HK1168840A

HK1168840A - Pyridine and pyrimidine derivatives as mglur2 antagonists

Info

Publication number: HK1168840A
Application number: HK12108990.9A
Authority: HK
Inventors: Silvia Gatti Mcarthur; Erwin Goetschi; Juergen Wichmann; Thomas Johannes Woltering
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 2006-03-29
Filing date: 2012-09-13
Publication date: 2013-01-11

Description

Pyridine and pyrimidine derivatives as mGluR2 antagonists

This application is a divisional application of PCT application PCT/EP2007/052560 filed 3/19/2007 and entitled "pyridine and pyrimidine derivatives as mGluR2 antagonists" on the date of entry into the national phase of china at 2008/10/6, with application number 200780012002.0.

Technical Field

The present invention relates to compounds of formula (I), processes for their production, their use in the manufacture of medicaments for the treatment of CNS disorders and pharmaceutical compositions containing them.

In particular, the present invention relates to compounds of general formula (I):

wherein:

one of X or Y is N, the other is CH, or X and Y are both N;

a is aryl or 5-or 6-membered heteroaryl, each of which is optionally substituted by C_1-6-alkyl substitution;

b is H, cyano, or

Is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are selected from the group consisting of:

the halogen(s) are selected from the group consisting of,

the nitro group(s),

c optionally substituted by hydroxy_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H, C_1-6-alkyl or- (CO) -C_1-6-an alkyl group,

-S-C_1-6-an alkyl group,

-(SO₂)-OH，

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

C_1-6-an alkoxy group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

-(CH₂CH₂O)_nCHR^ewherein R is^eIs H or CH₂OH, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

-(CH₂)_maryl, where m is 1 or 2, aryl being optionally substituted by halogen or C_1-6-an alkoxy group substitution,

-(CH₂)_p-C_3-6cycloalkyl, wherein p is 0 or 1,

a 5-or 6-membered heterocycloalkyl group,

-(SO₂)-NR^fR^gwherein R is^fAnd R^gTogether with the nitrogen atom to which they are attached form a compound optionally containing a nitrogen, oxygen, sulfur or SO group₂Wherein the 4, 5 or 6 membered heterocycloalkyl ring of the other heteroatom of (a), wherein the 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted with a substituent selected from the group consisting of:

Hydroxy, C_1-6-alkyl, C optionally substituted by hydroxy_1-6-alkoxy and 5-or 6-membered heteroaryloxy,

NHSO₂-C_1-6-an alkyl group,

NHSO₂-NR^hRⁱwherein R is^hAnd RⁱIndependently is H, C_1-6Alkyl, - (CO) O-C_1-6-alkyl, or R^hAnd RⁱTogether with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by C_1-6-alkyl substitution;

R¹is H, halogen, C optionally substituted by hydroxy_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-haloalkyl group, C_3-6-a cycloalkyl group;

R²is H, cyano, halogen, C_1-6-haloalkyl group, C_1-6-alkoxy, C_1-6-haloalkoxy, C_1-6-alkyl or C_3-6-a cycloalkyl group;

R³is halogen, H, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6Alkyl radical, C_3-6-cycloalkyl, C_1-6-a halogenated alkoxy group,

or is NR^jR^kWherein R is^jAnd R^kIndependently selected from the group consisting of:

H、C_3-8-cycloalkyl, aryl, heteroaryl with 5-12 ring atoms and C optionally substituted by one or more substituents selected from the group consisting of_1-6-an alkyl group: halogen, hydroxy, C_3-8-cycloalkyl, aryl, heteroaryl with 5-12 ring atoms and-NR^lR^mWherein

R^lAnd R^mIndependently selected from H and C_1-6-an alkyl group;

or R^lAnd R^mMay form, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclic group comprising 5 to 12 ring atoms and optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, wherein the heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from: halogen, hydroxy 、C_1-6-alkyl and C_1-6-a haloalkyl group;

or R²And R³Can together form a dioxo bridge;

R⁴is H or halogen.

Background

It has surprisingly been found that the compounds of the general formula I are metabotropic glutamate receptor antagonists. The compounds of formula I are distinguished by valuable therapeutic properties.

In the Central Nervous System (CNS), transmission of stimuli occurs through the interaction of neurotransmitters produced by neurons with neuroreceptors.

L-glutamate is the most common neurotransmitter in the central nervous system and plays a critical role in a variety of physiological processes. Glutamate-dependent stimulus receptors fall into two major classes. The first major group forms ion pathways that are controlled by ligands. Metabotropic glutamate receptors (mGluRs) form the second major class and also belong to the G-protein coupled receptor family.

Currently, 8 different mglurs are known, some of them even with subtypes. These 8 receptors can be subdivided into three subclasses according to structural parameters, different effects on the synthesis of secondary metabolites and different affinities for low molecular weight compounds: mGluR1 and mGluR5 belonging to class I, mGluR2 and mGluR3 belonging to class II, mGluR4, mGluR6, mGluR7 and mGluR8 belonging to class III.

Ligands of metabotropic glutamate receptors belonging to class II may be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits.

Other treatable indications in the present invention are restricted brain function due to the following reasons: bypass surgery or transplantation, cerebral insufficiency, spinal cord injury, head injury, hypoxia induced by pregnancy, cardiac arrest and hypoglycemia. Other treatable indications are chronic and acute pain, huntington's chorea, Amyotrophic Lateral Sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments and diseases which lead to glutamate dysfunction, such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia, depression, colon cancer, sleep disorders, circadian rhythm disorders and gliomas, since mGluR2 antagonists have been found to be able to reduce cell proliferation in human glioma cells (j. neurochem. march 2003, 84 (6): 1288-95).

Disclosure of Invention

The present invention is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof as pharmaceutically active substances, their manufacture, medicaments containing a compound of the invention and their manufacture, the use of a compound of the invention in the control or prevention of the above mentioned diseases and in the manufacture of corresponding medicaments.

The compounds of formula (I) may also be used in the form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycerol amide esters (glycoamide ester), glycerol ester conjugates, and the like. Prodrugs may enhance the value of the compounds of the invention in terms of absorption, distribution of pharmacokinetics and transport to the brain.

Unless otherwise indicated, the following terms used in the present specification have the definitions given below. The term "alkyl" represents a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms (C)_1-6Alkyl), preferably having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-butyl, t-butyl and those groups illustrated in the compounds of the invention exemplified hereinafter.

The term "C_1-6-haloalkyl "represents C as defined above_1-6Alkyl which may be substituted by one or more halogen atoms, in particularIs substituted by Cl, F or I, preferably by three Cl or by two or three F, i.e. CCl ₃、CHF₂And CF₃And may also be substituted by those groups set forth in the compounds of the invention exemplified below.

The term "C_1-6-alkoxy "represents C as defined above, linked by an oxygen atom_1-6-an alkyl group. "C_1-6Examples of "alkoxy" include methoxy, ethoxy, isopropoxy, and those groups set forth in the compounds of the present invention exemplified below.

“C_1-6-haloalkoxy "represents C as defined above substituted by one or more halogen atoms_1-6Alkoxy, said halogen atom being in particular Cl, F or I, preferably three Cl or two or three F, i.e. OCHF₂And OCF₃、OCH₂CHF₂、OCH₂CF₃And those groups set forth in the compounds of the invention exemplified below.

The term "aryl" represents a monovalent cyclic aromatic hydrocarbon group, such as phenyl, naphthyl, biphenyl, or indanyl.

The term "heteroaryl, 5-or 6-membered heteroaryl or heteroaryl having 5 to 12 ring atoms" means an aromatic having 5 to 6 or 5 to 12 ring atoms, which contains one or more (in particular 1, 2, 3, 4 or 5) heteroatoms selected from nitrogen, oxygen or sulfur. Examples of such heteroaryl groups include thienyl, imidazolyl,Oxadiazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, especially [1, 2, 4 ] ]Oxadiazolyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, thiazol-2-yl and thiophen-2-yl groups as well as those groups illustrated in the compounds of the present invention exemplified below.

The term "heteroaryloxy" represents a heteroaryl group as defined above attached through an oxygen atom, including 5 or 6-membered heteroaryl groups or heteroaryl groups having 5 to 12 ring atoms.

The term "halogen" includes fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

The term "C_3-6-cycloalkyl or C_5-8By cycloalkyl is meant cycloalkyl containing 3 to 6 or 5 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and those groups illustrated in the compounds of the invention exemplified hereinafter.

The term "5 or 6-membered or 5-12-membered heterocycloalkyl" represents a heterocyclic ring having 5 or 6-or 5-12-membered ring containing at least 2 carbon atoms as ring members and 1, 2 or 3 other heteroatoms selected from N, O or S, the remaining ring members being carbon atoms. Examples of 5 or 12 membered heterocycloalkyl rings include, but are not limited to, 1H-tetrazole; 2H-tetrazole; 1, 2, 3-and 1, 2, 4-triazoles; imidazole; pyrrole; 1, 2, 3-, 1, 3, 4-or 1, 2, 5-thiadiazines; 1,4-An oxazine; 1, 2-or 1, 4-thiazine; 4-morpholinyl; 1-pyrrolidinyl; 1-piperazinyl, preferably 4-morpholinyl, 1-pyrrolidinyl or 1-piperazinyl, and those groups illustrated in the compounds of the invention exemplified below. Such substituents of 5-or 6-membered heterocyclic rings include, but are not limited to, halogen, amino, nitro, cyano, hydroxy, C optionally substituted by hydroxy _1-6Alkyl radical, C_1-6-alkoxy, C_1-6-alkenyl, C_3-8-cycloalkyl or CF₃Preferably C_1-6-alkyl or CF₃And those groups set forth in the compounds of the invention exemplified below.

