 3H), 1.40 (s, 12H).

Compound 50.3. Methyl 4-chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoate. To methyl 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 50.2, 600 mg, 2.02 mmol) in dioxane (20 ml ) 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5, 538 mg, 2.42 mmol) and Pd(dppf)Cl ₂ ⋅DCM (165 mg, 0.20 mmol) were added. The mixture was degassed with argon and stirred for 10 minutes at room temperature, then an aqueous solution of potassium carbonate (1 M, 10 ml) was added and the mixture was stirred at 90°C for 18 hours. The mixture was cooled and diluted with EtOAc, then filtered through Celite ( Celite®). The filtrate was washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by flash chromatography (SiO ₂ ; 0-100% EtOAc in hexanes) to give 270 mg (50%) of the title compound as a foam, m/z (ES+) 265 (M+H) ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 8.07 (d, J=2.2 Hz, 1H), 7.90 (dd, J=8.4, 2.2 Hz, 1H), 7, 50 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H).

Compound 50.4. 4-Chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoic acid. Methyl 4-chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoate (compound 50.3, 270 mg, 1.02 mmol) was dissolved in methanol (20 ml) and aqueous NaOH (2 M, 6 ml), then heated to 50° C. for 16 hours. Volatile solvents were removed under reduced pressure and the resulting aqueous phase was acidified to pH 5-6 with aqueous HCl (2 M). The precipitated solids were filtered and dried to give 230 mg (94%) of the title compound as a white solid, m/z (ES-) 249 (M-H) ^- .

Compound 50 4-(1-(4-Chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained as a white solid (77 mg, 54%) using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 4-chloro-3-(2,4-dimethyl -1H-imidazol-5-yl)benzoic acid (compound 50.4, 85 mg, 0.34 mmol) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 419 (M+H) ⁺ .

Compound 51.1. Methyl 4-methyl-3-(1H-pyrazol-5-yl)benzoate. To methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 800 mg, 2.9 mmol) in dioxane (30 ml ) 5-iodo-1H-pyrazole (674 mg, 3.5 mmol) and Pd(dppf)Cl ₂ ⋅DCM (237 mg, 0.29 mmol) were added. The mixture was degassed with argon and stirred for 10 minutes, then an aqueous solution of potassium carbonate (2 M, 8 ml) was added. The mixture was heated at 90°C for 18 h, then cooled and diluted with EtOAc and filtered through Celite (Celite®). The filtrate was washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by flash chromatography (SiO ₂ ; 0-30% EtOAc in hexanes) to give 258 mg (41%) of the title compound as a solid, m/z (ES+) 217 (M+H) ⁺ .

Compound 51.2. Methyl 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoate. Methyl 4-methyl-3-(1H-pyrazol-5-yl)benzoate (compound 51.1, 385 mg, 1.78 mmol) was dissolved in 1,2-dichloroethane (60 ml), then N-chlorosuccinimide (250 mg , 1.87 mmol). The mixture was stirred at room temperature for 16 hours, then washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by flash chromatography (SiO ₂ ; 0-20% EtOAc in hexanes) to give 152 mg (34%) of the title compound as an oil. m/z (ES+) 251 (M+H) ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 8.07-7.94 (m, 2H), 7.63 (d, J=0.7 Hz, 1H), 7.47-7.34 (m , 1H), 3.93 (s, 3H), 2.36 (s, 3H).

Compound 51.3. 3-(4-Chloro-1H-pyrazol-5-yl)-4-methylbenzoic acid. Methyl 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoate (compound 51.2, 133 mg, 0.53 mmol) was dissolved in a mixture of aqueous NaOH (2 M, 3 ml) and methanol (10 ml ). The solution was heated at 50°C for 16 h, then the volatiles were removed under reduced pressure. Added aqueous HCl (2 M) to adjust the pH to 4-5, then concentrated to obtain 150 mg of white matter, which was used in the next stage without further purification, m/z (ES-) 235 (M-H) ^- .

Compound 51 4-(1-(3-(4-Chloro-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained as a white solid (69 mg, 34% over 2 steps) using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 3-(4-chloro-1H- pyrazol-5-yl)-4-methylbenzoic acid (compound 51.3, ~0.53 mmol) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 377 (M+H) ⁺ .

Compound 52 4-(1-(3-(4-Chloro-1H-pyrazol-5-yl)-4-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 51.3) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 13.4) instead of 4-( azetidin-3-yl)benzonitrile (compound 5.2). m/z (ES+) 423 (M+H) ⁺ .

Compound 53 4-(1-(3-(4-Chloro-1H-pyrazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 51.3) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidine- 3-yl)benzonitrile (compound 5.2). m/z (ES+) 405 (M+H) ⁺ .

Compound 54 4-(1-(3-(4-Chloro-3-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used for compound 51 and compound 5, except for the use of 3-bromo-5-methyl-1H-pyrazole instead of 5-iodo-1H-pyrazole. m/z (ES+) 391 (M+H) ⁺ . ¹ H NMR (300 MHz, methanol-d4): δ 7.77-7.69 (m, 3H), 7.64-7.59 (m, 3H), 7.46 (d, J=8.1 Hz, 1H), 4.84 (m, 1H), 4.64 (m, 1H), 4.48 (m, 1H), 4.23 (m, 1H), 4.09 (m, 1H), 2.34 (s, 3H), 2.33 (s, 3H).

Compound 55 4-(1-(3-(4-Chloro-3-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used for compound 51 and compound 5, except for the use of 3-bromo-5-methyl-1H-pyrazole instead of 5-iodo-1H-pyrazole and hydrochloride 4-(3-fluoroazetidin-3-yl)benzonitrile (compound 43.4) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 409 (M+H) ⁺ .

The compounds listed in Table 2 were prepared using standard chemistry and procedures similar to those used to prepare compounds 51, 52, 53, 54 and 55.

Compound 56.1. 5-Iodine-4-methyl-1H-pyrazole. To a solution of 4-methyl-1H-pyrazole (2.15 g, 26.1 mmol) dissolved in DMF (20 ml) was added N-iodosuccinimide (6.19 g, 26.1 mmol). The mixture was stirred at RT for 16 hours and then diluted with water and filtered. The filtrate was extracted with EtOAc (2×50 ml), then the combined organic extracts were washed with saline, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by flash chromatography (SiO ₂ ; 0-50% EtOAc in hexanes) to give 2.19 g (41%) of the title compound as a white solid, m/z (ES+) 209 (M +H) ⁺ .

Compound 56 4-(1-(4-Methyl-3-(4-methyl-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-iodo-4-methyl-1H-pyrazole (compound 56.1) instead of 5-iodo-2,4- dimethyl-1H-imidazole (compound 5.5) to give the title compound as a white solid, m/z (ES+) 357 (M+H) ⁺ .

Compound 57 4-(1-(4-Methyl-3-(4-methyl-1H-pyrazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-iodo-4-methyl-1H-pyrazole (compound 56.1) instead of 5-iodo-2,4- dimethyl-1H-imidazole (compound 5.5) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 385 (M+H) ⁺ .

Compound 58 4-(3-Fluoro-1-(4-methyl-3-(4-methyl-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-iodo-4-methyl-1H-pyrazole (compound 56.1) instead of 5-iodo-2,4- dimethyl-1H-imidazole (compound 5.5) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 375 (M+H) ⁺ .

The compounds listed in Table 3 were prepared using standard chemistry and procedures similar to those used to prepare compounds 51, 56, 57 and 58.

Compound 59.1. 5-Iodine-3,4-dimethyl-1H-pyrazole. NIS (5.62 g, 24.9 mmol) was added portionwise to a solution of 3,4-dimethyl-1H-pyrazole (2.0 g, 20.8 mmol) in CH ₃ CN (50 ml). The mixture was heated at 80° C. for 16 hours, after which dense off-white solids formed. The mixture was cooled to room temperature and the solids were filtered, washed with cold CH ₃ CN and dried under reduced pressure to give 4.32 g (94%) of the title compound as an off-white solid, m/z (ES+ ) 223 (M+H) ⁺ .

Compound 59.2. Methyl 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoate. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5.6, except for the use of 5-iodo-3,4-dimethyl-1H-pyrazole (compound 59.1) instead of 5-iodo-2, 4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 245 (M+H) ⁺ .

Compound 59.3. 3-(3,4-Dimethyl-1H-pyrazol-5-yl)-4-methylbenzoic acid. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of methyl 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoate ( compound 59.2) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 231 (M+H) ⁺ .

Compound 59 4-(1-(3-(3,4-Dimethyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 59.3) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 371 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 12.43-12.17 (br, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.63 (d, J=8 .4 Hz, 2H), 7.60 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 4.71(m, 1H), 4.54-4.35(m, 2H), 4.09-4.00(m, 2H), 2.24(s , 3H), 2.17 (s, 3H), 1.83 (s, 3H).

Compound 60 4-(1-(3-(3,4-Dimethyl-1H-pyrazol-5-yl)-4-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 59.3) and 4-(3-fluoroazetidin-3-yl)benzonitrile (compound 43.4) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and hydrochloride 4- (azetidin-3-yl)benzonitrile (compound 5.2), respectively, m/z (ES+) 389 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 12.45-12.26 (br, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.79 (d, J=8 .0 Hz, 2H), 7.65 (d, J=7.2 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.98-4.42 (m, 4H), 2.25 (s, 3H), 2.17 (s, 3H), 1.83 (s, 3H).

Compound 61 4-(1-(4-Methyl-3-(5-methyl-1H-pyrazol-4-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 4-bromo-5-methyl-1H-pyrazole instead of 5-iodo-2,4-dimethyl-1H- imidazole (compound 5.5) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 385 (M+H) ⁺ .

Compound 62.1. 4-Cyclobutyl-5-iodo-2-methylbenzoic acid. Aqueous sodium hydroxide (12.7 g , 318 mmol in 100 ml of water). The resulting mixture was stirred for 3 hours at 60°C, then cooled to air temperature, and volatile organic substances were removed under reduced pressure. The pH of the remaining aqueous substance was adjusted to ~4 with hydrogen chloride (aqueous, 2 M). The resulting solids were collected by filtration and dried in an oven under reduced pressure to give the title compound as a white solid (31.0 g, 93%).

Compound 62.2. 4-Cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid. A solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 62.1, 1.50 g, 4.74 mmol) in methanol (20 ml) was placed in a 50 ml high pressure autoclave. Pd(dppf)Cl ₂ (320 mg, 0.44 mmol) and triethylamine (1.27 ml, 9.09 mmol) were added and carbon monoxide (gas, 40 atm) was introduced. (Warning: highly toxic gas under high pressure. All necessary precautions have been taken). The resulting mixture was stirred overnight at 90°C, then cooled to room temperature. The mixture was carefully degassed, taking the necessary precautions, then the resulting mixture was concentrated under reduced pressure. The precipitate was dissolved in water (20 ml) and the pH of the solution was adjusted to 3-4 with aqueous HCl (1 M) and the resulting mixture was extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/2-1/1) as eluent to give the title compound as a white solid (1.0 g, 85%).

Compound 62.3. 4-Cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid. 4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid (compound 62.2, 1.0 g, 4.0 mmol) and methylamine (30% in ethanol) (8 ml) were placed in a 20 ml sealed tube. The resulting solution was stirred overnight at 120° C. behind a shock shield, then cooled and diluted with H ₂ O (20 ml). The pH of the solution was adjusted to 4-5 with hydrogen chloride (1M) and the solids were collected by filtration. The crude product was recrystallized from ethyl acetate/petroleum ether 1:10 to give the title compound as an off-white solid (500 mg, 50%).

Compound 62.4. tert-Butyl-4-(1H-indazol-5-yl)piperidine-1-carboxylate. Into a 50 ml three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a suspension of Zn (990 mg, 15.1 mmol) in DMA (1 ml). 7:5 v/v was added dropwise. mixture of TMSCl/1,2-dibromoethane (0.12 ml) at a rate sufficient to maintain the temperature below 65°C, then the mixture was stirred for another 10 minutes. A solution of tert-butyl 4-iodopiperidine-1-carboxylate (3.17 g, 10.2 mmol) in DMA (2 ml) was added dropwise and stirred at 40-45° C. for 30 minutes. The resulting mixture was added to a mixture of 5-bromo-1H-indazole (1.00 g, 5.08 mmol), CuI (80 mg, 0.42 mmol) and Pd(dppf)Cl ₂ (260 mg, 0.36 mmol) in DMA (1 ml) in a 50 ml round bottom flask under nitrogen. The resulting mixture was stirred overnight at 85°C, then cooled and diluted with ethyl acetate (50 ml) and washed with brine (3×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/5) as eluent to give the title compound as a yellow solid (200 mg, 12%).

Compound 62.5. 5-(Piperidin-4-yl)-1H-indazole. A solution of tert-butyl 4-(1H-indazol-5-yl)piperidine-1-carboxylate (compound 62.4, 200 mg, 0.60 mmol) in dichloromethane (3 ml) and trifluoroacetic acid ( 1 ml). The resulting solution was stirred for 1 hour at room temperature, then the pH of the solution was carefully adjusted to 8-9 with aqueous sodium bicarbonate (aq. sat.). The mixture was extracted with dichloromethane (3×30 ml) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow oil (100 mg, 75%).

Compound 62 5-(4-(1H-Indazol-5-yl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide. A solution of 5-(piperidin-4-yl)-1H-indazole (compound 62.5, 100 mg, 0.50 mmol) in N,N-dimethylformamide (3 ml) was placed in a 50 ml round bottom flask. Added EDC⋅HCl (192 mg, 1.00 mmol), 4-dimethylaminopyridine (122 mg, 1.00 mmol) and 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3.122 mg, 0 .49 mmol) and the resulting solution was stirred for 4 hours at room temperature. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×25 ml). The combined organic layers were washed with brine (2×15 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by silica gel column chromatography with ethyl acetate as eluent, followed by further purification by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD, 5 µm, 19 *150 mm; mobile phase, water with 0.05% TFA and CH ₃ CN (30% CH ₃ CN to 47% in 7 min, to 100% in 3 min, to 30% in 1 min); Detector, Waters 2489, 254&220 nm. Fractions containing the pure compound were combined and lyophilized to give the title compound as a white solid (71.2 mg, 33%). m/z (ES+) 431 (M+H) ⁺ .

Compound 63.1. 1-Bromo-3-(2,2-diethoxyethoxy)benzene. A solution of 3-bromophenol (50.00 g, 289.0 mmol) in N,N-dimethylformamide (1 L) was placed in a 3 L three-necked round bottom flask. The system was purged with nitrogen and the solution was cooled to 0° C., then sodium hydride (60%, 12.8 g, 320 mmol) was added portionwise. To the resulting mixture was added 2-bromo-1,1-diethoxyethane (53.1 ml, 345 mmol) dropwise at 0°C. The resulting mixture was stirred overnight at 120°C behind a shock shield (Warning: NaH and DMF can cause an uncontrolled reaction. All necessary precautions have been observed). The mixture was cooled to room temperature, then diluted with ethyl acetate (3 L). The mixture was washed with brine (4×500 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50-1/30) as eluent to give the title compound as a light yellow oil (78.9 g, 94%).

Compound 63.2 and Compound 63.3. 6-Bromo-3a,7a-dihydrobenzofuran and 4-bromo-3a,7a-dihydrobenzofuran. A mixture of 1-bromo-3-(2,2-diethoxyethoxy)benzene (compound 63.1, 62.9 g, 218 mmol) and polyphosphoric acid (157 g) in chlorobenzene (320 ml) was carefully placed in a 1 L round bottom flask. The mixture was stirred overnight at 90°C, then the mixture was cooled to room temperature and concentrated under reduced pressure. The precipitate was carefully and slowly diluted with water (200 ml) and extracted with EtOAc (3×200 ml). The organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:50-1:30) as eluent to give a mixture of title compounds as a brown oil (20 g, crude).

Compound 63.4 and Compound 63.5. tert-Butyl-4-(benzofuran-6-yl)piperidine-1-carboxylate and tert-butyl-4-(benzofuran-4-yl)piperidine-1-carboxylate. Into a 50 ml three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a suspension of Zn (1.13 g, 17.3 mmol) in DMA (5 ml). 7:5 v/v was added to the reaction flask. a mixture of TMSCl/1,2-dibromoethane (0.5 ml) dropwise to keep the temperature below 65°C, then the mixture was stirred for another 10 minutes. A solution of tert-butyl 4-iodopiperidine-1-carboxylate (5.40 g, 17.4 mmol) in DMA (40 ml) was added dropwise to this mixture with stirring, and the resulting mixture was stirred at room temperature for 1 hour. The above mixture was filtered and added to a mixture of 6-bromo-3a,7a-dihydrobenzofuran (compound 63.2) and 4-bromo-3a,7a-dihydrobenzofuran (compound 63.3) (2.83 g, 14.2 mmol) and CuI (274 mg , 1.44 mmol), Pd(dppf)Cl ₂ (1.18 g, 1.6 mmol) in DMA (30 ml). The resulting mixture was stirred overnight at 85°C, then cooled to room temperature. Solids were removed by filtration and the filtrate was diluted with ethyl acetate (200 ml) and washed with brine (3×80 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/30~1/20) as eluent to give t-butyl 4-(1-benzofuran-6-yl)piperidine-1-carboxylate (compound 63.4 ) as a colorless oil (267 mg, 6%) and tert-butyl 4-(1-benzofuran-4-yl)piperidine-1-carboxylate (compound 63.5) as an off-white solid (320 mg, 7% ).

Compound 63.6. 4-(Benzofuran-6-yl)piperidine. A solution of tert-butyl-4-(1-benzofuran-6-yl)piperidine-1-carboxylate (compound 63.4, 200 mg, 0.66 mmol) in dichloromethane (3 ml) and trifluoroacetic acid ( 1 ml). The resulting solution was stirred at 15°C for 1 hour, then the pH was carefully adjusted to ~9 with aqueous sodium hydroxide (2 M). The mixture was diluted with H ₂ O (20 ml) and the layers were separated. The aqueous phase was extracted with dichloromethane (4×20 ml) and the combined organic layers were washed with brine (30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a brown oil ( 150 mg, crude).

Compound 63 5-(4-(Benzofuran-6-yl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide. A solution of 4-(benzofuran-6-yl)piperidine (compound 63.6) (110 mg, 0.55 mmol), 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3 .135 mg, 0.55 mmol), EDC⋅HCl (210 mg, 1.10 mmol) and 4-dimethylaminopyridine (133.5 mg, 1.09 mmol) in N,N-dimethylformamide (3 mL). The resulting solution was stirred for 2 h at 15°C, then diluted with EtOAc (60 ml). The resulting mixture was washed with aqueous saturated NH ₄ Cl (2×20 ml) and brine (20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product (110 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.05% TFA and CH ₃ CN (51.0% CH ₃ CN to 60.0% in 9 min, to 100.0% in 5 min, to 51.0% in 1 min); Detector, Waters 2489, 254&220 nm. Fractions containing the pure compound were combined and lyophilized to give the title compound as a white solid (46.0 mg, 20%). m/z (ES+) 431 (M+H) ⁺ .

Compound 64.1. (Aminooxy)diphenylphosphine oxide. Into a 500 ml three neck round bottom flask was placed a solution of hydroxylamine hydrochloride (30.0 g, 432 mmol) in H ₂ O/dioxane (90/45 ml). The solution was cooled to 0-5°C, then sodium bicarbonate (36.5 g, 434 mmol) was added portionwise over 10 minutes and the mixture was stirred at 0-5°C for 30 minutes. A solution of diphenylphosphinoyl chloride (41.0 g, 173 mmol) in dioxane (45 ml) was added dropwise at 0-5° C. over 30 minutes, then the resulting mixture was stirred for another 2 hours at air temperature. The resulting solids were collected by filtration and washed with water (200 ml), NaOH (0.25 M, 200 ml) and PE (200 ml). The product was dried to give the title compound as a white solid (20 g, imp.).

Compound 64.2. 1-Amino-4-bromopyridin-1-ia iodide. A 250 ml round bottom flask was charged with a solution of 4-bromopyridine hydrochloride (13.8 g, 71.0 mmol) in water (50 ml). The solution was cooled to 0-5°C, then sodium bicarbonate (12.0 g, 141 mmol) was added portionwise over 10 minutes and the mixture was stirred at 0-5°C for 30 minutes. The mixture was extracted with DCM (4×50 ml) and the combined organic layers were washed with brine (50 ml), dried (Na ₂ SO ₄ ) and filtered. The filtrate was placed in a 500 ml round bottom flask, which was then purged and kept under an inert nitrogen atmosphere. (Aminooxy)diphenylphosphine oxide (compound 64.1, 20 g, ~70% pure, 60 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was carefully quenched with aqueous HI (8 ml, 45%) and stirred for 30 minutes. The solids were collected by filtration and washed with DCM (200 ml) and hexanes (200 ml) to give the title compound as a brown solid (15 g, imp.).

Compound 64.3. Ethyl 5-bromopyrazolo[1,5- a ]pyridine-3-carboxylate. A solution of 1-amino-4-bromopyridin-1-ium iodide (compound 64.2, 15 g, ~50% pure, 24.9 mmol) in N,N-dimethylformamide (80 ml) was placed in a 250 ml three-necked round bottom flask. Potassium carbonate (10.6 g, 76.7 mmol) was added in portions followed by ethyl propiolate (11.7 mL, 115 mmol) added dropwise over 10 minutes. The resulting mixture was stirred overnight at room temperature, then diluted with EtOAc (300 ml) and water (100 ml). Solids were removed by filtration and the organic layer was washed with brine (3×50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:10) as eluent to give the title compound as a brown solid (300 mg, 6%).

Compound 64.4. 5-Bromopyrazolo[1,5- a ]pyridine. Ethyl 5-bromopyrazolo[1,5- a ]pyridine-3-carboxylate (compound 64.3, 100 mg, 0.37 mmol) was placed in a 50 ml round bottom flask. Sulfuric acid (50%, 4 ml) was carefully added in portions at room temperature, then the resulting solution was stirred overnight at 80°C. After cooling to room temperature, the pH of the solution was carefully adjusted to 8-9 with aqueous sodium hydroxide (5 M) and then extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with brine (20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:10) as eluent to give the title compound as a brown solid (40 mg, 55%).

Compound 64 2-Cyclobutyl-N,4-dimethyl-5-(4-(pyrazolo[1,5- a ]pyridin-5-yl)piperidine-1-carbonyl)benzamide. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 62, except for the use of 5-bromopyrazolo[1,5- a ]pyridine (compound 64.4) instead of 5-bromo-1H-indazole with obtaining the title compound as a white solid, m/z (ES+) 431 (M+H) ⁺ .

Compound 65 ) methanone. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1, except for the use of 4-cyclobutyl-3-iodobenzoic acid (compound 9.3) instead of 5-iodo-2,4-dimethylbenzoic acid ( compound 1.3) and 7-(piperidin-4-yl)imidazo[1,5- a ]pyridine hydrochloride (compound 39.5) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) to give the title compound , m/z (ES+) 454 (M+H) ⁺ .

Compound 66.1. 1-(4-Bromopyridin-2-yl)ethanamine. Into a 500 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was charged a solution of methylmagnesium bromide (3 M in THF) (63.4 ml, 190 mmol) in THF (100 ml). A solution of 4-bromopyridine-2-carbonitrile (11.6 g, 63.4 mmol; US Pat. No. 20090239876 A1, Example 2) in THF (40 mL) was added dropwise at room temperature over 40 minutes. Methanol (40 mL) was then added dropwise, after which sodium borohydride (11.8 g, 312 mmol) was added portionwise in several portions. The resulting mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate (200 ml). The pH of the mixture was adjusted to 9 with aqueous sodium hydroxide (1M) and the solids were removed by filtration. The filtrate was extracted with ethyl acetate (2×100 ml) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 10.3 g (imp.) of the title compound as a yellow oil.

Compound 66.2. 1-Methyl-7-(piperidin-4-yl)imidazo[1,5- a ]pyridine hydrochloride. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 39.5, except for the use of 1-(4-bromopyridin-2-yl)ethanamine (compound 66.1) instead of (4-bromopyridin-2- yl)methanamine (compound 39.1).

Compound 67.1. N-((4-Bromopyridin-2-yl)methyl)acetamide. In a 500 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of (4-bromopyridin-2-yl)methanamine (compound 39.1, 4.5 g, 24.1 mmol) in dichloromethane (160 ml). Triethylamine (6.72 ml, 48.2 mmol) and acetic anhydride (2.29 ml, 24.2 mmol) were added carefully and the resulting solution was stirred at room temperature for 12 hours. The volatiles were removed under reduced pressure and the precipitate slowly extinguished with water (200 ml). The pH of the solution was slowly adjusted to 9-12 with aqueous sodium carbonate (3 M) and the aqueous phase was extracted with ethyl acetate (3×60 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane/methanol (100:1-10:1) as eluent to give 4.0 g (73%) of the title compound as a yellow oil.

Compound 67.2. 3-Methyl-7-(piperidin-4-yl)imidazo[1,5- a ]pyridine hydrochloride. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 39.5, except for the use of N-((4-bromopyridin-2-yl)methyl)acetamide (compound 67.1) instead of N-(( 4-bromopyridin-2-yl)methyl)formamide (compound 39.2).

Compound 68.1 and Compound 68.2. tert-Butyl-4-(1-chloroimidazo[1,5- a ]pyridin-7-yl)piperidine-1-carboxylate and tert-butyl-4-(3-chloroimidazo[1,5- a ]pyridine-7- yl) piperidine-1-carboxylate. A solution of tert-butyl 4-(imidazo[1,5- a ]pyridin-7-yl)piperidine-1-carboxylate (compound 39.4, 170 mg, 0.56 mmol) in CCl ₄ ( 3 ml). N-chlorosuccinimide (75 mg, 0.56 mmol) was added and the resulting mixture was stirred for 5 hours at room temperature. The mixture was diluted with EtOAc (30 ml) and washed with brine (3×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by preparative TLC with ethyl acetate/petroleum ether (1/1) to give 45 mg (24%) tert-butyl-4-(1-chloroimidazo[1,5- a ]pyridin-7-yl)piperidin-1 -carboxylate (compound 68.1) as a yellow solid and 64 mg (34%) tert-butyl 4-(3-chloroimidazo[1,5- a ]pyridin-7-yl)piperidine-1-carboxylate (compound 68.2) as a yellow solid.

Compound 68.3. 1-Chloro-7-(piperidin-4-yl)imidazo[1,5- a ]pyridine hydrochloride. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1.2, except for the use of tert-butyl-4-(1-chloroimidazo[1,5- a ]pyridin-7-yl)piperidine -1-carboxylate (compound 68.1) instead of tert-butyl-4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1) to give the title compound as a yellow solid.

Compound 71.1. 3-Chloro-7-(piperidin-4-yl)imidazo[1,5- a ]pyridine hydrochloride. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1.2, except for the use of tert-butyl-4-(3-chloroimidazo[1,5- a ]pyridin-7-yl)piperidine -1-carboxylate (compound 68.2) instead of tert-butyl-4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1) to give the title compound as a yellow solid.

The compounds listed in Table 4 were prepared using standard chemistry and procedures using readily available starting materials or starting reagents described herein. The procedures used were similar to those used to prepare compound 1, using 5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 1.8) and the corresponding amines (compound 5.2. compound 39.5 connection 66.2, connection 67.2, connection 68.3 or connection 71.1).

Compound 72 -yl) methanone. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1, except for the use of methyl 4-cyclopropyl-3-propionyl benzoate (compound 10.7) instead of methyl-2,4-dimethyl-5- propionyl benzoate (compound 1.5) and 1-methyl-7-(piperidin-4-yl)imidazo[1,5- a ]pyridine hydrochloride (compound 66.2) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 454 (M+H) ⁺ .

Compound 73 -yl) methanone. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 1, except for the use of methyl 4-cyclopropyl-3-propionyl benzoate (compound 10.7) instead of methyl 2,4-dimethyl-5-propionyl benzoate (compound 1.5) and 3-methyl-7-(piperidin-4-yl)imidazo[1,5- a ]pyridine hydrochloride (compound 67.2) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 454 (M+H) ⁺ .

Compound 74.1. 1-(4-Bromophenyl)-1H-pyrazole. In a 100 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a mixture of 1-bromo-4-iodobenzene (2.82 g, 9.97 mmol), 1H-pyrazole (680 mg, 9.99 mmol), CuI (380 mg, 2.00 mmol), DMEDA (430 μl, 4.00 mmol, 0.40 eq.), Cs ₂ CO ₃ (6.52 g, 20.00 mmol) in CH ₃ CN (40 ml ). The resulting mixture was stirred overnight at 82°C. After cooling to air temperature, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:12) as eluent to give the title compound as a white solid (2.1 g, 94%).

Compound 74 5-(4-(4-(1H-Pyrazol-1-yl)phenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 62, except for the use of 1-(4-bromophenyl)-1H-pyrazole (compound 74.1) instead of 5-bromo-1H-indazole with obtaining the title compound as a white solid, m/z (ES+) 457 (M+H) ⁺ .

Compound 75.1. 4-(4-Bromophenyl)-4H-1,2,4-triazole. A solution of 4-bromoaniline (1.71 g, 9.94 mmol), N'-formylformohydrazide (2.64 g, 30.0 mmol) and triethylamine (9.74 ml, 69.9 mmol) was placed in a 100 ml round bottom flask. , 7.00 eq.) in pyridine (40 ml). Chlorotrimethylsilane (19.2 ml, 151 mmol) was added dropwise and the resulting solution was stirred for 18 h at 100° C., then cooled to room temperature. The resulting mixture was concentrated under reduced pressure and the residue was diluted with brine (50 ml) and extracted with ethyl acetate (6×50 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The precipitate was washed with ether (30 ml) and the solids were collected by filtration to give the title compound as a pink solid (1.6 g, 72%).

Compound 75 5-(4-(4-(4H-1,2,4-Triazol-4-yl)phenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 62, except for the use of 4-(4-bromophenyl)-4H-1,2,4-triazole (compound 75.1) instead of 5- bromo-1H-indazole to give the title compound as a yellow solid, m/z (ES+) 458 (M+H) ⁺ .

Compound 76.1. ((4-Bromophenyl)ethynyl)trimethylsilane. Into a 100 ml three neck round bottom flask, which was kept under an inert nitrogen atmosphere, was placed a solution of 1-bromo-4-iodobenzene (1.00 g, 3.53 mmol) in tetrahydrofuran/TEA (9:1) (30 ml). PdCl ₂ (PPh ₃ ) ₂ (50 mg, 0.07 mmol), CuI (13.4 mg, 0.07 mmol) and ethynyltrimethylsilane (748 μl, 5.29 mmol) were added and the mixture was stirred for 18 h at room temperature, then concentrated under reduced pressure. The precipitate was diluted with water (50 ml) and extracted with ethyl acetate (3×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as eluent to give the title compound as a light yellow solid (0.83 g, 93%).

Compound 76.2. tert-Butyl-4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 62.4, except for the use of ((4-bromophenyl)ethynyl)trimethylsilane (compound 76.1, 850 mg, 3.36 mmol) instead of 5- bromo-1H-indazole to give the title compound as a yellow oil (0.80 g, 67%).

Compound 76.3. tert-Butyl 4-(4-ethynylphenyl)piperidine-1-carboxylate. A solution of tert-butyl 4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate (compound 76.2, 1.34 g, 3.75 mmol) in tetrahydrofuran (20 ml) was placed in a 50 ml round bottom flask. . Tetrabutylammonium fluoride (1.95 g, 7.47 mmol) was added and the resulting solution was stirred for 10 minutes at room temperature. The mixture was diluted with water (30 ml) and extracted with EtOAc (3×20 ml). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a brown oil (1.0 g, crude).

Compound 76.4. 4-(4-Ethynylphenyl)piperidine hydrochloride. A solution of tert-butyl 4-(4-ethynylphenyl)piperidine-1-carboxylate (compound 76.3, 1.0 g, 3.5 mmol) in ethyl acetate (20 ml) was placed in a 100 ml round bottom flask. Hydrogen chloride (gas) was introduced into the solution by blowing, and the resulting solution was stirred for 1 hour at room temperature. The resulting solids were collected by filtration and washed with hexanes (3×10 ml) to give the title compound as a brown solid (630 mg, 81%).

Compound 76 2-Cyclobutyl-5-(4-(4-ethynylphenyl)piperidine-1-carbonyl)-N,4-dimethylbenzamide. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 62, except for the use of 4-(4-ethynylphenyl)piperidine hydrochloride (compound 76.4, 178 mg, 0.81 mmol) instead of 5- (piperidin-4-yl)-1H-indazole (compound 62.5) to give the title compound as a white solid (20.1 mg, 12%). m/z (ES+) 415 (M+H) ⁺ .

Compound 77.1. 1-Bromo-4-(prop-1-yn-1-yl)benzene. Into a 250 ml three-necked round bottom flask, which was kept under an inert nitrogen atmosphere, was placed 1-bromo-4-iodobenzene (2.00 g, 7.07 mmol), PdCl ₂ (PPh ₃ ) ₂ (99.2 mg, 0. 14 mmol), CuI (26.8 mg, 0.14 mmol), trimethyl(prop-1-yn-1-yl)silane (2.08 ml, 14.1 mmol) and tetrahydrofuran/TEA (9:1) (100 ml). Stirring was started and tetrabutylammonium fluoride (3.69 g, 14.1 mmol) was quickly added to the mixture. The resulting mixture was stirred for 18 hours at room temperature, then concentrated under reduced pressure. The precipitate was diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). The organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as eluent to give the title compound as a light yellow oil (1.0 g, 73%).