The term "dioxo bridge" represents a group having the formula:

the term "optionally substituted" means that the chemical group in question may be substituted with one or more substituents as described herein, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substituents, depending on the valency and available positions of the chemical group.

The term "pharmaceutically acceptable addition salt" refers to any salt derived from an inorganic acid or base or an organic acid or base.

In all the embodiments of the compounds of the invention which are described hereinbelow, independently of one another and independently of one another of the groups, where A is aryl, it is preferably optionally substituted by C_1-6-alkyl substituted phenyl.

In all the embodiments described hereinafter for the compounds of the invention which are independent of one another and of each group, in the case where A is phenyl optionally substituted by phenyl, this phenyl is preferably substituted by B in the meta or para position.

In all the embodiments described hereinafter in relation to the compounds of the invention which are independent of one another, each group being independent of one another, in the case where A is a 5-or 6-membered heteroaryl group, it is preferably selected from imidazolyl, [1, 2, 4 ] 4 ]Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1, 2, 4 ]]Triazolyl, thiazolyl, pyrimidinyl and thienyl, each of which is optionally substituted by C_1-6-alkyl substitution.

In all the embodiments described hereinafter in relation to the compounds of the invention which are independent of one another, each group being independent of one another, in the case where A is a 5-or 6-membered heteroaryl group, this 5-or 6-membered heteroaryl group is preferably substituted in the 3-or 4-position.

In all the embodiments described hereinafter in respect of the compounds of the invention which are independent of one another and of each group, where B is optionally substituted aryl, it is preferably phenyl.

In all the embodiments of the compounds according to the invention which are described below in each case independently of one another and independently of one another in each group, where B is optionally substituted aryl, the substituents are preferably in the meta-or para-position.

In all the embodiments described hereinafter in relation to the compounds of the invention which are independent of one another and of each group, where B is optionally substituted aryl, the substituents are preferably selected from the following groups:

the halogen(s) are selected from the group consisting of,

the nitro group(s),

c optionally substituted by hydroxy_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C _1-6-an alkyl group,

-S-C_1-6-an alkyl group,

-(SO₂)-OH，

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

C_1-6-an alkoxy group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

-(CH₂)_maryl, where m is 1 or 2, aryl (e.g. phenyl) optionally substituted by halogen or C_1-6-an alkoxy group substitution,

-(CH₂)_p-C_3-6cycloalkyl, wherein p is 0 or 1,

5 or 6-membered heterocycloalkyl (e.g., - (SO)₂)-NR^fR^gWherein R is^fAnd R^gTogether with the nitrogen atom to which they are attached form a compound optionally containing a nitrogen, oxygen, sulfur or SO group₂Wherein the 4, 5 or 6 membered heterocycloalkyl ring of the other heteroatom of (a), wherein the 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted with a substituent selected from the group consisting of:

a hydroxyl group(s),

C_1-6-an alkyl group,

c optionally substituted by hydroxy_1-6-alkoxy, and

5-or 6-membered heteroaryloxy (e.g., pyrimidinyloxy),

NHSO₂-C_1-6-alkyl, and

NHSO₂-NR^hRⁱwherein R is^hAnd RⁱIndependently is H, C_1-6-alkyl or- (CO) O-C_1-6-an alkyl group.

In all the embodiments described hereinafter in respect of the compounds of the invention which are independent of one another, each group being independent of one another, in the case where B is an optionally substituted 5-or 6-membered heteroaryl group, it is preferably selected from the groups pyridyl, pyrimidinyl, thienyl, thiazolyl and imidazolyl.

In all the embodiments described hereinafter in relation to the compounds of the invention which are independent of one another, each group being independent of one another, where B is an optionally substituted 5-or 6-membered heteroaryl group, the substituents are preferably selected from the following groups:

C_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-alkyl, and

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-alkyl, and

NR^hSO₂-NRⁱR^jwherein R is^hIs H, RⁱAnd R^jIndependently is H or- (CO) O-C_1-6-an alkyl group.

In all the embodiments described hereinafter which are independent of one another, each group being independent of one another, for the compounds according to the invention, R¹Preferably C_1-6-alkyl or C_1-6Haloalkyl, preferably also methyl, ethyl, i-propyl, CF₃Or CHF₂。

In all the embodiments described hereinafter which are independent of one another, each group being independent of one another, for the compounds according to the invention, R²Preferably halogen or C_1-6Haloalkyl, preferably also Cl, F or CF₃。

In all the embodiments described hereinafter which are independent of one another, each group being independent of one another, for the compounds according to the invention, R³Is H, halogen, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6-alkyl and C_1-6Haloalkoxy, further preferably F, Cl, methoxy, ethoxy, CF ₃Methyl and trifluoroethoxy.

In all the embodiments described hereinafter which are independent of one another, each group being independent of one another, for the compounds according to the invention, R⁴Is H.

In particular embodiments of the compounds of the invention, the compounds of formula (I) are those in which the groups are defined as follows:

wherein:

one of X or Y is N, the other is CH, or X and Y are both N;

b is H or cyano;

R¹is halogen, C optionally substituted by hydroxy_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-haloalkyl group, C_3-6-a cycloalkyl group;

R²is halogen, C_1-6-haloalkyl group, C_1-6-alkoxy, C_1-6-haloalkoxy, C_1-6-alkyl or C_3-6-a cycloalkyl group;

R^lAnd R^mIndependently selected from H and C_1-6-an alkyl group;

or R^lAnd R^mMay form, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclic group comprising 5 to 12 ring atoms and optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, wherein the heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from: halogen, hydroxy, C_1-6-alkyl and C_1-6-a haloalkyl group;

or R²And R³Dioxo bridges may be formed together.

wherein:

one of X or Y is N, the other is CH, or X and Y are both N;

b is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are selected from the group consisting of:

the halogen(s) are selected from the group consisting of,

the nitro group(s),

c optionally substituted by hydroxy_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group,

-S-C_1-6-an alkyl group,

-(SO₂)-OH，

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

C_1-6-an alkoxy group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C _1-6-an alkyl group,

-(CH₂)_p-C_3-6cycloalkyl, wherein p is 0 or 1,

a 5-or 6-membered heterocycloalkyl group,

NHSO₂-C_1-6-alkyl, and

R³is halogen, H, C _1-6-alkoxy, C_1-6-haloalkyl group, C_1-6Alkyl radical, C_3-6-cycloalkyl, C_1-6-a halogenated alkoxy group,

R^lAnd R^mIndependently selected from H and C_1-6-an alkyl group;

or R^lAnd R^mMay form, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclic group comprising 5 to 12 ring atoms and optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, wherein the heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from: halogenElement, hydroxy group, C_1-6-alkyl and C_1-6-a haloalkyl group;

or R²And R³Dioxo bridges may be formed together.

wherein:

one of X or Y is N, the other is CH, or X and Y are both N;

a is aryl or is 5-or 6-membered heteroaryl;

b is H or optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are selected from the group consisting of:

C_1-6-an alkyl group,

-NR^aR^bwherein R is^aAnd R^bIndependently is H, C_1-6-alkyl, - (CO) -C_1-6-alkyl, - (SO)₂)-NR^cR^dWherein R is^cAnd R^dIndependently is H, C_1-6-alkyl, - (CO) -C_1-6-an alkyl group;

R¹is H, halogen, C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-haloalkyl group, C_3-6-a cycloalkyl group;

R²is H, halogen, C_1-6-haloalkyl group, C_1-6-alkyl or C_3-6-a cycloalkyl group;

R³is halogen, H, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6Alkyl radical, C_3-6-a cycloalkyl group,C_1-6-a halogenated alkoxy group,

or is NR^eR^fWherein R is^eAnd R^fIndependently selected from the group consisting of:

H、C_3-8-cycloalkyl, aryl, heteroaryl with 5-12 ring atoms and C optionally substituted by one or more substituents selected from the group consisting of_1-6-an alkyl group: halogen, hydroxy, C_3-8-cycloalkyl, aryl, heteroaryl with 5-12 ring atoms and-NR^gR^hWherein

R^hAnd R^hIndependently selected from H and C_1-6-an alkyl group;

or R^bAnd R^cMay form, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclic group containing 5 to 12 ring atoms, wherein the substituents are selected from halogen, hydroxy, C_1-6-alkyl and C_1-6-haloalkyl.

The compounds of formula (I) of the present invention also include compounds of formula (Ia):

a, B, R therein¹、R²、R³And R⁴As defined above for formula (I).

In certain embodiments of the invention, the compounds of formula (Ia) are those wherein the groups are defined as follows:

b is H or cyano;

R¹is C_1-6-alkyl or C_1-6-a haloalkyl group;

R²is halogen or C_1-6-a haloalkyl group;

R³is H, halogen, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6-alkyl and C_1-6-a haloalkoxy group;

R⁴is H or halogen.