Compound 77 2-Cyclobutyl-N,4-dimethyl-5-(4-(4-(prop-1-yn-1-yl)phenyl)piperidine-1-carbonyl)benzamide. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 62, except for the use of 1-bromo-4-(prop-1-yn-1-yl)benzene (compound 77.1) instead of 5 -bromo-1H-indazole to give the title compound as a white solid, m/z (ES+) 429 (M+H) ⁺ .

Compound 78.1. Methyl 5-carbamothioyl-4-cyclobutyl-2-methylbenzoate. Methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (compound 6.4, 3.63 g, 0.015 mol), O,O'-diethyldithiophosphate (10 ml) and water (1 ml) were added to a round bottom flask. The reaction mixture was heated to 80°C for 3 hours (Warning: significant gas evolution - this and all other reactions described in this application must be carried out in well-ventilated fume hoods). After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was washed successively with saturated aqueous NaHCO ₃ (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (hexanes/ethyl acetate = 80/20 to 50/50) to give the title compound as a yellow solid (3.06 g, 78% yield). m/z (ES+) 264 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 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 78.2. Methyl 4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate. Methyl 5-carbamothioyl-4-cyclobutyl-2-methylbenzoate (compound 78.1, 861 mg, 3.27 mmol) in THF (10 mL) was added to a round bottom flask. Iodomethane (400 μl, 6.42 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography (ethyl acetate to ethyl acetate/methanol = 95/5) to give the title compound as a yellowish oil (807 mg, 89% yield). m/z (ES+) 278 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.67 (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 78.3. Methyl 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate. Methyl 4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate (compound 78.2, 556 mg, 2.00 mmol) and acetohydrazide (223 mg, 3.00 mol) in acetic acid ( 6 ml). The mixture was heated at 90°C for 3 hours, then cooled to room temperature. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (50 ml) and the organic layer was washed with brine (2×50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (hexanes/ethyl acetate = 50/50 to 30/70) to give the title compound as a white solid (243 mg, 43% yield). m/z (ES+) 286 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.23 (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 78.4. 4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid. To a solution of methyl 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate (compound 78.3, 240 mg, 0.842 mmol) in methanol (5 ml) aqueous NaOH (6 ml, 1 M) was added. The resulting mixture was heated to 50°C for 6 hours, then cooled to air temperature and acidified to pH 2 with aqueous 1M HCl and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a white solid (260 mg, quant.). m/z (ES+) 272 (M+H) ⁺ .

Compound 78.5. 6-(Piperidin-4-yl)imidazo[1,2- a ]pyridine hydrochloride. The title compound was prepared using standard chemistry and procedures similar to those used to obtain compound 1.2, except for the use of 6-bromoimidazo[1,2- a ]pyridine (500 mg) instead of 4-bromobenzonitrile to give the compound indicated as title, as a brown solid (400 mg, 66% over 2 steps).

Compound 78 -yl)piperidin-1-yl)methanone. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 62, except for the use of 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazole -3-yl)benzoic acid (compound 78.4, 100 mg) instead of 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3) and 6-(piperidin-4-yl)imidazo[1,2] hydrochloride - a ]pyridine (compound 78.5, 88 mg) instead of 5-(piperidin-4-yl)-1H-indazole (compound 62.5). The title compound was obtained as a white solid (35.6 mg, 21%). m/z (ES+) 455 (M+H) ⁺ .

Compound 79 . The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 62, except for the use of 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazole -3-yl)benzoic acid (compound 78.4) instead of 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 5-(piperidin-4-yl)-1H-indazole (compound 62.5). m/z (ES+) 430 (M+H) ⁺ .

Connection 80.1. 3-Methoxypropanehydrazide. In a 500 ml round bottom flask was placed a solution of methyl 3-methoxypropanoate (30.0 g, 254 mmol) in ethanol (100 ml) and hydrazine hydrate (24.7 ml, 507 mmol). The resulting solution was stirred overnight at 80° C., then cooled and concentrated under reduced pressure to give 26.3 g (88%, imp.) of the title compound as a colorless oil.

Compound 80 yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to prepare compound 78, except for the use of 3-methoxypropanehydrazide (compound 80.1) instead of acetohydrazide and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride ( compound 43.4) instead of 6-(piperidin-4-yl)imidazo[1,2- a ]pyridine hydrochloride (compound 78.5). m/z (ES+) 474 (M+H) ⁺ .

Compound 81 . The title compound was prepared using standard chemistry and procedures similar to those used for compound 78, except for the use of 3-methoxypropanehydrazide (compound 80.1) instead of acetohydrazide and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2 ) instead of 6-(piperidin-4-yl)imidazo[1,2- a ]pyridine hydrochloride (compound 78.5). m/z (ES+) 456 (M+H) ⁺ .

Compound 82.1. 1-tert-butyl-4-ethyl-5-oxoazepane-1,4-dicarboxylate. To a solution of tert-butyl-4-oxo-piperidine-1-carboxylate (20.0 g, 100 mmol) in diethyl ether (60 ml) under a nitrogen atmosphere at -30°C was added dropwise a solution of BF ₃ ⋅Et ₂ O (16, 0 ml, 130 mmol) in ether (20 ml). After stirring for 30 minutes at -30°C, a solution of ethyl 2-diazoacetate (16.0 g, 140 mmol) in ether (20 ml) was added dropwise to the reaction mixture at -30°C. The resulting solution was stirred for 1 h at -30°C, then at room temperature for 2 h. The reaction mixture was carefully quenched with 30% aqueous potassium carbonate (100 ml) and the resulting mixture was extracted with ethyl acetate (2×250 ml). The combined organic extracts were washed with brine (2×50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/10) as eluent to give 19 g (66%) of the title compound as a light yellow oil.

Compound 82.2. tert-butyl-4-oxoazepan-1-carboxylate. Sodium hydroxide solution (4 .00 g, 100 mmol) in water (100 ml). The resulting mixture was stirred at room temperature overnight. Then the pH was adjusted to 4-5 with hydrogen chloride (aq. 3 M) and the resulting solution was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (2×10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:3) as eluent to give 11 g (77%) of the title compound as a yellow oil.

Compound 82.3. tert-butyl-4-bromo-5-oxoazepan-1-carboxylate. To a solution of tert-butyl 4-oxoazepane-1-carboxylate (compound 82.2, 11.0 g, 51.6 mmol) in chloroform (220 ml) at 0° C. 6 mmol) in chloroform (110 ml). The resulting mixture was stirred at room temperature overnight, then the resulting solids were collected by filtration and dissolved in dichloromethane (200 ml). Triethylamine (16.8 ml, 121 mmol) and (Boc) ₂ O (8.70 g, 40.3 mmol) were added to the mixture at 0°C, and the resulting solution was stirred for 3 h at room temperature, and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:10) as eluent to give 4.0 g (27%) of the title compound as a yellow oil.

Compound 82.4. 4-Cyclobutyl-5-formyl-2-methylbenzoic acid. In a three-necked round-bottom flask, which was purged and kept under an inert atmosphere of nitrogen, was placed a solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 62.1, 5.00 g, 80%, 12.7 mmol) in a solvent mixture consisting from tetrahydrofuran and Et ₂ O (50 ml/50 ml). The solution was cooled to -78°C, then n-butyl lithium (15 ml, 2.5 M in hexanes) was added dropwise with stirring. N,N-dimethylformamide (2.64 ml, 34.2 mmol) was added and the resulting mixture was stirred for 1 h at -78°C, then carefully quenched by slow addition of aqueous NH ₄ Cl (sat., 50 ml). The pH was adjusted to 1-2 with aqueous hydrogen chloride (6 M), then diluted with ethyl acetate (100 ml) and washed with brine (4×50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) as eluent to give 1.62 g (41%) of the title compound as a white solid.

Compound 82.5. Methyl 4-cyclobutyl-5-formyl-2-methylbenzoate. A mixture of 4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound 82.4, 500 mg, 2.29 mmol) in N,N-dimethylformamide (10 ml) and sodium bicarbonate (390 mg, 4 .64 mmol). Methyl iodide (430 μl, 6.90 mmol) was added dropwise with stirring, and the resulting mixture was stirred for 5 hours at room temperature. The reaction mixture was then diluted with EtOAc (50 ml) and the mixture was washed with brine (4×10 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 0.40 g (impure) of the title compound as a brown oil

Compound 82.6. tert-Butyl-2-(2-cyclobutyl-5-(methoxycarbonyl)-4-methylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate. A mixture of methyl 4-cyclobutyl-5-formyl-2-methylbenzoate (compound 82.5, 300 mg, 1.29 mmol), ammonium acetate (449 mg, 5.83 mmol), tert-butyl- 4-bromo-5-oxoazepane-1-carboxylate (compound 82.3, 564 mg, 1.93 mmol) and ammonium hydroxide (25%) (597 μl, 3.87 mmol) in N,N-dimethylformamide (8 ml). The resulting mixture was stirred for 4 h at 130°C, then cooled and quenched with ice water (10 ml). The aqueous phase was extracted with ethyl acetate (2×30 ml) and the combined organic layers were washed with brine (3×10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/1) as eluent to give 0.10 g (18%) of the title compound as a white solid.

Compound 82.7. Methyl 4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoate hydrochloride. A solution of tert-butyl-2-(2-cyclobutyl-5-(methoxycarbonyl)-4-methylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6 (1H)-carboxylate (compound 82.6, 200 mg, 0.46 mmol) in EtOAc (10 ml). Hydrogen chloride (gas) was introduced into the solution by blowing, and the solution was stirred for 30 minutes at room temperature. The resulting mixture was concentrated under reduced pressure to give 136 mg (impure) of the title compound as a yellow solid.

Compound 82.8. Methyl 4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoate. A mixture of methyl 4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoate hydrochloride (compound 82.7, 40 mg, 0.11 mmol), NaBH(OAc) ₃ (75 mg, 0.35 mmol) and formaldehyde (37% wt.) (26 μl, 0.33 mmol) in tetrahydrofuran (4 ml). The resulting mixture was stirred for 2 hours at 40°C, then cooled, and the pH of the solution was adjusted to 8-9 with sodium bicarbonate (sat.). The aqueous phase was extracted with ethyl acetate (2×20 ml) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 20 mg (imp.) of the title compound as a yellow solid.

Compound 82.9. 4-Cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoic acid. A mixture of methyl 4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl )benzoate (compound 82.8, 40 mg, 0.11 mmol) and NaOH (18 mg, 0.44 mmol) in methanol (4 ml), water (2 ml). The resulting solution was stirred for 2 hours at 60°C. After cooling to room temperature, the volatiles were removed under reduced pressure. The pH of the residual solution was adjusted to about 1 with hydrogen chloride (3 M) and concentrated under reduced pressure to give 0.10 g (crude) of the title compound in hydrochloric acid salt form as a yellow solid.

Compound 82 benzoyl)azetidin-3-yl)benzonitrile. A mixture of 4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoic acids (compound 82.9, 40 mg, 0.12 mmol), EDC⋅HCl (45.4 mg, 0.24 mmol, 2.00 eq.), 4-dimethylaminopyridine (29 mg, 0.24 mmol) and hydrochloride 4 -(azetidin-3-yl)benzonitrile (compound 5.2, 23 mg, 0.12 mmol) in N,N-dimethylformamide (5 ml). The resulting solution was stirred for 4 hours at room temperature, then quenched by adding ice water (10 ml). The resulting mixture was extracted with ethyl acetate (2×20 ml) and the combined organic layers washed with brine (2×10 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a crude product which was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, XBridge Shield RP18 OBD , 5 microns, 19*150mm; mobile phase, water with 0.03% NH ₄ OH and CH ₃ CN (30% CH ₃ CN to 43% in 8 min, to 100% in 4 min, to 30% in 2 min); Detector, Waters 2489, 254&220 nm. Fractions containing pure product were combined to give 2.2 mg (4%) of the title compound as a white solid, m/z (ES+) 480 (M+H) ⁺ .

Compound 83.1. 5-Formyl-2,4-dimethylbenzoic acid. n-BuLi (2, 5 M in THF, 18 ml, 45 mmol). The mixture was stirred at -78°C for 1 h, and then DMF (5.3 ml, 68 mmol) was added dropwise. The resulting mixture was stirred at -78°C for 0.5 h and then carefully quenched by the slow addition of water (50 ml). The pH of the mixture was adjusted to ~3-4 with aqueous HCl (6 M) and then extracted with ethyl acetate (3×200 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:10-1:5) as eluent to give the title compound as a white solid (2.4 g, 74%).

Compound 83.2. Methyl 5-formyl-2,4-dimethylbenzoate. In a 250 ml round bottom flask were placed 5-formyl-2,4-dimethylbenzoic acid (compound 83.1, 2.00 g, 11.2 mmol) and methanol (50 ml). Concentrated sulfuric acid (2 ml) was carefully added dropwise, and the resulting solution was stirred for 2 h at 80° C., then cooled and devolatilized under reduced pressure. The pH of the residue was adjusted to 9 with sodium bicarbonate (sat.), then the aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (2×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 2.0 g (imp.) of the title compound as a yellow oil. The crude product was used in the next step without further purification.

Compound 83.3. tert-Butyl 2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate. Methyl 5-formyl-2,4-dimethylbenzoate (compound 83.2, 500 mg, 2.60 mmol), tert-butyl-4-bromo-5-oxoazepane-1-carboxylate (compound 82.3, 1.1 g, 3.8 mmol), ammonium hydroxide (25%) (1.2 ml, 7.8 mmol), ammonium acetate (900 mg, 11.7 mmol) in N,N-dimethylformamide (6 ml) . The resulting mixture was stirred for 3 hours at 130° C. behind a blast shield, then cooled to room temperature and diluted with ethyl acetate (150 ml). The mixture was washed with brine (5×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane/methanol (10:1) as eluent to give 0.80 g (46%) of the title compound as a yellow oil.

Compound 83.4. Methyl 5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate. A solution of tert-butyl-2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d)azepine-6(1H) -carboxylate (compound 83.3, 800 mg, 2.00 mmol) in dichloromethane (16 ml). Trifluoroacetic acid (4 ml) was added dropwise and the resulting solution was stirred for 5 hours at room temperature. The pH of the solution was carefully adjusted to 8-9 with NaHCO ₃ (sat.) and the aqueous phase was extracted with DCM (3×30 ml) and the combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to obtain 0 .60 mg (crude) of title compound as brown oil.

Compound 83.5. Methyl 5-(6-isopropyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate. Methyl 5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate (compound 83.4, 347 mg , 0.84 mmol), 2-bromopropane (790 μl, 8.40 mmol), N,N-diisopropylethylamine (1.46 ml, 8.4 mmol) in N,N-dimethylformamide (5 ml). The solution was stirred for 4 hours at 80° C., then cooled to room temperature. The resulting solution was diluted with ethyl acetate (50 ml) and washed with brine (4×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 0.22 g (imp.) of the title compound in brown oil.

Compound 83 -3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 82, except for the use of methyl 5-(6-isopropyl-1,4,5,6,7,8-hexahydroimidazo[4 ,5-d]azepin-2-yl)-2,4-dimethylbenzoate (compound 83.5) instead of 4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo [4,5-d]azepin-2-yl)benzoate (compound 82.8). m/z (ES+) 468 (M+H) ⁺ .

Compound 84 azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 82, except for the use of methyl 5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d ]azepin-2-yl)-2,4-dimethylbenzoate (compound 83.4) instead of methyl-4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin- 2-yl)-2-methylbenzoate (compound 82.7). m/z (ES+) 440 (M+H) ⁺ .

Compound 85.1. 3-(4-Chlorophenyl)azetidine hydrochloride. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5,2, except for the use of (4-chlorophenyl)boronic acid instead of (4-cyanophenyl)boronic acid. The title compound was obtained in 20% yield in two steps.

Compound 85 ]azepin-2-yl)phenyl)methanone. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 82, except for the use of methyl 5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d ]azepin-2-yl)-2,4-dimethylbenzoate (compound 83.4) instead of methyl-4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin- 2-yl)-2-methylbenzoate (compound 82.7) and 3-(4-chlorophenyl)azetidine hydrochloride (compound 85.1) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 449 (M+H) ⁺ .

Compound 86.1. Methyl 4-cyclopropyl-2-methylbenzoate. _Potassium carbonate (6.10 g , 44.1 mmol), cyclopropylboronic acid (2.30 g, 26.8 mmol), Pd(dppf)Cl ₂ (900 mg, 1.23 mmol) and Pd(OAc) ₂ (250 mg, 1.12 mmol ). The reaction mixture was purged with nitrogen and stirred at 80° C. overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:50) as eluent to give 2.68 g (61%) of the title compound as a colorless oil.

Compound 86.2. Methyl 4-cyclopropyl-5-iodo-2-methylbenzoate. To a solution of methyl 4-cyclopropyl-2-methylbenzoate (compound 86.1, 2.68 g, 13.4 mmol, 95%) in AcOH (50 ml) was added NaIO ₄ (1.51 g, 7.08 mmol), iodine (3.58 g, 14.1 mmol) and sulfuric acid (106 μl, 2.0 mmol, 0.15 eq.). The reaction mixture was stirred overnight at 110°C. After cooling to air temperature, water (100 ml) was added slowly and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with Na ₂ S ₂ O ₃ (aq., sat., 3×30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50) as eluent to give 2.0 g (45%) of the title compound as a colorless oil.

Compound 86.3. 4-Cyclopropyl-5-iodo-2-methylbenzoic acid. In a 500 ml round bottom flask was placed a solution of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate (compound 86.2, 15.0 g, 47.5 mmol) in methanol (150 ml). A solution of sodium hydroxide (5.70 g, 143 mmol) in water (75 ml) was added and the resulting solution was stirred for 4 h at 60° C., then cooled to room temperature. The volatiles were removed under reduced pressure and the remaining solution was adjusted to pH 3 with aqueous hydrogen chloride (12 M). The mixture was extracted with ethyl acetate (2×200 ml) and the combined organic extracts washed with NH ₄ Cl (aq.) (2×400 ml) and brine (400 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 13.0 g (91%) of the title compound as a light yellow solid.

Compound 86.4. Methyl 4-cyclopropyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 83.4, except for the use of 4-cyclopropyl-5-iodo-2-methylbenzoic acid (compound 86.3) instead of 5-iodo-2,4 -dimethylbenzoic acid (compound 1.3).

Compound 86 benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 82, except for the use of methyl 4-cyclopropyl-5-(1,4,5,6,7,8-hexahydroimidazo[4 ,5-d]azepin-2-yl)-2-methylbenzoate (compound 86.4) instead of methyl 4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d] hydrochloride azepin-2-yl)-2-methylbenzoate (compound 82.7). m/z (ES+) 466 (M+H) ⁺ .

Compound 87.1. Methyl 4-cyclopropyl-5-formyl-2-methylbenzoate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 83.2, except for the use of 4-cyclopropyl-5-iodo-2-methylbenzoic acid (compound 86.3) instead of 5-iodo-2,4 -dimethylbenzoic acid (compound 1.3).

Compound 87.2. Methyl 4-cyclopropyl-5-(3H-imidazo[4,5-c]pyridin-2-yl)-2-methylbenzoate. A mixture of methyl 4-cyclopropyl-5-formyl-2-methylbenzoate (compound 87.1, 500 mg, 2.29 mmol), pyridine-3,4-diamine (500 mg, 4.58 mmol) was placed in a 100 ml round bottom flask. , NH ₄ OAC (1.42 g, 18.4 mmol) and ethanol (50 ml). The resulting mixture was stirred under the access of air for 3 days at 70°C, then cooled to room temperature and diluted with aqueous sodium bicarbonate (sat., 50 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate as eluent to give 268 mg (38%) of the title compound as a yellow semi-solid.

Compound 87.3. 2-(2-Cyclopropyl-5-(methoxycarbonyl)-4-methylphenyl)-5-methyl-3H-imidazo[4,5-c]pyridin-5-ium iodide. A solution of methyl 4-cyclopropyl-5-(3H-imidazo[4,5-c]pyridin-2-yl)-2-methylbenzoate (compound 87.2, 500 mg, 1.63 mmol) in dichloromethane (15 ml). Iodomethane (203 μl, 3.26 mmol) was added dropwise and the resulting solution was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to give 0.30 g (41%) of the title compound as a yellow solid.

Compound 87.4. Methyl 4-cyclopropyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoate. A mixture of 2-(2-cyclopropyl-5-(methoxycarbonyl)-4-methylphenyl)-5-methyl-3H-imidazo[4,5-c]pyridin-5-ium iodide (compound 87.3, 300 mg, 0.67 mmol) and NaBH ₄ (1.42 g, 37.5 mmol) in methanol (30 ml). The resulting mixture was stirred for 4 hours at room temperature, then concentrated under reduced pressure. The precipitate was diluted with EtOAc (120 ml) and the mixture was washed with brine (2×40 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/MeOH (20/1) as eluent to give 170 mg (78%) of the title compound as a light yellow oil.

Compound 87 benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 82, except for the use of methyl-4-cyclopropyl-2-methyl-5-(5-methyl-4,5,6,7 -tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoate (compound 87.4) instead of 4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7, 8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoate (compound 82.8). m/z (ES+) 452 (M+H) ⁺ .

Compound 88.1. Methyl 4-cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 87.4, except for the use of methyl 4-cyclobutyl-5-formyl-2-methylbenzoate (compound 82.5) instead of methyl 4-cyclopropyl- 5-formyl-2-methylbenzoate (compound 87.1).

Compound 88 benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 82, except for the use of methyl-4-cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7 -tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoate (compound 88.1) instead of 4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7, 8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoate (compound 82.8). m/z (ES+) 466 (M+H) ⁺ .

Compound 89.1. Methyl 2-bromo-4-methylbenzoate. A solution of 2-bromo-4-methylbenzoic acid (10.0 g, 46.5 mmol) in MeOH (50 ml) was cooled to 0°C, then concentrated sulfuric acid (10 ml) was added carefully. The mixture was heated at 70°C for 2 hours. After cooling to room temperature, volatile organic substances were removed under reduced pressure, and the precipitate was poured into a mixture of ice and water (100 ml). The mixture was extracted with EtOAc (×2) and the combined organic extracts were washed with water. NaHCO ₃ , brine, dried (MgSO ₄ ), filtered and concentrated to give 10.5 g (99%) of the title compound as a clear oil. ¹ H 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 89.2. Methyl 2-cyclobutyl-4-methylbenzoate. Cyclobutylzinc (II) bromide (50 ml, 0.5 M in THF, 25.0 mmol) was added to a mixture of methyl 2-bromo-4-methylbenzoate (compound 89.1, 5.0 g, 21.8 mmol) and PdCl ₂ (dppf)CH ₂ Cl ₂ (1.78 g, 2.20 mmol). The mixture was degassed with argon, then heated at 65° C. under argon for 24 hours. The mixture was cooled to 0° C., then carefully quenched with water (10 ml). The mixture was diluted with EtOAc (200 ml) and washed with water then brine. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 30:1 to 20:1) to give 3.6 g (81%) of the title compound. ¹ H 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 89.3. Methyl 2-cyclobutyl-5-iodo-4-methylbenzoate. To a solution of methyl 2-cyclobutyl-4-methylbenzoate (compound 89.2, 4.77 g, 23.3 mmol) in concentrated sulfuric acid (100 ml) at 0°C was added N-iodosuccinimide (5.25 g, 23 .3 mmol). The mixture was stirred at 0° C. for 30 minutes and then at RT for 2 hours. The thick dark mixture was again cooled to 0° C., then MeOH (100 ml) was added slowly and carefully. The mixture was heated at 60°C for 2 hours. After cooling to room temperature, the volatile solvents were removed under reduced pressure and carefully poured into ice water (200 ml). The mixture was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, aqueous NaHCO ₃ (1 M), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 30:1 to 20:1) to give 5.0 g (65%) of the title compound as a clear oil. ¹ H 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 89.4. Methyl 5-cyano-2-cyclobutyl-4-methylbenzoate. A mixture of methyl 2-cyclobutyl-5-iodo-4-methylbenzoate (compound 89.3, 3.0 g, 9.1 mmol), Zn(CN) ₂ (2.3 g, 19.6 mmol) and Pd(PPh ₃ ) ₄ (0.55 g, 0.47 mmol) in DMF (50 ml) was degassed and argon was introduced into the system. The mixture was heated at 100°C overnight, then cooled to room temperature. The mixture was quenched with saturated aqueous FeSO ₄ (20 ml), then diluted with EtOAc (200 ml). Solids were removed by filtration through Celite® and the filtrate was partitioned between water and EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 30:1 to 20:1) to give 2.0 g (96%) of the title compound. ¹ H 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 89.5. 5-cyano-2-cyclobutyl-4-methylbenzohydrazide. To a solution of methyl 5-cyano-2-cyclobutyl-4-methylbenzoate (compound 89.4, 2.0 g, 8.73 mmol) in EtOH (10 ml) was added anhydrous hydrazine (2 ml, excess) at room temperature. The mixture was heated at 90° C. overnight, then the mixture was cooled to room temperature and partitioned between water (60 ml) and EtOAc (200 ml). The organic layer was washed with water (×2), brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give 1.9 g (95%) of the title compound as a white solid, m/z (ES+ ) 230 (M+H) ⁺ . ¹ H 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 89.6. 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile. NaHCO _{3 (} 0.55 g 6.55 mmol). After stirring the mixture at room temperature for 5 minutes, BrCN (1.3 ml, 5 M in CH ₃ CN, 6.55 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes, after which white solids formed. The mixture was diluted with EtOAc and washed with water then brine. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 1:1 to EtOAc) to give 0.55 g (theor.) of the title compound as a white solid, m/z (ES+) 255 (M+ H) ⁺ . ¹ H 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 (t, 1H).

Compound 89.7. 4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile. To a solution of 5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile (compound 89.6, 0.5 g, 2.0 mmol) in MeOH (40 ml) was added KOH (1.11 g, 20.0 mmol). The mixture was heated at 85°C overnight, then cooled to 0°C and neutralized to pH 7 with aqueous 1M HCl. The mixture was extracted with EtOAc (×2) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 1:1 to EtOAc) to give 0.2 g (34%) of the title compound as a white solid, m/z (ES+) 269 (M+ H) ⁺ . ¹ H 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 89.8. 4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide. To a solution of 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile (compound 89.7, 0.15 g, 0.53 mmol) in EtOH (10 ml ) NH ₄ OH (0.18 ml, 2.66 mmol, 14.8 M in H ₂ O) was added followed by H ₂ O ₂ (1.8 ml, 26.6 mmol, 50% in H ₂ O). The mixture was stirred at room temperature overnight, then cooled to 0°C and carefully quenched with 1 M Na ₂ S ₂ O ₃ (26 ml). The mixture was extracted with EtOAc (×2) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The precipitate was purified by preparative TLC (5% MeOH in CH ₂ Cl ₂ ) to give 0.1 g (63%) of the title compound as a white solid, m/z (ES+) 287(M+H) ⁺ . ¹ H NMR (400 MHz, 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 89.9. 4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. To a solution of 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide (compound 89.8, 0.1 g, 0.33 mmol) in TFA (5 ml ) at 0° C., NaNO ₂ (46 mg, 0.66 mmol) was added. The mixture was stirred at 0°C for 1 hour, then at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 0.1 g (theor.) of the title compound as a clear oil, m/z (ES+) 288 (M+H) ⁺ .

Compound 89 4-(1-(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl )-2-methylbenzoic acid (compound 89.9) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 428 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 13.63-13.17 (br, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.58 (d, J=8 .4 Hz, 2H), 7.49 (s, 1H), 7.39 (s, 1H), 4.48 (m, 1H), 4.32 (m, 1H), 4.15 (m, 1H ), 4.07-3.95 (m, 3H), 3.93 (s, 3H), 2.41 (s, 3H), 2.21-2.11 (m, 2H), 2.06- 1.97 (m, 2H), 1.94-1.84 (m, 1H), 1.78-1.68 (m, 1H).

Compound 90 4-(1-(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl )-2-methylbenzoic acid (compound 89.9) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2), respectively, m/z (ES+) 446 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 13.64-13.05 (br, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.56(s, 1H), 7.41(s, 1H), 4.61-4.38(m, 4H), 4.19(m, 1H), 3.92(s , 3H), 2.42 (s, 3H), 2.16 (m, 1H), 2.02 (m, 1H), 1.89 (m, 1H), 1.75 (m, 1H).

Compound 91.1. Methyl 4-cyclopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. Methyl 4-cyclopropyl-5-iodo-2-methylbenzoate mixture (compound 86.2, 4.0 g, 12.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl -2,2'-bi(1,3,2-dioxaborolane) (3.86 g, 15.2 mmol), PdCl ₂ (dppf)CH ₂ Cl ₂ (0.52 g, 0.64 mmol) and acetate potassium (3.73 g, 38.10 mmol) in DMSO (50 ml) was degassed with argon. The mixture was heated at 80° C. for 18 hours under argon, then cooled to room temperature and diluted with ethyl acetate (300 ml). The mixture was washed with water, aq. HCl (1 M), saturated aq. NaHCO ₃ and brine, then dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 50:1 to 30:1) to give 2.63 g (65.6%) of the title compound as a white solid, m/z (ES+) 317 (M+H) ⁺ .

Compound 91.2. 4-Benzyl-3,5-dibromo-4H-1,2,4-triazole. NaH (60% in mineral oil, 0.58 g, 14.5 mmol) (Warning: NaH and DMF may cause an uncontrolled reaction. All necessary precautions have been observed). After stirring the mixture at 0° C. for 30 minutes, benzyl bromide (1.57 ml, 13.2 mmol) was added. The mixture was stirred at 0° C. for 2 hours, then the mixture was partitioned between EtOAc (150 ml) and water (30 ml). The organic layer was washed with brine (2×30 ml), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 50:1 to 10:1) to give 3.71 g (89%) of the title compound as a white solid, m/z (ES+) 316, 318, 320 (M+H) ⁺ .

Compound 91.3. 4-Benzyl-3-bromo-5-methoxy-4H-1,2,4-triazole. NaOMe (1.26 g, 23 4 mmol), and the mixture was heated under reflux for 18 hours. The mixture was cooled to some extent and additional NaOMe (1.26 g, 23.4 mmol) was added. The mixture was heated at reflux for another 5 hours, then cooled to room temperature and the solvent was removed under reduced pressure. The precipitate was dissolved in EtOAc (200 ml) and washed with water (30 ml). The organic layer was dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give 3.13 g (theor.) of the title compound as a clear oil, m/z (ES+) 269 (M+H) ⁺ .

Compound 91.4. Methyl 5-(4-benzyl-5-methoxy-4H-1,2,4-triazol-3-yl)-4-cyclopropyl-2-methylbenzoate. 4-Benzyl-3-bromo-5-methoxy-4H-1,2,4-triazole mixture (compound 91.3, 1.2 g, 4.48 mmol), methyl-4-cyclopropyl-2-methyl-5-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (compound 91.1, 1.56 g, 4.93 mmol), PdCl ₂ (dppf)CH ₂ Cl ₂ (0.37g , 0.45 mmol) and potassium carbonate (3.10 g, 22.5 mmol) in dioxane (50 ml) and water (20 ml) were degassed with argon. The mixture was heated at 90° C. for 18 hours under argon, then cooled to room temperature. The mixture was diluted with ethyl acetate (300 ml) and washed with water, then brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc 10:1 to 4:1) to give 1.51 g (89%) of the title compound as a thick oil, m/z (ES+) 378 (M +H) ⁺ .

Compound 91.5. Methyl 4-cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoate. Vial with methyl 5-(4-benzyl-5-methoxy-4H-1,2,4-triazol-3-yl)-4-cyclopropyl-2-methylbenzoate (compound 91.4, 0.55 g, 1.46 mmol ) and Pd/C (10%, 0.25 g) were purged with nitrogen, then MeOH (10 ml) and HCl (4M in dioxane, 37 μl, 0.15 mmol) were added carefully. Hydrogen was then introduced into the system and the mixture was stirred at room temperature for 3 hours. After completion of the process, the system was purged with nitrogen, then the mixture was neutralized by adding a few drops of NH ₄ OH and filtered through Celite (Celite®). The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (hexanes: EtOAc 1:1) to give 0.3 g (71%) of the title compound as a clear oil, m/z (ES+) 288 ( M+H) ⁺ .

Compound 91.6. 4-Cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5,7, except for the use of methyl-4-cyclopropyl-5-(5-methoxy-4H-1,2,4-triazole -3-yl)-2-methylbenzoate (compound 91.5) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 274 (M+H) ⁺ .

Compound 91 4-(1-(4-Cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 4-cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl )-2-methylbenzoic acid (compound 91.6) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 414 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 13.84-12.92 (br, 1H), 7.86-7.80 (m, 2H), 7.61-7.53 (m, 3H) , 6.85 (s, 1H), 4.47 (m, 1H), 4.32 (m, 1H), 4.08-3.94 (m, 3H), 2.79 (m, 1H), 0.94 (m, 2H), 0.70 (m, 2H).