In certain embodiments of the invention, formula (Ia) is a compound wherein the groups are defined as follows:

a is aryl or is 5-or 6-membered heteroaryl;

c optionally substituted by hydroxy_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group,

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-an alkyl group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

-(CH₂)_m-aryl, wherein m is 1 or 2,

-(CH₂)_p-C_3-6-cycloalkyl, wherein pIs a number of 0 or 1, and,

-(SO₂)-NR^fR^gwherein R is^fAnd R^gTogether with the nitrogen atom to which they are attached form a compound optionally containing a nitrogen, oxygen, sulfur or SO group₂Wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally selected from hydroxy or C _1-6-substituent substitution of alkyl:

NHSO₂-C_1-6-alkyl, and

NHSO₂-NR^hRⁱwherein R is^hAnd RⁱIndependently is H or C_1-6-an alkyl group;

R¹is C_1-6-alkyl or C_1-6-a haloalkyl group;

R²is halogen or C_1-6-a haloalkyl group;

R⁴is H or halogen.

The compounds of formula (I) of the present invention also include compounds of formula (Ia 1):

b, R therein¹、R²、R³And R⁴Alkyl is alkyl as defined above for formulae (I) and (Ia).

In certain embodiments of the invention, the compounds of formula (Ia1) are those wherein the groups are defined as follows:

b is H or cyano;

R¹is C_1-6-alkyl or C_1-6-a haloalkyl group;

R²is halogen or C_1-6-a haloalkyl group;

R⁴is H or halogen.

c optionally substituted by hydroxy_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H, and the compound is,

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy _1-6-an alkyl group,

NHSO₂-C_1-6-alkyl, and

R¹is C_1-6-alkyl or C_1-6-a haloalkyl group;

R²is halogen or C_1-6-a haloalkyl group;

R⁴is H or halogen.

In certain embodiments of the invention, the compound of formula (Ia1) is a compound wherein B is unsubstituted aryl or unsubstituted 5-or 6-membered heteroaryl, for example the following compounds:

2- (3-pyridin-3-yl-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine;

4- (4-chloro-phenyl) -2- (3-pyridin-3-yl-phenyl) -6-trifluoromethyl-pyrimidine; and

4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3' ] bipyridinyl.

In certain embodiments of the invention, the compounds of formula (Ia1) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are selected from C optionally substituted with hydroxy_1-6-an alkyl group:

2- [3- (2, 6-dimethyl-pyridin-4-yl) -phenyl ] -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine; and

{ 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-4-yl } -methanol.

In certain embodiments of the invention, the compounds of formula (Ia1) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are selected from the group NR ^aR^bWherein R is^aAnd R^bIndependently H, for example the following compounds:

5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -pyrimidin-2-ylamine;

5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -pyrimidin-2-ylamine;

5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-4-ylamine;

5- {3- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyrimidin-2-ylamine;

5- {3- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- (3- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } -phenyl) -pyridin-2-ylamine;

5- (3- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } -phenyl) -pyrimidin-2-ylamine;

5- {3- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine;

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-ylamine; and

5- {3- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine.

In certain embodiments of the invention, the compounds of formula (Ia1) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are selected from- (SO) ₂)-C_1-6-alkyl or- (SO)₂)-NR^cR^dWherein R is^cAnd R^dIndependently is H or C optionally substituted by hydroxy_1-6Alkyl, such as the following compounds:

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide;

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

3' - [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide;

3' - [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

3' - [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonic acid tert-butylamide;

5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

5- {3- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

3' - [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

3' - [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

3' - [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

3' - [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

2- (3' -methanesulfonyl-biphenyl-3-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine;

3' - [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

5- {3- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid (2-hydroxy-ethyl) -amide;

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid bis- (2-hydroxy-ethyl) -amide;

3' - [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

3' - [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

3' - [4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

3' - [4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

3' - [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

3' - [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

3' - [4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide; and

5- {3- [4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide.

In certain embodiments of the invention, the compounds of formula (Ia1) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is NHSO₂-C_1-6Alkyl, such as the following compounds: n- { 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-biphenyl-3-yl } -methanesulfonamide.

In certain embodiments of the invention, the compounds of formula (Ia1) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is NHSO₂-NR^hRⁱWherein R is^hAnd RⁱIndependently is H, C_1-6Alkyl, such as the following compounds: n- { 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-biphenyl-3-yl } -sulfonamide and N- { 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-biphenyl-3-yl } -N ', N' -dimethyl-sulfonamide.

The compounds of formula (I) of the present invention include compounds of formula (Ia 2):

b, R therein¹、R²、R³And R⁴As defined above for formula (I), alkyl is an alkyl group.

The 5-or 6-membered heteroaryl group may be selected from the following groups: imidazolyl group, [1, 2, 4 ]]Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1, 2, 4 ] ]Triazolyl, thiazolyl, pyrimidinyl and thienyl, preferably imidazolyl, [1, 2, 4]Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl and [1, 2, 4 ]]A triazolyl group.

In certain embodiments of the invention, the compounds of formula (Ia2) are those wherein the groups are defined as follows:

b is H or cyano;

R¹is C_1-6-alkyl or C_1-6-a haloalkyl group;

R²is halogen or C_1-6-a haloalkyl group;

R⁴is H or halogen.

In certain embodiments of the invention, the compounds of formula (Ia2) are those wherein B is H, for example the following compounds:

4- (4-chloro-phenyl) -2-imidazol-1-yl-6-trifluoromethyl-pyrimidine;

2-imidazol-1-yl-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine;

2-pyrrol-1-yl-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine;

4- (4-chloro-phenyl) -2-pyrrol-1-yl-6-trifluoromethyl-pyrimidine;

2-pyridin-3-yl-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine;

4-difluoromethyl-2-pyridin-4-yl-6- (4-trifluoromethyl-phenyl) -pyrimidine; and

2-pyridin-4-yl-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine.

c optionally substituted by hydroxy_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group,

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-an alkyl group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

-(CH₂)_m-aryl, wherein m is 1 or 2,

-(CH₂)_p-C_3-6-cycloalkyl, wherein p is 0 or 1, and

-(SO₂)-NR^fR^gwherein R is^fAnd R^gTogether with the nitrogen atom to which they are attached form a compound optionally containing a nitrogen, oxygen, sulfur or SO group₂Wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally selected from hydroxy or C_1-6-substituent substitution of alkyl;

R¹is C_1-6-alkyl or C_1-6-a haloalkyl group;

R²is halogen or C_1-6-a haloalkyl group;

R⁴is H or halogen.

In certain embodiments of the invention, compounds of formula (Ia2) are those wherein B is unsubstituted aryl or unsubstituted 5-or 6-membered heteroaryl compounds, for example the following compounds:

2- (4-pyridin-3-yl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine;

4- (4-chloro-phenyl) -2- (4-pyridin-3-yl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine;

4- (4-chloro-phenyl) -2- (4-pyridin-4-yl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine;

4- (4-chloro-phenyl) -2- (3-pyridin-4-yl- [1, 2, 4]Oxadiazol-5-yl) -6-trifluoromethyl-pyrimidine;

4- (4-chloro-phenyl) -2- (3-pyridin-3-yl- [1, 2, 4]Oxadiazol-5-yl) -6-trifluoromethyl-pyrimidine;

4- (4-chloro-phenyl) -6-methyl-2- (4-pyridin-3-yl-imidazol-1-yl) -pyrimidine;

4-methyl-2- (4-pyridin-3-yl-imidazol-1-yl) -6- (4-trifluoromethyl-phenyl) -pyrimidine;

4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3' ] bipyridinyl;

4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 4' ] bipyridinyl;

2- (3-pyridin-4-yl- [1, 2, 4] triazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine;

2- (3-pyridin-3-yl- [1, 2, 4] triazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine.

In certain embodiments of the invention, the compounds of formula (Ia2) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is NR ^aR^bWherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6Alkyl, such as the following compounds:

4- {5- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

5- {5- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

5- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

4- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-pyrazol-4-yl } -pyridin-2-ylamine;

5- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyrimidin-2-ylamine;

5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-5-yl } -pyridin-2-ylamine;

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-5-yl } -pyridin-2-ylamine;

4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

5- {1- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {5- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

5- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine;

5- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine;

5- {1- [4- (4-chloro-phenyl) -6-cyclopropyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [4- (4-chloro-phenyl) -6-cyclopropyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine;

5- {1- [4- (4-chloro-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

4- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

5- {5- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

4- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

5- {1- [4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

n- (5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-yl) -acetamide;

5- {5- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

5- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyrimidinyl-2' -yl ] -pyridin-2-ylamine;

5- {1- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

4- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

5- {1- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {5- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

4- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

4- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -phenylamine;

4- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

5- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

4- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

5- {1- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine;

5- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine;

5- {5- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

5- {5- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ]-[1，2，4]IIOxazol-3-yl } -pyridin-2-ylamine;

4- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

5- (1- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } -1H-imidazol-4-yl) -pyridin-2-ylamine;

4- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } - [2, 3 '] bipyridinyl-6' -ylamine;

5- {5- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

5- {1- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine;

4- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

5- { 2-methyl-1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- { 2-methyl-1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine;

5- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine;

5- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

4- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine;

5- { 2-methyl-1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H- [1, 2, 4] triazol-3-yl } -pyridin-2-ylamine;

5- {1- [ 4-isopropyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [ 4-isopropyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine;

5- { 5-methyl-1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine;

5- {1- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine; and

5- {1- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine.

In certain embodiments of the invention, the compounds of formula (Ia2) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-C_1-6Alkyl, such as the following compounds:

4- (4-chloro-phenyl) -2- [4- (3-methanesulfonyl-phenyl) -imidazol-1-yl ] -6-methyl-pyrimidine;

4- (3, 4-dichloro-phenyl) -2- [4- (3-methanesulfonyl-phenyl) -imidazol-1-yl ] -6-methyl-pyrimidine;

2- [4- (3-methanesulfonyl-phenyl) -imidazol-1-yl ] -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine; and

2- [2- (3-methanesulfonyl-phenyl) -pyridin-4-yl ] -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine.

In certain embodiments of the invention, the compounds of formula (Ia2) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-NR^cR^dWherein R is^cAnd R^dIndependently are: h; c optionally substituted by hydroxy_1-6-an alkyl group; optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group; - (CH)₂CH₂O)_nCHR^eWherein R is^eIs H or CH₂OH, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; - (CH)₂)_m-aryl, wherein m is 1 or 2; or- (CH)₂)_p-C_3-6Cycloalkyl, where p is 0 or 1, such as the following compounds:

3- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ]-[1，2，4]Oxadiazol-5-yl } -benzenesulfonamide;

3- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-5-yl } -benzenesulfonamide;

4- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

3- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

4- {5- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

3- {5- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-5-yl } -thiophene-2-sulfonamide;

5-{3-[4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-5-yl } -thiophene-2-sulfonamide;

4- {5- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

3- {5- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

4- {5- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

3- {5- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

4- {5- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

3- {5- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

3- {5- [4- (4-chloro) -4-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

4- {5- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

3- {5- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

4- {5- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]IIOxazol-3-yl } -benzenesulfonamide;

3- {5- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]IIOxazol-3-yl } -benzenesulfonamide;

4- {5- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

n-tert-butyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

4- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

5- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide;

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

5- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide;

3- {4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

5- {4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide;

5- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

4- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

3- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

3- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

3- {4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

4- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide;

2- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide;

4- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

3- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

3- {1- [4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

5- {1- [4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

3- {4- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

5- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

5- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

5- {4- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide;

3- {4- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

5- {4- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide;

5- {4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide;

3- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

4- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

2- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide;

2- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide;

3- {4- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

5- {4- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide;

5- {1- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

5- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

4- {1- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

4- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

3- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

3- {1- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

5- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

3- {1- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

5- {1- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

n-tert-butyl-3- {6- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

3- {6- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

n, N-bis- (2- {2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethoxy } -ethyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n, N-bis- (2-hydroxy-ethyl) -3- [6 ' methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n- (2- {2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethoxy } -ethyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

-propionyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

5- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid propionyl-amide;

n- (2-hydroxy-ethyl) -3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

n- (2-hydroxy-1, 1-dimethyl-ethyl) -3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

n, N-bis- (2-hydroxy-ethyl) -3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

5- {1- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

5- {1- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

3- {1- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

3- {1- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

5- {4- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide;

3- {4- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

5- {4- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide;

3- {4- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

n, N-dimethyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

n-methyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

N-isobutyl-N-methyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

N-methyl-N-propyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

n-benzyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

n-phenethyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

n-cyclopropylmethyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

n-cyclopropyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

5- {4- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide;

3- {4- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

n-tert-butyl-3- {6- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

3- {6- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

n-tert-butyl-3- {6- [4- (4-cyano-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

3- {6- [4- (4-cyano-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

3- (4- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } -pyridin-2-yl) -benzenesulfonamide;

3- {4- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

3- {4- [4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

5- {4- [4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide;

3- {4- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

5- {4- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide;

3- {4- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide; and

5- {4- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide.

In certain embodiments of the invention, the compounds of formula (Ia2) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-NR^fR^gWherein R is^fAnd R^gTogether with the nitrogen atom to which they are attached form a compound optionally containing a nitrogen, oxygen, sulfur or SO group₂A 4, 5 or 6 membered heterocycloalkyl ring of the other heteroatom(s), wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by hydroxy or C_1-6Alkyl substitution, such as the following compounds:

4- (3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonyl) -morpholine;

2- {2- [3- (4-methyl-piperazine-1-sulfonyl) -phenyl ] -pyridin-4-yl } -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine;

2- {2- [3- (pyrrolidine-1-sulfonyl) -phenyl ] -pyridin-4-yl } -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine; and

(RS) -1- (3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonyl) -pyrrolidin-3-ol.

The compounds of formula (I) of the present invention also include compounds of formula (Ib):

a, B, R therein¹、R²And R³As defined above for formula (I).

b is H, cyano, or

the halogen(s) are selected from the group consisting of,

the nitro group(s),

c optionally substituted by hydroxy_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group,

-S-C_1-6-an alkyl group,

-(SO₂)-OH，

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

C_1-6-an alkoxy group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

-(CH₂)_p-C_3-6cycloalkyl, wherein p is 0 or 1,

a 5-or 6-membered heterocycloalkyl group,

-(SO₂)-NR^fR^gwherein R is^fAnd R^gTogether with the nitrogen atom to which they are attached form a compound optionally containing a nitrogen, oxygen, sulfur or SO group ₂Wherein the 4, 5 or 6 membered heterocycloalkyl ring of the other heteroatom of (a), wherein the 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted with a substituent selected from the group consisting of:

NHSO₂-C_1-6-alkyl, and

NHSO₂-NR^hRⁱwherein R is^hAnd RⁱIndependently is H, C_1-6Alkyl, - (CO) O-C_1-6-alkyl, or R^hAnd RⁱTogether with the nitrogen atom to which they are attached form a 4-, 5-or 6-membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, wherein said

4. The 5-or 6-membered heterocycloalkyl ring being optionally substituted by C_1-6-alkyl substitution;

or is NR^jR^kWherein R is^jAnd R^kIndependent selectionFrom the following groups:

H、C_3-8-cycloalkyl, aryl, heteroaryl with 5-12 ring atoms and C optionally substituted by one or more substituents selected from the group consisting of_1-6-an alkyl group: halogen, hydroxy, C_3-8-cycloalkyl, aryl, heteroaryl with 5-12 ring atoms and-NR ^lR^mWherein

R^lAnd R^mIndependently selected from H and C_1-6-an alkyl group;

or R²And R³Can together form a dioxo bridge;

R⁴is H or halogen.

b is H or cyano;

R³is H, halogen, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6-alkyl and C_1-6Haloalkoxy, preferably F, Cl, methoxy, ethoxy, CF₃Methyl and trifluoroethoxy;

or R²And R³Can together form a dioxo bridge;

R⁴Is H or halogen.

the halogen(s) are selected from the group consisting of,

the nitro group(s),

C_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group,

-S-C_1-6-an alkyl group,

-(SO₂)-OH，

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

C_1-6-an alkoxy group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

-(CH₂)_p-C_3-6cycloalkyl, wherein p is 0 or 1,

a 5-or 6-membered heterocycloalkyl group,

NHSO₂-C_1-6-alkyl, and

NHSO₂-NR^hRⁱwherein R is^hAnd RⁱIndependently is H, C_1-6-alkyl or- (CO) O-C_1-6-an alkyl group;

R²is H, cyano, halogen, C_1-6-haloalkyl group, C_1-6-alkoxy, C_1-6-haloalkoxy, C_1-6-alkanesRadical or C_3-6-a cycloalkyl group;

or R²And R³Can together form a dioxo bridge;

R⁴is H or halogen.

The compounds of formula (I) of the present invention include compounds of formula (Ib):

b, R therein¹、R²、R³And R⁴Alkyl is alkyl as defined above for formulae (I) and (Ib).

In certain embodiments of the invention, the compounds of formula (Iab1) are those wherein B is unsubstituted aryl or unsubstituted 5-or 6-membered heteroaryl, for example the following compounds:

2-methyl-6- (3-pyridin-3-yl-phenyl) -4- (4-trifluoromethyl-phenyl) -pyridine;

2-cyclopropyl-6- (3-pyridin-3-yl-phenyl) -4- (4-trifluoromethyl-phenyl) -pyridine; and

2-methyl-6- (3-pyridin-4-yl-phenyl) -4- (4-trifluoromethyl-phenyl) -pyridine.

In certain embodiments of the invention, compounds of formula (Ib1) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is cyano, such as the following compounds: 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -benzonitrile.

In certain embodiments of the invention, compounds of formula (Ib1) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are halogen, for example the following compounds: 4, 6-difluoro-3' - [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide.

In certain embodiments of the invention, compounds of formula (Ib1) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is C_1-6Alkyl, such as the following compounds: 2-methyl-6- [3- (4-methyl-imidazol-1-yl) -phenyl]-4- (4-trifluoromethyl-phenyl) -pyridine.

In certain embodiments of the invention, compounds of formula (Ib1) are those in which B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is NR ^aR^bWherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6Alkyl, such as the following compounds:

5- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [ 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine;

5- {3- [4- (4-chloro-phenyl) -6-methyl-pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine;

5- {3- [4- (4-chloro-phenyl) -6-methyl-pyridin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine;

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine;

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyridin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [4- (3, 4-dichloro-phenyl) -6-methyl-pyridin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- {3- [4- (3, 4-dichloro-phenyl) -6-methyl-pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine;

5- {3- [ 6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine;

5- {3- [ 6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridin-2-ylamine;

5- [3- (4-benzo [1, 3] dioxol-5-yl-6-methyl-pyridin-2-yl) -phenyl ] -pyridin-2-ylamine; and

4- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -thiazol-2-ylamine.

In certain embodiments of the invention, compounds of formula (Ib1) are those in which B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-C_1-6Alkyl, such as the following compounds: 2- (3' -methanesulfonyl-biphenyl-3-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine.