Compound 92 4-(1-(4-Cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 4-cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl )-2-methylbenzoic acid (compound 91.6) and 4-(3-fluoroazetidin-3-yl)benzonitrile (compound 43.4) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2), respectively, m/z (ES+) 432 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 13.66-13.01 (br, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.61 (s, 1H), 6.86 (s, 1H), 4.60-4.38 (m, 4H), 3.91 (s, 3H), 2.82 (m, 1H ), 2.34 (s, 3H), 0.94 (m, 2H), 0.71 (m, 2H).

The compounds listed in Table 5 were prepared using standard chemistry and procedures similar to those used to prepare compounds 78 and 79.

The compounds listed in Table 6 were prepared using standard chemistry and procedures similar to those used to prepare compounds 89, 90, 91 and 92.

The compounds listed in Table 7 were prepared using standard chemistry and procedures similar to those used to prepare compounds 62, 63 and 64.

The compounds listed in Table 8 were prepared using standard chemistry and procedures similar to those used to prepare compounds 78, 79, 80 and 81.

The compounds listed in Table 9 were prepared using standard chemistry and procedures similar to those used to prepare compounds 78, 79, 80 and 81.

Compound 95 4-(1-(3-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 250, except for the use of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1 ). m/z (ES+) 391 (M+H) ⁺ .

Connection 101.1. 4-Fluoro-5-iodo-2-methylbenzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 1.3, except for the use of 4-fluoro-2-methylbenzoic acid instead of 2,4-dimethylbenzoic acid.

Compound 101.2. Methyl 4-fluoro-5-iodo-2-methyl benzoate. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 6.1, except for the use of 4-fluoro-5-iodo-2-methylbenzoic acid (compound 101.1) instead of 4-bromo-2-methylbenzoic acids.

Compound 101.3. Methyl 5-cyano-4-fluoro-2-methylbenzoate. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 6.4, except for the use of methyl 4-fluoro-5-iodo-2-methylbenzoate (compound 101.2) instead of methyl 4-cyclobutyl- 5-iodo-2-methylbenzoate (compound 6.3).

Connection 101.4. 4-(1-(4-Fluoro-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 78, except for the use of methyl 5-cyano-4-fluoro-2-methylbenzoate (compound 101.3) instead of methyl 5-cyano- 4-cyclobutyl-2-methylbenzoate (compound 6.4) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 6-(piperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride (compound 78.5 ).

Compound 101 yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 25, except for the use of 4-(1-(4-fluoro-2-methyl-5-(5-methyl-4H-1 ,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 101.4) instead of 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4 -fluorobenzoyl)piperidin-4-yl)benzonitrile (compound 25.1) and piperidine instead of azetidine hydrochloride. m/z (ES+) 469 (M+H) ⁺ .

The compounds listed in Table 10 were prepared using standard chemistry and procedures similar to those used to prepare compound 101.

Compound 132.1. Methyl 4-fluoro-3-iodobenzoate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 6.1, except for the use of 4-fluoro-3-iodobenzoic acid instead of 4-bromo-2-methylbenzoic acid.

Compound 132.2. Methyl 3-(2-bromoacetyl)-4-fluorobenzoate. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 27.3, except for the use of methyl 4-fluoro-3-iodobenzoate (compound 132.1) instead of methyl 3-(2-bromoacetyl)- 4-methylbenzoate (compound 27.2).

Compound 132.3. 4-(1-(4-Fluoro-3-(2-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 1, except for the use of methyl 3-(2-bromoacetyl)-4-fluorobenzoate (compound 132.1) instead of methyl-5-(2 -bromopropanoyl)-2,4-dimethylbenzoate (compound 1.6).

Compound 132 4-(1-(4-(Azetidin-1-yl)-3-(2-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 25, except for the use of 4-(1-(4-fluoro-3-(2-methyl-1H-imidazol-5-yl )benzoyl)piperidin-4-yl)benzonitrile (compound 132.3) instead of 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile (compound 25.1). m/z (ES+) 426 (M+H) ⁺ .

Compound 139 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-methyl-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-) hydrochloride yl)benzonitrile (compound 1.2). m/z (ES+) 382 (M+H) ⁺ .

Compound 151.1. 2-(Morpholin-4-yl)-5-nitropyridine-4-amine. A solution of 2-chloro-5-nitropyridine-4-amine (500 mg, 2.88 mmol) in N,N-dimethylformamide (20 ml) and morpholine (503 μl, 5.77 mmol) were placed in a 50 ml sealed tube. The reaction mixture was stirred overnight at 55°C. The reaction mixture was then quenched by adding 100 ml of water. The reaction mixture was extracted with 3×150 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This gave 733 mg (impure) of the title compound as a yellow solid.

Compound 151.2. 6-Morpholinopyridine-3,4-diamine. 2-(morpholin-4-yl)-5-nitropyridine-4-amine (compound 151.1, 350 mg, 1.56 mmol), methanol (20 ml), THF (10 ml) and Pd /C (35 mg). The above solution was purged with N ₂ and then with H ₂ . The reaction mixture was stirred for 4 hours at room temperature. Solids were filtered off. The resulting mixture was concentrated under reduced pressure. This resulted in 280 mg (92%) of the title compound as a pink solid.

Compound 151.3. 5-Formyl-2,4-dimethylbenzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 4.1, except for the use of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3) instead of 3-bromo-4-methylbenzoic acid.

Compound 151.4. 4-(1-(5-Formyl-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. A solution of 5-formyl-2,4-dimethylbenzoic acid (compound 151.3, 500 mg, 2.81 mmol) in DCM (10 ml) was placed in a 50 ml round bottom flask. 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 545 mg, 2.80 mmol), DIEA (1.4 ml, 8.41 mmol) and HBTU (1.60 g, 4.22 mmol) was added . The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with 150 ml EtOAc, then washed with 2×50 ml NH ₄ Cl (sat.) and 1×50 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/1) as eluent to give 480 mg (54%) of the title compound as a white solid.

Compound 151 4-(1-(2,4-Dimethyl-5-(6-morpholino-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)azetidin-3-yl)benzonitrile. A solution of 4-(1-(5-formyl-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile (compound 151.4, 159 mg, 0.50 mmol) in ethanol (16 ml) was placed in a 50 ml round bottom flask. 6-morpholinopyridine-3,4-diamine (compound 151.2.194 mg, 1.00 mmol) and NH ₄ OAc (308 mg, 4.00 mmol) were added to the reaction mixture. The reaction mixture was stirred for 3 days at 70° C. under air. The pH of the solution was adjusted to 8-9 with sodium bicarbonate (sat.). The reaction mixture was extracted with 1x100 ml of ethyl acetate. The organic layer was washed with 3×50 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-010(Waters)): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.05% TFA and CH ₃ CN (20.0% CH ₃ CN to 36.0% in 10 min, to 100.0% in 1 min, to 20.0% in 2 min); Detector, UV 254 and 220 nm. This resulted in 94.1 mg (38%) of the title compound as a brown solid, m/z (ES+) 493 (M+H) ⁺ .

Compound 152 4-(1-(4-Methyl-3-(6-morpholino-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 151, except for the use of 3-formyl-4-methylbenzoic acid (compound 4.1) instead of 5-formyl-2,4-dimethylbenzoic acid ( compound 151.3). m/z (ES+) 479 (M+H) ⁺ .

Compound 153.1. 6-(Pyrrolidin-1-yl)pyridin-3,4-diamine. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compounds 151.1 and 151.2, except for the use of pyrrolidine instead of morpholine.

Compound 153 yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 151, except for the use of 6-(pyrrolidin-1-yl)pyridin-3,4-diamine (compound 153.1) instead of 6-morpholinopyridine -3,4-diamine (compound 151.2). m/z (ES+) 477 (M+H) ⁺ .

Compound 154 benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 151, except for the use of 3-formyl-4-methylbenzoic acid (compound 4.1) instead of 5-formyl-2,4-dimethylbenzoic acid ( compound 151.3) and 6-(pyrrolidin-1-yl)pyridin-3,4-diamine (compound 153.1) instead of 6-morpholinopyridine-3,4-diamine (compound 151.2). m/z (ES+) 463 (M+H) ⁺ .

Compound 155.1. 6-(Azetidin-1-yl)pyridine-3,4-diamine. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compounds 151.1 and 151.2, except for the use of azetidine instead of morpholine.

Compound 155 . The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 151, except for the use of 3-formyl-4-methylbenzoic acid (compound 4.1) instead of 5-formyl-2,4-dimethylbenzoic acid ( compound 151.3) and 6-(azetidin-1-yl)pyridine-3,4-diamine (compound 155.1) instead of 6-morpholinopyridine-3,4-diamine (compound 151.2). m/z (ES+) 449 (M+H) ⁺ .

Compound 156.1. 3-(2-(Methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 2.3, except for the use of 3-iodobenzoic acid instead of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3).

Compound 156 4-(1-(3-(2-(Methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 2, except for the use of 3-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoic acid ( compound 156.1) instead of 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 2.3). m/z (ES+) 415 (M+H) ⁺ .

Compound 157.1. Methyl 3-(2-(2-hydroxyethyl)-1H-imidazol-5-yl)-4-methylbenzoate. In a 250 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of methyl 3-(2-bromoacetyl)-4-methylbenzoate (compound 27.2, 10 g, 36.89 mmol) in N,N-dimethylformamide ( 150 ml). K ₂ CO ₃ (30 g, 215.5 mmol) and 3-hydroxypropanimidamide hydrochloride (compound 23.1, 15 g, 120.4 mmol) were added to the reaction mixture. The reaction mixture was stirred for 12 hours at 80° C., then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (2:1) as eluent to give 2 g (21%) of the title compound as a light yellow oil.

Compound 157.2. Methyl 3-(2-(2-(azetidin-1-yl)ethyl)-1H-imidazol-5-yl)-4-methylbenzoate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compounds 24.1 and 24, except for the use of methyl-3-(2-(2-hydroxyethyl)-1H-imidazol-5-yl)- 4-methylbenzoate (compound 157.1) instead of 4-(1-(3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile ( compound 23) and azetidine instead of dimethylamine.

Compound 157.3. 3-(2-(2-(Azetidin-1-yl)ethyl)-4-chloro-1H-imidazol-5-yl)-4-methylbenzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compounds 27.4 and 27.5, except for the use of methyl-3-(2-(2-(azetidin-1-yl)ethyl)-1H- imidazol-5-yl)-4-methylbenzoate (compound 157.2) instead of methyl 3-(2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.3).

Compound 157 benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 27, except for the use of 3-(2-(2-(azetidin-1-yl)ethyl)-4-chloro-1H- imidazol-5-yl)-4-methylbenzoic acid (compound 157.3) instead of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5) and hydrochloride 4- (azetidin-3-yl)benzonitrile (compound 5.2) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 460 (M+H) ⁺ .

Compound 158 benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 27, except for the use of 3-(2-(2-(azetidin-1-yl)ethyl)-4-chloro-1H- imidazol-5-yl)-4-methylbenzoic acid (compound 157.3) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 488 (M+H) ⁺ .

Compound 159.1. 2-Isopropyl-4-methyl-1H-imidazole. A solution of isobutyric aldehyde (4.5 ml, 50 mmol) in ethanol (25 ml) was treated with ammonium hydroxide (28% w/w, 25 ml) at 55°C. Methylglyoxal (40% in H ₂ O, 28 ml, 63 mmol) was added dropwise. The resulting mixture was stirred at 60°C for 16 hours, and the solvent was removed under reduced pressure. The precipitate was partitioned between EtOAc (50 ml) and water (30 ml). The organic phase was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ ; 0-4% MeOH in dichloromethane) to give 3.96 g (64%) of the title compound as a yellow solid, m/z (ES+) 125 (M +H) ⁺ .

Compound 159.2. 5-iodine-2-isopropyl-4-methyl-1H-imidazole. 2-Isopropyl-4-methyl-1H-imidazole (3.96 g, 32 mmol) and N-iodosuccinimide (8.33 g, 35 mmol) were dissolved in acetonitrile (100 ml) and heated to boiling for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (50 ml) and water (50 ml). The organic phase was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ ; 0-40% EtOAc in hexane) to give 4.87 g (61%) of the title compound as a yellow solid, m/z (ES+) 251 (M +H) ⁺ .

Connection 160.1. Methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5.4, except for the use of methyl 5-iodo-2,4-dimethylbenzoate (compound 31.1) instead of methyl-3-iodo-4- methyl benzoate (compound 5.3). m/z (ES+) 291(M+H) ⁺ .

Compound 160.2. 2-Cyclopropyl-5-iodo-4-methyl-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 159.2, except for the use of cyclopropanecarbaldehyde instead of isobutyric aldehyde.

Compound 160.3. Methyl 5-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.6, except for the use of methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4 ) and 2-cyclopropyl-5-iodo-4-methyl-1H-imidazole (compound 160.2) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 285 (M+H) ⁺ .

Compound 160.4. 5-(2-Cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of methyl-5-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-2, 4-dimethylbenzoate (compound 160.3) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 271 (M+H) ⁺ .

Compound 160 4-(1-(5-(2-Cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 5-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4- dimethylbenzoic acid (compound 160.4) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 411 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.51 (br, 1H), 7.85-7.80 (m, 2H), 7.62-7.56 (m, 2H), 7.20 and 7.13 (2 singlets, Ar-H, 1H), 7.10 and 7.07 (2 singlets, Ar-H, 1H), 4.49-4.40 (m, 1H), 4.36- 4.28 (m, 1H), 4.06-3.88 (m, 3H), 2.33 and 2.30 (2 singlets, CH ₃ 3H), 2.23 and 2.18 (2 singlets, CH ₃ 3H), 2.07 and 1.93 (2 singlets, amide rotamers, CH ₃ 3H), 1.89-1.82 (m, 1H), 0.88-0.74 (m, 4H).

Compound 161 4-(1-(5-(2-Cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 5-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4- dimethylbenzoic acid (compound 160.4) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4 ) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 429 (M+H) ⁺ . 1 H NMR (400 MHz, DMSO-d6): δ 11.52 (br, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.76 (dd, J=8.4 Hz, 3.2 Hz, 2H), 7.21 (d, J=6.8 Hz, 1H), 7.13 (s, 1H), 4.56-4.34 (m, 4H), 2.35 and 2.32 (2 singlets, CH ₃ 3H), 2.43 and 2.18 (2 singlets, CH ₃ 3H), 2.07 and 1.93 (2 singlets, CH ₃ 3H), 1.90-1, 80(m, 1H), 0.88-0.74(m, 4H).

Compound 159.3. 5-(2-Isopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of 5-iodo-2-isopropyl-4-methyl-1H-imidazole (compound 159.2) instead of 5-iodo- 2,4-dimethyl-1H-imidazole (compound 5.5) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4).

Compound 159 4-(1-(5-(2-Isopropyl-5-methyl-1H-imidazol-4-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. Mixture of 5-(2-isopropyl-5-methyl-1H-imidazol-4-yl)-2,4-dimethylbenzoic acid (compound 159.3, 250 mg, 0.92 mmol), 4-(azetidin-3-yl) hydrochloride benzonitrile (compound 5.2.195 mg, 1.0 mmol), EDCI (264 mg, 1.4 mmol), HOBt (170 mg, 1.0 mmol) and DIEA (640 µl, 3.7 mmol) in DMF (10 ml) was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated NaHCO ₃ and extracted with EtOAc (60 ml). The organic phase was washed with brine (3×20 ml), dried over MgSO ₄ and concentrated under reduced pressure. The precipitate was purified by preparative TLC with 8% methanol in dichloromethane and lyophilized to give 85 mg (22%) of the title compound as a white solid, m/z (ES+) 413 (M+H) ⁺ .

Compound 162 4-(1-(3-(2-Isopropyl-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 159, except for the use of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1 ). m/z (ES+) 399 (M+H) ⁺ .

Compound 163 4-(1-(3-(2-Isopropyl-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 159, except for the use of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-) hydrochloride yl)benzonitrile (compound 5.2) and methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl-2,4 -dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1). m/z (ES+) 427 (M+H) ⁺ .

Compound 164.1. 5-Iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 159.2, except for the use of tetrahydro-2H-pyran-4-carbaldehyde instead of isobutyric aldehyde.

Compound 164.2. 2,4-Dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoic acid. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of 5-iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H- imidazole (compound 164.1) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4).

Compound 164 yl)benzonitrile. 2,4-Dimethyl-5-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)-benzoic acid mixture (compound 164.2, 157 mg, 0.5 mmol) , 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 126 mg, 0.65 mmol), EDCI (143 mg, 0.75 mmol), HOBt (93 mg, 0.55 mmol), and DIEA (345 μl, 2.00 mmol) in DMF (4 ml) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc (30 ml). The organic phase was washed with saturated NaHCO ₃ (10 ml), brine (3×20 ml), dried over MgSO ₄ and concentrated under reduced pressure. The precipitate was purified by preparative TLC with 5% methanol in dichloromethane and lyophilized to give 95 mg (42%) of the title compound as a white solid, m/z (ES+) 455 (M+H) ⁺ .

Compound 165 yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 164, except for the use of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-) hydrochloride yl)benzonitrile (compound 5.2). m/z (ES+) 483 (M+H) ⁺ .

Compound 166 4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 164, except for the use of 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 13.4) instead of 4-(azetidine- 3-yl)benzonitrile (compound 5.2). m/z (ES+) 501 (M+H) ⁺ .

Compound 167 -3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 164, except for the use of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 4-(azetidine- 3-yl)benzonitrile (compound 5.2). m/z (ES+) 459 (M+H) ⁺ .

Compound 168.1. 4-Methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoic acid. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of 5-iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H- imidazole (compound 164.1) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).

Compound 168 benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 164, except for the use of 4-methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl) -1H-imidazol-5-yl)benzoic acid (compound 168.1) instead of 2,4-dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl )benzoic acid (compound 164.2). m/z (ES+) 441 (M+H) ⁺ .

Compound 169 benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 164, except for the use of 4 methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)- 1H-imidazol-5-yl)benzoic acid (compound 168.1) instead of 2,4-dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl) benzoic acid (compound 164.2) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) m/z (ES+) 469 (M+H) ⁺ .

Compound 170 3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 164, except for the use of 4-methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl) -1H-imidazol-5-yl)benzoic acid (compound 168.1) instead of 2,4-dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl )benzoic acid (compound 164.2) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 459 (M+H) ⁺ .

Compound 171.1. 5-Iodo-4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 159.2, except for the use of tetrahydrofuran-3-carbaldehyde instead of isobutyric aldehyde.

Compound 171.2. 2,4-Dimethyl-5-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoic acid. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of 5-iodo-4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazole (compound 171.1 ) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4).

Compound 171 4-(1-(2,4-Dimethyl-5-(5-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-4-yl)benzoyl)azetidin-3-yl)benzonitrile. A mixture of 2,4-dimethyl-5-(5-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-4-yl)benzoic acid (compound 171.2, 100 mg, 0.30 mmol), hydrochloride 4- (azetidin-3-yl)benzonitrile (compound 5.2, 71 mg, 0.37 mmol), EDCI (95 mg, 0.50 mmol), HOBt (20 mg, 0.10 mmol) and DIEA (207 µl, 1, 20 mmol) in DMF (5 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with saturated NaHCO ₃ (10 ml) and extracted with EtOAc (30 ml). The organic phase was washed with brine (3×10 ml), dried over MgSO ₄ and concentrated under reduced pressure. The precipitate was purified by preparative TLC with 6% methanol in dichloromethane and lyophilized to give 16 mg (12%) of the title compound as a white solid, m/z (ES+) 441 (M+H) ⁺ .

Compound 172.1. 4-Methyl-3-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoic acid. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of 5-iodo-4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazole (compound 171.1 ) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).

Compound 172 4-(1-(4-Methyl-3-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 171, except for the use of 4-methyl-3-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazole -5-yl)benzoic acid (compound 172.1) instead of 2,4-dimethyl-5-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoic acid (compound 171.2). m/z (ES+) 427 (M+H) ⁺ .

Compound 173.1. 5-Iodo-4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 159.2, except for the use of tetrahydrofuran-2-carbaldehyde instead of isobutyric aldehyde, m/z (ES+) 279 (M+H) ⁺ .

Compound 173.2. 2,4-Dimethyl-5-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazol-5-yl)benzoic acid. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of 5-iodo-4-methyl-2-tetrahydrofuran-2-yl)-1H-imidazole (compound 173.1) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4).

Compound 173 4-(1-(2,4-Dimethyl-5-(5-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazol-4-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 171, except for the use of 2,4-dimethyl-5-(4-methyl-2-(tetrahydrofuran-2-yl)-1H -imidazol-5-yl)benzoic acid (compound 173.2) instead of 2,4-dimethyl-5-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoic acid (compound 171.2 ). m/z (ES+) 441 (M+H) ⁺ .

Compound 174.1. 4-Methyl-3-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazol-5-yl)benzoic acid. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of 5-iodo-4-methyl-2-(tetrahydrofuran-2-yl)-1H imidazole (compound 173.1) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).

Compound 174 4-(1-(4-Methyl-3-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 171, except for the use of 4-methyl-3-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazole -5-yl)benzoic acid (compound 174.1) instead of 2,4-dimethyl-5-(4-methyl-2(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoic acid (compound 171.2). m/z (ES+) 427 (M+H) ⁺ .

Compound 175.1. 4-Methyl-2-(3-methyloxetan-3-yl)-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to obtain compound 16.2, except for the use of 3-methyloxetane-3-carbaldehyde in place of acetaldehyde and 2-oxopropanal in place of 3,3,3-trifluoro-2- oxopropanal (compound 16.1). m/z (ES+) 153 (M+H) ⁺ .

Compound 175.2. 5-Iodo-4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole. NIS (2.61 g, 11.58 mmol) was added portionwise to a solution of 4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.1, 1.76 g, 11.58 mmol) in acetonitrile (60 ml). The mixture was stirred at room temperature for 1 hour, then partitioned between EtOAc (300 ml) and water (80 ml). The organic layer was washed with saturated sodium thiosulfate (50 ml), brine (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to give the title compound as a light yellow solid (3.0 g, 93 %). m/z (ES+) 279 (M+H) ⁺ .

Compound 175.3. Methyl 2,4-dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.6, except for the use of methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4 ) and 5-iodo-4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.2) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 315 (M+H) ⁺ .

Compound 175.4. 2,4-Dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoic acid. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of methyl-2,4-dimethyl-5-(4-methyl-2-(3-methyloxetane-3- yl)-1H-imidazol-5-yl)benzoate (compound 175.3) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 301 (M+H) ⁺ .

Compound 175 benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 2,4-dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl) -1H-imidazol-5-yl)benzoic acid (compound 175.4) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 441 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.72 (br, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.21 and 7.18 (2 singlets, Ar-H, 1H), 7.13 (s, 1H), 4.90 (d, J=4.8 Hz, 2H), 4.5- 4.43 (m, 1H), 4.12 (d, J=5.6 Hz, 2H), 4.36-4.28 (m, 1H), 4.07-3.90 (m, 3H) , 2.32 (s, 3H), 2.28 and 2.18 (2 singlets, CH ₃ , 3H), 2.13 and 2.00 (2 singlets, CH ₃ 3H), 1.67 (s, 3H ).

Compound 176 -yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 2,4-dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl) -1H-imidazol-5-yl)benzoic acid (compound 175.4) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidine) hydrochloride -3-yl)benzonitrile (compound 43.4) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 459 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.73 (br, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.25 and 7.24 (2 singlets, Ar-H, 1H), 7.19 and 7.16 (2 singlets, Ar-H, 1H), 4.94-4.86 (m, 2H ), 4.57-4.35 (m, 6H), 2.36 and 2.34 (2 singlets, CH ₃ 3H), 2.29 and 2.19 (2 singlets, CH ₃ 3H), 2.14 and 2.00 (2 singlets, CH ₃ 3H), 1.67 (s, 3H).

Compound 177.1. Methyl 4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoate. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5.6, except for the use of 5-iodo-4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole ( compound 175.2) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 301 (M+H) ⁺ .

Compound 177.2. 4-Methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoic acid. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of methyl-4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl) -1H-imidazol-5-yl)benzoate (compound 177.1) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 287 (M+H) ⁺ .

Compound 177 4-(1-(4-Methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H -imidazol-5-yl)benzoic acid (compound 177.2) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 427 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.79 (br, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.60-7.46 (m, 2H), 7.42-7.28 (m, 1H), 4.91 (d, J=5.2 Hz, 2H), 4.76-4 .67 (m, 1H), 4.52-4.36 (m, 4H), 4.09-3.97 (m, 2H), 2.34 and 2.24 (2 singlets, CH ₃ 3H), 2.16 and 2.02 (2 singlets, CH ₃ 3H), 1.68 (s, 3H).

Compound 178 yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H -imidazol-5-yl)benzoic acid (compound 177.2) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidine) hydrochloride -3-yl)benzonitrile (compound 43.4) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 445 (M+H) ⁺ . 1 H NMR (400 MHz, DMSO-d6): δ 11.80 (br, 1H), 7.96 (dd, J=8.0 Hz, 2.4 Hz, 2H), 7.80 (d, J= 8.4 Hz, 2H), 7.67-7.52 (m, 2H), 7.44-7.33 (m, 1H), 4.95-4.89 (m, 2H), 4.89 -4.46 (m, 4H), 4.46-4.40 (m, 2H), 3.36 and 2.26 (2 singlets, CH ₃ 3H), 2.17 and 2.03 (2 singlets, CH ₃ 3H), 1.69 and 1.68 (2 singlets, CH ₃ 3H).

Compound 179 4-(1-(4-Methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H -imidazol-5-yl)benzoic acid (compound 177.2) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(piperidin-4-yl) hydrochloride )benzonitrile (compound 1.2) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 455 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.78 (br, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.40-7.23 (m, 3H), 4.92 (t, J=6.0 Hz, 5.2 Hz, 2H), 4.78-4.52 (m, 1H), 4.43 (t, J=5.2 Hz, 4.8 Hz, 2H), 3.91-3.71 (m, 1H), 3.24-3.08 (m, 1H), 2.98 -2.88 (m, 2H), 2.34 and 2.25 (2 singlets, CH ₃ 3H), 2.16 and 2.03 (2 singlets, amide rotamers, CH ₃ 3H), 1.91-1 .59 (m, 4H), 1.69 and 1.68 (2 singlets, CH ₃ 3H).

Compound 180.1. 4-Methyl-2-(oxetan-3-yl)-1H-imidazole. Dess-Martin reagent (4.33 g, 10.21 mmol) was added to a solution of oxetan-3-ylmethanol (0.9 g, 10.21 mmol) in CH ₂ Cl ₂ (10 ml) at 0°C. The mixture was stirred at 0°C for 30 minutes and at room temperature for 2 hours. CH ₂ Cl ₂ was then removed under reduced pressure. The precipitate was dissolved in EtOH (10 ml). NH ₄ OH (5 ml) was added followed by 2-oxopropanal (40% in water, 2.76 ml, 15.32 mmol). The mixture was stirred at room temperature for 4 hours. Water (10 ml) was added to the mixture and the mixture was lyophilized. The dried residue was purified by column chromatography (2.5% MeOH to 5% MeOH in CH ₂ Cl ₂ ) to give the title product as a brown oil (0.61 g, 43.3% over two steps), m/z (ES+) 139 (M+H) ⁺ .

Compound 180.2. 5-Iodo-4-methyl-2-(oxetan-3-yl)-1H-imidazole. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 175.2, except for the use of 4-methyl-2-(oxetan-3-yl)-1H-imidazole (compound 180.1) instead of 4- methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.1). m/z (ES+) 265 (M+H) ⁺ .

Compound 180.3. Methyl 2,4-dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.6, except for the use of methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4 ) and 5-iodo-4-methyl-2-(oxetan-3-yl)-1H-imidazole (compound 180.2) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 301 (M+H) ⁺ .

Compound 180.4. 2,4-Dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoic acid. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of methyl-2,4-dimethyl-5-(4-methyl-2-(oxetan-3-yl) -1H-imidazol-5-yl)benzoate (compound 180.3) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 287 (M+H) ⁺ .

Compound 180 4-(1-(2,4-Dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 2,4-dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H -imidazol-5-yl)benzoic acid (compound 180.4) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 427 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.81 (br, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7 .26-7.10(m, 2H), 4.87-4.75(m, 4H), 4.51-4.42(m, 1H), 4.37-4.21(m, 2H) , 4.07-3.91 (m, 3H), 2.33 (s, 3H), 2.27 and 2.19 (2 singlets, CH ₃ 3H), 2.12 and 2.02 (2 singlets, CH ₃ 3H).

Compound 181 ) benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 2,4-dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H -imidazol-5-yl)benzoic acid (compound 180.4) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidine-3) hydrochloride -yl)benzonitrile (compound 43.4) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 445 (M+H) ⁺ . 1 H NMR (400 MHz, DMSO-d6): δ 11.80 (br, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 7.18 (d, J=7.2 Hz, 2H), 4.87-4.75 (m, 4H), 4.60-4.36 (m , 4H), 4.31-4.21 (m, 1H), 2.35 (s, CH ₃ , 3H), 2.90 and 2.20 (2 singlets, CH ₃ 3H), 2.13 and 2 .02 (2 singlets, CH ₃ 3H).

Compound 182.1. tert-Butyl 4-(5-iodo-4-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 159.2, except for the use of tert-butyl-4-formylpiperidine-1-carboxylate instead of isobutyric aldehyde, m/z (ES+) 392 (M +H) ⁺ .

Compound 182.2. 3-(2-(1-(T-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of tert-butyl-4-(5-iodo-4-methyl-1H-imidazol-2-yl)piperidine -1-carboxylate (compound 182.1) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5)

Compound 182.3. tert-Butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate. A mixture of 3-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 182.2, 506 mg), hydrochloride 4-( azetidin-3-yl)benzonitrile (Compound 5.2, 296 mg, 1.52 mmol), EDCI (315 mg, 1.65 mmol), HOBt (107 mg, 0.64 mmol) and DIEA (877 µl, 5.08 mmol) in DMF (25 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with saturated NaHCO ₃ (20 ml) and extracted with EtOAc (50 ml). The organic phase was washed with brine (3×10 ml), dried over MgSO ₄ and concentrated under reduced pressure. The precipitate was purified by preparative TLC with 8% methanol in dichloromethane to give 476 mg (69%) of the title compound as a foam, m/z (ES+) 540 (M+H) ⁺ .

Compound 182 4-(1-(4-Methyl-3-(4-methyl-2-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. To a solution of tert-butyl-4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1- carboxylate (compound 182.3, 475 mg, 0.88 mmol) in 20 ml CH ₂ Cl ₂ , trifluoroacetic acid (4 ml) was added. The reaction mixture was stirred for 1.5 hours and concentrated under reduced pressure, neutralized with 10 ml of Na ₂ CO ₃ (1 M) and lyophilized to obtain 4-(1-(4-methyl-3-(4-methyl-2-( piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. Mixture of 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (135 mg, 0 .31 mmol), formic acid (300 μl, 6.76 mmol), formaldehyde (37% in water, 300 μl, 3.41 mmol) and water (1.5 ml) were heated to boiling for 10 hours. The reaction mixture was diluted with saturated NaHCO ₃ to reach pH 9 and was extracted with CH ₂ Cl ₂ (3×20 ml). The precipitate was purified by preparative TLC with 10% methanol and 1% ammonium hydroxide in dichloromethane and lyophilized to give 43 mg (30% two steps) of the title compound as a white solid, m/z (ES+) 540 (M +H) ⁺ .

Compound 183 4-(1-(3-(2-(1-Acetylpiperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. To a solution of tert-butyl-4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1- carboxylate (compound 182.3, 475 mg, 0.88 mmol) in 20 ml DCM was added trifluoroacetic acid (4 ml). The reaction mixture was stirred for 1.5 hours, concentrated under reduced pressure and neutralized with 10 ml of Na ₂ CO ₃ (1 M) to obtain the crude product after lyophilization. Mixture of 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (252 mg, 0 .57 mmol), acetic anhydride (71 μl, 0.75 mmol) and triethylamine (120 μl, 0.86 mmol) were stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, then diluted with saturated NaH ₂ PO ₄ (20 ml) and extracted with EtOAc (3×20 ml). The organic phase was dried over MgSO ₄ and concentrated under reduced pressure. The precipitate was purified by preparative TLC with 10% methanol in dichloromethane and lyophilized to give 235 mg (80% - 2 steps) of the title compound as a white solid, m/z (ES+) 482 (M+H) ⁺ .

Compound 184 . To a solution of tert-butyl-4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidin-1- carboxylate (compound 182.3, 227 mg, 0.42 mmol) in CH ₂ Cl ₂ (10 ml) trifluoroacetic acid (2 ml) was added. The reaction mixture was stirred for 1.5 hours and concentrated under reduced pressure. The reaction mixture was neutralized with 2 ml of Na ₂ CO ₃ (1 M) to give the crude intermediate after lyophilization. Mixture of 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (185 mg, 0 .42 mmol) and diisopropylethylamine (363 μl, 2.1 mmol) were dissolved in DMF (6 ml). Methyl chloroformate (36 μl, 0.46 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, diluted with saturated NaH ₂ PO ₄ (20 ml) and was extracted with EtOAc (3×20 ml). The organic phase was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The precipitate was purified by preparative TLC with 10% methanol in dichloromethane and lyophilized to give 141 mg (67%, over 2 steps) of the title compound as a white solid, m/z (ES+) 498 (M+H) ⁺ .