In certain embodiments of the invention, compounds of formula (Ib1) are those in which B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-NR^cR^dWherein R is^cAnd R^dIndependently are: h; c optionally substituted by hydroxy_1-6-an alkyl group; c_1-6-a haloalkyl group; c_1-6-an alkoxy group; optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group; - (CH)₂CH₂O)_nCHR^eWherein R is^eIs H or CH₂OH, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; - (CH)₂)_mAryl, where m is 1 or 2, aryl being optionally substituted by halogen or C_1-6-alkoxy substitution; - (CH) ₂)_p-C_3-6-cycloalkyl, wherein p is 0 or 1; or 5 or 6-membered heterocycloalkyl, for example the following compounds:

3' - [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridine-3-sulfonamide;

5- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridine-3-sulfonamide;

5- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridine-3-sulfonic acid (2-hydroxy-1, 1-dimethyl-ethyl) -amide;

3' - [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid methoxy-amide;

3' - [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid (2-hydroxy-1, 1-dimethyl-ethyl) -amide;

3' - [ 6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide;

3' - [ 6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide;

4, 6-difluoro-3' - [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -thiophene-2-sulfonamide;

3' - [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide; and

n- (tert-butoxycarbonyl) -N' - (4- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -thiazol-2-yl) -sulfonamide.

The compounds of formula (I) of the present invention include compounds of formula (Ib 11):

b, R therein¹、R²、R³And R⁴Alkyl is alkyl as defined above for formulas (I), (Ib) and (Ib 1).

The compounds of formula (I) of the present invention include compounds of formula (Ib 2):

b, R therein¹、R²、R³And R⁴Alkyl is an alkyl group, as defined above for formula (I).

The 5-or 6-membered heteroaryl group may be selected from the following groups: imidazolyl group, [1, 2, 4 ]]Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1, 2, 4 ]]Triazolyl, thiazolyl, pyrimidinyl and thienyl, preferably thiazolyl, imidazolyl, [1, 2, 4 ]]Oxadiazolyl, pyridinyl, pyrimidinyl, thienyl and [1, 2, 4 ]]A triazolyl group.

In certain embodiments of the invention, the compounds of formula (Ib2) are those wherein the groups are defined as follows:

b is H or cyano, preferably H;

R¹is C_1-6-alkyl or C_1-6-a haloalkyl group;

R²is halogen or C_1-6-a haloalkyl group;

R⁴Is H or halogen.

In certain embodiments of the invention, compounds of formula (Ib2) are those wherein B is H, for example the following compounds:

2-imidazol-1-yl-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine;

4- (3, 4-dichloro-phenyl) -2-imidazol-1-yl-6-methyl-pyridine; and

2-methyl-6-thiazol-2-yl-4- (4-trifluoromethyl-phenyl) -pyridine.

In certain embodiments of the invention, compounds of formula (Ia3) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are selected from the group consisting of:

the nitro group(s),

c optionally substituted by hydroxy_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group,

-S-C_1-6-an alkyl group,

NHSO₂-C_1-6-an alkyl group,

NHSO₂-NR^hRⁱwherein R is^hAnd RⁱIndependently is H, C_1-6-alkyl or- (CO) O-C_1-6-alkyl- (SO)₂)-C_1-6-an alkyl group,

-(SO₂)-OH，

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy or halogen_1-6-an alkyl group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

-(CH₂)_p-C_3-6cycloalkyl, wherein p is 0 or 1,

5 or 6-membered heterocycloalkyl, and

hydroxy, C_1-6-alkyl, C optionally substituted by hydroxy_1-6-alkoxy or heteroaryloxy;

R¹is C_1-6-alkyl or C_1-6-a haloalkyl group;

R²is halogen or C_1-6-a haloalkyl group;

R⁴is H or halogen.

In certain embodiments of the invention, compounds of formula (Ia2) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is nitro, for example the following compounds: 6-methyl-2 '- (3-nitro-phenyl) -4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl and 4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -2- (3-nitro-phenyl) -pyrimidine.

5- {1- [ 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3'; 5', 3 "] terpyridin-6" -ylamine;

5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3 '] bipyridinyl-5' -yl ] -pyrimidin-2-ylamine;

6-cyclopropyl-4- (4-trifluoromethyl-phenyl) - [2, 3'; 5', 3 "] terpyridin-6" -ylamine;

6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2'; 6', 3 "] terpyridin-6" -ylamine;

5- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -pyrimidin-2-ylamine;

6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4'; 2', 3 "] terpyridin-6" -ylamine;

5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -pyrimidin-2-ylamine;

6-cyclopropyl-4- (4-trifluoromethyl-phenyl) - [2, 4'; 2', 3 "] terpyridin-6" -ylamine;

5- [ 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -pyrimidin-2-ylamine;

5- {1- [4- (4-chloro-phenyl) -6-methyl-pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

4- (4-chloro-phenyl) -6-methyl- [2, 3'; 5', 3 "] terpyridin-6" -ylamine;

5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -pyridin-2-ylamine;

5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -pyrimidin-2-ylamine;

5- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

5- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine;

5- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -pyridin-2-ylamine;

4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] - [2, 5 '] bipyrimidinyl-2' -ylamine;

5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-4-yl } -pyridin-2-ylamine;

5- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiophen-2-yl } -pyridin-2-ylamine;

5- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiophen-2-yl } -pyrimidin-2-ylamine;

5- {5- [4- (3, 4-dichloro-phenyl) -6-methyl-pyridin-2-yl ] -thiophen-2-yl } -pyridin-2-ylamine;

5- {5- [4- (3, 4-dichloro-phenyl) -6-methyl-pyridin-2-yl ] -thiophen-2-yl } -pyrimidin-2-ylamine;

5- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiophen-3-yl } -pyridin-2-ylamine;

3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -phenylamine;

3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -phenylamine;

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -phenylamine;

n- (3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -phenyl) -acetamide;

n- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -phenyl } -acetamide;

6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2'; 6', 4 "] terpyridin-2" -ylamine;

4- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -pyridin-2-ylamine; and

3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -phenylamine.

In the inventionIn certain embodiments, the compounds of formula (Ia2) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is-S-C _1-6Alkyl, such as the following compounds: 6-methyl-6 '- (3-methylsulfanyl-phenyl) -4- (4-trifluoromethyl-phenyl) - [2, 2']Bipyridine.

In certain embodiments of the invention, the compounds of formula (Ia2) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are S (O)₂-C_1-6Alkyl, such as the following compounds: 2- (3-methanesulfonyl-phenyl) -4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-pyrimidine and 6 '- (3-methanesulfonyl-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2']Bipyridine.

In certain embodiments of the invention, the compounds of formula (Ia2) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-NR^cR^dWherein R is^cAnd R^dIndependently are: h; c optionally substituted by hydroxy or halogen_1-6-an alkyl group; optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group; - (CH)₂CH₂O)_nCHR^eWherein R is^eIs H or CH₂OH, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; optionally substituted by halogen or C_1-6-alkoxy substituted- (CH)₂)_mAryl, where m is 1 or 2, aryl being optionally substituted by halogen or C_1-6-alkoxy substitution; - (CH)₂)_p-C_3-6-cycloalkyl, wherein p is 0 or 1; 5-or 6-membered heterocycloalkyl, for example the following compounds:

4- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

3- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

n-tert-butyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n-tert-butyl-3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -benzenesulfonamide;

n-tert-butyl-3- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -benzenesulfonamide;

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -benzenesulfonamide;

3- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -benzenesulfonamide;

n-tert-butyl-3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide;

n-tert-butyl-3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3 '] bipyridinyl-5' -yl ] -benzenesulfonamide;

3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide;

n-tert-butyl-3- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3 '] bipyridinyl-5' -yl ] -benzenesulfonamide;

3- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

4-methyl-2- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonic acid tert-butylamide;

5- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide;

2- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonic acid tert-butylamide;

5- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -thiophene-2-sulfonic acid tert-butylamide;

5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonic acid tert-butylamide;

5- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -thiophene-2-sulfonic acid tert-butylamide;

4-methyl-2- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide;

2- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide;

5- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

5- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -thiophene-2-sulfonamide;

5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonamide;

5- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -thiophene-2-sulfonamide;

5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide;

5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl- ] thiazol-4-yl } -thiophene-2-sulfonamide;

4- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -benzenesulfonamide;

4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide;

n-tert-butyl-3- [4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide;

5- [4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonic acid tert-butylamide;

3- [4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide;

5- [4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonamide;

n- (2-hydroxy-ethyl) -3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide;

n- (2-hydroxy-1, 1-dimethyl-ethyl) -3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide;

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -N-propionyl-benzenesulfonamide;

n- (2-hydroxy-ethyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n- (2-hydroxy-1, 1-dimethyl-ethyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n- (2-methoxy-ethyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n- [2- (2-hydroxy-ethoxy) -ethyl ] -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n- [2- (2-methoxy-ethoxy) -ethyl ] -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n- {2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethyl } -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

N-methyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n, N-dimethyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n-cyclopropyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

N-cyclopropyl-N-methyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n-benzyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n- (4-methoxy-benzyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n- (4-fluoro-benzyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n-tert-butyl-3- [6 ' -methyl-4 ' - (4-trifluoromethoxy-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

3- [6 ' -methyl-4 ' - (4-trifluoromethoxy-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n-tert-butyl-3- [6 ' -methyl-4 ' - (3-methyl-4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

3- [6 ' -hydroxymethyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

3- [6 ' -methyl-4 ' - (3-methyl-4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n-acetyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -N- (tetrahydro-pyran-4-yl) -benzenesulfonamide;

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -N- (2, 2, 2-trifluoro-ethyl) -benzenesulfonamide;

n-ethyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

n-butyryl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide; and

n-isobutyryl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide.

In certain embodiments of the invention, the compound of formula (Ia2) is a compound wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is NHSO₂-C_1-6Alkyl, such as the following compounds:

n- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -phenyl } -methanesulfonamide;

n- (3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -phenyl) -methanesulfonamide; and

N- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -phenyl } -methanesulfonamide.

In certain embodiments of the invention, the compound of formula (Ia2) is wherein B isOptionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is-SO₂-OH, for example the following compounds: 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]-benzenesulfonic acid.

In certain embodiments of the invention, the compound of formula (Ia2) is a compound wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is NHSO₂-NR^hRⁱWherein R is^hAnd RⁱIndependently is H, C_1-6-alkyl or- (CO) O-C_1-6Alkyl, such as the following compounds:

n- (tert-butoxycarbonyl) -N '- {3- [ 6' -methyl-4 '- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl-6-yl ] -phenyl } -sulfonamide;

n- (tert-butoxycarbonyl) -N' - (3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -phenyl) -sulfonamide;

n- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -phenyl } -sulfonamide;

n- (3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -phenyl) -sulfonamide; and

N, N- (dimethyl) -N '- {3- [ 6' -methyl-4 '- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl-6-yl ] -phenyl } -sulfonamide.

In certain embodiments of the invention, the compound of formula (Ia2) is a compound wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-NR^fR^gWherein R is^fAnd R^gTogether with the nitrogen atom to which they are attached form a compound optionally containing a nitrogen, oxygen, sulfur or SO group₂Wherein the 4, 5 or 6 membered heterocycloalkyl ring of the other heteroatom of (a), wherein the 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted with a substituent selected from the group consisting of: hydroxy, C_1-6-alkyl, optionally substituted by hydroxy and heteroaryloxyC_1-6Alkoxy, such as the following compounds:

6-methyl-2 '- [3- (morpholine-4-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl;

6-methyl-2 '- [3- (thiomorpholine-4-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl;

6-methyl-2 '- [3- (4-methyl-piperazine-1-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl;

morpholine-4-sulfonic acid {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -phenyl } -amide;

6 '- [3- (1, 1-dioxo-1 □ 6-thiomorpholine-4-sulfonyl) -phenyl ] -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl;

6-methyl-6 '- [3- (pyrrolidine-1-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl;

6-methyl-6 '- [3- (4-methyl-piperazine-1-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl;

6-methyl-6 '- [3- (morpholine-4-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl;

6 '- [3- (azetidine-1-sulfonyl) -phenyl ] -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl;

1- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonyl } -piperidin-4-ol;

1- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonyl } -azetidin-3-ol;

6 '- [3- (4-methoxy-piperidine-1-sulfonyl) -phenyl ] -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl;

2- (1- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonyl } -piperidin-4-yloxy) -ethanol;

6-methyl-6 '- {3- [4- (pyridin-4-yloxy) -piperidine-1-sulfonyl ] -phenyl } -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl; and

6-methyl-6 '- {3- [4- (pyrimidin-2-yloxy) -piperidine-1-sulfonyl ] -phenyl } -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl.

The compounds of formula (I) according to the invention also include compounds of formula (Ic):

a, B, R therein¹、R²And R³As defined above for formula (I).

In certain embodiments, the compounds of formula (Ic) of the present invention are those wherein the groups are defined as follows:

b is H or cyano;

R^lAnd R^mIndependently selected from H and C_1-6-an alkyl group;

or R^lAnd R^mMay form, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclic group comprising 5 to 12 ring atoms and optionally containing further heteroatoms selected from nitrogen, oxygen or sulfur,

Wherein said heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 groups selected from: halogen, halogen,

Hydroxy, C_1-6-alkyl and C_1-6-a haloalkyl group;

or R²And R³Dioxo bridges may be formed together.

the halogen(s) are selected from the group consisting of,

the nitro group(s),

c optionally substituted by hydroxy_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group,

-S-C_1-6-an alkyl group,

-(SO₂)-OH，

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

C_1-6-an alkoxy group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

-(CH₂)_p-C_3-6cycloalkyl, wherein p is 0 or 1,

a 5-or 6-membered heterocycloalkyl group,

NHSO₂-C_1-6-alkyl, and

R^lAnd R^mIndependently selected from H and C_1-6-an alkyl group;

or R²And R³Dioxo bridges may be formed together.

The compounds of formula (I) of the present invention include compounds of formula (Ic 1):

b, R therein¹、R²、R³And R⁴Alkyl is alkyl as defined above for formulae (I) and (Ic).

In certain embodiments, the compounds of formula (Ic1) of the present invention are those wherein B is unsubstituted aryl or unsubstituted 5-or 6-membered heteroaryl, for example the following compounds: 2- (3-pyridin-3-yl-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine.

In certain embodiments, the compounds of formula (Ic1) of the present invention are those wherein B is unsubstituted aryl or unsubstituted 5-or 6-membered heteroaryl, wherein the substituent is NR^aR^bWherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6Alkyl, such as the following compounds: 5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ]-phenyl } -pyridin-2-ylamine and 5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-phenyl } -pyridine-3-sulphonamide.

In certain embodiments, the compounds of formula (Ic1) of the present invention are those wherein B is unsubstituted aryl or unsubstituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-NR^cR^dWherein R is^cAnd R^dIndependently is H; c optionally substituted by hydroxy_1-6-an alkyl group; c_1-6-a haloalkyl group; c_1-6-an alkoxy group; optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group; - (CH)₂CH₂O)_nCHR^eWherein R is^eIs H or CH₂OH, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; - (CH)₂)_mAryl, where m is 1 or 2, aryl being optionally substituted by halogen or C_1-6-alkoxy substitution; - (CH)₂)_p-C_3-6-cycloalkyl, wherein p is 0 or 1; 5-or 6-membered heterocycloalkyl, for example the following compounds:

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide;

5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -thiophene-2-sulfonic acid tert-butylamide;

5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -thiophene-2-sulfonamide; and

3' - [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonamide.

The compounds of formula (I) of the present invention include compounds of formula (Ic 11):

B, R therein¹、R²、R³And R⁴Alkyl is alkyl as defined above for formulas (I), (Ic) and (Ic 1).

The compounds of formula (I) of the present invention include compounds of formula (Ic 2):

The 5-or 6-membered heteroaryl group may be selected from the following groups: imidazolyl group, [1, 2, 4 ]]Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1, 2, 4 ]]Triazolyl, thiazolyl, pyrimidinyl and thienyl, preferably imidazolyl, [1, 2, 4]Oxadiazolyl, pyridinyl, pyrimidinyl and [1, 2, 4 ]]A triazolyl group.

In certain embodiments, the compounds of formula (Ic2) of the present invention are those wherein B is unsubstituted aryl or unsubstituted 5-or 6-membered heteroaryl, for example the following compounds: 2- (4-chloro-phenyl) -6- (4-pyridin-3-yl-imidazol-1-yl) -4-trifluoromethyl-pyridine.

In certain embodiments, the compounds of formula (Ic2) of the present invention are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is C_1-6Alkyl, such as the following compounds:

4-methyl-2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonic acid tert-butylamide; and

4-methyl-2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide.

In certain embodiments, the compounds of formula (Ic2) of the present invention are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is NR^aR^bWherein R is^aAnd R^bIndependently is H or- (CO) -C₁-C₆Alkyl, such as the following compounds:

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine;

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine;

4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4'; 2', 3 "] terpyridin-6" -ylamine;

5- {1- [6- (4-chloro-phenyl) -4-trifluoromethyl-pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine; and

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H- [1, 2, 4] triazol-3-yl } -pyridin-2-ylamine.

In certain embodiments, the compounds of formula (Ic2) of the present invention are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-C₁-C₆Alkyl, such as the following compounds: 2- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ]-1H-imidazol-4-yl } -thiazole-5-sulfonamide and 2- [4- (3-methanesulfonyl-phenyl) -imidazol-1-yl]-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine.

In certain embodiments, compounds of formula (Ic2) are those wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-NR^cR^dWherein R is^cAnd R^dIndependently is H; c optionally substituted by hydroxy_1-6-an alkyl group; c_1-6-a haloalkyl group; c_1-6-an alkoxy group; optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group; - (CH)₂CH₂O)_nCHR^e，

Wherein R is^eIs H or CH₂OH, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; - (CH)₂)_mAryl, where m is 1 or 2, aryl being optionally substituted by halogen or C_1-6-alkoxy radicalSubstitution; - (CH)₂)_p-C_3-6-cycloalkyl, wherein p is 0 or 1; 5-or 6-membered heterocycloalkyl, for example the following compounds:

3- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamide;

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide;

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide;

n-tert-butyl-3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonic acid tert-butylamide;

3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H- [1, 2, 4] triazol-3-yl } -benzenesulfonamide;

3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide;

n-tert-butyl-3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide;

3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide;

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -pyridine-3-sulfonamide;

n- (2-hydroxy-1, 1-dimethyl-ethyl) -3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

4-methyl-2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonic acid tert-butylamide;

4-methyl-2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide;

N-tert-butyl-3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide;

n-tert-butyl-3- {1- [6- (4-chloro-phenyl) -4-methyl-pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

n-tert-butyl-3- [4 ' -methyl-6 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

3- {4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -benzenesulfonamide;

3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide;

3- [4 ' -methyl-6 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide;

3- {1- [6- (4-chloro-phenyl) -4-methyl-pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide;

5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonic acid tert-butylamide;

5- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonic acid tert-butylamide;

5- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonamide; and

5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonamide.