Compound 185.1. tert-Butyl 4-(5-iodo-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 159.2, except for the use of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate instead of isobutyric aldehyde, m/z (ES+ ) 406 (M+H) ⁺ .

Compound 185.2. 3-(2-(1-(tert-Butoxycarbonyl)-4-methylpiperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of tert-butyl-4-(5-iodo-4-methyl-1H-imidazol-2-yl)- 4-methylpiperidine-1-carboxylate (compound 185.1) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).

Compound 185.3. tert-Butyl-4-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)-4-methylpiperidin-1 -carboxylate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 182.3, except for the use of 3-(2-(1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl)-4 -methyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 185.2) instead of 3-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-imidazol-5 -yl)-4-methylbenzoic acid (compound 182.2).

Compound 185 1-carboxylate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 184, except for the use of tert-butyl-4-(5-(5-(3-(4-cyanophenyl)azetidine-1- carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate (compound 185.3) instead of tert-butyl-4-(4-(5-(3-(4 -cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3). m/z (ES+) 512 M+H ⁺ .

Compound 186 -methylpiperidine-1-carboxylate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 184, except for the use of tert-butyl-4-(5-(5-(3-(4-cyanophenyl)azetidine-1- carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate (compound 185.3) instead of tert-butyl-4-(4-(5-(3-(4 -cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 434) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 530 (M+H) ⁺ .

Compound 187 -yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 159, except for the use of 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde instead of isobutyric aldehyde and methyl-4-methyl- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl-2,4-dimethyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1). m/z (ES+) 455 (M+H) ⁺ .

Compound 188.1. Ethyl 4-methyltetrahydro-2H-pyran-4-carboxylate. A 500 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was charged with a solution of ethyl tetrahydro-2H-pyran-4-carboxylate (8 g, 50.6 mmol) in tetrahydrofuran (100 ml). After that, LDA (50 ml, 101.1 mmol, 2 M in THF) was added dropwise at -78°C and stirred for 3 h. A solution of CH ₃ I (9.5 ml, 151.9 mmol) in tetrahydrofuran (50 ml) at -78°C. The reaction mixture was stirred for 3 h at -78°C, then carefully quenched with 400 ml of NH ₄ Cl (sat.). The aqueous phase was extracted with 300 ml of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 8 g (92%) of the title compound as a yellow oil.

Compound 188.2. (4-Methyltetrahydro-2H-pyran-4-yl)methanol. Into a 100 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of ethyl 4-methyltetrahydro-2H-pyran-4-carboxylate (compound 188.1, 500 mg, 2.90 mmol) in tetrahydrofuran (12 ml) . Lithium aluminum hydride (221 mg, 5.82 mmol) was then added in portions at 0°C. The reaction mixture was stirred for 1 h at room temperature, then carefully quenched with 1.2 ml H ₂ O, 1.2 ml NaOH (15%), 3.5 ml H ₂ O. Solids were removed by filtration, and the filtrate was concentrated under reduced pressure. This gave 300 mg (impure) of the title compound as a yellow oil.

Compound 188.3. 4-Methyltetrahydro-2H-pyran-4-carbaldehyde. A solution of (4-methyltetrahydro-2H-pyran-4-yl)methanol (compound 188.2, 300 mg, 2.30 mmol) in dichloromethane (15 ml) was placed in a 100 ml three-necked round bottom flask. The Dess-Martin reagent (1.17 g, 2.76 mmol) was added to the reaction mixture. The reaction mixture was stirred for 2 h at room temperature, then quenched with 15 ml of water. The aqueous phase was extracted with 20 ml dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 200 mg (68%) of the title compound as a yellow oil.

Compound 188 yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 159, except for the use of 4-methyltetrahydro-2H-pyran-4-carbaldehyde (compound 188.3) instead of isobutyric aldehyde and methyl-4-methyl -3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl-2,4-dimethyl-5-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1). m/z (ES+) 455 (M+H) ⁺ .

Compound 189.1. tert-Butyl 3-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)azetidine-1-carboxylate. The title compound was prepared using standard chemistry and procedures similar to those used for compound 182.3, except for the use of t-butyl-3-formylazetidine-1-carboxylate instead of t-butyl-formylpiperidine-1-carboxylate.

Compound 189.2. 4-(1-(3-(2-(Azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. A solution of tert-butyl-3-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazole-2- yl)azetidine-1-carboxylate (compound 189.1, 2 g, 3.91 mmol) in 1,4-dioxane (20 ml). Hydrogen chloride (4 M) (10 ml) was added to the reaction mixture. The reaction mixture was stirred for 2 hours at 30° C., then concentrated under reduced pressure. The pH of the solution was adjusted to 7-8 with sodium bicarbonate (sat.). The resulting mixture was concentrated under reduced pressure to give 800 mg (impure) of the title compound as a white solid.

Compound 189 4-(1-(3-(2-(1-Acetylazetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. A solution of 4-(1-(3-(2-(azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl) was placed into a 25 ml round bottom flask. benzonitrile (compound 189.2, 80 mg, 0.19 mmol) in N,N-dimethylformamide (1 ml). Triethylamine (27 μl, 0.20 mmol) and acetic anhydride (19 μl, 0.20 mmol) were added to the reaction mixture. The reaction mixture was stirred for 2 h at room temperature, then quenched with 10 ml of water. The aqueous phase was extracted with 3×3 ml of ethyl acetate and the combined organic extracts were concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC under the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 50 mmol NH ₄ HCO ₃ and MeCN (28% MeCN to 40% in 7 minutes, to 100% in 2 minutes, to 28% in 1 minute); Detector, Waters 2489 255 and 220 nm. This resulted in 32.8 mg (37%) of the title compound as a white solid, m/z (ES+) 454 (M+H) ⁺ .

Compound 190 . A solution of 4-(1-(3-(2-(azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl) was placed into a 25 ml round bottom flask. benzonitrile (compound 189.2, 100 mg, 0.24 mmol) in N,N-dimethylformamide (2 ml). Methyl chloroformate (33 μl, 0.42 mmol) and triethylamine (34 μl, 0.25 mmol) were added to the reaction mixture. The reaction mixture was stirred for 2 h at room temperature, then quenched with 10 ml of water. The aqueous phase was extracted with 3×5 ml of ethyl acetate. The combined organic layers were washed with 3×3 ml brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography with dichloromethane/methanol (10:1). The crude product (100 mg) was purified by preparative HPLC under the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 50 mmol NH ₄ HCO ₃ and MeCN (33.0% MeCN to 45.0% in 7 minutes, to 100.0% in 2 minutes, to 33.0% in 1 minute); Detector, Waters 2489, 254 and 220 nm. This resulted in 21.5 mg (19%) of the title compound as a white solid, m/z (ES+) 470 (M+H) ⁺ .

Compound 191 4-(1-(4-Methyl-3-(4-methyl-2-(1-methylazetidin-3-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. A solution of 4-(1-(3-(2-(azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl) was placed into a 50 ml round bottom flask. benzonitrile (compound 189.2, 50 mg, 0.12 mmol) in tetrahydrofuran (1 ml). Formaldehyde (65 µl, 37 wt%, 0.57 mmol) and NaBH ₃ CN (30 mg, 0.48 mmol) were added to the reaction mixture. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with 3x3 ml ethyl acetate and the combined organic extracts were washed with 3x1 ml brine and concentrated under reduced pressure. The crude product (20 mg) was purified by preparative HPLC under the following conditions (Prep-HPLC-020): Column, XBridge Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.03% NH ₃ H ₂ O and MeCN (26.0% MeCN to 40.0% in 7 minutes, to 100.0% in 2 minutes, to 26.0% in 1 minute); Detector, Waters 2489, 254 and 220 nm. This resulted in 1.8 mg (3%) of the title compound as a white solid, m/z (ES+) 426 (M+H) ⁺ .

Compound 192.1. 4-Methyl-1-((2-(trimethylylyl)ethoxy)methyl)-1H-imidazole. Into a 1 L three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 4-methyl-1H-imidazole (10 g, 121.8 mmol) in tetrahydrofuran (200 ml). Sodium hydride (7.32 g, 182.7 mmol, 60%) was then added in portions at 0° C. and stirred for 1 hour at room temperature. SEM-Cl (30.5 g, 199.7 mmol) was added to the mixture at 0°C. The mixture was stirred for 1 hour at room temperature, then carefully quenched with 50 ml of brine. The aqueous phase was extracted with 1×800 ml of ethyl acetate. The organic layer was washed with 1 x 300 ml brine, 2 x 300 ml sodium bicarbonate (sat.), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/ethyl acetate-petroleum ether (1:1) as eluent to give 9 g (35%) of the title compound as a yellow oil.

Compound 192.2. 3-(4-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol. Into a 1000 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound 192.1, 9 g, 42.38 mmol) in tetrahydrofuran (200 ml). Then n-BuLi (34 ml, 2.5M in THF) was added dropwise at -78°C and stirred for 1 h. Oxetan-3-one solution (6.11 g, 84.79 mmol ) in tetrahydrofuran (30 ml) at -78°C. The reaction mixture was stirred for 1 h at -78°C, then quenched with 50 ml of NH ₄ Cl (sat.). The aqueous phase was extracted with 1×600 ml of ethyl acetate. The organic layer was washed with 3×300 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gave 13 g (impure) of the title compound as a light yellow solid.

Compound 192.3. 3-(5-Iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol. A solution of 3-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol (compound 192.2, 200 mg, 0 .70 mmol) in ACN (10 ml). NIS (237.7 mg, 1.06 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The reaction mixture was diluted with 40 ml EtOAc. The organic layer 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 with ethyl acetate/petroleum ether (2:3) as eluent to give 100 mg (35%) of the title compound as an orange oil.

Compound 192.4. Methyl 3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-4-methylbenzoate. Into a 100 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of methyl 4-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 282.7 mg, 1.02 mmol) in dioxane (12 ml). To the reaction mixture was added a solution of K ₃ PO ₄ (904.9 mg, 4.26 mmol) in water (1.2 ml), 3-(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-imidazol-2-yl)oxetan-3-ol (compound 192.3, 350 mg, 0.85 mmol) and Pd(dppf) ₂ Cl ₂ (62.4 mg, 0.09 mmol). The mixture was stirred for 7 hours. The reaction mixture was cooled, then diluted with 60 ml of EtOAc. The solids were removed by filtration, the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (2:3) as eluent to give 220 mg (60%) of the title compound as an orange oil.

Compound 192.5. Methyl 3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate. Methyl-3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl) was placed into a 100 ml round bottom flask. -4-methylbenzoate (compound 192.4, 180 mg, 0.42 mmol), Et ₃ SiH (1 ml) and trifluoroacetic acid (2 ml). The reaction mixture was stirred for 4 hours at room temperature. The pH of the solution was adjusted to 8 with sodium hydroxide (1M). The reaction mixture was diluted with 100 ml of brine. The aqueous phase was extracted with 2×30 ml of ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gave 150 mg (impure) of the title compound as an orange oil.

Compound 192 4-(1-(3-(2-(3-Hydroxyoxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of methyl-3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1H-imidazole -5-yl)-4-methylbenzoate (compound 192.5) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 429 (M+H) ⁺ .

Compound 193 4-(1-(3-(2-(3-Fluoroxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. Into a 50 ml three-neck round-bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 4-(1-(3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1H-imidazol-5- yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 192, 200 mg, 0.47 mmol) in dichloromethane (5 mL). Then a solution of DAST (76.2 μl, 0.58 mmol) in dichloromethane (1 ml) was added dropwise at -78°C. The resulting solution was stirred for 1 hour at room temperature, then quenched by adding 2 ml of sodium bicarbonate (sat.). The resulting solution was diluted with 60 ml of EtOAc and additional water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eluent. The crude product (50 mg) was purified by preparative HPLC under the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (18.0% MeCN to 28.0% in 9 min, to 100.0% in 2 min, to 18.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 15.1 mg (8%) of the title compound as a white solid, m/z (ES+) 431 (M+H) ⁺ .

Compound 194.1. 5-Iodo-2-(3-methoxyoxetan-3-yl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole. A solution of 3-(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol (compound 192.3, 800 mg, 1.95 mmol) in tetrahydrofuran (30 ml). Sodium hydride (156.2 mg, 3.9 mmol, 60%) was then added at 0° C. and stirred for 20 minutes at room temperature. CH ₃ I (554.1 mg, 3.90 mmol) was added to the mixture at 0°C. The resulting solution was stirred for 5 h at room temperature, then quenched with 30 ml of Na ₂ S ₂ O ₃ (sat.). The aqueous phase was extracted with 3×40 ml ethyl acetate, the combined organic layers were washed with 3×40 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as eluent to give 700 mg (85%) of the title compound as a colorless oil.

Compound 194 4-(1-(3-(2-(3-Methoxyoxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 192, except for the use of 5-iodo-2-(3-methoxyoxetan-3-yl)-4-methyl-1-(( 2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound 194.1) instead of 3-(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl )oxetan-3-ol (compound 192.3). m/z (ES+) 443 (M+H) ⁺ .

Compound 195 ) benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 192, except for the use of dihydro-2H-pyran-4(3H)-one instead of oxetan-3-one. m/z (ES+) 457 (M+H) ⁺ .

Compound 196 ) benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 194, except for the use of dihydro-2H-pyran-4(3H)-one instead of oxetan-3-one. m/z (ES+) 471 (M+H) ⁺ .

Compound 197.1. Pyrrolidine-1-carboximidamide hydrochloride. In a 100 ml round bottom flask was placed a solution of pyrrolidine (5.8 ml, 70.30 mmol) in CH ₃ CN (30 ml). Triethylamine (9.8 ml, 70.17 mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (10.2 g, 69.59 mmol) were added to the reaction mixture. The reaction mixture was stirred overnight at 60°C. The product was collected by filtration to give 7.5 g (71%) of the title compound as a white solid.

Compound 197.2. Methyl 3-(2-bromopropanoyl)-4-methylbenzoate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 1.6, except for the use of 4-methylbenzoic acid instead of 2,4-dimethylbenzoic acid.

Compound 197.3. Methyl 4-methyl-3-(4-methyl-2-(pyrrolidin-1-yl)-1H-imidazol-5-yl)benzoate. In a 50 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of methyl 3-(2-bromopropanoyl)-4-methylbenzoate (compound 197.2, 500.0 mg, 1.75 mmol) in N,N- dimethylformamide (15 ml). Pyrrolidine-1-carboximidamide hydrochloride (compound 197.1, 260.8 mg, 1.75 mmol) was treated with K ₂ CO ₃ then added to the reaction mixture. The reaction mixture was stirred for 1 h at 50°C. The reaction mixture was diluted with 30 ml H ₂ O. The aqueous phase was extracted with 3×30 ml ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The precipitate was purified by silica gel chromatography with PE/EtOAc (1:1)~EtOAc/methanol (15:1) as eluent to give 230.0 mg (44%) of the title compound as a dark blue solid substances.

Compound 197 4-(1-(4-Methyl-3-(4-methyl-2-(pyrrolidin-1-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to prepare compound 1, except for the use of methyl-4-methyl-3-(4-methyl-2-(pyrrolidin-1-yl)-1H -imidazol-5-yl)benzoate (compound 197.3) instead of methyl 5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 1.7) and 4-(azetidine-3) hydrochloride -yl)benzonitrile (compound 5.2) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 426 (M+H) ⁺ .

Compound 198.1. 1-(4-Methyl-1H-imidazol-2-yl)ethanone. An aqueous solution of 2-oxopropanal (25.2 ml, 222.0 mmol, 50%) was placed in a 500 ml round bottom flask. Ammonium acetate (85 g, 1.10 mol) and acetic acid (200 ml) were added to the reaction mixture. The reaction mixture was stirred overnight at 100°C, then concentrated under reduced pressure. The precipitate was diluted with 300 ml EtOAc. The organic layer 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 chromatography with ethyl acetate/hexane (1:1) as eluent to give 1.5 g (11%) of the title compound as a yellow solid.

Compound 198.2. Methyl 5-(2-acetyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.6, except for the use of methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4 ) and 1-(4-,ethyl-1H-imidazol-2-yl)ethanone (compound 198.1) instead of 2,4-dimethyl-1H-imidazole.

Compound 198.3. Methyl 5-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate. A solution of methyl 5-(2-acetyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 198.2, 300 mg, 1.10 mmol) in methanol ( 30 ml). Then NaBH ₄ (84 mg, 2.22 mmol) was added portionwise at 0°C. The resulting solution was stirred for 1 h at room temperature, then carefully quenched with 1 ml of aqueous hydrogen chloride (2 M). The resulting mixture was concentrated under reduced pressure. This gave 330 mg (impure) of the title compound as a white solid.

Compound 198 4-(1-(5-(2-(1-Hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of methyl 5-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl )-2,4-dimethylbenzoate (compound 198.3) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 415 (M+H) ⁺ .

Compound 199 . The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 198, except for the use of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 4-(azetidine- 3-yl)benzonitrile (compound 5.2). m/z (ES+) 433 (M+H) ⁺ .

Connection 200.1. Methyl 3-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 198.3, except for the use of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1 ).

Compound 200 4-(1-(3-(2-(1-Hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 198, except for the use of methyl-3-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl )-4-methylbenzoate (compound 200.1) instead of methyl 5-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 198.3). m/z (ES+) 401 (M+H) ⁺ .

Compound 201 4-(3-Fluoro-1-(3-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to prepare compound 200, except for the use of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 4-(azetidine- 3-yl)benzonitrile (compound 5.2). m/z (ES+) 419 (M+H) ⁺ .

Connection 202.1. 2-(3-Methyloxetan-3-yl)-4-(trifluoromethyl)-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 16.2, except for the use of 3-methyloxetane-3-carbaldehyde instead of acetaldehyde. m/z (ES+) 207 (M+H) ⁺ .

Connection 202.2. 5-Iodo-2-(3-methyloxetan-3-yl)-4-(trifluoromethyl)-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 175.2, except for the use of 2-(3-methyloxetan-3-yl)-4-(trifluoromethyl)-1H-imidazole (compound 202.1 ) instead of 4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.1). m/z (ES+) 333 (M+H) ⁺ .

Connection 202.3. 5-Iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 16.3, except for the use of 5-iodo-2-(3-methyloxetan-3-yl)-4-(trifluoromethyl)-1H- imidazole (compound 202.2) instead of 2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2). m/z (ES+) 290 (M+H) ⁺ .

Connection 202.4. Methyl 3-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-4-methylbenzoate. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5.6, except for the use of 5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile ( compound 202.3) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 312 (M+H) ⁺ .

Connection 202.5. 3-(4-Cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-4-methylbenzoic acid. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of methyl-3-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazole -5-yl)-4-methylbenzoate (compound 202.4) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 298 (M+H) ⁺ .

Compound 202 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 3-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5 -yl)-4-methylbenzoic acid (compound 202.5) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 438 (M+H) ⁺ . 1 H NMR (400 MHz, DMSO-d6): δ 13.13 (br, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.73-7.66 (m, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.0 Hz, 1H), 4.95 (d, J=5.6 Hz, 2H), 4. 78-4.70 (m, 1H), 4.57-4.45 (m, 2H), 4.46 (d, J=5.6 Hz, 2H), 4.11-4.01 (m, 2H), 2.39 (s, 3H), 1.71 (s, 3H).

Compound 203.1. Methyl 5-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.6, except for the use of methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4 ) and 5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile (compound 202.3) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 326 (M+H) ⁺ .

Connection 203.2. 5-(4-Cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5.7, except for the use of methyl 5-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazole -5-yl)-2,4-dimethylbenzoate (compound 203.1) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 312 (M+H) ⁺ .

Compound 203 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5 -yl)-2,4-dimethylbenzoic acid (compound 203.2) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 452 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 13.01 (br, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.38 (s, 1H), 7.24 (s, 1H), 4.94 (d, J=5.2 Hz, 2H), 4.53-4.32 (m, 4H), 4.09-3.96 (m, 3H), 2.36 (s, 3H), 2.35 (s, 3H), 1.68 (s, 3H).

Compound 204 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-cyclopropyl-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of cyclopropanecarbaldehyde instead of acetaldehyde and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-( piperidin-4-yl)benzonitrile (compound 1.2). m/z (ES+) 408 (M+H) ⁺ .

Compound 205 5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-2-cyclopropyl-1H-imidazole-4-carbonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 16, except for the use of cyclopropanecarbaldehyde instead of acetaldehyde. m/z (ES+) 436 (M+H) ⁺ .

Compound 206 5-(5-(3-(4-Cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2,4-dimethylphenyl)-2-cyclopropyl-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of cyclopropanecarbaldehyde instead of acetaldehyde and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of hydrochloride 4 -(piperidin-4-yl)benzonitrile (compound 1.2) and methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 440 (M+H) ⁺ .

Compound 207 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-2-cyclopropyl-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of cyclopropanecarbaldehyde instead of acetaldehyde, 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-( piperidin-4-yl)benzonitrile (compound 1.2) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 422 (M+H) ⁺ .

Compound 208 5-(5-(3-(4-Cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2,4-dimethylphenyl)-2-methyl-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 4-(piperidine- 4-yl)benzonitrile (compound 1.2) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl -4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 414 (M+H) ⁺ .

Compound 209 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-2-methyl-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-) hydrochloride yl)benzonitrile (compound 1.2) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl-4 -methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 396 (M+H) ⁺ .

Compound 210 5-(5-(3-(4-Cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2,4-dimethylphenyl)-2-isopropyl-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 4-(piperidine- 4-yl)benzonitrile (compound 1.2), methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl -4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and isobutyric aldehyde instead of acetaldehyde. m/z (ES+) 442 (M+H) ⁺ .

Compound 211 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-) hydrochloride yl)benzonitrile (compound 1.2) and tetrahydro-2H-pyran-4-carbaldehyde instead of acetaldehyde. m/z (ES+) 452 (M+H) ⁺ .

Compound 212 carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-) hydrochloride yl)benzonitrile (compound 1.2), tetrahydro-2H-pyran-4-carbaldehyde instead of acetaldehyde and methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 466 (M+H) ⁺ .

Compound 213 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-(tetrahydrofuran-2-yl)-1H-imidazole-4-carbonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 16, 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) and tetrahydrofuran-2-carbaldehyde instead of acetaldehyde. m/z (ES+) 438 (M+H) ⁺ .

Compound 214 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-(tetrahydrofuran-3-yl)-1H-imidazole-4-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-) hydrochloride yl)benzonitrile (compound 1.2) and tetrahydrofuran-3-carbaldehyde instead of acetaldehyde. m/z (ES+) 438 (M+H) ⁺ .

Compound 215 carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-) hydrochloride yl)benzonitrile (compound 1.2) and 4-methyltetrahydro-2H-pyran-4-carbaldehyde (compound 188.3) instead of acetaldehyde. m/z (ES+) 466 (M+H) ⁺ .

Compound 216.1. 4-(Trifluoromethyl)-1H-imidazole. A solution of 3,3,3-trifluoro-2-oxopropanal (143 ml, 111.1 mmol) in a solvent mixture of methanol and water (200/200 ml) was placed in a 1000 ml round bottom flask. An aqueous solution of formaldehyde (350 ml, 116.67 mmol, 35%) and ammonium hydroxide (30 ml, 25%) were added to the reaction mixture. The resulting solution was stirred for 2 hours at room temperature, then concentrated under reduced pressure. The solids were collected by filtration to give 2 g (13%) of the title compound as a white solid.

Compound 216.2. 4-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole. Into a 250 ml three-neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 4-(trifluoromethyl)-1H-imidazole (compound 216.1, 5 g, 36.74 mmol) in tetrahydrofuran (100 ml). Sodium hydride (1.6 g, 40.00 mmol, 60%) was then added portionwise at 0°C and stirred for 1 hour at 0°C. SEMCl (7.1 ml, 40.36 mmol) was added dropwise to the mixture at 0°C. The resulting solution was stirred for 4 hours at 0°C, then carefully quenched with 100 ml of saline. The pH of the solution was adjusted to 7-8 with hydrogen chloride (1 M). The aqueous phase was extracted with 2×100 ml of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:5) as eluent to give 6 g (61%) of the title compound as a light yellow oil.

Compound 216.3. 4-(4-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)tetrahydro-2H-pyran-4-ol. Into a 100 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound 216.2, 5 g, 18 .77 mmol) in tetrahydrofuran (50 ml). Then n-butyllithium (9 ml, 22.5 mmol, 2.5N in hexane) was added dropwise at -78°C and stirred for 1 h at -60°C. Dihydro-2H-pyran-4(3H)-one (6 g, 59.93 mmol) was added to the mixture. The resulting solution was stirred for 4 hours at 0° C. in an ice/salt bath, then quenched with 10 ml of water. The resulting solution was diluted with 100 ml of NH ₄ Cl (sat.). The aqueous phase was extracted with 2×100 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:4) as eluent to give 6 g (87%) of the title compound as a light yellow oil.

Compound 216.4. 4-(4-(Trifluoromethyl)-1H-imidazol-2-yl)tetrahydro-2H-pyran-4-ol. 4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxymethyl)-1H-imidazol-2-yl)tetrahydro-2H-pyran-4-ol (compound 216.3, 2 g, 5.46 mmol), Et ₃ SiH (2 ml) and trifluoroacetic acid (4 ml).The resulting solution was stirred for 2 h at room temperature.The pH of the solution was adjusted to 8 with sodium hydroxide (1 M).The resulting solution diluted with 100 ml brine The aqueous phase was extracted with 2 x 100 ml ethyl acetate The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.2 g (93%) of the title compound as white solid.

Compound 216 carbonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 16, except for the use of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)tetrahydro-2H-pyran-4 -ol (compound 216.4) instead of 2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-yl) hydrochloride )benzonitrile (compound 1.2). m/z (ES+) 468 (M+H) ⁺ .

Compound 217.1. 2-(4-Methoxytetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole. Into a 250 ml three-necked round-bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) tetrahydro-2H-pyran-4-ol (compound 216.3, 2 g, 5.46 mmol) in tetrahydrofuran (100 ml). Sodium hydride (262 mg, 6.55 mmol, 60%) was then added at -70° C. and stirred for 30 minutes. MeI (930 mg, 6.55 mmol) was added to the mixture. The resulting solution was stirred for 1 h at room temperature, then carefully quenched with 10 ml of water. The resulting mixture was diluted with 50 ml of saline. The aqueous phase 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 reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) as eluent to give 1.6 g (77%) of the title compound as a light brown oil.

Compound 217.2. 2-(4-Methoxytetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole. 2-(4-Methoxytetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound 217.1, 1.3 g, 3.42 mmol), trifluoroacetic acid (4 ml), Et ₃ SiH (2 ml). The resulting solution was stirred overnight at 20°C, then extinguished by adding 20 ml of water. The pH of the solution was adjusted to 8 with sodium hydroxide (1M). The aqueous phase was extracted with 2×100 ml of ethyl acetate. The combined organic layers were washed with 2×50 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gave 1 g (impure) of the title compound as a light yellow oil.

Compound 217 carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of 2-(4-methoxytetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H- imidazole (compound 217.2) instead of 2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-yl) hydrochloride benzonitrile (compound 1.2).m/z (ES+) 482 (M+H) ⁺ .

Compound 218.1. 5-Iodo-2-methyl-4-(trifluoromethyl)-1H-imidazole. In a 50 ml round bottom flask was placed a solution of 2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2, 1.72 g, 11.46 mmol) in CH ₃ CN (25 ml). NIS (3.87 g, 17.20 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at 85°C. The reaction mixture was diluted with 50 ml of H ₂ O and was extracted with 3×30 ml of ethyl acetate. The combined organic layers were washed with 2×20 ml Na ₂ S ₂ O ₃ (sat.) and 2×20 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gave 4.32 g (crude) of the title compound as a brown oil.

Compound 218 4-(1-(4-Methyl-3-(2-methyl-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of 5-iodo-2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 218.1) instead of 2- methyl-1H-imidazole-4-carbonitrile (compound 16.3). m/z (ES+) 425 (M+H) ⁺ .

Compound 219.1. 2-((Benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazole. A solution of 3,3,3-trifluoro-2-oxopropanal (2 g, 15.87 mmol) in methanol (30 ml) was placed in a 100 ml round bottom flask. To the reaction mixture were added 2-(benzyloxy)acetaldehyde (2.8 g, 18.64 mmol) and ammonium hydroxide (25%) (36 ml, 63.48 mmol). The reaction mixture was stirred for 15 hours at 20° C., then concentrated under reduced pressure. The precipitate was diluted with 20 ml H ₂ O. The aqueous phase was extracted with 2×30 ml ethyl acetate and the combined organic layers were washed with 2×20 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gave 4.2 g (crude) of the title compound as a yellow crude oil.

Compound 219.2. 2-((Benzyloxy)methyl)-5-iodo-4-(trifluoromethyl)-1H-imidazole. A solution of 2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazole (compound 219.1, 1.5 g, 5.85 mmol) in CH ₃ CN (18 ml) was placed in a 50 ml round bottom flask. NIS (1.6 g, 7.02 mmol) was added to the reaction mixture. The reaction mixture was stirred for 15 h at 85°C. The reaction mixture was diluted with 30 ml H ₂ O. The aqueous phase was extracted with 2×30 ml ethyl acetate. The combined organic layers were washed with 2×20 ml Na ₂ S ₂ O ₃ (sat.) and 2×20 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:100-1:2) as eluent to give 0.7 g (31%) of the title compound as a yellow oil.

Compound 219.3. Methyl 5-(2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate. Into a 50 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 2-((benzyloxy)methyl)-5-iodo-4-(trifluoromethyl)-1H-imidazole (compound 219.2, 500 mg, 1, 31 mmol) in dioxane (8 ml). Methyl 2,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1, 450 mg, 1.55 mmol), Pd(dppf)Cl2 (0 .1 g) and an aqueous solution of potassium carbonate (2 M) (3.25 ml). The reaction mixture was stirred for 1 h at 80° C., then diluted with 20 ml H ₂ O. The aqueous phase was extracted with 2×30 ml ethyl acetate. The combined organic layers were washed with 2×30 ml of brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/20-1/4) as eluent to give 0.2 g (37%) of the title compound as a light yellow solid.

Compound 219.4. Methyl 5-(2-(hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate. A solution of methyl 5-(2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 219.3, 150 mg, 0.36 mmol) in methanol (8 ml). Carbon-supported palladium catalyst (150 mg, 1.00 eq.) and HCl (4 M, 2 ml) were added to the reaction mixture under nitrogen atmosphere. Hydrogen (1 atm) was added to these substances. The reaction mixture was stirred for 2 hours at room temperature. The system was purged with nitrogen, then the solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 100 mg (85%) of the title compound as a light yellow oil.

Compound 219.5. Methyl 5-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate. A solution of methyl 5-(2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 219.4, 100 mg, 0 .30 mmol) in ammonium hydroxide (5%) (30 ml). The reaction mixture was stirred for 2 h at 60°C. The reaction mixture was extracted with 2×50 ml dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 80 mg (92%) of the title compound as a light yellow oil.

Compound 219.6. 5-(4-Cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid. A solution of methyl 5-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 219.6, 100 mg, 0.35 mmol) in methanol (10 ml) and a solution of NaOH (0.14 g, 3.5 mmol) in water (5 ml). The reaction mixture was stirred for 15 hours at room temperature, then concentrated under reduced pressure. The pH of the solution was adjusted to 1-2 with hydrogen chloride (4 M). The resulting mixture was concentrated under reduced pressure. Methanol (5 ml) was added to the precipitate. The salt was filtered off and the filtrate was concentrated under reduced pressure to give 200 mg (impure) of the title compound as a light yellow solid.

Compound 219 5-(5-(3-(4-Cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2,4-dimethylphenyl)-2-(hydroxymethyl)-1H-imidazole-4-carbonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 5-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2, 4-dimethylbenzoic acid (compound 219.6) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride ( compound 43.4) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 430 (M+H) ⁺ .

Compound 220 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-2-(hydroxymethyl)-1H-imidazole-4-carbonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 5-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2, 4-dimethylbenzoic acid (compound 219.6) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 412 (M+H) ⁺ .

Compound 221.1. 3-(4-Cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 219.6, except for the use of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1 ).

Compound 221 4-(1-(4-Methyl-3-(4-methyl-2-(pyrrolidin-1-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 3-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-4- methylbenzoic acid (compound 221.1) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 398 (M+H) ⁺ .

Compound 222.1. 2-(Methoxymethyl)-4-methyl-4,5-dihydro-1H-imidazole. In a 500 ml round bottom flask was placed a solution of 2-methoxyacetic acid (20 g, 222.0 mmol) in toluene (200 ml). Propane-1,2-diamine (50 g, 674.5 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at 130°C, then concentrated under reduced pressure. This gave 25 g (impure) of the title compound as a yellow oil.

Compound 222.2. 2-(Methoxymethyl)-4-methyl-1H-imidazole. A solution of 2-(methoxymethyl)-4-methyl-4,5-dihydro-1H-imidazole (compound 222.1, 19 g, 148.4 mmol) in acetonitrile (200 ml) was placed in a 500 ml round bottom flask. Al ₂ O ₃ (19 g, 182.7 mmol) was added to the reaction mixture. Potassium permanganate (58 g, 367.1 mmol) was then added in portions at 0°C. The reaction mixture was stirred for 2 h at 0° C., then warmed to room temperature overnight. The reaction mixture was quenched with 20 ml of sodium sulfite (sat.). Solids were removed by filtration and the filtrate was concentrated under reduced pressure. This gave 19 g (impure) of the title compound as a yellow oil.

Compound 222.3. 5-Iodo-2-(methoxymethyl)-4-methyl-1H-imidazole. A solution of 2-(methoxymethyl)-4-methyl-1H-imidazole (compound 222.2, 1.9 g, 15.06 mmol) in aqueous sodium hydroxide solution (30 ml, 2 M) was placed in a 100 ml round bottom flask. Then a solution of iodine (7.7 g, 30.34 mmol) in dichloromethane (30 ml) was added. The reaction mixture was stirred for 1 hour at room temperature. The aqueous phase was collected and the pH was adjusted to 4 with hydrogen chloride (2M). The reaction mixture was extracted with 4×30 ml of dichloromethane, and the organic layers were combined. The resulting mixture was washed with 2×20 ml of sodium sulfite (sat.) and 3×30 ml of saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 1.2 g (32%) of the title compound as a yellow solid.

Compound 222.4. Methyl 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate. Into a 50 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 5-iodo-2-(methoxymethyl)-4-methyl-1H-imidazole (compound 222.3, 400 mg, 1.59 mmol) in 1 ,4-dioxane (15 ml). To the reaction mixture was added methyl 2,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1, 510 mg, 1.76 mmol), potassium carbonate solution (662 mg, 4.79 mmol) in water (1 ml) and Pd(dppf)Cl2 (234 mg, 0.32 mmol). The reaction mixture was stirred overnight at 90°C. Solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography with dichloromethane/ethyl acetate (1:1) as eluent to give 220 mg (48%) of the title compound as a yellow solid.

Compound 222.5. 5-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid. Methyl 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 222.4, 220 mg, 0.76 mmol) and HBr (20 ml, 40% in HOAc). The reaction mixture was stirred overnight at 80°C. The resulting mixture was concentrated under reduced pressure. This gave 190 mg (impure) of the title compound as a brown solid.

Compound 222.6. 5-(2-(Cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid. A solution of trimethylsilanecarbonitrile (376 mg, 3.79 mmol) in acetonitrile (20 ml) was placed in a 100 ml round bottom flask. Tetrabutylammonium fluoride (3.8 ml, 1 M in THF) was added to the reaction mixture. Then 5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.5, 190 mg, 0.73 mmol) was added portionwise. The reaction mixture was stirred for 1 hour at room temperature, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1) as eluent to give 190 mg (97%) of the title compound as a yellow solid.

Compound 222 4-(1-(5-(2-(Cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. A solution of 5-(2-(cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.6, 190 mg, 0.71 mmol) and HBTU was placed in a 100 ml round bottom flask. (538 mg, 1.42 mmol) in N,N-dimethylformamide (3 ml). To this mixture was added dropwise a solution of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4, 160 mg, 0.75 mmol) and triethylamine (197 μl, 1.42 mmol) in N,N-dimethylformamide ( 3 ml). The reaction mixture was stirred for 1 hour at room temperature. The crude product (150 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, XBridge Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 50 mmol NH ₄ HCO ₃ and acetonitrile (30% acetonitrile to 44% in 7 minutes, then 44% in 1 minute, to 100% in 1 minute, to 30% in 1 minute); Detector, Waters 2489, 254 and 220 nm. This resulted in 45.9 mg (15%) of the title compound as a white solid, m/z (ES+) 428 (M+H) ⁺ .

Compound 223 4-(1-(3-(2-(Cyanomethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 222, except for the use of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1 ) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4). m/z (ES+) 396 (M+H) ⁺ .

Compound 224 4-(1-(5-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 222, except for the use of 5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2, 4-dimethylbenzoic acid (compound 222.5) instead of 5-(2-(cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.6) and 4-(azetidine-3- yl)benzonitrile (compound 5.2) instead of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4). m/z (ES+) 401 (M+H) ⁺ .

Compound 225 4-(3-Fluoro-1-(5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 222, except for the use of 5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2, 4-dimethylbenzoic acid (compound 222.5) instead of 5-(2-(cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.6). m/z (ES+) 419 (M+H) ⁺ .

Compound 226.1. 3-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare 5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.5), except for the use of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl-2,4-dimethyl -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1).

Compound 226 4-(1-(3-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 222, except for the use of 3-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-4- methylbenzoic acid (compound 226.1) instead of 5-(2-(cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.6). m/z (ES+) 387 (M+H) ⁺ .

Compound 227.1. 3-(Benzyloxy)propanal. Into a 100 ml three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was charged DMSO (5.1 ml, 71.79 mmol) in dichloromethane (40 ml). Then oxalyl chloride (3.1 ml, 54.16 mmol) was added dropwise at -78°C and stirred for 30 minutes at -78°C. A solution of 3-(benzyloxy)propan-1-ol (4.8 ml, 30.08 mmol) in dichloromethane (10 ml) was added dropwise to the mixture at -78°C. The resulting solution was stirred for 1 h at -78°C, then triethylamine (16.5 ml, 118.59 mmol) was added to the reaction mixture. The resulting solution was stirred for 1 h at -78 to -20°C, then quenched with 50 ml of NH ₄ Cl (sat.). The aqueous phase was extracted with 2×50 ml dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc:PE (1:5) as eluent to give 2.0 g (40%) of the title compound as a light yellow oil.

Compound 227.2. 2-(2-(Benzyloxy)ethyl)-5-iodo-4-methyl-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 160.2, except for the use of 3-(benzyloxy)propanal (compound 227.1) instead of cyclopropanecarbaldehyde.

Compound 227.3. Methyl 3-(2-(2-(benzyloxy)ethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5.6, except for the use of 2-(2-(benzyloxy)ethyl)-5-iodo-4-methyl-1H-imidazole (compound 227.2) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).

Compound 227.4. Methyl 3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate. A solution of methyl 3-(2-(2-(benzyloxy)ethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 227.3, 100 mg, 0.27 mmol) in methanol (10 ml). To the reaction mixture under N ₂ was added carbon-supported palladium catalyst (100 mg), hydrogen chloride (4 M) (2.5 ml). Hydrogen was introduced to the above mixture. The reaction mixture was stirred for 3 hours at room temperature. The solids were filtered off and the filtrate was concentrated under reduced pressure. The pH of the solution was adjusted to 7 with sodium bicarbonate (sat.). The resulting solution was extracted with 4×20 ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 60 mg (80%) of the title compound as a yellow oil.

Compound 227 4-(1-(3-(2-(2-Hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to prepare compound 5, except for the use of methyl-3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl )-4-a (compound 227.4) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 401 (M+H) ⁺ .

Compound 228 5-(5-(3-(4-Cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-1H-imidazole-2-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 14, except for the use of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 4-(azetidine- 3-yl)benzonitrile (compound 5.2) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl -4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 414 (M+H) ⁺ .

Compound 229 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-1H-imidazole-2-carbonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 14, except for the use of methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4 ). m/z (ES+) 396 (M+H) ⁺ .

Compound 230.1. 2-(Methoxymethyl)-4,5-dihydro-1H-imidazole. A 250 ml round bottom flask was charged with a solution of 2-methoxyacetic acid (20 g, 222.03 mmol) in toluene (60 ml). Ethane-1,2-diamine (133 g, 2.22 mol) was added to the reaction mixture. The reaction mixture was stirred for 2 days at 130°C. The resulting mixture was concentrated under reduced pressure. This resulted in 20 g (79%) of the title compound as a crude yellow oil.

Compound 230.2. 2-(Methoxymethyl)-1H-imidazole. A solution of 2-(methoxymethyl)-4,5-dihydro-1H-imidazole (compound 230.1, 20 g, 175.21 mmol) in ACN (150 ml) was placed in a 500 ml three-necked round bottom flask. Al ₂ O ₃ (9 g, 87.6 mmol), KMnO ₄ (27.7 g, 175.21 mmol) were added to the reaction mixture. The reaction mixture was stirred for 6 h at room temperature, then quenched with 30 ml of Na ₂ SO ₃ (sat.). Solids were removed by filtration and the filtrate was concentrated under reduced pressure. This gave 15 g (impure) of the title compound as a yellow solid.

Compound 230.3. 4,5-Diiodine-2-(methoxymethyl)-1H-imidazole. A solution of 2-(methoxymethyl)-1H-imidazole (compound 230.2, 15 g, 133.77 mmol) in aqueous sodium hydroxide solution (100 ml, 2 M) was placed in a 500 ml round bottom flask. A solution of I ₂ (60 g, 236.22 mmol) in dichloromethane (100 ml) was added to the reaction mixture. The reaction mixture was stirred for 3 h at 25°C. The aqueous phase was collected and diluted with 50 ml Na ₂ SO ₃ (aq.). The pH of the solution was adjusted to 6-7 with hydrogen chloride (2M). The reaction mixture was extracted with 3×50 ml dichloromethane. The aqueous layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/hexane (1:2) as eluent to give 4 g (8%) of the title compound as a white solid.

Compound 230.4. 5-Iodo-2-(methoxymethyl)-1H-imidazole. A solution of 4,5-diiodo-2-(methoxymethyl)-1H-imidazole (compound 230.3, 2 g, 5.50 mmol) in ethanol (40 ml) was placed in a 250 ml round bottom flask. A solution of Na ₂ SO ₃ (5.9 g, 46.83 mmol) in water (80 ml) was added to the reaction mixture. The reaction mixture was stirred overnight at 90°C. The resulting mixture was concentrated under reduced pressure. The precipitate was extracted with 3×20 ml dichloromethane and the organic layers were combined and concentrated under reduced pressure. This resulted in 1 g (76%) of the title compound as a yellow oil.

Compound 230.5. Methyl 5-(2-(methoxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate. Into a 100 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 5-iodo-2-(methoxymethyl)-1H-imidazole (compound 230.4, 70 mg, 0.29 mmol) in dioxane (10 ml) . Pd(dppf)Cl ₂ (22 mg, 0.029 mmol), a solution of potassium carbonate (160 mg, 1.16 mmol) in water (2 ml), methyl-2,4-dimethyl-5-(tetramethyl- 1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1, 168 mg, 0.58 mmol). The reaction mixture was stirred overnight at 90° C., then quenched with 10 ml H ₂ O. The aqueous phase was extracted with 3×10 ml ethyl acetate and the combined organic layers were washed with 1×10 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure . The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1) as eluent to give 70 mg (87%) of the title compound as a white solid.

Compound 230.6. Methyl 5-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate. A solution of methyl 5-(2-(methoxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 230.5, 70 mg, 0.26 mmol) in chloroform (6 ml ). NCS (35 mg, 0.26 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature, then quenched with 1 ml of water. The aqueous phase was extracted with 2×5 ml dichloromethane and the combined organic layers were concentrated under reduced pressure. The precipitate was chromatographed on silica gel with ethyl acetate/petroleum ether (1:10) as eluent to give 30 mg (38%) of the title compound as a white crude solid.

Compound 230.7. 5-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid. A solution of methyl 5-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 230.5, 20 mg, 0.06 mmol) in HBr (5 ml, 40% in AcOH). The reaction mixture was stirred overnight at 90°C. The resulting mixture was concentrated under reduced pressure. This resulted in 10 mg (55%) of the title compound as a yellow crude solid.

Compound 230 4-(1-(5-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. A solution of 5-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 230.6, 180 mg, 0.64 mmol) in N ,N-dimethylformamide (15 ml). To the reaction mixture were added 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4, 165 mg, 0.78 mmol), EDC⋅HCl (245 mg, 1.28 mmol), and 4-dimethylaminopyridine (310 mg, 2.54 mmol). The reaction mixture was stirred overnight at 25°C. The reaction mixture was then quenched with 5 ml of water. The reaction mixture was extracted with 3×10 ml of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 5×10 ml of saline. The resulting mixture was concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.05% TFA and ACN (26.0% ACN to 39.0% in 10 min, to 100.0% in 2 min, to 26.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 84 mg (30%) of the title compound as a white solid, m/z (ES+) 439 (M+H) ⁺ .

Compound 231 4-(1-(5-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 230, except for the use of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(3-fluoroazetidine- 3-yl)benzonitrile (compound 43.4). m/z (ES+) 421 (M+H) ⁺ .

Compound 232.1. Ethyl 4-oxobutanoate. Into a 500 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of ethyl 4-chloro-4-oxobutanoate (12 g, 72.91 mmol) in tetrahydrofuran (200 ml). The system was purged with nitrogen and a carbon-supported palladium catalyst (2 g) was added to the reaction mixture. Thiethylsilane (16.5 mL, 103.20 mmol) was then added dropwise with stirring at room temperature. The reaction mixture was stirred for 2 hours at room temperature. The solids were filtered off and the filtrate was concentrated under reduced pressure to give 18 g (imp.) of the title compound as a light yellow solid.

Compound 232.2. Methyl 3-(4-methyl-1H-imidazol-2-yl)propanoate. A 500 ml round bottom flask was charged with a solution of ethyl 4-oxobutanoate (compound 232.1, 5.4 g, 41.49 mmol) in methanol (125 ml). An aqueous solution of 2-oxopropanal (35%) (28.5 ml, 49.96 mmol) and ammonium hydroxide (25%) (100 ml, 165.9 mmol) were added to the reaction mixture. The reaction mixture was stirred for 2 hours at 50°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eluent to give 600 mg (8%) of the title compound as a light yellow oil.

Compound 232.3. 3-(4-Methyl-1H-imidazol-2-yl)propanamide. A solution of ethyl 3-(4-methyl-1H-imidazol-2-yl)propanoate (compound 232.2, 500 mg, 2.97 mmol) in methanol (10 ml) was placed in a 100 ml round bottom flask. NH ₃ (g) was introduced into the above mixture by blowing through the solution. The reaction mixture was stirred overnight at 50°C. The resulting mixture was concentrated under reduced pressure. This resulted in 346 mg (82%) of the title compound as a light yellow solid.

Compound 232.4. 3-(4-Methyl-1H-imidazol-2-yl)propanenitrile. Into a 250 ml three-necked round-bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 3-(4-methyl-1H-imidazol-2-yl)propanamide (compound 232.3, 2 g, 13.06 mmol) in toluene (100 ml) and P ₂ O ₅ (2 g, 14.08 mmol). The reaction mixture was stirred for 12 h at 120° C., then quenched with 100 ml of water. The aqueous phase was extracted with 2×200 ml ethyl acetate and the combined organic layers were washed with 2×100 ml sodium carbonate (sat.), dried over sodium sulfate and concentrated under reduced pressure. This resulted in 1 g (57%) of 3-(4-methyl-1H-imidazol-2-yl)propanenitrile as a light yellow oil.

Compound 232 4-(1-(5-(2-(2-Cyanoethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 3-(4-methyl-1H-imidazol-2-yl)propanenitrile (compound 232.4) instead of 2,4 -dimethyl-1H-imidazole, methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl-4- methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4), and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4 ) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 442 (M+H) ⁺ .

The compounds listed in Table 11 were prepared using standard chemistry and procedures similar to those used to prepare compounds 222, 223, 231 and 232.

Compound 233 4-(1-(3-(2-(2-Cyanoethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 3-(4-methyl-1H-imidazol-2-yl)propanenitrile (compound 232.4) instead of 2,4 -dimethyl-1H-imidazole. m/z (ES+) 410 (M+H) ⁺ .

Compound 234.1. 1H-Imidazole-2-carbonitrile. A solution of 1H-imidazole-2-carbaldehyde (5 g, 52.04 mmol) in N,N-dimethylformamide (200 ml) was placed in a 1 L round bottom flask. To the reaction mixture were added triethylamine (10.8 ml, 77.97 mmol), hydroxylamine hydrochloride (3.95 g, 56.84 mmol, 1.10 eq.), a solution of 1-propanephosphonic anhydride, and a solution of 2,4,6- tripropyl-1,3,5,2,4,6-trioxatrifphosphorinan-2,4,6-trioxide (T ₃ P) (36.4 g, 114.40 mmol). The reaction mixture was stirred for 4 hours at 100°C, cooled and then quenched with 500 ml of a mixture of water and ice. The aqueous phase was extracted with 3×1 L of ethyl acetate, then the combined organic layers were washed with 2×1 L of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/2) as eluent to give 2 g (41%) of the title compound as an off-white solid.

Compound 234.2. 5-Iodine-1H-imidazole-2-carbonitrile. In a 100 ml round bottom flask was placed a solution of 1H-imidazole-2-carbonitrile (compound 234.1, 3.39 g, 36.42 mmol) in sodium hydroxide (54.7 ml, 2 M). Iodine (9.26 g, 36.46 mmol) was added to the reaction mixture. The reaction mixture was stirred for 5 hours at room temperature. The pH of the solution was adjusted to 5 with HCl (2 M). The aqueous phase was extracted with 3×80 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/1.5) as eluent to give 1.02 g (13%) of the title compound as a white solid.

Compound 234.3. Methyl 3-(2-cyano-1H-imidazol-5-yl)-4-methylbenzoate. In a 100 ml three-necked round-bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 5-iodo-1H-imidazole-2-carbonitrile (compound 234.2, 700 mg, 3.20 mmol) in a solvent mixture consisting of DME and H ₂ O (30/3 ml). To the reaction mixture was added methyl 4-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 1.06 g, 3.84 mmol), K ₃ PO ₄ (2, 71 g, 12.8 mmol), Xphos (152 mg, 0.32 mmol), Pd(PPh ₃ ) ₄ (369 mg, 0.32 mmol). The reaction mixture was stirred overnight at 90°C, then concentrated under reduced pressure. The precipitate was diluted with 50 ml of ethyl acetate, then 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 with ethyl acetate/petroleum ether (1/2) as eluent to give 160 mg (21%) of the title compound as a white solid.

Compound 234.4. Methyl 3-(4-chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoate. A solution of methyl 3-(2-cyano-1H-imidazol-5-yl)-4-methylbenzoate (compound 234.3, 290 mg, 1.20 mmol) in a solvent mixture of DMF and CHCl was placed in a 50 ml round bottom flask. ₃ (4/20 ml). NCS (161 mg, 1.21 mmol, 1.00 eq) was added to the above reaction mixture. The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The precipitate was diluted with 30 ml EtOAc, then washed with 3×15 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/10-1/7) as eluent to give 160 mg (48%) of the title compound as a light yellow oil.

Compound 234.5. 3-(4-Chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoic acid. A solution of methyl 3-(4-chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoate (compound 234.4, 130 mg, 0.47 mmol) in methanol (4 ml ). Then a solution of LiOH (45.4 mg, 1.90 mmol) in water (2 ml) was added to the reaction mixture. The reaction mixture was stirred overnight at 30°C, then concentrated under reduced pressure. The pH of the solution was adjusted to 3 with hydrogen chloride (1M) and concentrated under reduced pressure. Methanol (5 ml) was added to the precipitate. The salt was filtered off and the filtrate was concentrated under reduced pressure to give 150 mg (impure) of the title compound as a white solid.

Compound 234 4-Chloro-5-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-1H-imidazole-2-carbonitrile. A solution of 3-(4-chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 234.5, 60 mg, 0.23 mmol) in N,N-dimethylformamide was placed in a 25 ml round bottom flask. (2 ml). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 61 mg, 0.27 mmol), HBTU (131 mg, 0.35 mmol), DIEA (123 μl, 0.69 mmol) was added to the reaction mixture. The reaction mixture was stirred for 30 minutes at 15°C. The reaction mixture was diluted with 40 ml EtOAc, then washed with 2×30 ml brine and 2×30 ml NH ₄ Cl (sat.), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (160 mg) was purified by preparative HPLC under the following conditions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (49.0% MeCN to 62.0% in 7 minutes, to 100.0% in 3 minutes, to 49.0% in 1 minute); Detector, Waters 2489, 254 and 220 nm. This resulted in 25.1 mg (25%) of the title compound as a white solid, m/z (ES+) 430 (M+H) ⁺ .

Compound 235 4-Chloro-5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-1H-imidazole-2-carbonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 234, except for the use of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-) hydrochloride. yl)benzonitrile (compound 1.2). m/z (ES+) 402 (M+H) ⁺ .

Compound 236.1. 5-Iodine-2-methyl-1H-imidazole-4-carbaldehyde. Into a 100 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 2-methyl-1H-imidazole-4-carbaldehyde (1.5 g, 13.6 mmol) in CH ₃ CN (50 ml). NIS (3.7 g, 16.4 mmol) was added to the reaction mixture. The reaction mixture was stirred for 4 hours at 80° C., then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (3:1) as eluent to give 2.11 g (66%) of the title compound as a yellow solid.

Compound 236.2. Methyl 5-(4-formyl-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate. In a 100 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 5-iodo-2-methyl-1H-imidazole-4-carbaldehyde (compound 236.1, 600 mg, 2.54 mmol) in dioxane (30 ml). Methyl 2,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1, 800 mg, 2.76 mmol), potassium carbonate solution (1.8 g, 13.0 mmol) in water (10 ml) and Pd(dppf)Cl ₂ (400 mg, 0.55 mmol, 0.20 eq.). The reaction mixture was stirred overnight at 80° C., then quenched with 20 ml of water. The aqueous phase was extracted with 2×100 ml ethyl acetate and the combined organic layers were washed with 2×50 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (3:1) as eluent to give 400 mg (58%) of the title compound as a light yellow solid.

Compound 236.3. Methyl 5-(4-(hydroxymethyl)-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate. A solution of methyl 5-(4-formyl-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 236.2, 400 mg, 1.47 mmol) in methanol ( 20 ml). NaBH ₄ (100 mg, 2.64 mmol) was then added in portions at 0°C. The reaction mixture was stirred for 1 hour at room temperature, then used directly in the next step.

Compound 236 4-(1-(5-(4-(Hydroxymethyl)-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of methyl-5-(4-(hydroxymethyl)-2-methyl-1H-imidazol-5-yl)- 2,4-dimethylbenzoate (compound 236.3) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 401 (M+H) ⁺ .

Compound 237.1. Methyl 3-(4-(hydroxymethyl)-2-methyl-1H-imidazol-5-yl)-4-methylbenzoate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 236.3, except for the use of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1 ).

Compound 237 4-(1-(3-(4-(Hydroxymethyl)-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of methyl-3-(4-(hydroxymethyl)-2-methyl-1H-imidazol-5-yl)- 4-methylbenzoate (compound 237.1) instead of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 387 (M+H) ⁺ .

Compound 238.1. 2-Cyclopropyl-1H-imidazole. In a 500 ml round bottom flask was placed a solution of cyclopropanecarbaldehyde (10.7 ml, 142.7 mmol) in methanol (60 ml). An aqueous solution of hydroxyaldehyde (18.0 mL, 157.1 mmol, 40%) was added to the reaction mixture. Then NH ₄ OH (89 ml, 571.4 mmol) was added dropwise at 0° C. over 30 minutes. The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The resulting solution was extracted with 3×100 ml of ethyl acetate. The combined organic layers were washed with 2×30 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gave 12 g (impure) of the title compound as a brown solid.

Compound 238.2. 2-Cyclopropyl-N,N-dimethyl-1H-imidazole-1-sulfonamide. In a 500 ml round bottom flask was placed a solution of 2-cyclopropyl-1H-imidazole (compound 238.1, 12 g, 110.9 mmol) in dichloromethane (60 ml). Triethylamine (31.4 ml, 225.3 mmol), N,N-dimethylsulfamoyl chloride (13.2 ml, 121.87 mmol, 1.10 eq.) was added to the reaction mixture. The reaction mixture was stirred for 4 hours at room temperature, then quenched with 20 ml of water. The aqueous phase was extracted with 3×100 ml dichloromethane. The combined organic layers were washed with 2x20 ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:4) as eluent to give 16 g (67%) of the title compound as a white solid.

Compound 238.3. 2-Cyclopropyl-1H-imidazole-4-carbaldehyde. Into a 500 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 2-cyclopropyl-N,N-dimethyl-1H-imidazole-1-sulfonamide (compound 238.2, 5 g, 23.23 mmol) in tetrahydrofuran (100 ml). Then n-butyllithium (11.2 ml, 2.5 M in THF) was added dropwise at -78°C over 30 minutes. DMF (11.8 ml, 152.55 mmol) was added to the mixture. The resulting solution was stirred for 30 minutes at -50° C., then hydrogen chloride (50 ml, 1 M) was added. The reaction mixture was stirred for 2 hours at room temperature. The pH of the solution was adjusted to 7-8 with sodium bicarbonate (sat.). The resulting solution was extracted with 3×30 ml of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×10 ml of saline. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 3 g (97%) of the title compound as a white solid.

Compound 238 4-(1-(3-(2-Cyclopropyl-4-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 236, except for the use of 2-cyclopropyl-1H-imidazole-4-carbaldehyde (compound 238.3) instead of 2-methyl-1H-imidazole- 4-carbaldehyde and methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl-2,4-dimethyl-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1). m/z (ES+) 413 (M+H) ⁺ .

Compound 239.1. Ethyl 4-methyl-1H-imidazole-2-carboxylate. A 50 ml round bottom flask was charged with a solution of ethyl 2-oxoacetate (400 mg, 3.92 mmol) in methanol (4 ml). An aqueous solution of 2-oxopropanal (565 mg, 3.92 mmol, 50%), ammonia (25%) (8.8 ml, 15.68 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/1) as eluent to give 200 mg (33%) of the title compound as a yellow solid.

Compound 239.2. Ethyl 5-iodine-4-methyl-1H-imidazole-2-carboxylate. In a 100 ml round bottom flask was placed a solution of ethyl 4-methyl-1H-imidazole-2-carboxylate (compound 239.1, 100 mg, 0.65 mmol) in CH ₃ CN (10 ml). NIS (218 mg, 0.97 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The precipitate was dissolved in 30 ml of EtOAc, then washed with 2×20 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 80 mg (44%) of the title compound as a yellow solid.

Compound 239.3. 5-Iodo-4-methyl-1H-imidazole-2-carboxylic acid. A solution of ethyl 5-iodo-4-methyl-1H-imidazole-2-carboxylate (compound 239.2, 200 mg, 0.71 mmol) in methanol (4 ml) was placed in a 100 ml round bottom flask. A solution of sodium hydroxide (114 mg, 2.85 mmol) in water (2 ml) was added to the reaction mixture. The reaction mixture was stirred for 2 h at 60°C. The pH of the solution was adjusted to 1-2 with hydrogen chloride (1M). The resulting mixture was concentrated under reduced pressure. Methanol (5 ml) was added to the precipitate. The salt was filtered off and the filtrate was concentrated under reduced pressure to give 290 mg (impure) of the title compound as a white solid.

Compound 239.4. 5-Iodine-N,N,4-trimethyl-1H-imidazole-2-carboxamide. A solution of 5-iodo-4-methyl-1H-imidazole-2-carboxylic acid (compound 239.3, 200 mg, 0.79 mmol) in N,N-dimethylformamide (4 ml) was placed in a 100 ml round bottom flask. HBTU (602 mg, 1.59 mmol), dimethylamine hydrochloride (96 mg, 1.18 mmol) and triethylamine (552 μl, 3.96 mmol) were added to the reaction mixture. The reaction mixture was stirred for 3 h at room temperature, then diluted with 50 ml of EtOAc. The organic layer was washed with 2×20 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 150 mg (68%) of the title compound as a yellow oil.

Compound 239 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-N,N,4-trimethyl-1H-imidazole-2-carboxamide. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-iodo-N,N,4-trimethyl-1H-imidazole-2-carboxamide (compound 239.4) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 442 (M+H) ⁺ .

Compound 240.1. 5-Iodo-4-methyl-2-(trifluoromethyl)-1H-imidazole. In a 250 ml round bottom flask was placed a solution of 4-methyl-2-(trifluoromethyl)-1H-imidazole (compound 14.1, 4.41 g, 29.38 mmol) in CH ₃ CN (100 ml). NIS (6.6 g, 29.34 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The reaction mixture was diluted with 300 ml EtOAc. The organic layer was washed with 3×150 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/30-1/20) as eluent to give 2.125 g (26%) of the title compound as a light yellow solid.

Compound 240 4-(1-(4-Methyl-3-(4-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 16, except for the use of 5-iodo-4-methyl-2-(trifluoromethyl)-1H-imidazole (compound 240.1) instead of 5- iodo-2-methyl-1H-imidazole-4-carbonitrile (compound 16.4). m/z (ES+) 425 (M+H) ⁺ .

Compound 241.1. 5-Iodine-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 44.3, except for the use of tetrahydro-2H-pyran-4-carbaldehyde instead of cyclopropanecarbaldehyde.

Compound 241.2. Methyl 4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoate. Into a 50 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 5-iodo-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (compound 241.1, 400 mg, 1.44 mmol) in dioxane (15 ml). To the reaction mixture was added methyl 4-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 397 mg, 1.44 mmol), potassium carbonate (993 mg, 7.18 mmol), water (1.5 ml) and Pd(dppf)Cl ₂ (105 mg, 0.14 mmol, 0.10 eq.). The reaction mixture was stirred overnight at 90°C, then diluted with 120 ml EtOAc. The organic layer was washed with 3×40 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eluent to give 260 mg (60%) of the title compound as a red oil.

Compound 241.3. Methyl 3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoate. A solution of methyl 4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoate (compound 241.2, 260 mg, 0.87 mmol) in chloroform (3 ml). NCS (116 mg, 0.87 mmol) was added to the reaction mixture. The reaction mixture was stirred for 4 hours at 25° C., then concentrated under reduced pressure. The precipitate was dissolved in 50 ml EtOAc, then washed with 3×20 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gave 313 mg (impure) of the title compound as a brown oil.

Compound 241.4. 3-(4-Chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoic acid. A solution of methyl 3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 241.3, 290 mg, 0.87 mmol) in methanol (6 ml). Then a solution of sodium hydroxide (139 mg, 3.48 mmol) in water (3 ml) was added to the reaction mixture. The reaction mixture was stirred for 1 hour at 60° C., then concentrated under reduced pressure. The pH of the solution was adjusted to 1 with hydrogen chloride (2M). The resulting mixture was concentrated under reduced pressure. Methanol (10 ml) was added to the precipitate. The salt was filtered off and the filtrate was concentrated under reduced pressure to give 300 mg of the title compound as a brown solid.

Compound 241 . A solution of 3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 241.4, 150 mg, 0 .47 mmol) in N,N-dimethylformamide (3 ml). To the reaction mixture were added 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 91 mg, 0.47 mmol), EDC⋅HCl (180 mg, 0.94 mmol), 4-dimethylaminopyridine (114 mg, 0.47 mmol). 93 mmol). The reaction mixture was stirred for 3 h at 25°C, then diluted with 80 ml EtOAc. The organic layer was washed with 3×50 ml of brine, 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-001(SHIMADZU)): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.05% TFA and ACN (25.0% ACN to 39.0% in 8 min, the same 39.0% in 1 min, to 100.0% in 3 min, to 25.0 % for 1 min); Detector, Waters 2489, 254 and 220 nm. This gave 133.3 mg (62%) of the title compound as a light yellow solid, m/z (ES+) 461 (M+H) ⁺ .

Compound 242.1. Methyl 5-(3,4-dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 59.2, except for the use of methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4 ). m/z (ES+) 259 (M+H) ⁺ .

Compound 242.2. 5-(3,4-Dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 59.3, except for the use of methyl-5-(3,4-dimethyl-1H-pyrazol-5-yl)-2,4- dimethylbenzoate (compound 242.1) instead of methyl 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoate (compound 59.2). m/z (ES+) 245 (M+H) ⁺ .

Compound 242 4-(1-(5-(3,4-Dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 59, except for the use of 5-(3,4-dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid (compound 242.2) instead of 3-(3,4-dimethyl-1#-pyrazol-5-yl)-4-methylbenzoic acid (compound 59.3). m/z (ES+) 385 (M+H) ⁺ .

Compound 243 4-(1-(5-(3,4-Dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 60, except for the use of 5-(3,4-dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid (compound 242.2) instead of 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 59.3). m/z (ES+) 403 (M+H) ⁺ .

Compound 244.1. 1-Benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Into a 100 ml three-necked round bottom flask was placed a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.60 g, 18.6 mmol) in THF (50 ml). Sodium hydride (742 mg, 18.6 mmol, 60% dispersion in mineral oil) was carefully added in portions at 0°C. The resulting mixture was stirred for 30 minutes at 0° C., then benzyl bromide (2.21 ml, 18.6 mmol) was added. The resulting mixture was stirred overnight at room temperature, then carefully quenched with water (10 ml). The pH of the mixture was adjusted to 9-10 with aqueous HCl (2 M) and the aqueous phase was extracted with EtOAc (300 ml). The combined organic layers were washed with brine (2×150 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/2) as eluent to give the title compound as a yellow oil (3.47 g, 66%).

Compound 244.2. 1-Benzyl-1H-pyrazol-4-ol. A solution of 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (compound 244.1, 3.47 g , 12.2 mmol) in tetrahydrofuran (35 ml). Sodium hydroxide (980 mg, 24.5 mmol) was added and then the mixture was cooled to 0°C. Hydrogen peroxide (2.51 mL, 24.4 mmol) was carefully added dropwise and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was carefully quenched with aqueous Na ₂ S ₂ O ₃ (sat.) (20 ml). The aqueous phase was extracted with EtOAc (300 ml) and the combined organic layers were washed with brine (2×150 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/1) as eluent to give the title compound as a white solid (1.64 g, 77%).