As indicated above, the present invention also relates to pharmaceutical compositions comprising a compound of formula (I), (Ia), (Ib) or (Ic) for use in the prevention or treatment of diseases or conditions in which activation of mGluR2 plays a role or is associated with activation of mGluR 2. In particular, the pharmaceutical composition of the present invention is useful for preventing or treating acute and/or chronic neurological diseases such as psychosis, schizophrenia, alzheimer's disease, cognitive diseases, memory deficits, colon cancer, sleep disorders, circadian rhythm disorders, and glioma.

The invention also relates to the use of a compound of formula (I), (Ia), (Ib) or (Ic) for the manufacture of a medicament for the treatment or prevention of diseases or disorders in which activation of mGluR2 plays a role or is associated with activation of mGluR2, in particular for the treatment and/or prevention of acute and/or chronic neurological diseases including psychosis, schizophrenia, alzheimer's disease, cognitive diseases, memory deficits, colon cancer, sleep disorders, circadian rhythm disorders and gliomas.

The invention also relates to a process for the preparation of compounds of formula (I), (Ia), (Ib) or (Ia) and to compounds of formula (I), (Ia), (Ib) or (Ia) prepared by this process.

In certain embodiments, there is provided the preparation wherein a is A process for the preparation of a compound of formula (I), (Ia), (Ib) or (Ia) according to the invention (hereinafter referred to as compound of formula (XIII)) of an oxadiazole group, comprising the following steps:

reacting a compound of formula (VIII):

with a compound of formula (XI):

thereby obtaining a compound of formula (XIII):

b, R therein¹、R²And R³As defined above for formula (I), (Ia), (Ib) or (Ia).

In another embodiment, there is provided the preparation wherein A isA process for the preparation of a compound of formula (I), (Ia), (Ib) or (Ia) of the invention (hereinafter referred to as compound of formula (XIV)) of the oxadiazole group, which process comprises the following steps:

reacting a compound of formula (IV):

with a compound of formula (XII):

thereby obtaining a compound of formula (XIV):

In another embodiment, there is provided a process for the preparation of a compound of formula (I), (Ia), (Ib) or (Ia) of the present invention wherein a is as defined above for formula (I), (Ia), (Ib) or (Ia) (hereinafter referred to as compound of formula (XV)), comprising the steps of:

reacting a compound of formula (X):

and formula B-B (OH)₂To obtain a compound of formula (XV):

Synthesis of 2-chloro-, 2-iodo-and 2-methanesulfonyl-pyrimidines as intermediates for the preparation of the compounds of the present invention:

General procedure I

The urea route:

step 1: to a stirred solution of the compound of formula (I) (either commercially available or prepared as described below) in an organic solvent (e.g. tert-butyl methyl ether) at room temperature is added a solution of sodium methoxide in methanol, followed by a solution of the compound of formula (II) in an organic solvent (e.g. tert-butyl methyl ether). Placing the reaction mixture in a chamberStirred at room temperature for about 19h, cooled, acidified and extracted (e.g. with ether). The combined organic layers are washed and dried (e.g., MgSO)₄) Evaporation gives the crude compound of formula (III), which can be used without further purification.

Step 2: to a stirred solution of compound of formula III (1eq) and urea (2eq) in an organic solvent (e.g., MeOH) was added concentrated HCl (e.g., MeOH/HCl 10: 1). The reaction mixture was heated at reflux for about 40h, water was added and the mixture was stirred at 0 ℃ for 1 h. The precipitate is collected by filtration, washed with water and recrystallized (e.g., diethyl ether/hexane) to provide the compound of formula IVa.

And step 3: to a stirred solution of the phosphorus oxychloride of the compound of formula IVa was added DMF (5-10 drops) and the reaction mixture was stirred at 115 ℃ for about 16h, evaporated and ice water was added. The aqueous layer is extracted 2 times (e.g., with diethyl ether), the combined organic layers are washed (first with water, then with brine), dried (e.g., MgSO) ₄) And evaporated to give the compound of formula Va.

And 4, step 4: to a stirred solution of the compound of formula Va (1eq) in an organic solvent such as 2-butanone was added sodium iodide (3.5eq) and hydroiodic acid (57% in water, 1 eq). The reaction mixture was heated at reflux for 16-72h, cooled and poured into ice/saturated sodium bicarbonate solution. The aqueous layer is extracted 2 times (e.g., with diethyl ether), the combined organic layers are washed (first with water, then with brine), dried (e.g., MgSO)₄) And evaporated. Purification by silica gel column chromatography (e.g., toluene elution) affords compounds of formula VIa.

The thiourea route:

step 1: the compound of formula III was prepared using the same method as step 1 in the urea route.

Step 2: (scheme a, using S-methylthiourea): a stirred solution of the compound of formula III (1eq) and S-methylthiourea sulfate (1eq) in an organic solvent (e.g. EtOH) is heated at reflux for about 48h, water is added and the mixture is stirred at 0 ℃ for 1 h. The precipitate is collected by filtration, washed with water and recrystallized (e.g. ether/hexane) to give a compound of formula XXVIIa.

Step 2: (scheme b, using thiourea): 1.) A stirred solution of a compound of formula III (1eq), thiourea (1eq) and a catalytic amount (0.1-0.5eq.) of an inorganic acid (e.g. sulfuric acid) in an organic solvent (e.g. EtOH) is heated at reflux for about 48h, water is added and the mixture is stirred at 0 ℃ for 1 h. The precipitate is collected by filtration, washed with water and recrystallized (e.g. ether/hexane) to give a compound of formula XXVIa.

2.) to a stirred mixture of a compound of formula XXVIa (1eq.) and a base (1.2-1.3eq.) (e.g. NaHCO)₃Or Na₂CO₃) To a solution of the organic solvent (e.g., DMF) is added a methylating agent (1eq.) (e.g., methyl iodide or dimethyl sulfate), and the mixture is stirred at room temperature for 2-24 h. Diluted with EtOAc, the organic layer was washed with water and brine, and finally over Na₂SO₄And (5) drying. Removal of the solvent gives a crude residue which is recrystallized (e.g. ether/heptane) or purified by silica gel column chromatography (ethyl acetate/heptane) to give the compound of formula XXVIIa.

And step 3: to a stirred solution of the compound of formula XXVIIa (1eq.) in an organic solvent (e.g. dichloromethane) is added an oxidant (2eq.) such as mCPBA and the mixture is stirred at room temperature for about 16 h. Pouring NaHCO₃The saturated solution was extracted with dichloromethane, and the organic layer was dried over sodium sulfate. The solvent is removed in vacuo to give the crude product, which is recrystallized (e.g. diethyl ether/heptane) to give pure compound of formula XXVIIIa.

Synthesis of 2-chloro-, 2-bromo-, 2-iodo-and 2-trifluoromethanesulfonyloxy-4-aryl-and-6-aryl-pyridines as intermediates for the preparation of the compounds of the invention:

general procedure Ia

General procedure Ib

General procedure Ic

General procedure Id

Process a (R)¹Alkyl, CF₃)：

Step 1 scheme a (R) ¹Is CF₃): to a 1, 3-diketo-compound of formula III (wherein R is¹Is CF₃(ii) a Prepared as described in general procedure I, step 1) and a protic solvent for the cyanoacetamide (e.g. ethanol) a catalytic amount (about 0.1eq.) of piperidine is added and the mixture is stirred at reflux temperature for 16-24 h. The reaction mixture was concentrated in vacuo and then treated with ice water, acidified with 1M aqueous hydrochloric acid to pH 1, the precipitate filtered, washed with water and dried in air at 60-70 ℃ to give the crude compound of formula XVI, which was used without further purification (according to org. Prep. proced. int.1993, 25(1), 116-.

Step 1 scheme b (R)¹Is an alkyl group): to a 1, 3-diketo-compound of formula III (wherein R is¹Is an alkyl group; for example according to the general procedure I, step 1, using the corresponding acetophenone and R1-carboxylic acid derivatives of the general formula I, Synthesis 1991, (3), 195; monatsh. chem.1996, 127(8-9), 895-; angew. chem. int. Ed. Engl.1993, 32(8), 1151-; chem.1993, 58(11), 3185 and 3187; fluorine chem.1986, 32(2), 229-; org.synth.col.vol.iii, 387; j.am.chem.soc.1953, 75, 626 and 4109; am. J. Chem.soc.1941, 63, 2785; to a mixture of chem. be.1970, 103, 1088) and malononitrile (1.33eq.) in a protic solvent (e.g. ethanol) was added a catalytic amount of diethylamine (0.2eq.) and the mixture was stirred at 20-25 ℃ for about 3 h. The mixture was then heated under reflux conditions for about 16-48 h. After cooling to room temperature, the mixture was diluted with 1M HCl, stirred for 30 minutes, the precipitate filtered, washed with ethanol, dried overnight in air at 60 ℃ to give the crude product, which was purified by trituration with ethanol/diethyl ether/acetic acid (acetic acid) to give the pure product (according to j.indian chem.soc.1930, 7, 815).