Compound 244.3.1-Benzyl-4-methoxy-1H-pyrazole. A solution of 1-benzyl-1H-pyrazol-4-ol (compound 244.2, 1.40 g, 8.04 mmol) in N,N-dimethylformamide (20 ml) was placed in a 100 ml round bottom flask. Iodomethane (703 μl, 11.3 mmol) and CS ₂ CO ₃ (3.68 g, 11.3 mmol) were added and the resulting mixture was stirred for 3 h at room temperature. The mixture was concentrated under reduced pressure, then diluted with EtOAc (200 ml). The mixture was washed with brine (3×80 ml) and the organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow oil (1.30 g, 86%).

Compound 244.4. 4-Methoxy-1H-pyrazole. In a 100 ml round bottom flask was placed a solution of 1-benzyl-4-methoxy-1H-pyrazole (compound 244.3, 666 mg, 3.54 mmol) in methanol (10 ml). Hydrogen chloride (1 M, 1 ml) and Pd(OH) ₂ /C (20 wt.%, 670 mg) were added and the mixture was purged with nitrogen, then hydrogen was introduced into it. The mixture was stirred under a hydrogen atmosphere overnight at room temperature, then purged with nitrogen. Solids were removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound as a brown oil (0.36 g, crude).

Compound 244.5. 3-iodine-4-methoxy-1H-pyrazole. In a 50 ml round bottom flask was placed 4-methoxy-1H-pyrazole (compound 244.4, 360 mg, 3.67 mmol) in N,N-dimethylformamide (4 ml). NIS (830 mg, 3.69 mmol) was added in portions and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (40 ml), then washed with brine (3×10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to give the title compound as a white solid (0.54 g, 66%).

Compound 244.6. Methyl 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate. Into a 50 ml three-necked round-bottom flask, which was purged and kept under a nitrogen atmosphere, was placed a solution of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (414 mg, 1.50 mmol) in dioxane (6 ml). To the reaction mixture was added potassium carbonate (2 M, 2.5 ml, 5.00 mmol), 3-iodo-4-methoxy-1H-pyrazole (compound 244.5, 224 mg, 1.00 mmol), Pd(dppf)Cl ₂ (73 mg, 0.10 mmol) and the resulting mixture was stirred overnight at 90°C. The resulting mixture was cooled, then diluted with EtOAc (80 ml) and washed with brine (2×30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/1) as eluent to give the title compound as a yellow oil (180 mg, 73%).

Compound 244.7. 3-(4-Methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid. A solution of methyl 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate (compound 244.6, 180 mg, 0.73 mmol) in methanol (4 ml) was placed in a 50 ml round bottom flask. Sodium hydroxide (117 mg, 2.92 mmol) in water (2 ml) was added and the resulting solution was stirred for 3 h at 60°C, then concentrated under reduced pressure. The pH of the residue was adjusted to 1 with aqueous hydrogen chloride (1 M), then concentrated under reduced pressure. Methanol (5 ml) was added to the precipitate and the solids were filtered from the solution. The filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (353 mg, imp.).

Compound 244 4-(1-(3-(4-Methoxy-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. A solution of 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7, 60 mg, 0.26 mmol) in N,N-dimethylformamide (2 ml) was placed in a 25 ml round bottom flask. . 4-(azetidin-3-yl)benzonitrile hydrochloride (75 mg, 0.39 mmol), EDC⋅HCl (99 mg, 0.52 mmol) and 4-dimethylaminopyridine (63 mg, 0.52 mmol) were added and a solution stirred for 2 h at room temperature. The reaction mixture was diluted with EtOAc (30 ml) and washed with brine (3×15 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product (150 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-010(Waters)): Column, SunFire Prep C18 OBD, 5 µm, 19*150 mm; mobile phase, water with 0.05% TFA and CH ₃ CN (35.0% CH ₃ CN to 50.0% in 10 min, to 100% in 1 min, to 35.0% in 2 min); Detector, UV 254&220 nm. Fractions containing pure product were combined and lyophilized to give the title compound as an off-white solid (44.3 mg, 46%). m/z (ES+) 373 (M+H ⁺ ).

Compound 245 4-(1-(3-(4-Methoxy-1H-pyrazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-) hydrochloride. yl)benzonitrile (compound 5.2). m/z (ES+) 401 (M+H ⁺ ).

Compound 246 4-(3-Fluoro-1-(3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 4-(azetidine- 3-yl)benzonitrile (compound 5.2). m/z (ES+) 391 (M+H ⁺ ).

Compound 247 4-(1-(5-(4-Methoxy-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 244, except for the use of methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4 ). m/z (ES+) 387 (M+H ⁺ ).

Compound 248.1. 1-Benzyl-4-bromo-3-methyl-1H-pyrazole. A solution of 4-bromo-3-methyl-1H-pyrazole (20.0 g, 124 mmol) in N,N-dimethylformamide (100 ml) was placed in a 500 ml three-necked round bottom flask. The system was purged with nitrogen, then the solution was cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 10.0 g, 250 mmol) was carefully added in portions and the resulting mixture was then stirred for 30 minutes at room temperature. The mixture was cooled to 0° C., then benzyl bromide (22.1 ml, 186 mmol) was added dropwise and the resulting mixture was stirred overnight at room temperature. The mixture was carefully quenched by adding water dropwise (40 ml), then the mixture was extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed with brine (4×100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow oil (24.9 g, 80%).

Compound 248.2. 1-Benzyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Into a 250 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 1-benzyl-4-bromo-3-methyl-1H-pyrazole (compound 248.1, 24.5 g, 97.6 mmol) in DMSO (160 ml). 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (29.9 g, 118 mmol), Pd( dppf)Cl ₂ (7.16 g, 9.79 mmol) and KOAc (28.8 g, 293 mmol). The resulting mixture was stirred overnight at 90° C., then cooled and quenched with water (100 ml). The mixture was extracted with ethyl acetate (3×100 ml) and the combined organic extracts were washed with brine (4×100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20) as eluent to give the title compound as a yellow oil (10.64 g, 37%).

Compound 248 4-(1-(3-(4-Methoxy-3-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 244, except for the use of 1-benzyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1H-pyrazole (compound 248.2) instead of 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (compound 244.1). m/z (ES+) 387 (M+H⁺).

Compound 249.1. Ethyl 2-methyl-3-oxopropanoate. Into a 500 ml three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of ethyl propionate (11.3 ml, 97.9 mmol) in tetrahydrofuran (160 ml). The solution was cooled to 0°C, then sodium hydride (4.1 g, 103 mmol, 60%) dispersion in mineral oil was added portionwise. The mixture was stirred at 0° C. for 10 minutes, then ethyl formate (7.92 ml, 98.5 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was carefully quenched by adding water dropwise (100 ml) and the mixture was extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by distillation under reduced pressure (50 mmHg) and a fraction between 70-80°C was collected to give the title compound as a colorless liquid (3.0 g, 24%).

Compound 249.2. 1-Benzyl-4-methyl-1H-pyrazol-5-ol. A solution of ethyl 2-methyl-3-oxopropanoate (compound 249.1, 500 mg, 3.84 mmol) in ethanol (15 ml) was placed in a 100 ml round bottom flask. Benzylhydrazine hydrochloride (730 mg, 4.66 mmol) was added and the reaction mixture was stirred for 5 h at 80° C., then concentrated under reduced pressure. The residue was purified by silica gel chromatography with dichloromethane/methanol (30:1) as eluent to give the title compound as a yellow oil (430 mg, 59%).

Compound 249.3. 1-Benzyl-5-methoxy-4-methyl-1H-pyrazole. A solution of 1-benzyl-4-methyl-1H-pyrazol-5-ol (compound 249.2, 2.0 g, 10.6 mmol) in N,N-dimethylformamide (15 ml) was placed in a 100 ml round bottom flask. The solution was cooled to 0°C, then sodium hydride (600 mg, 15.00 mmol, 60% dispersion in mineral oil) was added portionwise and the resulting mixture was stirred for 10 min at 0°C. Iodomethane (878 μl, 14.1 mmol) was added and the resulting mixture was stirred for 3 hours at room temperature, then carefully quenched by dropwise addition of water (10 ml). The mixture was extracted with ethyl acetate (3×40 ml) and the combined organic extracts were washed with brine (3×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:8) as eluent to give the title compound as a yellow oil (500 mg, 23%).

Compound 249.4. 5-Methoxy-4-methyl-1H-pyrazole. A solution of 1-benzyl-5-methoxy-4-methyl-1H-pyrazole (compound 249.3, 300 mg, 1.48 mmol) in DMSO (10 ml) was placed in a 100 ml round bottom flask. Potassium tert-butoxide (11 mL, 11 mmol, 1 M in THF) was added slowly and the resulting mixture was stirred overnight at room temperature under dry air conditions. The pH of the solution was adjusted to 7-8 with aqueous HCl (2M), further diluted with water, and the mixture was extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with brine (3×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:8) as eluent to give the title compound as a yellow oil (150 mg, 90%).

Compound 249 4-(1-(5-(3-Methoxy-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 5-methoxy-4-methyl-1H-pyrazole (compound 249.4) instead of 4-methoxy-1H-pyrazole ( compound 244.4) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl-4-methyl-3 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) m/z (ES+) 401 (M+H ⁺ ).

Compound 250.1. 5-Iodine-4-methyl-1H-pyrazole. NIS (5.62 g, 24.98 mmol) was added portionwise to a solution of 4-methyl-1H-pyrazole (Aldrich, 2.05 g, 24.97 mmol) in acetonitrile (50 mL). The mixture was heated at 60°C for 30 minutes, then cooled to room temperature. The mixture was partitioned between EtOAc (300 ml) and water (80 ml). The organic layer was washed with saturated sodium thiosulfate (50 ml), brine (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc, 5:1) to give the title compound as a white solid (2.3 g, 45%). m/z (ES+) 209 (M+H) ⁺ .

Compound 250.2. 5-Iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. NaH (0.48 g, 12.2 mmol, 60%) was added to a solution of 5-iodo-4-methyl-1H-pyrazole (compound 250.1, 2.3 g, 11.1 mmol) in THF (20 ml) at 0°C. The mixture was stirred at 0° C. for 30 minutes, then 2-(trimethylsilyl)ethoxymethyl chloride (2.15 ml, 12.2 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours and then carefully quenched with a small amount of water and partitioned between EtOAc (200 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc, 10:1) to give the title compound as a light yellow oil (3.15 g, 84%). m/z (ES+) 339 (M+H) ⁺ .

Compound 250.3. Methyl 2,4-dimethyl-5-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)benzoate. Methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1, 2.7 g, 9.32 mmol), 5 -iodine-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (compound 250.2, 3.15 g, 9.32 mmol), K ₂ CO ₃ (6.42 g, 46 .6 mmol) and PdCl ₂ (dppf)⋅CH ₂ Cl ₂ (0.76 g, 0.93 mmol) were added to a round bottom flask. The flask was purged with argon, then dioxane (50 ml) and water (20 ml) were added and the mixture was heated at 90° C. for 16 hours. The mixture was cooled to room temperature and then partitioned between EtOAc (300 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes: EtOAc, 10:1) to give the title compound as a light brown oil (3.0 g, 86%). m/z (ES+) 375(M+H) ⁺ .

Compound 250.4. Methyl 5-(3-chloro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate. To a solution of methyl 2,4-dimethyl-5-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)benzoate (compound 250.3, 3.0 g, 8 .02 mmol) in acetonitrile (20 mL) NCS (1.07 g, 8.02 mmol) was added. The mixture was stirred at room temperature overnight, then partitioned between EtOAc (200 ml) and water (50 ml). The organic layer was washed with saturated sodium thiosulfate (50 ml), brine (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc, 20:1) to give the title compound as a colorless oil (2.0 g, 61%). m/z (ES+) 409 (M+H) ⁺ .

Compound 250.5. Methyl 5-(3-chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoate. TFA (10 ml) was carefully added to a solution of 5-(3-chloro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound 250.4, 2.0 g, 4.90 mmol) in CH₂Cl₂ (10 ml). The mixture was stirred at room temperature for 2 hours, then the solvents were removed under reduced pressure. The precipitate was dissolved in EtOAc (200 ml) and washed with sat. NaHCO₃ (50 ml), brine (50 ml), dried (MgSO_four) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc, 4:1) to give the title compound as a white foam (1.13 g, 83%). m/z (ES+) 279(M+H)⁺.

Compound 250.6. 5-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid. NaOH (2 M in water, 8 ml, 16 mmol) was added to a solution of methyl 5-(3-chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound 250.5,1,10 g, 3.96 mmol) in MeOH (10 ml). The mixture was stirred at room temperature overnight and the solvents were removed under reduced pressure. The precipitate was cooled to 0°C and oxidized to pH~3-4 with 1 M HCl in water. The resulting white solids were filtered, washed with water and dried to give the title compound as a white solid (1.07g, 90%). m/z (ES+) 265 (M+H) ⁺ .

Compound 250 4-(1-(5-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-(3-chloro-4-methyl-1H-pyrazol-5-yl)-2,4- dimethylbenzoic acid (compound 250.6) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 405 (M+H) ⁺ .

Compound 251 4-(1-(5-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of 5-(3-chloro-4-methyl-1H-pyrazol-5-yl)-2,4- dimethylbenzoic acid (compound 250.6) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4 ) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 423 (M+H) ⁺ .

Compound 252.4-(1-(3-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 250, except for the use of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1 ) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 409 (M+H ⁺ ).

Compound 253 4-(1-(3-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 250, except for the use of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1 ) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 419 (M+H ⁺ ).

Compound 136 4-(1-(5-(4-Chloro-3-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 51, except for the use of 5-bromo-3-methyl-1H-pyrazole instead of 5-iodo-1H-pyrazole. m/z (ES+) 405 (M+H ⁺ ).

Compound 255.1. 5-(Methoxycarbonyl)-2,4-dimethylbenzoic acid. A solution of 5-iodo-2,4-dimethylbenzoic acid (5.0 g, 18.1 mmol) in methanol (45 ml) was added to a 100 ml (40 atm) pressure reactor. Triethylamine (7.57 ml, 54.3 mmol) and Pd(dppf)Cl ₂ (1.3 g, 1.8 mmol) were added and the system was purged with nitrogen. CO (d) was introduced very carefully. Caution: Carbon monoxide is a highly toxic gas. The reaction mixture was heated at 90°C overnight, then cooled to room temperature and very carefully pumped out. The solvent was removed under reduced pressure. The pH of the residue was adjusted to 1-2 with water. HCl (6 M), further diluted with water, then extracted with EtOAc (2×100 ml). The combined organic extracts were washed with brine (3×10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/hexane (1:1) as eluent to give the title compound as a red solid (2.3 g, 61%).

Compound 255.2. Methyl 5-(chlorocarbonyl)-2,4-dimethylbenzoate. A solution of 5-(methoxycarbonyl)-2,4-dimethylbenzoic acid (compound 255.1, 100 mg, 0.48 mmol) in dichloromethane (10 ml) was placed in a 100 ml round bottom flask. Oxalyl chloride (80 µl, 0.95 mmol) was added and the resulting solution was stirred for 1 h at 40° C., then concentrated under reduced pressure to give the title compound as a white solid (80 mg, 74%) .

Compound 255.3. Methyl 5-(2-(difluoromethylene)butanoyl)-2,4-dimethylbenzoate. Into a 100 ml three neck round bottom flask, which was purged and kept under an inert argon atmosphere, was placed a solution of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1.00 g, 3.93 mmol) in THF (30 ml). The solution was cooled to -78°C, then n-BuLi (5.0 ml, 1.6 M in hexane, 8.0 mmol) was added dropwise and the mixture was stirred at -78°C for 40 min. Triethylborane (TEB) (5.0 ml, 1 Mb THF, 5.0 mmol) was added slowly and the mixture was stirred at -78°C for 1 h, then at room temperature for 3 h. The solution was cooled to 0°C then added hexamethylphosphoramide (HMPA) (6 ml) and CuI (1.5 g, 7.9 mmol) and the mixture was stirred at room temperature for 30 minutes. A solution of methyl 5-(chlorocarbonyl)-2,4-dimethylbenzoate (compound 255.2, 530 mg, 2.34 mmol) in THF (30 ml) was added carefully and stirred at room temperature for 30 minutes. The pH of the mixture was carefully adjusted to 7 with aqueous H ₃ PO ₄ and the mixture was separated. The aqueous phase was extracted with ethyl acetate (3×20 ml) and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:40) as eluent to give the title compound as a yellow oil (250 mg, 38%).

Compound 255.4. Methyl 5-(4-ethyl-3-fluoro-1H-pyrazol-5-yl)-2,4-dimethylbenzoate. A solution of methyl 5-(2-(difluoromethylene)butanoyl)-2,4-dimethylbenzoate (compound 255.3, 175 mg, 0.62 mmol) in THF (100 ml) was placed in a 250 ml round bottom flask. Hydrazine hydrate (120 μl, 2.48 mmol) was added at room temperature followed by trifluoroacetic acid (144 μl, 1.88 mmol), then the solution was stirred at 50°C for 1.5 h. The reaction mixture was cooled to room temperature, carefully diluted with water and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/hexane (1:10) as eluent to give the title compound as a yellow oil (90 mg, 53%).

Compound 255 4-(1-(5-(4-Ethyl-3-fluoro-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 244, except for the use of methyl-5-(4-ethyl-3-fluoro-1H-pyrazol-5-yl)-2, 4-dimethylbenzoate (compound 255.4) instead of methyl 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate (compound 244.6). m/z (ES+) 403 (M+H ⁺ ).

Compound 256.1. 3-iodine-1H-pyrazole-4-carbonitrile. A solution of 3-amino-1H-pyrazole-4-carbonitrile (1.00 g, 9.25 mmol) in hydrogen chloride (12 M, 8 ml) was placed in a 100 ml three-necked round bottom flask. The reaction solution was cooled to 0°C, then a solution of sodium nitrite (800 mg, 11.6 mmol) in water (5.8 ml) was carefully added dropwise, and the mixture was stirred for 1 hour at 0°C. KI (1.91 g, 11.6 mmol) was added and the resulting mixture was stirred for 3 hours at room temperature. The pH of the solution was carefully adjusted to 10 with aqueous sodium hydroxide (3 M) and then extracted with ethyl acetate (3×100 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a white solid (700 mg, 35%).

Compound 256.2. 3-Iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile. In a 100 ml round bottom flask was placed a solution of 3-iodo-1H-pyrazole-4-carbonitrile (compound 256.1, 5.00 g, 22.8 mmol) in tetrahydrofuran (10 ml). The solution was cooled to 0° C. under nitrogen, then sodium hydride (1.1 g, 27.4 mmol, 60% dispersion in mineral oil) was added portionwise. The resulting mixture was stirred at 0°C for 30 minutes, then (2-(chloromethoxy)ethyl)trimethylsilane (6.05 ml, 34.2 mmol) was added to the reaction mixture. The resulting mixture was stirred overnight at room temperature, then carefully quenched with a mixture of water and ice (30 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (20:1) as eluent to give the title compound as a colorless oil (7.2 g, 90%).

Compound 256.3. Methyl 3-(4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-methylbenzoate. Into a 250 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (compound 256.2, 2, 73 g, 7.82 mmol, 1.00 eq.) in dioxane (30 ml). To the reaction mixture was added methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.59 g, 9.38 mmol), Pd( dppf)Cl ₂ (570 mg, 0.78 mmol) and a solution of potassium carbonate (3.24 g, 23.4 mmol) in water (3 ml). The resulting mixture was stirred over night at 90°C, then cooled and diluted with EtOAc (500 ml). The resulting mixture was washed with brine (2×100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (40:1) as eluent to give the title compound as a yellow oil (1.9 g, 65%).

Compound 256.4. Methyl 3-(4-cyano-1H-pyrazol-5-yl)-4-methylbenzoate. A solution of methyl 3-(4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-methylbenzoate (compound 256.3, 1.9 g, 5.11 mmol) in triethylsilane (4 ml) and trifluoroacetic acid (8 ml). The resulting solution was stirred for 4 hours at room temperature, then concentrated under reduced pressure. The pH of the precipitate was carefully adjusted to 7-8 with aqueous sodium bicarbonate (sat.), then the aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (20/1) as eluent to give the title compound as a white solid (600 mg, 49%).

Compound 256.5.3-(4-Cyano-1H-pyrazol-5-yl)-4-methylbenzoic acid. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 244.7, except for the use of methyl 3-(4-cyano-1H-pyrazol-5-yl)-4-methylbenzoate (compound 256.4 ) instead of methyl 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate (compound 244.6).

Compound 256 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-1H-pyrazole-4-carbonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 3-(4-cyano-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 256.5) instead of 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7). m/z (ES+) 368 (M+H ⁺ ).

Compound 257.1. 3-Oxobutanenitrile. In a 250 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, (Z)-3-aminobut-2-ennitrile (20.0 g, 244 mmol) and aqueous hydrogen chloride (6 M) (80 ml) were carefully placed. The mixture was stirred for 3 hours at 80°C, then the solids were removed by filtration. The filtrate was extracted with ethyl acetate (3×100 ml) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow solid (10 g, 49%).

Compound 257.2. (Z)-2-(Ethoxymethylene)-3-oxobutanenitrile. Into a round-bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 3-oxobutanenitrile (compound 257.1, 16.0 g, 193 mmol) in acetic anhydride (48 ml). Triethylorthoformate (96 ml, 577 mmol) was added and the reaction mixture was stirred for 2 h at 130° C., then concentrated under reduced pressure to give the title compound as a red solid (10 g, 37%).

Compound 257.3. 3-Methyl-1H-pyrazole-4-carbonitrile. A solution of (Z)-2-(ethoxymethylene)-3-oxobutanenitrile (compound 257.2, 5.00 g, 35.9 mmol) in ethanol (10 ml) was placed in a 50 ml round bottom flask. The solution was cooled to 0°C, then hydrazine monohydrate (2.09 ml, 43.1 mmol) was added and the reaction mixture was stirred for 1 h at 10°C. The reaction mixture was diluted with water (10 ml) and then extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:10) as eluent to give the title compound as a yellow solid (2.0 g, 52%).

Compound 257.4. 5-Iodo-3-methyl-1H-pyrazole-4-carbonitrile. A solution of 3-methyl-1H-pyrazole-4-carbonitrile (compound 257.3, 2.0 g, 18.7 mmol) in DCE (6 ml) was placed in a 10 ml sealed tube. NIS (4.20 g, 18.7 mmol) was added to the reaction mixture and the mixture was subjected to microwave irradiation for 1 hour at 150°C. The reaction mixture was cooled then carefully quenched with aqueous Na ₂ S ₂ O ₃ (sat., 20 ml). The mixture was separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with brine (5×30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to give the title compound as a yellow solid (900 mg, 21%).

Compound 257.5. 3-(4-Cyano-3-methyl-1H-pyrazol-5-yl)-4-methylbenzoic acid. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 256.5, except for the use of 5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (compound 257.4) instead of 3-iodo- 1H-pioazole-4-carbonitrile (compound 256.1).

Compound 257 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-3-methyl-1H-pyrazole-4-carbonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 244, except for the use of 3-(4-cyano-3-methyl-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 257.5) instead of 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7). m/z (ES+) 382 (M+H ⁺ ).

Compound 258.1. Ethyl 5-iodine-4-methyl-1H-pyrazole-3-carboxylate. Into a 250 ml round bottom flask was placed a solution of ethyl 4-methyl-1H-pyrazole-3-carboxylate (600 mg, 3.89 mmol) in N,N-dimethylformamide (20 ml). NIS (2.2 g, 9.78 mmol) was added and the resulting mixture was stirred for 6 h at 50° C. then quenched with water (10 ml). The mixture was extracted with ethyl acetate (3×40 ml) and the combined organic extracts washed with aqueous Na ₂ S ₂ O ₃ (sat., 2×30 ml) and brine (2×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to give the title compound as a white solid (800 mg, 73%).

Compound 258.2. 5-Iodine-4-methyl-1H-pyrazole-3-carboxamide. A solution of ethyl 5-iodo-4-methyl-1H-pyrazole-3-carboxylate (compound 258.1, 500 mg, 1.79 mmol) in methanol (5 ml) was placed in a 100 ml round bottom flask. Then was added ammonium hydroxide (15 ml, 25% aq.), and the resulting solution was stirred over night at 60°C. The mixture was concentrated under reduced pressure to give the title compound as a white solid (400 mg, 89%).

Compound 258.3. 5-Iodo-4-methyl-1H-pyrazole-3-carbonitrile. A solution of 5-iodo-4-methyl-1H-pyrazole-3-carboxamide (compound 258.2, 800 mg, 3.19 mmol) in dichloromethane (10 ml) was placed in a 100 ml round bottom flask. The solution was cooled to 0°C, then trifluoroacetic anhydride (1.32 ml, 9.5 mmol) and triethylamine (3.16 ml, 22.7 mmol) were carefully added dropwise. The mixture was stirred for 2 hours at 0° C., then the pH was carefully adjusted to 7-8 with aqueous sodium bicarbonate (10%). The aqueous phase was extracted with ethyl acetate (2×40 ml) and the combined organic layers were washed with 2×10 ml brine (2×10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to give the title compound as a white solid (280 mg, 38%).

Compound 258 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-pyrazole-3-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 5-iodo-4-methyl-1H-pyrazole-3-carbonitrile (compound 258.3) instead of 3-iodo- 4-methoxy-1H-pyrazole (compound 244.5). m/z (ES+) 382 (M+H ⁺ ).

Compound 259 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-1H-pyrazole-3-carbonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 258, except for the use of methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4 ). m/z (ES+) 396 (M+H ⁺ ).

Compound 260.1. Methyl 5-nitro-1H-pyrazole-3-carboxylate. A 100 ml round bottom flask was charged with a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (3.0 g, 19.1 mmol) in methanol (50 ml). Sulfuric acid (3 ml) was added carefully and the resulting solution was stirred overnight at 80° C., then concentrated under reduced pressure. The pH of the solution was carefully adjusted to 7 with aqueous sodium bicarbonate (sat.), then extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (3×50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow solid (2.3 g, 70%).

Compound 260.2. Methyl 5-amino-1H-pyrazole-3-carboxylate. In a 100 ml round bottom flask was placed a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (compound 260.1, 2.5 g, 14.6 mmol) in methanol (10 ml). The system was purged with nitrogen, then palladium/carbon (10 wt% Pd, 0.8 g) was added. Hydrogen (1 atm) was introduced into the system and the mixture was stirred overnight at room temperature. The system was purged with nitrogen, then the solids were removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound as an off-white solid (1.5 g, 73%).

Compound 260.3. Methyl 5-iodine-1H-pyrazole-3-carboxylate. Into a 100 ml three-neck round-bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of methyl 5-amino-1H-pyrazole-3-carboxylate (compound 260.2, 1.0 g, 7.1 mmol) in a carefully prepared solution sulfuric acid (15 ml) in water (30 ml) (Note: the addition of sulfuric acid to water is an exothermic reaction). The solution was cooled to 0°C, then a solution of NaNO ₂ (0.53 g, 7.7 mmol) in water (5 ml) was added dropwise. The resulting mixture was stirred for 2 h at 0°C, then a solution of KI (1.4 g, 8.4 mmol) in water (5 ml) was added dropwise at 0°C. The resulting mixture was stirred overnight at room temperature, then the pH of the mixture was carefully adjusted to 7 with aqueous sodium bicarbonate (sat.). The mixture was extracted with ethyl acetate (3×50 ml) and the combined organic extracts were washed with brine (3×50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:5) as eluent to give the title compound as a yellow solid (0.6 g, 30%).

Compound 260.4. 5-Iodine-1H-pyrazole-3-carboxamide. A solution of methyl 5-iodo-1H-pyrazole-3-carboxylate (compound 260.3, 900 mg, 3.57 mmol) in methanol (5 ml) was placed in a 100 ml round bottom flask. Ammonia (25% aq.) (15 ml) was added and the resulting solution was stirred overnight at 60° C., then cooled and concentrated under reduced pressure to give the title compound as a white solid (0.8 g , 95%).

Compound 260.5. 5-Iodine-1H-pyrazole-3-carbonitrile. A solution of 5-iodo-1H-pyrazole-3-carboxamide (compound 260.4, 1.00 g, 4.22 mmol) in dichloromethane (10 ml) was placed in a 100 ml round bottom flask. The solution was cooled to 0°C, then trifluoroacetic anhydride (1.8 ml, 12.9 mmol) and triethylamine (4.11 ml, 29.5 mmol) were added dropwise carefully. The mixture was stirred for 2 hours at 0° C., then the pH was carefully adjusted to 7-8 with aqueous sodium bicarbonate (10%). The aqueous phase was extracted with ethyl acetate (3×30 ml) and the combined organic layers were washed with brine (2×20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to give the title compound as a light yellow solid (180 mg, 19%).

Compound 260.6. 4-Chloro-5-iodine-1H-pyrazole-3-carbonitrile. A solution of 5-iodo-1H-pyrazole-3-carbonitrile (compound 260.5, 100 mg, 0.46 mmol) in N,N-dimethylformamide (10 ml) was placed in a 50 ml round bottom flask. NCS (61.6 mg, 0.46 mmol) was added and the resulting mixture was stirred for 2 h at 50° C. then quenched with water (10 mL). The mixture was extracted with ethyl acetate (3×10 ml) and the combined organic extracts were washed with brine (3×10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:2) as eluent to give the title compound as a yellow oil (100 mg, 86%).

Compound 260 4-Chloro-5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-1H-pyrazole-3-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 4-chloro-5-iodo-1H-pyrazole-3-carbonitrile (compound 260.6) instead of 3-iodo- 4-methoxy-1H-pyrazole (compound 244.5). m/z (ES+) 402 (M+H ⁺ ).

Compound 261.1. (E)-4-Ethoxy-1,1,1-trifluoro-3-methylbut-3-en-2-one. Into a 50 ml three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of trifluoroacetic anhydride (3.31 ml, 23.8 mmol) and diethyl ether (20 ml). The solution was cooled to -10°C, then a solvent mixture consisting of (E)-1-ethoxyprop-1-ene (2.82 ml, 25.5 mmol) and pyridine (1.94 ml, 24.0 mmol), at -10°C. The resulting solution was stirred overnight at room temperature, then diluted with diethyl ether (50 ml). Solids were removed by filtration and the filtrate was concentrated under reduced pressure. The precipitate was diluted with water (100 ml) and extracted with DCM (3×50 ml). The combined organic extracts were washed with water. HCl (0.1 M, 3×100 ml) and water (100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a colorless oil (2.6 g , 60%).

Compound 261.2. 4-Methyl-3-(trifluoromethyl)-1H-pyrazole. (E)-4-ethoxy-1,1,1-trifluoro-3-methylbut-3-en-2-one (compound 261.1, 2.6 g, 14.3 mmol) in EtOH was placed in a 100 ml round bottom flask. (20 ml). Hydrazine hydrate (1.8 ml, 38 mmol) was added and the resulting solution was stirred for 2 h at 80°C. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil (2 g, imp.).

Compound 261 4-(1-(2,4-Dimethyl-5-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 4-methyl-3-(trifluoromethyl)-1H-pyrazole (compound 261.2) instead of 4-methoxy-1H- pyrazole (compound 244.4) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl-4-methyl -3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 439 (M+H ⁺ ).

Compound 262.1. (Z)-4-(Dimethylamino)-3-(trifluoromethyl)but-3-en-2-one. In a 100 ml round bottom flask was placed 4,4,4-trifluorobutan-2-one (1.7 ml, 15.86 mmol, 1.00 eq.) in toluene (45 ml). 1,1-Dimethoxy-N,N-dimethylmethanamine (4.21 mL, 31.7 mmol) was added and the resulting solution was stirred for 4 h at 100° C., then concentrated under reduced pressure to give the title compound, as a yellow oil (2.0 g, crude).

Compound 262.2. 3-Methyl-4-(trifluoromethyl)-1H-pyrazole. A solution of (Z)-4-(dimethylamino)-3-(trifluoromethyl)but-3-en-2-one (compound 262.1, 2.0 g, 11.0 mmol) in ethanol (30 ml). Hydrazine hydrate (3.7 ml, 77 mmol) was added and the resulting solution was stirred overnight at 75° C., then cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as eluent to give the title compound as a white solid (1.0 g, 61%).

Compound 262 4-(1-(2,4-Dimethyl-5-(3-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 3-methyl-4-(trifluoromethyl)-1H-pyrazole (compound 262.2) instead of 4-methoxy-1H- pyrazole (compound 244.4) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl-4-methyl -3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 439 (M+H ⁺ ).

Compound 263.1. N-Methoxy-N-methyltetrahydrofuran-3-carboxamide. A solution of tetrahydrofuran-3-carboxylic acid (10 g, 86.1 mmol) in dichloromethane (200 ml) was placed in a 250 ml round bottom flask. EDC⋅HCl (18.2 g, 94.9 mmol), N,O-dimethylhydroxylamine hydrochloride (10 g, 103 mmol) and triethylamine (24.0 ml, 172 mmol) were added and the resulting mixture was stirred overnight at room temperature. temperature. The mixture was diluted with DCM (50 ml) and washed with aqueous HCl (1 M, 3×10 ml), sodium bicarbonate (sat., 2×30 ml) and brine (3×20 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a light yellow oil (6.71 g, 49%).

Compound 263.2. 1-(Tetrahydrofuran-3-yl)propan-1-one. A solution of N-methoxy-N-methyltetrahydrofuran-3-carboxamide (compound 263.1, 6.71 g, 42.2 mmol) in tetrahydrofuran (100 ml) was placed in a 250 ml three-necked round bottom flask. The system was purged with nitrogen, then cooled to 0°C. Ethyl magnesium bromide (3 M in diethyl ether, 17 mL, 51 mmol) was added dropwise at 0° C. over 30 minutes. The resulting solution was stirred overnight at 40°C, then cooled and carefully extinguished with aqueous HCl (1 M, 10 ml). The resulting mixture was concentrated under reduced pressure and the residue was diluted with water (10 ml). The mixture was extracted with ethyl acetate (3×30 ml) and the combined organic extracts were washed with brine (2×10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The title compound was obtained as a light yellow oil (4.5 g, 83%).

Compound 263.3. 2-Methyl-3-oxo-3-(tetrahydrofuran-3-yl)propanal. In a 100 ml round bottom flask were placed 1-(tetrahydrofuran-3-yl)propan-1-one (compound 263.2, 2.5 g, 19.5 mmol), sodium methoxide (1.4 g, 25.9 mmol) and ethyl formate (20 ml). The mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20 to 1:5) as eluent to give the title compound as a yellow solid (2.0 g, 66%).

Compound 263.4. 4-Methyl-5-(tetrahydrofuran-3-yl)-1H-pyrazole. A solution of 2-methyl-3-oxo-3-(tetrahydrofuran-3-yl)propanal (compound 263.3, 3.00 g, 19.2 mmol) in ethanol (25 ml) was placed in a 100 ml round bottom flask. Hydrazine hydrate (1.16 ml, 24 mmol) was added and the resulting solution was stirred for 3 hours at 80°C. The resulting mixture was concentrated under reduced pressure to give the title compound as a colorless oil (3.5 g, imp.).

Compound 263 4-(1-(4-Methyl-3-(4-methyl-3-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 4-methyl-5-(tetrahydrofuran-3-yl)-1H-pyrazole (compound 263.4) instead of 4- methoxy-1H-pyrazole (compound 244.4). m/z (ES+) 427 (M+H⁺).

Compound 264.1. 1-Cyclopropylpropan-1-one. Into a 250 ml three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was charged cyclopropanecarbonitrile (20.0 g, 22.0 ml, 298 mmol) in diethyl ether (100 ml). The solution was cooled to 10° C., then ethyl magnesium bromide (3 M in diethyl ether, 109 mL, 327 mmol) was added dropwise over 10 min. The resulting solution was stirred overnight at 40°C, then cooled and carefully quenched with aqueous NH ₄ Cl (sat., 100 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with brine (3×200 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by distillation under reduced pressure (50 mmHg) and the phase that was collected at 50°C was the title compound. (11 g, 38%).

Compound 264 4-(1-(3-(3-Cyclopropyl-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to prepare compound 263, except for the use of 1-cyclopropylpropan-1-one (compound 264.1) instead of 1-(tetrahydrofuran-3-yl)propan-1 -one (compound 263.2). m/z (ES+) 397 (M+H) ⁺ .

Compound 265 4-(1-(5-(3-Cyclopropyl-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to prepare compound 263, except for the use of 1-cyclopropylpropan-1-one (compound 264.1) instead of 1-(tetrahydrofuran-3-yl)propan-1 -one (compound 263.2) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl-4- methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 411 (M+H ⁺ ).

Compound 266.1. 2-Cyclopropyl-3-oxobutanenitrile. Into a 100 ml three neck round bottom flask, which was purged and kept under an inert argon atmosphere, was placed a solution of 2-cyclopropylacetonitrile (3.70 ml, 40.1 mmol) in THF (20 ml). The solution was cooled to -78°C, then LDA (2 M in THF, 30 ml, 60 mmol) was added dropwise and the mixture was stirred for 1 h at -78°C. A solution of acetic anhydride (4.54 ml, 48.0 mmol) in tetrahydrofuran (10 ml) was added dropwise at -78°C. The mixture was stirred for 1 h at 15°C, then carefully quenched with citric acid (10% aq., 200 ml). The mixture was extracted with diethyl ether (2×70 ml) and the combined organic extracts were washed with brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound, which was used in the next step. without further purification.

Compound 266.2. 4-Cyclopropyl-3-methyl-1H-pyrazole-5-amine. A solution of 2-cyclopropyl-3-oxobutanenitrile (compound 266.1, 4.0 g, 32.5 mmol) in ethanol (18 ml) was placed in a 250 ml round bottom flask. AcOH (3 ml) and hydrazine hydrate (3.15 ml, 65 mmol) were added and the reaction mixture was stirred overnight at 80°C. The reaction mixture was cooled, then the pH was carefully adjusted to 9 with NaHCO ₃ (aq. sat.). The mixture was diluted with water, then extracted with ethyl acetate (6×60 ml) and the combined organic extracts were washed with brine (80 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as brown oil (4.17 g, crude), which was used in the next step without further purification.

Compound 266.3. 4-Cyclopropyl-5-iodo-3-methyl-1H-pyrazole. A solution of 4-cyclopropyl-3-methyl-1H-pyrazole-5-amine (compound 266.2, 3.8 g, 27.7 mmol) in ACN (40 ml) was placed in a 250 ml three-necked round bottom flask. The solution was cooled to 0°C, then AcOH (4.8 ml, 83 mmol) was carefully added, after which a solution of KI (11.5 g, 69.3 mmol) in water (40 ml) was added dropwise. The mixture was stirred for 10 min at 0° C., then tert-butyl nitrite (8.24 ml, 69.3 mmol) in ACN (40 ml) was added dropwise. The resulting mixture was stirred at 0° C. for 10 minutes, then at room temperature for 2 hours. The pH of the reaction mixture was carefully adjusted to 8 with sodium bicarbonate (aq. sat.) and extracted with ethyl acetate (4×50 ml). The combined organic extracts were washed with Na ₂ S ₂ O ₃ (aq. sat., 80 ml) and brine (2×80 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as eluent to give the title compound as a yellow solid (1.71 g, 25%).

Compound 266 4-(1-(5-(4-Cyclopropyl-3-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 4-cyclopropyl-5-iodo-3-methyl-1H-pyrazole (compound 266.3) instead of 3-iodo- 4-methoxy-1H-pyrazole (compound 244.5) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 411 (M+H) ⁺ .

Compound 267.1. Methyl 4-cyclopropyl-2-methylbenzoate. Potassium carbonate ( ₆ .10 g, 44.1 mmol, 2.00 eq.), cyclopropylboronic acid (2.30 g, 26.8 mmol, 1.20 eq.), Pd(dppf)Cl ₂ (900 mg, 1.23 mmol , 0.05 eq.) and Pd(OAc) ₂ (250 mg, 1.12 mmol, 0.05 eq.). The reaction mixture was purged with nitrogen and stirred at 80° C. overnight. After cooling to room temperature, the mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with 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 267.2. Methyl 4-cyclopropyl-5-iodo-2-methylbenzoate. NaIO ₄ (1.51 g, 7 08 mmol, 0.50 eq.), I ₂ (3.58 g, 14.1 mmol, 1.00 eq.) and sulfuric acid (201 mg, 2.01 mmol, 0.15 eq., 98% ). The reaction mixture was stirred at 110°C overnight. After cooling to air temperature, 100 ml of water was added. The resulting mixture was diluted with 100 ml of ethyl acetate, then washed with 3×30 ml of Na ₂ S ₂ O ₃ (aq., sat.) and 1×30 ml of saline. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50) as eluent to give 2.00 g (45%) of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate as a colorless oil.

Compound 267.3. Methyl 4-cyclopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5.4, except for the use of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate (compound 267.2) instead of methyl 3-iodo- 4-methylbenzoate (compound 5.3).

Compound 267 4-(1-(4-Cyclopropyl-5-(3,4-dimethyl-1H-pyrazol-5-yl)-2-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to prepare compound 59, except for the use of methyl-4-cyclopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (compound 267.3) instead of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate ( compound 5.4). m/z (ES+) 411 (M+H) ⁺ .

Compound 268.1. Ethyl 1-benzyl-4-methyl-1H-pyrazole-3-carboxylate. A solution of ethyl 4-methyl-1H-pyrazole-3-carboxylate (1.0 g, 6.5 mmol) in tetrahydrofuran (20 ml) was placed in a 100 ml three-necked round bottom flask. The solution was cooled to 0° C., then sodium hydride (360 mg, 9.00 mmol, 60% dispersion in mineral oil) was added portionwise and the mixture was stirred for 20 minutes. Benzyl bromide (904 μl, 7.60 mmol) was added at 0° C., then the resulting mixture was stirred for 1.5 h at room temperature. The reaction mixture was carefully quenched by adding water dropwise (35 ml) and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (3×100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:20-1:2) as eluent to give the title compound as a yellow solid (1.0 g, 63%).

Compound 268.2. (1-Benzyl-4-methyl-1H-pyrazol-3-yl)methanol. In a 100 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of ethyl 1-benzyl-4-methyl-1H-pyrazole-3-carboxylate (compound 268.1.2.3 g, 9.42 mmol) in THF (30 ml). The solution was cooled to 0° C., then LiAlH ₄ (360 mg, 9.49 mmol, 1.00 eq.) was added carefully in portions. The resulting mixture was stirred for 1 h at room temperature, then carefully quenched by adding water dropwise (400 μl), then aqueous NaOH (10%, 400 μl), then additional water (1.2 ml). Solids were removed by filtration and the filtrate was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow oil (1.7 g, 89%).

Compound 268.3.1-Benzyl-3-(methoxymethyl)-4-methyl-1H-pyrazole. A solution of (1-benzyl-4-methyl-1H-pyrazol-3-yl)methanol (compound 268.2.1.7 g, 8.4 mmol) in THF (50 ml) was placed in a 250 ml three-necked round bottom flask. The solution was cooled to 0°C, then sodium hydride (470 mg, 11.8 mmol, 60% dispersion in mineral oil) was added portionwise at 0°C, and then the mixture was stirred for 20 min. Iodomethane (750 μl, 12 mmol) was added at 0°C, then the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was carefully quenched by adding water dropwise (30 ml) and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (3×100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to give the title compound as a yellow oil (1.5 g, 83%).

Compound 268.4. 3-(Methoxymethyl)-4-methyl-1H-pyrazole. A solution of 1-benzyl-3-(methoxymethyl)-4-methyl-1H-pyrazole (compound 268.3, 700 mg, 3.24 mmol) in methanol (10 ml) was placed in a 100 ml round bottom flask. The system was purged with nitrogen, then Pd(OH) ₂ /C (70 mg, 20 wt.%) and aqueous HCl (2 M, 0.3 ml) were carefully added. Then hydrogen (1 atm) was introduced into the system, and the resulting mixture was stirred for 2 days at room temperature. The system was purged with nitrogen, then the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The pH of the residue was adjusted to 7 with aqueous sodium bicarbonate (sat.) and was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (2×30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow oil (500 mg, crude).

Compound 268 4-(1-(5-(3-(Methoxymethyl)-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 3-(methoxymethyl)-4-methyl-1H-pyrazole (compound 268.4) instead of 4-methoxy-1H- pyrazole (compound 244.4) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl-4-methyl -3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) m/z (ES+) 415 (M+H) ⁺ .

Compound 269 4-(1-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 3-iodobenzoic acid instead of 3-iodo-4-methylbenzoic acid and 4-bromo-3,5-dimethyl- 1H-pyrazole instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 357 (M+H) ⁺ .

The compounds listed in Table 12 were prepared using standard chemistry and procedures similar to those used to prepare compound 263.

The compounds listed in Table 13 were prepared using standard chemistry and procedures similar to those used to prepare compound 268.

The compounds listed in Table 14 were prepared using standard chemistry and procedures similar to those used to prepare compound 249.

Compound 279 4-(1-(5-(3-Chloro-4-methoxy-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compounds 244 and 250. m/z (ES+) 421 (M+H) ⁺ .

Compound 281.1. 3-(Methoxymethyl)-1H-pyrazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 268.4, except for the use of methyl 1H-pyrazole-3-carboxylate instead of methyl 4-methyl-1H-pyrazole-3-carboxylate.

Compound 281.2. 4-Chloro-3-(methoxymethyl)-1H-pyrazole. To a solution of 3-(methoxymethyl)-1H-pyrazole (compound 281.1, 200 mg, 1.78 mmol) in chloroform (20 ml) was added NCS (237 mg, 1.77 mmol). The reaction mixture was stirred overnight at room temperature, then extinguished with 20 ml H ₂ O. The aqueous phase was extracted with 3×50 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. The precipitate was purified by silica gel chromatography with EtOAc:PE (1:2) as eluent to give 50 mg (19%) of the title compound as a white solid.

Compound 281.3. Methyl 5-(4-chloro-3-(methoxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 244.6, except for the use of 4-chloro-3-(methoxymethyl)-1H-pyrazole (compound 281.2) instead of 4-methoxy-1H- pyrazole (compound 244.4).

Compound 281 4-(1-(5-(4-Chloro-3-(methoxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of methyl-5-(4-chloro-3-(methoxymethyl)-1H-pyrazol-5-yl)- 2,4-dimethylbenzoate (compound 281.3) instead of methyl 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate (compound 244.6). m/z (ES+) 435 (M+H) ⁺ .

Connection 304.1. 5-(3-(Bromomethyl)-4-chloro-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid. Mixture of methyl 5-(4-chloro-3-(methoxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound 281.3, 20 mg, 0.06 mmol) and HBr-HOAc (5 ml) stirred overnight at 80° C., then concentrated under reduced pressure to give 20 mg (90%) of the title compound as a yellow oil.

Connection 304.2. 5-(4-Chloro-3-(hydroxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid. A mixture of 5-(3-(bromomethyl)-4-chloro-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid (compound 304.1, 200 mg, 0.58 mmol) and NaHCO ₃ (0.3 M, 10 ml) was stirred for 30 minutes at room temperature, then concentrated under reduced pressure. This gave 200 mg (impure) of the title compound as a white solid.

Compound 304 4-(1-(5-(4-Chloro-3-(hydroxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 244, except for the use of 5-(4-chloro-3-(hydroxymethyl)-1H-pyrazol-5-yl)-2, 4-dimethylbenzoic acid (compound 304.2) instead of 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7). m/z (ES+) 421 (M+H) ⁺ .

Compound 280.1. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. Into a 250 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.82 g, 30.0 mmol ) in tetrahydrofuran (80 ml). NaH (70%) (2.05 g, 85.4 mmol) was then added portionwise at 0°C. SEMCl (6.4 ml, 36.1 mmol) was added dropwise to the mixture. The reaction mixture was stirred overnight at room temperature, then extinguished with 50 ml of NH ₄ Cl (sat.). The aqueous phase was extracted with 2×100 ml of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 7 g (72%) of the title compound as a colorless oil.

Compound 280.2. 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol. To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (compound 280.1, 9 .7 g, 30.0 mmol) in THF (100 ml) was added dropwise with 2M sodium hydroxide (aq.) (30 ml). H ₂ O ₂ (30%) (22.7 ml) was added dropwise to the mixture at 0°C. The reaction mixture was stirred for 2 h at room temperature, then quenched with 50 ml of water. The aqueous phase was extracted with 2×150 ml of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 4.3 g (67%) of the title compound as a white solid.

Compound 280.3. 4-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol (compound 280.2, 2.14 g, 10.0 mmol) in tetrahydrofuran (50 ml) was added Cs ₂ CO ₃ in portions (6.5 g, 20.0 mmol). CH ₃ I (1.25 ml, 20.0 mmol) was added dropwise to the mixture. The reaction mixture was stirred for 3 hours at room temperature, then concentrated under reduced pressure. The resulting precipitate was dissolved in 100 ml EtOAc. The solids were filtered off and the filtrate was concentrated under reduced pressure. This resulted in 2.1 g (92%) of the title compound as a colorless oil.

Compound 280.4. 4-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid. Into a 250 ml three-necked round-bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (compound 280.3, 4.6 g, 20 .0 mmol) in tetrahydrofuran (50 ml). Then n-BuLi (2.5 M in hexane) (10 ml) was added dropwise at -78°C. The reaction mixture was stirred for 1 h at -60°C. CO ₂ (TV) (5 g) was added to the mixture with stirring at -78°C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h, then quenched with 10 ml of NH ₄ Cl (sat.). The pH value of the solution was adjusted to 5-6 with HCl (1 M). The aqueous phase was extracted with 2×100 ml of ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. This resulted in 5 g (92%) of the title compound as a white solid.

Compound 280.5. 4-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamide. To a solution of 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid (compound 280.4, 5 g, 18.4 mmol) in N,N-dimethylformamide (50 ml) EDC⋅HCl (7 g, 36.5 mmol), NH ₄ Cl (1.97 g, 36.8 mmol) and 4-dimethylaminopyridine (8.95 g, 73.3 mmol) were added. The mixture was stirred for 2 h at room temperature, then heated to 50° C. for 3 h. The reaction mixture was quenched with 30 ml of NH ₄ Cl (sat.). The aqueous phase was extracted with 2×100 ml of ethyl acetate. The combined organic layers were washed with 3×100 ml NH ₄ Cl (sat.), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:5) as eluent to give 1.3 g (26%) of the title compound.

Compound 280.6. 4-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile. To a solution of 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamide (compound 280.5, 1.08 g, 4.0 mmol) in toluene (25 ml) was added dropwise POCl ₃ (1.86 ml, 20.0 mmol) at 0°C. The mixture was stirred for 2 h at 50° C., then quenched with 30 ml of sodium bicarbonate (sat.). The aqueous phase was extracted with 2×100 ml of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:6) as eluent to give 500 mg (49%) of the title compound as a white solid.

Compound 280.7. 4-Methoxy-1H-pyrazole-3-carbonitrile. Mixture of 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile (compound 280.6, 500 mg, 1.97 mmol) and trifluoroacetic acid (10 ml) in TES (5 ml ) was stirred for 2 h at room temperature, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as eluent to give 210 mg (86%) of the title compound as a white solid.

Compound 280.8. 5-Iodine-4-methoxy-1H-pyrazole-3-carbonitrile. To a solution of 4-methoxy-1H-pyrazole-3-carbonitrile (compound 280.7, 200 mg, 1.62 mmol) in N,N-dimethylformamide (15 mL) was added NIS (549 mg, 2.44 mmol). The reaction mixture was stirred for 2 h at 70°C, then quenched with 20 ml of Na ₂ S ₂ O ₃ (sat.). The aqueous phase was extracted with 2×50 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:6) as eluent to give 330 mg (82%) of the title compound as a white solid.

Compound 280 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-4-methoxy-1H-pyrazole-3-carbonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 5-iodo-4-methoxy-1H-pyrazole-3-carbonitrile (compound 280.8) instead of 4-chloro- 5-iodo-1H-pyrazole-3-carbonitrile (compound 260.6) and methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 412 (M+H ⁺ ).

Compound 294.1. (E)-3-(Dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one. 1-(Tetrahydro-2H-pyran-4-yl)ethanone (3.00 g, 23.4 mmol) and DMF-DMA (6.2 ml, 46.8 mmol) were added to a sealed tube. The reaction mixture was heated at 100°C overnight. The resulting mixture was concentrated under reduced pressure to give 4.00 g (impure) of the title compound as a light yellow oil.

Compound 294.2. 3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazole. To a solution of (E)-3-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one (compound 294.1, 4.3 g, 23.4 mmol) in ethanol (20 ml) was added NH ₂ NH ₂ ⋅H ₂ O (1.41 g, 28.2 mmol). The reaction mixture was stirred for 3 h at 80°C. The resulting mixture was concentrated under reduced pressure to give 4.45 g (impure) of the title compound as a light yellow solid.

Compound 294.3.4-Chloro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole. NCS (3.4 g, 25.4 mmol). The reaction mixture was stirred overnight at 40°C. The resulting mixture was concentrated under reduced pressure. This gave 4.75 g (impure) of the title compound as a light yellow solid.

Compound 294.4.4-Chloro-5-iodo-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole. NIS ( 7.26 g, 32.3 mmol). The reaction mixture was stirred overnight at 80°C. The reaction mixture was diluted with 50 ml of Na ₂ S ₂ O ₃ (sat.). 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 reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/8-1/5) as eluent to give 4.05 g (81%) of the title compound as a white solid.

Compound 294 ) benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 244, except for the use of 4-chloro-5-iodo-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrazole (compound 294.4) instead of 4-methoxy-1H-pyrazole (compound 244.4) and methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 475 (M+H) ⁺ .

Compound 293.1. 4-Chloro-3-cyclopropyl-5-iodo-1H-pyrazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 294.4, except for the use of 1-cyclopropyl ethanone instead of 1-(tetrahydro-2H-pyran-4-yl)ethanone.

Compound 293 4-(1-(5-(4-Chloro-3-cyclopropyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 294, except for the use of 4-chloro-3-cyclopropyl-5-iodo-1H-pyrazole (compound 293.1) instead of 4-chloro- 5-iodo-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (compound 294.4). m/z (ES+) 431(M+H) ⁺ .

Connection 305.1. N,N,4-Trimethyl-1H-pyrazole-1-sulfonamide. Into a 500 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 4-methyl-1H-pyrazole (10.4 g, 127.2 mmol) in CH ₂ Cl ₂ (200 ml). N,N-dimethylsulfamoyl chloride (17.14 ml, 167.1 mmol) and triethylamine (35 ml, 251.1 mmol) were added to the reaction mixture. The reaction mixture was stirred for 30 minutes at 0° C. in an ice water bath and then stirred overnight at room temperature. The reaction mixture was quenched with NaHCO ₃ (sat.) (40 ml) and the aqueous phase was extracted with 3×200 ml EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/hexanes (1:6) as eluent to give the title compound (22.2 g, 92%) as a light yellow oil.

Connection 305.2. 3-(2-Hydroxyethyl)-N,N,4-trimethyl-1H-pyrazole-1-sulfonamide. Into a 50 ml three-necked round-bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of N,N,4-trimethyl-1H-pyrazole-1-sulfonamide (compound 305.1, 1.19 g, 6.26 mmol) in THF (24 ml). n-BuLi (3 ml, 7.5 mmol, 2.5 M in hexanes) was added dropwise to the reaction mixture at -78°C. The resulting mixture was stirred for 30 minutes at -78°C. Then a solution of oxirane (5.6 ml, 113.51 mmol) in THF (4 ml) was added at -78°C. The reaction mixture was then brought to room temperature and stirred for 3 hours. The reaction mixture was quenched with 10 ml of NH ₄ Cl (sat.), and the aqueous phase was extracted with 3×50 ml of EtOAc. The combined organic layers were dried over Na ₂ SO ₄ . The solvent was removed to give the crude product, which was purified using silica gel chromatography with hexanes/EtOAc (3:1) as eluent to give 636 mg (44%) of the title compound as a light yellow oil.

Connection 305.3. 3-(2-Methoxyethyl)-N,N,4-trimethyl-1H-pyrazole-1-sulfonamide. In a 50 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 3-(2-hydroxyethyl)-N,N,4-trimethyl-1H-pyrazole-1-sulfonamide (compound 305.2, 636 mg, 2. 73 mmol) in THF (10 ml). Sodium hydride (131 mg, 60% in mineral oil, 3.27 mmol) was added at 0°C and stirred for 30 minutes at 0°C. CH ₃ I (204 μl, 3.28 mmol) was then added. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched with 10 ml of NH ₄ Cl (sat.), and the aqueous phase was extracted with 3×50 ml of EtOAc. The combined organic phases were dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel chromatography with hexanes/EtOAc (15:1-8:1) as eluent to give 452 mg (67%) of the title compound as yellow oil.

Connection 305.4. 3-(2-Methoxyethyl)-4-methyl-1H-pyrazole. In a 50 ml round-bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 3-(2-methoxyethyl)-N,N,4-trimethyl-1H-pyrazole-1-sulfonamide (compound 305.3, 440 mg, 1. 78 mmol) in dioxane (10 ml). HCl (10 ml, 6 M, 30 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 h at 85°C, then cooled to room temperature and carefully neutralized with water. NaHCO ₃ (sat.) to pH ~ 8. The aqueous phase was extracted with 3×50 ml EtOAc and the combined organic layers were dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give a crude product which was used in the next step without further purification.

Connection 305.5. 5-Iodo-3-(2-methoxyethyl)-4-methyl-1H-pyrazole. In a 50 ml (1 atm) round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 3-(2-methoxyethyl)-4-methyl-1H-pyrazole (compound 305.4, 249 mg, 1.78 mmol) in N,N-dimethylformamide (10 ml). NIS (482 mg, 2.14 mmol, 1.20 eq) was added to the reaction mixture. The reaction mixture was stirred for 2 h at 60° C., then cooled and quenched with 5 ml of NH ₄ Cl (sat.). The aqueous phase was extracted with 3×30 ml EtOAc, and the combined organic layers were dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel chromatography with hexanes/EtOAc (5:1) as eluent to give 328 mg (69% after two steps) of the title compound in brown oil.

Compound 305 4-(1-(5-(3-(2-Methoxyethyl)-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 5-iodo-3-(2-methoxyethyl)-4-methyl-1H-pyrazole (compound 305.5) instead of 3-iodo-4-methoxy-1H-pyrazole (compound 244.5) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 429 (M+H) ⁺ .

Compound 307.1.3-(2-Methoxyethyl)-1H-pyrazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 305.4, except for the use of 1H-pyrazole instead of 4-methyl-1H-pyrazole.

Connection 307.2. 4-Chloro-5-iodine-3-(2-methoxyethyl)-1H-pyrazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 294.4, except for the use of 3-(2-methoxyethyl)-1H-pyrazole (compound 307.1) instead of 3-(tetrahydro-2H-pyran -4-yl)-1H-pyrazole (compound 294.2).

Compound 307 4-(1-(5-(4-Chloro-3-(2-methoxyethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 4-chloro-5-iodo-3-(2-methoxyethyl)-1H-pyrazole (compound 307.2) instead of 3-iodo-4-methoxy-1H-pyrazole (compound 244.5) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 449 (M+H) ⁺ .

Compound 357.1. (Z)-Methyl-2-((dimethylamino)methylene)-3-oxobutanoate. Methyl 3-oxobutanoate (10.8 g, 92.6 mmol) and (dimethoxymethyl)dimethylamine (12.7 ml, 95.3 mmol) were placed in a 250 ml round bottom flask. The resulting solution was stirred for 2.5 h at 80° C., then concentrated under reduced pressure to give 14.5 g (imp.) of the title compound as a red solid.

Compound 357.2. Methyl 1-benzyl-3-methyl-1H-pyrazole-4-carboxylate. To a solution of (Z)-methyl 2-((dimethylamino)methylene)-3-oxobutanoate (15.8 g, 92.5 mmol) in ethanol (50 ml) was added 1-benzylhydrazine dihydrochloride (18 g, 92.3 mmol) . The resulting solution was stirred for 3.5 hours at 80°C, then concentrated under reduced pressure. The precipitate was dissolved in 200 ml of ethyl acetate. The organic layer was washed with 1×40 ml of water and 2×40 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:4) as eluent to give 12.4 g (58%) of the title compound as a yellow solid.

Compound 357 4-(1-(5-(4-(Methoxymethyl)-3-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 268, except for the use of methyl 1-benzyl-3-methyl-1H-pyrazole-4-carboxylate (compound 357.2) instead of ethyl- 1-benzyl-4-methyl-1H-pyrazole-3-carboxylate (compound 268.1). m/z (ES+) 415 (M+H) ⁺ .

Connection 314.1. 1-Benzyl-3-methyl-1H-pyrazole. To a solution of 3-methyl-1H-pyrazole (5.00 g, 60.9 mmol) in tetrahydrofuran (30 ml) was added sodium hydride (60%) (4.88 g, 203 mmol) in portions at 0°C and stirred for 30 minutes under nitrogen atmosphere. Benzyl bromide (8.7 ml, 73.1 mmol) was added to the above mixture. The reaction mixture was stirred for 1 hour at room temperature, then carefully quenched with 150 ml of water. The aqueous phase was extracted with 3×30 ml EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5.66 g (54%) of the title compound as a light yellow oil.

Compound 314.2. 1-Benzyl-3-methyl-1H-pyrazole-4-carbaldehyde. POCl ₃ (493 μl, 5.28 mmol ). The reaction mixture was stirred for 3 hours at 90° C. under nitrogen. The reaction mixture was diluted with 50 ml H ₂ O. The pH of the solution was adjusted to 7 with sodium hydroxide (2 M). The aqueous phase was extracted with 3 x 20 ml ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.42 g (imp.) of the title compound as a brown oil.

Compound 314.3. 1-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethanol. To a solution of 1-benzyl-3-methyl-1H-pyrazole-4-carbaldehyde (compound 314.2, 1.20 g, 5.99 mmol) in tetrahydrofuran (15 ml) was added CF ₃ SiMe ₃ (1.33 ml, 9. 01 mmol) and TBAF (0.11 ml, 0.11 mmol, 1M solution in THF). The mixture was stirred for 10 minutes at room temperature under nitrogen. Aqueous HCl (6 M) (1 ml) was then added. The reaction mixture was stirred for another 10 min at room temperature, then diluted with 50 ml H ₂ O. The aqueous phase was extracted with 3×20 ml of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/5-1/2) as eluent to give 1.15 g (71%) of the title compound as a light yellow solid.

Compound 314.4. O-(1-(1-Benzyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl) O-phenylcarbonothioate. To a solution of 1-(1-benzyl-3-methyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethanol (compound 314.3, 1.15 g, 4.26 mmol) in toluene (15 ml) was added 4-dimethylaminopyridine (1.47 g, 12.0 mmol) and phenylchloromethanethioate (1.04 g, 6.02 mmol). The reaction mixture was stirred for 1 hour at 60° C. under nitrogen, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/15) as eluent to give 1.34 g (77%) of the title compound as a light yellow oil.

Compound 314.5. 1-Benzyl-3-methyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole. To a solution of O-(1-(1-benzyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl) O-phenylcarbonothioate (compound 314.4, 1.34 g, 3.30 mmol) in toluene (20 ml) was added Bn ₃ SnH (3.84 ml, 13.2 mmol), AIBN (320 mg, 1.95 mmol). The reaction mixture was stirred for 1 hour at 80° C. under nitrogen, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:20) as eluent to give 650 mg (78%) of the title compound as a colorless oil.

Compound 314.6. 3-Methyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole. A carbon-supported palladium catalyst ( 700 mg, 10 wt.%) and HCl (4 M) (3 ml). The reaction mixture was hydrogenated for 48 hours at room temperature under 1 atmosphere of hydrogen. Solids were removed by filtration. The filtrate was evaporated under reduced pressure and diluted with 50 ml of water. The pH of the solution was adjusted to 7 with NaOH (2 M). The aqueous phase was extracted with 5 x 20 ml ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 230 mg (51%) of the title compound as a light yellow oil.

Compound 314 4-(1-(2,4-Dimethyl-5-(3-methyl-4-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl) benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 244, except for the use of 3-methyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole (compound 314.6) instead of 4-methoxy-1H-pyrazole (compound 244.4) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 453 (M+H) ⁺ .

Connection 313.1. 1-Benzyl-4-methyl-1H-pyrazole-3-carbaldehyde. To a solution of (1-benzyl-4-methyl-1H-pyrazol-3-yl)methanol (compound 268.2, 3 g, 14.8 mmol) in dichloromethane (100 ml) was added PDC (11.3 g, 30.1 mmol ), molecular sieves (3 g) and NaOAc (300 mg) were added to the reaction mixture. The reaction mixture was stirred for 4 hours at room temperature. Solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/10) as eluent to give 1 g (34%) of the title compound as a colorless oil.

Compound 313 benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 314, except for the use of 1-benzyl-4-methyl-1H-pyrazole-3-carbaldehyde (compound 313.1) instead of 1-benzyl- 3-methyl-1H-pyrazole-4-carbaldehyde (compound 314.2). m/z (ES+) 453 (M+H) ⁺ .

Compound 374.1. N,N,4-Trimethyl-1H-pyrazole-3-carboxamide. To a mixture of 4-methyl-1H-pyrazole-3-carboxylic acid (1.00 g, 7.93 mmol), HOBT (1.07 g, 7.93 mmol) and EDCI (2.27 g, 11.89 mmol) in DMF (10 ml) was added DIEA (2.74 ml, 15.86 mmol). After the mixture was stirred at room temperature for 16 hours, dimethylamine (2M in THF, 11.89 mL, 23.79 mmol) was added. The mixture was stirred at room temperature for 3 hours, then partitioned between EtOAc (300 ml) and water (30 ml). The organics were washed with brine (3×30 ml) and the combined aqueous material was subjected to back extraction with EtOAc (2×50 ml). All organic extracts were combined, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% MeOH in CH ₂ Cl ₂ ) to give the title compound as a brown oil (1.1 g, 92%). m/z (ES+) 154 (M+H) ⁺ .

Compound 374.2. 5-Iodine-N,N,4-trimethyl-1H-pyrazole-3-carboxamide. NIS (1.59 g, _7.04 mmol). The mixture was stirred at room temperature for 16 hours, then quenched with sat. Na ₂ SO ₃ (5 ml). The mixture was partitioned between EtOAc (200 ml) and water (30 ml). The EtOAc layer was washed with brine (30 ml), dried (MgSO ₄ ) and concentrated. The residue was purified by column chromatography (50% EtOAc in hexanes to 100% EtOAc) to give the product as a brown solid (1.79 g, 100%). m/z (ES+) 280 (M+H) ⁺ .

Compound 374 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-N,N,4-trimethyl-1H-pyrazole-3-carboxamide. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-iodo-N,N,4-trimethyl-1H-pyrazole-3-carboxamide (compound 374.2) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 442 (M+H) ⁺ .

Compound 375 5-(5-(3-Fluoro-3-(p-tolyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-N,N,4-trimethyl-1H-pyrazole-3-carboxamide. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-iodo-N,N,4-trimethyl-1H-pyrazole-3-carboxamide (compound 374.2) instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5), methyl-2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )benzoate (compound 160.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) and 4-(3- fluorazetidin-3-yl)benzonitrile (compound 43.4) instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 460 (M+H) ⁺ .

Compound 329. (3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-methylphenyl)(4-(4-methoxyphenyl)piperidin-1-yl)methanone. The title compound was prepared using standard chemical procedures and procedures similar to those used to prepare compound 5, except that 4-(4-methoxyphenyl)piperidine hydrochloride was used instead of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 404 (M+H) ⁺ .

Compound 284.1. Methyl 3-(2-(hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoate. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 219.4, except for the use of methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1 ).

Compound 284.2. 3-(2-(Hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid. Methyl 3-(2-(hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 284.1, 2 g, 6.36 mmol), HBr (40% in AcOH) (50 ml). The reaction mixture was stirred for 12 h at 80°C. The crude product (100 ml) was purified by preparative flash HPLC under the following conditions (IntelFlash-1): mobile phase, CH ₃ CN : H ₂ O=1:1; Detector, UV 254 nm yielding 1 g (52%) of the title compound as a light yellow solid.

Compound 284 4-(1-(3-(2-(Hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 3-(2-(hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)- 4-methylbenzoic acid (compound 284.2) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). m/z (ES+) 441 (M+H) ⁺ .

The compounds listed in Table 15 were prepared using standard chemistry and procedures similar to those used to prepare compound 284.

Compound 287.1. 5-Iodo-2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 202.2, except for the use of tetrahydro-2H-pyran-4-carbaldehyde instead of 3-methyloxetane-3-carbaldehyde.

Compound 287.2. Methyl 4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 202.4, except for the use of 5-iodo-2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)- 1H-imidazole (compound 287.1) instead of 5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile (compound 202.3).

Compound 287.3. 4-Methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoic acid. Methyl 4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoate solution (compound 287.2, 50 mg, 0.14 mmol ) in HCl (6 M) (2 ml) was stirred for 5 h at 80°C, then concentrated under reduced pressure. This gave 200 mg (impure) of the title compound as a brown solid which was used in the next step without further purification.

Compound 287 yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 202, except for the use of 4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-4-( trifluoromethyl)-1H-imidazol-5-yl)benzoic acid (compound 287.3) instead of 3-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-4-methylbenzoic acid (202.5 connection). m/z (ES+) 495 (M+H) ⁺ .

The compounds listed in Table 16 were prepared using standard chemistry and procedures similar to those used to prepare compounds 287 and 202.

The compounds listed in Table 17 were prepared using standard chemistry and procedures similar to those used to prepare compounds 230 and 231.

Compound 283. (4-Chloro-5-(5-(3-(4-cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2-methylphenyl)-1H-imidazol-2-yl)methyl acetate. A solution of 4-(1-(3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 29 , 40 mg, 0.09 mmol) in N,N-dimethylformamide (3 ml). Triethylamine (14 μl, 0.10 mmol) was added to the reaction mixture at 0°C followed by acetic anhydride (10 μl, 0.10 mmol). The reaction mixture was stirred for 2 hours at room temperature, then diluted with 10 ml of ethyl acetate. The organic layer was washed with 3×5 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (35 mg) was purified by preparative HPLC under the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD, 5 µm, 19*100 mm; mobile phase, water with 0.05% TFA and MeCN (10% MeCN up to 70% in 6 min, up to 95% in 1 min, up to 10% in 1 min); Detector, Waters 2489 254&220 nm. This resulted in 15 mg (34%) of the title compound as a white solid, m/z (ES+) 467 (M+H) ⁺ .

The compounds listed in Table 18 were prepared using standard chemistry and procedures similar to those used to prepare compounds 185, 192 and 194.

The compounds listed in Table 19 were prepared using standard chemistry and procedures similar to those used to prepare compounds 185 and 241.

The compounds listed in Table 20 were prepared using standard chemistry and procedures similar to those used to prepare compound 14.

The compounds listed in Table 21 were prepared using standard chemistry and procedures similar to those used to prepare compound 218.

Compound 282.1. N,N,2-Trimethyl-1H-imidazole-1-sulfonamide. To a solution of 2-methyl-1H-imidazole (10 g, 121.8 mmol) in dichloromethane (100 ml) was added N,N-dimethylsulfamoyl chloride (14.4 ml, 133.7 mmol) and triethylamine (34 ml, 244.1 mmol). The reaction mixture was stirred overnight at room temperature, then quenched with 10 ml of water and extracted with 1×50 ml of DCM. The organic layer was washed with 2×20 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as eluent to give 20 g (87%) of the title compound as a yellow oil.

Compound 282.2. 4-(2-Hydroxyethyl)-N,N,2-trimethyl-1H-imidazole-1-sulfonamide. Into a 250 ml three-necked round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of N,N,2-trimethyl-1H-imidazole-1-sulfonamide (compound 282.1, 6.4 g, 33.8 mmol) in tetrahydrofuran (50 ml). Then n-BuLi (2.5 M in hexane) (16.3 ml, 40.6 mmol) was added dropwise with stirring at -78°C. The reaction mixture was stirred for 1 h at -78°C. Oxirane (12.1 ml, 242.89 mmol) was added dropwise at -30°C. The reaction mixture was stirred for 2 h at room temperature, then quenched with 10 ml of water. The aqueous phase was extracted with 3×30 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. The residue was purified by silica gel chromatography with EtOAc:MeOH (40:1) as eluent to give 3.4 g (43%) of the title compound as a white solid.

Compound 282.3. 2-(2-Methyl-1H-imidazol-4-yl)ethanol. HCl ( 6 M, 30 ml). The reaction mixture was stirred for 4 h at 85°C, then concentrated under reduced pressure. The pH of the solution was adjusted to 7-8 with NaHCO ₃ (sat.). The resulting mixture was concentrated under reduced pressure to give 3 g (impure) of the title compound as a white solid.

Compound 282 4-(1-(3-(4-(2-Hydroxyethyl)-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 2-(2-methyl-1H-imidazol-4-yl)ethanol (compound 282.3) instead of 2,4 -dimethyl-1H-imidazole. m/z (ES+) 401 (M+H) ⁺ .

Compound 295.1. 4-(1-(3-(4-Formyl-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 5-iodo-2-methyl-1H-imidazole-4-carbaldehyde (compound 236.1) instead of 5-iodo- 2,4-dimethyl-1H-imidazole (compound 5.5).

Compound 295 4-(1-(3-(4-(Difluoromethyl)-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. To a solution of 4-(1-(3-(4-formyl-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 295.1, 100 mg, 0.26 mmol ) in dichloromethane (10 ml) was added DAST (103 μl, 0.78 mmol) at -70°C. The reaction mixture was stirred for 5 hours at room temperature. The pH of the solution was adjusted to 7 with sodium bicarbonate (sat.). The aqueous phase was extracted with 20 ml dichloromethane and the combined organic layers were washed with 3×10 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:20-1:2) as eluent. The crude product (100 mg) was purified by preparative HPLC under the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD, 5 µm, 19*100 mm; mobile phase, water with 0.05% TFA and ACN (16.0% to 30.0% in 7 minutes, to 95.0% in 1 minute, to 16.0% in 1 minute); Detector, Waters 2489 254&220 nm. This resulted in 48.7 mg (36%) of the title compound as a white solid, m/z (ES+) 407 (M+H) ⁺ .

Connection 300.1. Ethyl 4-methoxycyclohexane carboxylate. In a 100 ml round bottom flask was placed a solution of ethyl 4-hydroxycyclohexane-1-carboxylate (1 g, 5.81 mmol) in tetrahydrofuran (20 ml). Sodium hydride (349 mg, 8.72 mmol, 60%) was added portionwise to the reaction mixture at 0° C., followed by stirring for 20 minutes. Then CH ₃ I (865 µl, 11.6 mmol) was added at 0°C. The reaction mixture was stirred overnight at room temperature, quenched with 6 ml of saline and was extracted with 3×40 ml of ether. The combined organic layers were washed with 2×20 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 800 mg (74%) of the title compound as a colorless oil.

Connection 300.2. 4-Methoxycyclohexanecarbaldehyde. Into a 100 ml three neck round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was charged a solution of ethyl 4-methoxycyclohexane-1-carboxylate (1.3 g, 6.98 mmol) in dichloromethane (30 ml). DIBAL-H (1 M in hexanes) (9 ml, 9 mmol) was then added dropwise at -78°C. The reaction mixture was stirred for 3 h at -78°C, then quenched with 10 ml of NH ₄ Cl (sat.). The aqueous phase was extracted with 3×50 ml of ethyl acetate. The combined organic layers were washed with 3×50 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gave 1 g (impure) of the title compound as a colorless oil.

Connection 300.2. Methyl 3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate. The title compound was prepared using standard chemistry and procedures similar to those used to obtain compound 160.3, except for the use of 4-methoxycyclohexanecarbaldehyde (compound 300.2) instead of cyclopropanecarbaldehyde and methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1).

Connection 300.3. 3-(2-(4-Methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid. A solution of methyl 3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 300.2, 150 mg, 0.44 mmol) in methanol (4 ml). A solution of NaOH (70 mg, 1.75 mmol) in water (2 ml) was added to the reaction mixture. The reaction mixture was stirred for 3 hours at 50°C, then concentrated under reduced pressure. The reaction mixture was diluted with 2 ml of water. The pH of the solution was adjusted to 1 with HCl (2 M) and concentrated under reduced pressure. This gave 240 mg (impure) of the title compound as a light yellow solid.

Connections 300.A and 300.B. 4-(1-(3-(2-(4-Methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. A solution of 3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 300.3, 140 mg, 0.43 mmol) in N,N -dimethylformamide (3 ml). To the reaction mixture were added 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 82.8 mg, 0.43 mmol), HBTU (242.6 mg, 0.64 mmol) and DIEA (228 μl, 1. 28 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with 60 ml EtOAc. The organic layer was washed with 3×20 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (150 mg) was purified by preparative HPLC under the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD, 5 µm, 19*100 mm; mobile phase, and (20.0% to 27.0% in 10 min, up to 95.0% in 3 min, up to 20.0% in 1 min); Detector, Waters 2489 254&220 nm. This resulted in 18.4 mg (9%) of compound 300.A as a white solid and 59.2 mg (30%) of compound 300.B as an off-white solid, m/z (ES+) 469 ( M+H) ⁺ .

Connection 332.1. 3-(2-(4-Hydroxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid. Solution of methyl 3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 300.2, 300 mg, 0.88 mmol) in HI (45% in water) (3 ml) was stirred for 2 h at 60°C, then concentrated under reduced pressure. This gave 500 mg (impure) of the title compound as a brown oil which was used in the next step without further purification.

Compound 332 4-(3-(3-(2-(4-Hydroxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)cyclobutyl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 3-(2-(4-hydroxycyclohexyl)-4-methyl-1H-imidazol-5-yl)- 4-methylbenzoic acid (compound 332.1) instead of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid hydrochloride (compound 5.7). m/z (ES+) 455 (M+H) ⁺ .

Compound 355.1. 4-(1-(3-(2-Acetyl-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of 1-(4-methyl-1H-imidazol-2-yl)ethanone instead of 2,4-dimethyl-1H -imidazole.

Compound 355 4-(1-(3-(2-(1,1-Difluoroethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. In a 50 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of 4-(1-(3-(2-acetyl-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidine- 3-yl)benzonitrile (compound 355.1, 85 mg, 0.21 mmol) in dichloromethane (15 ml). DAST (82 μl, 0.62 mmol) was then added. The reaction mixture was stirred for 4 days at room temperature with an additional 15 equivalents of DAST over 4 days. The reaction mixture was then quenched by adding 10 ml of water. The aqueous phase was extracted with 3×50 ml dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/hexanes (6:1) as eluent. The crude product (54 mg) was purified by preparative HPLC under the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD, 5 µm, 19*100 mm; mobile phase, water with 0.05% TFA and MeCN (24.0% MeCN to 38.0% in 5 min, to 95.0% in 1 min, to 34.0% in 1 min); Detector, Waters 2489 254&220 nm. This gave 42.8 mg (38%) of the title compound (trifluoroacetic acid salt) as a white solid, m/z (ES+) 421 (M+H) ⁺ .

Compound 371.1. N,2-Dimethyl-1H-imidazole-4-carboxamide. 2-Methyl-1H-imidazole-4-carboxylic acid (378 mg, 3 mmol), EDCI (745 mg, 3.9 mmol), HOBt (253 mg, 1.5 mmol), DIEA (1.6 ml, 9 mmol) and methylamine (2M in THF) (3.6 ml, 7.2 mmol) were dissolved in DMF (10 ml) and stirred at room temperature for 16 hours. After DMF was removed, the precipitate was dry sampled and purified by flash chromatography (SiO ₂ ; 0-10% methanol in DCM and 1% NH ₄ OH) to give 280 mg (67%) of the title compound, m/ z (ES+) 140 (M+H) ⁺ .

Compound 371 5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-N,2-dimethyl-1H-imidazole-4-carboxamide. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 5, except for the use of N,2-dimethyl-1H-imidazole-4-carboxamide (compound 371.1) instead of 2,4-dimethyl- 1H-imidazole. m/z (ES+) 414 (M+H) ⁺ .

Compound 349.1. 4,4,4-Trifluoro-2-oxobutanal. To a solution of SeO ₂ (4.23 g, 38.1 mmol) in dioxane (25 ml) was added AcOH/H ₂ O (1 ml/1 ml). 4,4,4-trifluorobutan-2-one (3.81 ml, 31.7 mmol) was added dropwise to the above reaction mixture. The resulting solution was stirred overnight at 100°C. The solution was used in the next step without any further extraction or purification.

Compound 349.2. 2-Methyl-4-(2,2,2-trifluoroethyl)-1H-imidazole. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 159.1, except for the use of 4,4,4-trifluoro-2-oxobutanal (compound 349.1) instead of methylglyoxal.

Compound 349 benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 159, except for the use of 2-methyl-4-(2,2,2-trifluoroethyl)-1H-imidazole (compound 349.2) instead of 2-isopropyl-4-methyl-1H-imidazole (compound 159.1). m/z (ES+) 453 (M+H) ⁺ .

Compound 296 4-(1-(4-Methyl-3-(2-methyl-4-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was obtained using standard chemical procedures and procedures similar to those used to obtain compound 159, except for the use of 2-methyl-4-(2,2,2-trifluoroethyl)-1H-imidazole (compound 349.2) instead of 2-isopropyl-4-methyl-1H-imidazole (compound 159.1) and methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) instead of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1). m/z (ES+) 439 (M+H) ⁺ .

Compound 377.1. Methyl 4-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. Into a 250 ml round bottom flask, which was purged and kept under an inert nitrogen atmosphere, was placed a solution of methyl 4-fluoro-5-iodo-2-methylbenzoate (compound 101.2, 5.04 g, 17.1 mmol) in DMSO (50 ml ). 4,4,5,5-Tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.23 g, 20.6 mmol) was added to the reaction mixture , KOAc (5.04 g, 51.4 mmol), Pd(dppf)Cl ₂ (2.51 g, 3.43 mmol). The reaction mixture was stirred for 2 h at 90°C, then cooled and diluted with 300 ml EtOAc. The solids were filtered off and the filtrate was washed with 3 x 30 ml brine (sat.). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/30) as eluent to give 3.97 g (79%) of the title compound as an off-white solid.

Compound 377.2. 4-(1-(5-(3,4-Dimethyl-1H-pyrazol-5-yl)-4-fluoro-2-methylbenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to prepare compound 59, except for the use of methyl-4-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (compound 377.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate ( compound 5.4). m/z (ES+) 389 (M+H) ⁺ .

Compound 377 4-(1-(4-(Azetidin-1-yl)-5-(3,4-dimethyl-1H-pyrazol-5-yl)-2-methylbenzoyl)azetidin-3-yl)benzonitrile. A solution of 4-(1-(5-(3,4-dimethyl-1H-pyrazol-5-yl)-4-fluoro-2-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 377.2 , 120 mg, 0.31 mmol) in dioxane (3 ml). Azetidine (833 μl, 12.4 mmol) and CS ₂ CO ₃ (1.01 g, 3.09 mmol) were added to the reaction mixture. The reaction mixture was stirred for 20 hours at 120° C., then cooled with an ice bath. The resulting solution was diluted with 30 ml EtOAc. The organic layer was washed with 3×20 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC under the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD, 5 µm, 19*100 mm; mobile phase, water with 10 mmol NH ₄ HCO ₃ and MeCN (36.0% MeCN to 50.0% in 6 min, to 95.0% in 2 min, to 36.0% in 1 min); Detector, Waters 2489 254&220 nm. This resulted in 56 mg (43%) of the title compound as a white solid, m/z (ES+) 426 (M+H) ⁺ .

Compound 376.1. Methyl 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 377.1, except for the use of methyl 4-fluoro-3-iodobenzoate (compound 132.1) instead of methyl 4-fluoro-5-iodo- 2-methylbenzoate (compound 101.2).

Compound 376.2. 4-(1-(3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 5, except for the use of methyl-4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzoate (compound 376.1) instead of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4).

Compound 376 4-(1-(4-(Azetidin-1-yl)-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compound 377, except for the use of 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)- 4-fluorobenzoyl)azetidin-3-yl)benzonitrile (compound 376.2) instead of 4-(1-(5-(3,4-dimethyl-1H-pyrazol-5-yl)-4-fluoro-2-methylbenzoyl)azetidine- 3-yl)benzonitrile (compound 377.2). m/z (ES+) 412 (M+H) ⁺ .

The compounds listed in Table 22 were prepared using standard chemistry and procedures similar to those used to prepare compounds 14, 101, 375 and 376.

Compound 378 4-(1-(4-Chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemical procedures and procedures similar to those used to obtain compound 50, except for the use of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) instead of 4-(piperidin-4-) hydrochloride. yl)benzonitrile (compound 1.2). m/z (ES+) 391 (M+H) ⁺ .

Compound 379 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-(trifluoromethyl)benzoyl)azetidin-3-yl)benzonitrile. The title compound was prepared using standard chemistry and procedures similar to those used to prepare compounds 50 and 378. m/z (ES+) 425 (M+H) ⁺ .

Compound 380 . The title compound was prepared using standard chemistry and procedures similar to those used to prepare compounds 202, 287, 300A and 300 V. m/z (ES+) 523 (M+H) ⁺ .

Compound 381 . The title compound was prepared using standard chemistry and procedures similar to those used to prepare compounds 202, 287, 300A and 300 V. m/z (ES+) 523 (M+H) ⁺ .

Compounds according to the present application, shown in Table 26 below, were or can be obtained using the above methods, as well as standard chemical operations and methods similar to the above methods.

EXAMPLE 2

The activity of the compound according to the present application

Antiviral activity

The different antiviral activity of the compounds according to the present application was evaluated using the HCV1b replication system. The replicon was constructed using the ET cell line (luc-ubi-neo/ET), a human hepatoma Huh7 cell line containing an HCV replicon with a stable luciferase reporter (Luc) and three cell culture adaptive mutations (Pietschmann, et al (2002) J. Virol 76: 4008-4021). In an evaluation assay of the antiviral activity of HCV replicon, the effects of the compounds were studied at ten 3-fold dilutions. Subconfluent cultures of the ET line were seeded in 96-well plates designed for cell survival (cytotoxicity) or antiviral activity assays, and drugs were added to the appropriate wells the following day. Cells were analyzed 72 hours later when they were still subconfluent. The values of EC ₅₀ (concentrations inhibiting HCV RNA replicon by 50%), CC ₅₀ (concentration that reduces cell survival by 50%) and SI (selective index: CC ₅₀ /EC ₅₀ ) were determined. Replicon RNA levels were assessed using the Bright-Glo™ Luciferase Assay System (Promega) to determine replicon-induced Luc activity. The CellTiter-Glo™ Luminescent Cell Viability Assay (Promega) was used to evaluate cell viability. HCV inhibition for individual compounds is shown in Table 26. None of the compounds listed in Table 26 caused significant cytotoxicity at the highest concentrations tested.

Inhibition of FASN by compounds according to the present application

Determination of biochemical activity of FASN: The FASN enzyme was isolated from SKBr3 cells. SKBr3 is a human breast cancer cell line with high levels of FASN expression. It was found that FASN contains approximately 25% of the cytosolic proteins in this cell line. SKBr3 cells were homogenized in a Downs homogenizer, then centrifuged for 15 minutes at 4°C to remove solid impurities. The supernatant was then analyzed for protein content, diluted to the desired 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 by Teresa, P. et al. (Clin. Cancer Res. 2009; 15(24), 7608-7615).

The FASN activity of the SKBr3 cell extract was determined by measuring the oxidation of NADPH or the amount of thiol-containing coenzyme A (KoA) released during reactions with fatty acid synthase. The CPM dye (7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin) contains a reactive thiol group, the fluorescence of which increases upon reaction with KoA. The biochemical activities shown in Table 26 were determined using fluorescence measurement of KoA release by the method described by Chung C.C. et al. (Assay and Drug Development Technologies, 2008, 6(3), 361-374).

FASN inhibitors are effective against cancer

Experimental Methods

Cell survival assay: For drug treatment, PANC-1 cells were seeded in 96-well plates at a density of 1.0 x 10 ³ per well in media (Advanced MEM containing 1% or 10% PBS). Serial 3-fold dilutions of compounds 160, 161, 242, or 164 were prepared in DMSO, which were further diluted 1:10 in Advanced MEM to be added to the assay solution. 24 hours after seeding the cells, the compound diluted with advanced MEM was added to bring the final volume of the reaction mixture to 100 μl per well. The final concentrations of drugs in the analyzed wells were 10000, 3300, 1100, 370, 123, 41, 14, 5 and 0 nmol/l. The assay was done in triplicate at each drug concentration 10 days after addition of the compound. The number of viable cells was measured using the analysis of Cell Titer-Glo (Promega) according to the manufacturer's instructions. The luminosity per well was determined, and the signal intensity was analyzed relative to drug concentration. For each FASN inhibitor, the drug concentration resulting in 50% inhibition of the maximum signal was determined and this value was reported as the IC ₅₀ .

Investigation of the effectiveness of xenograft tumor growth inhibition: For xenograft tumor development and drug treatment, female BALB/c-nude mice of 8-9 weeks of age were injected subcutaneously into the right flank with PANC-1 tumor cells (5×10 ⁶ ) in 0.1 ml of PBS . The day of tumor cell injection was designated day 0. Drug treatment was started when the average tumor size reached 149 mm ³ (day 15). Drug administration to tumor bearing mice (n=10 per group) was performed as follows: Compound 161: 30 or 60 mg/kg once daily (Qd); compound 242: 30 or 60 mg/kg once a day (Qd); C75 (trans-4-methylene-2-octyl-5-oxo-tetrahydrofuran-3-carboxylic acid): 30 mg/kg once every 5 days (Q5d); gemcitabine 40 mg/kg once every 3 days (Q3d). The administered dose of C75 was reduced to 20 mg/kg once every 5 days after the first dose due to drug-induced weight loss and toxicity. Mice were assigned to treatment groups using a randomized block design based on tumor volumes to ensure comparability of all groups at the start of treatment. Tumor sizes were measured twice a week in two dimensions with a compass, and volumes were expressed in ^mm3 using the formula: V=0.5a×b2, where a and b were the long and short tumor diameters, respectively. The study was terminated 6 hours after the 18th Qd dose on day 32 post tumor injection. Inhibition of tumor growth (Tumor growth inhibition, TGI) was calculated as a percentage of tumor growth relative to tumor size at the beginning of treatment in groups treated with drugs, compared with groups treated with inert substances. The Mann-Whitney U test was used to determine the statistical significance of the mean tumor size between drug and inert groups.

results

FASN Inhibition Inhibits Tumor Cell Growth and Causes Cell Death: To test the effects of FASN inhibition on tumor cell survival, a pancreatic tumor cell line (PANC-1) was treated with a range of FASN inhibitors and IC ₅₀ values were determined from a 9-point cell viability assay in drug response. Cell survival IC ₅₀ values were determined 10 days after addition of FASN inhibitory compounds to tumor cells (Table 23). FASN cell survival IC ₅₀ values were consistent with previously determined biochemical and cellular FASN IC ₅₀ values in palmitate synthesis and HCV replicon assays. A series of IC ₅₀ values in phenotypic (cell survival) and mechanistic (palmitate synthesis) assays indicate that tumor cell death induced by treatment with FASN inhibitors is a direct result of FASN inhibition.

FASN Inhibition Inhibits Tumor Xenograft Growth In Vivo: To test the effects of FASN inhibition on tumor growth in vivo, female BALB/c-nude mice were injected subcutaneously with PANC-1 tumor xenografts. When xenograft tumors grew to an average of 149 mm ³ (day 15 after tumor cell injection), drug treatment was initiated using reversible inhibitors of FASN 3-V Biosciences (compound 161 or 242) or control compounds (C75 or gemcitabine) to determine inhibitory tumor growth activities of various compounds in the PANC-1 xenograft tumor model. The drug groups consisted of 10 tumor-bearing mice per group. The FASN inhibitors Compounds 161 and 242 both showed tumor growth inhibitory activity in a dose-response manner. Administration of compound 161 at a dose of 60 mg/kg once daily for 18 days resulted in a 52% inhibition of tumor growth compared to mice treated with an inert substance, and administration of compound 242 at a dose of 100 mg/kg once daily for 18 days resulted in a 57% inhibition of tumor growth compared to mice treated with an inert substance (Tables 24 and 25). The introduction of compounds 161 and 242 at a dosage of 30 mg/kg once a day led to the inhibition of tumor growth by 31% and 19%, respectively. C75, a control compound, an irreversible inhibitor of FASN, was initially administered at a dosage of 30 mg/kg once every 5 days; however, the toxicity of said compound necessitated a dose reduction to 20 mg/kg once every 5 days. In the C75 group, 65% inhibition of tumor growth was observed after 18 days (3 doses). Six out of ten mice in the C75 treated group died from C75 related toxicity during the 18 day study. In PANC-1 tumor-bearing mice treated with gemcitabine (40 mg/kg once every 3 days), tumor growth was inhibited by 96 percent. The inhibition of tumor growth induced by compounds 161 and 242, C75 and gemcitabine was statistically significant compared to mice treated with an inert substance. The results of this study show that the reversible FASN inhibitors discovered in 3-V Biosciences are well tolerated by mice carrying PANC-1 xenograft tumors, and that once-daily administration of the inhibitors in the form of a single agent anti-cancer drug is associated with statistically significant inhibition tumor growth compared to mice treated with an inert substance. Additional studies are planned to explore dosing levels, dosing regimen and combinations with the current standard of chemotherapy.

Tumor volumes

The tumor volumes of each treatment group at various time points are shown in Table 24.

Inhibition of tumor growth

Tumor growth inhibition (TGI) and statistical analysis of each treatment group at study completion (Day 32) is summarized in Table 25.

Although the present application shows and describes the preferred aspects of the implementation of the present invention, it will be obvious to specialists in this field that these aspects are given only as examples. Those skilled in the art will recognize numerous variations, changes, and substitutions that can be applied without deviating from the present invention. It should be understood that a variety of alternatives to the aspects of the present invention described in this application can be applied when using the invention in practice. It is intended that the following claims define the scope of the present invention and that the methods and structures included in the claims and their equivalents are covered by the claims.

All publications and patent applications referenced in this application are incorporated by reference herein as if each individual publication or patent application were separately identified as incorporated by reference.

Claims (81)

1. Compound structure III

or its pharmaceutically acceptable salts, where L-Ar is

Ar represents

R ¹ is -CN or halogen; each R ² is independently H, halogen or C ₁ -C ₄ alkyl; R ³ is H or F; R ²¹ is H, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, or azetidine; R ²² represents H, halogen or C ₁ -C ₂ alkyl; R ²⁴ is H, -CN, -(C ₁ -C ₄ alkyl) -CN, C ₁ -C ₄ alkyl, C ₁ -C ₂ haloalkyl, -(C ₁ -C ₄ alkyl) -OH -(C ₁ -C ₄ alkyl)-N(R ²⁴¹ ) ₂ , -(C ₃ -C ₆ cycloalkyl), -(C ₁ -C ₄ alkyl) _t -O _u -(4-6 membered heterocycle), where the heterocycle is selected from azetidine, tetrahydropyran, tetrahydrofuran and pyrrolidine, or -(C ₁ -C ₄ alkyl)-O-(C ₁ -C ₄ alkyl), where t is 0 or 1, u is 0 or 1 provided that when u is 1, t is 1; and each R ²⁴¹ is independently C ₁ -C ₂ alkyl; and R ²⁵ is halogen, -CN, C ₁ -C ₂ alkyl or cyclopropyl. 2. The connection according to claim 1, in which, when L-Ar is

Ar is not

3. The compound according to claim 1, in which R ²⁴ is H, -CH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OH, -(CH ₂ ) ₂ OCH ₃ , -( CH ₂ ) ₂ N(CH ₃ ) ₂ , isopropyl, cyclopropyl, -CN or -(C ₁ -C ₂ alkyl)-CN; or -(C ₁ -C ₂ alkyl)-O-(C ₁ -C ₂ alkyl), -CH ₂ -O-CH ₃ , C ₁ -C ₂ alkyl, C ₃ -C ₆ cycloalkyl. 4. Connection according to any one of paragraphs. 1-3, in which R ²⁵ represents -Cl. 5. Structure IIIb compound

or its pharmaceutically acceptable salts, where L-Ar represents

Ar represents

R ¹ is -CN; each R ² is hydrogen; R ³ is H or F; R ²¹ is C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, or azetidine; R ²² is H or C ₁ -C ₂ alkyl; and each R ²⁴ and R ²⁵ independently represents H, halogen, -CN, C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkyl)-OH, C ₃ -C ₅ cycloalkyl, -(C ₁ -C ₄ alkyl ) _t -O _u -(4-6-membered heterocycle), where the heterocycle is selected from tetrahydrofuran, tetrahydropyran and oxetane, or -(C ₁ -C ₄ alkyl) _t -O-(C ₁ -C ₄ alkyl), where each t is independently 0 or 1, each u is independently 0 or 1 and where the connection does not represent

6. The connection according to claim 5, in which, when L-Ar is

Ar is not

7. A compound according to claim 5 or 6, wherein R ²⁴ is -Cl, -(C ₁ -C ₂ alkyl)-O-(C ₁ -C ₂ alkyl) or -CH ₃ . 8. A compound according to claim 5 or 6, wherein R ²⁵ is methyl, ethyl cyclopropyl, -CN, -Cl or -O-(C ₁ -C ₂ alkyl). 9. Compound structure II

or its pharmaceutically acceptable salts, where L-Ar represents

Ar represents

R ¹ is -CN; each R ² is hydrogen; R ³ is H or F; R ²¹ is C ₃ -C ₅ cycloalkyl; R ²² is H or C ₁ -C ₂ alkyl; and R ²⁴ is C ₁ -C ₄ alkyl or -(C ₁ -C ₄ alkyl) _t -O-(C ₁ -C ₄ alkyl), where each t is independently 0 or 1. 10. A compound according to claim 9 wherein R ²⁴ is -(C ₁ -C ₂ alkyl) _t -O-(C ₁ -C ₂ alkyl). 11. Compound of structure I

or its pharmaceutically acceptable salts, where L ³ represents -NR ⁵⁰ -, where R ⁵⁰ represents C ₁ -C ₆ alkyl; n is 2; m is 1 or 2; L-Ar represents

Ar represents

R ¹ represents H, -CN or halogen; each R ² is hydrogen; R ³ is H; R ²¹ is C ₁ -C ₄ alkyl or C ₃ -C ₅ cycloalkyl; and R ²² is C ₁ -C ₂ alkyl. 12. The compound of claim 11 wherein L ³ is -N(CH ₃ )-. 13. The compound according to claim 11, in which m is 2. 14. Connection according to any one of paragraphs. 11-13, in which R ¹ is -CN. 15. Compound of structure VI

or its pharmaceutically acceptable salts, where each W, Y and Z is independently -CR ²⁶ -, X is -N-; each R ²⁶ is independently H or -N(R ²⁷ ) ₂ ; both R ²⁷ are C ₁ -C ₄ alkyl and are combined to form a 4-6 membered ring together with the N atom to which they are attached, and where the ring may contain one oxygen atom as one of the ring members; Ar represents

R ¹ is -CN; each R ² is hydrogen; R ³ is H; R ²¹ is C ₁ -C ₄ alkyl; and R ²² is H or C ₁ -C ₂ alkyl. 16. A pharmaceutical composition having antiviral, antitumor activity, as well as for the treatment of conditions characterized by dysregulation of the fatty acid synthase pathway, containing an effective amount of a compound according to any claim. 1-15 and a pharmaceutically acceptable carrier, excipient or diluent.