Step 2:

scheme a (if R²Or R³Is not CF₃): a mixture of the compound of the formula XVI in 50-85% aqueous sulfuric acid is heated to 150 ℃ and 180 ℃ for 16-24h with stirring. After cooling to room temperature, the reaction mixture is poured into ice water, the precipitate is filtered, washed thoroughly with water and dried in air at 60-70 ℃ to give the crude compound of formula IVb, which can be used without further purification.

Scheme b (if R²Or R³Is CF₃): a mixture of the compound of formula XIV in 48% aqueous hydrobromic acid and acetic acid or propionic acid (3: 2) is heated to 140 ℃ for 4-12 days with stirring. After cooling to room temperature, the reaction mixture was poured into ice water, the precipitate was filtered, washed thoroughly with water, dissolved in a minimum amount of THF, diluted with ethyl acetate, and the organic phase was washed 2 times with a saturated aqueous solution of sodium bicarbonate, then with brine, and finally dried over magnesium sulfate. Filtration and removal of the solvent in vacuo afforded the crude compound of formula IVb, which was used without further purification.

Method b (R)¹Alkyl, cycloalkyl):

step 1: stirred 1-aryl-prop-2-en-1-one-compounds of the formula XVII, in which R1 is alkyl, are prepared, for example, under the conditions described in the literature using, for example, the corresponding arylzinc chloride and R1-substituted acryloyl chloride, Tetr.Lett.1983, 24, 5181 or, for example, the corresponding arylcarboxylic acid esters and R1-formaldehyde according to the following scheme 1.) the arylcarboxylic acid esters are converted into dimethyl 2-oxo-2-aryl-ethyl-phosphonate, J.org.Chem.1998, 63(24), 8894-8897, by reaction of dimethyl methylphosphonate with n-BuLi, according to the literature. 2.) Horner-Emmons-Wadsworth reaction of phosphonate esters with R1-formaldehyde and cesium carbonate according to the following literature: j.chem.soc.perkin T21989, 503) and a mixture of 1-ethoxycarbonylmethylpyridine bromide available commercially [ CAS No. 17282-40-5] (1.1eq.) and ammonium acetate (5eq.) in a protic solvent (e.g., ethanol) was heated at reflux for about 16-48 h. After cooling to room temperature, the mixture was diluted with 1M HCl and water (until pH 1 was reached), stirred for 30min, the precipitate was filtered, washed with water, dried overnight at 60 ℃ in air to give the crude product, which was purified by trituration with ether/heptane to give the pure product of formula IVb.

Method c (R)¹Alkyl, cycloalkyl):

step 1: a stirred mixture of acetophenone of formula I, R1-formaldehyde of formula XIX, ethyl cyanoacetate (each 1.0eq.) and ammonium acetate (8eq.) in protic solvent (e.g. ethanol) is heated at reflux at room temperature for about 16-48 h. After cooling to room temperature, the mixture was diluted with 1M aqueous HCl (until pH 1) and water, stirred for 30 minutes, the precipitate was filtered, washed with water and dried overnight at 60 ℃ in air to give the crude product which was purified by trituration with diethyl ether/heptane to give the pure compound of the formula XVI (according to Farmaco 1999, 54(4), 195-.

And step 3: general procedure Ia procedure a completely analogous procedure to scheme a or b, using a cyanopyridone of general formula XVI gives a pyridinone of general formula IVb.

Method d (R)¹Alkyl, cycloalkyl and CF₃)：

Step 1: piperidine (0.2eq) is added to a stirred mixture of benzaldehyde of general formula XX and cyanoacetamide (1.02eq) in a protic solvent (e.g. EtOH) at 30 ℃ and stirring is continued for about 3-5h at 30 ℃ (almost complete conversion to Knovenagel condensation product). 3- (R1) -3-oxo-3-propanoate of formula XXI (1.05eq.) was then added and the reaction stirred at reflux for about 1-2 h. EtOH was removed in vacuo and the residue was dissolved in EtOAc, washed with brine containing 1N HCl and dried over sodium sulfate. The solvent is removed in vacuo and dried at 60 ℃ under high vacuum to give the compound of formula XXII as a pale yellow foam which can be used without further purification.

Step 2: thionyl chloride (6eq.) was added to the toluene solution of the compound of formula XXII prepared above at 23 ℃ to give a suspension, and the mixture was stirred at 80 ℃ for about 1-2h and then at 115 ℃ for about 4-5 h. Cooling to 100 deg.C, to this stirred hot solution was slowly added heptane (1-6 times the amount of toluene), stirred overnight to slowly cool to 23 deg.C, stirred to cool to 5 deg.C, the precipitate was filtered, washed with heptane and dried in air at 60 deg.C to give the crude product of formula XXIII as a brown solid which was used without further purification.

And step 3: general procedure Ia procedure a scheme a or b is carried out in a completely analogous manner using an alkyl cyanopyridonecarboxylate of the formula XXIII to give a pyridinone of the formula IVc.

Preparation of chlorides, bromides, iodides and triflates used as intermediates for the preparation of the compounds of the present invention:

all the general procedures Ia, Ib, Ic and Id apply to the preparation of the following chlorides, bromides, iodides and triflates:

preparation of chloride/bromide: to a stirred solution of phosphorus oxychloride or phosphorus oxybromide (in POBr) of a compound of formula IV₃In case toluene may be added to aid stirring) to the mixture DMF (0.3-0.4eq.) was added, the reaction mixture was stirred at 105 ℃ for about 16h, evaporated and ice water was added. Filtering the precipitated solid, dissolving it in an organic solvent (e.g. tert-butyl methyl ether or ethyl acetate), and saturating the organic layer with water And sodium bicarbonate solution, then brine, and finally dried over magnesium sulfate. Filtration and removal of the solvent in vacuo afforded the crude product, which was used without further purification, or purified by silica gel column chromatography to afford pure compounds of formula V or XXIV, Z being Cl or Br.

Preparation of iodide: carried out in a completely similar manner to general procedure I, step 4, using a compound of formula V wherein Z is Cl (1eq.) to give a compound of formula VI wherein Z is I. Alternatively, iodides of formula VI wherein Z is I may be prepared from compounds of formula V wherein Z is Br by treatment with sodium iodide (2.0eq.) copper (I) iodide (0.05eq.) and N, N' -dimethylethylenediamine (0.1eq.) in 1, 4-dioxane for about 1-2h at 110 ℃ according to the methods described in j.am.chem.soc.2002, 124(50), 14844.

Preparation of triflate salt/ester: trifluoromethanesulfonic anhydride (1.0-2.0eq.) is added to a pyridine or ethyldiisopropylamine/dichloromethane mixture of the compound of the formula IV at a temperature between-15 and 0 ℃ and stirring is continued at 0 ℃ for 0.5-16 h. Pouring into ice water, extracting with ethyl acetate, extracting with ice-cold 1M sulfuric acid, saturated NaHCO₃The solution was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to give the crude product as a brown solid which was purified by silica gel column chromatography eluting with heptane/EtOAc to give the pure triflate of formula XXV.

Preparation of triflate salt/ester: triflic anhydride (1.0eq.) is added to the pyridine mixture of the compound of formula IV at-15 ℃ and stirring is continued at 0 ℃ for 0.5-16 h. Poured into ice water, extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to give the crude product as a brown solid which was purified by silica gel column chromatography eluting with heptane/EtOAc to give the pure triflate of formula XXV.

Wherein A isSynthesis of Compounds of the formula (I), (Ia), (Ib) and (Ia) according to the invention of the oxadiazole group:general procedure V:

in the following schemes, the compounds of formula (XIII) and (XIV) are compounds of formula (I), (Ia), (Ib) and (Ia), wherein A isDiazoles, R¹、R²、R³And R⁴And B is as defined above for formula (I), (Ia), (Ib) or (Ia).

To a stirred solution of formic acid (1eq) of formula XI or IV in an organic solvent (e.g. DMF) at room temperature is added 1, 1' -carbonyl-diimidazole (1.5eq) and the reaction mixture is stirred at room temperature for about 2 h. N-hydroxy-amidines of the formula VIII or XII (1.5eq.) are added and the reaction mixture is stirred at 80 ℃ for about 15h and evaporated to dryness. Acetic acid was added and the stirred reaction mixture was heated at reflux for about 4h, cooled and evaporated. Purification by silica gel chromatography and crystallization gives the final product of formula XIII or XIV.

Wherein A is notSynthesis of compounds of formula (I), (Ia), (Ib) and (Ia) of the oxadiazole group: general procedure VI

In the following schemes, the compound of formula (XIV) is a compound of formula (I), (Ia), (Ib) or (Ia), wherein A is as defined above for formula (I), (Ia), (Ib) or (Ia) but is notDiazole group, wherein R¹、R²、R³And B is as defined above for formula (I), (Ia), (Ib) or (Ia).

To a stirred mixture of compound of formula X (1eq.) and boronic acid derivative of formula XVI (1.0-1.5eq.) and tetrakis triphenylphosphine palladium (0.02-0.1eq.) in an organic solvent, such as DME or dioxane, at room temperature was added 1M aqueous sodium carbonate solution (2-3eq.) and the reaction mixture was heated at reflux for about 18h, cooled, poured into ice water and extracted 2 times with ethyl acetate. The combined organic layers were washed 2 times with brine and dried (e.g., over MgSO)₄) And evaporated. The crude product is purified by column chromatography over silica gel (e.g. MeCl)₂/MeOH/NH₄OH 20: 1: 0.1) and crystallization (e.g., dichloromethane/MeOH/hexane) affords the compound of formula XV.

The compounds of formula (I) and their pharmaceutically acceptable salts are metabotropic glutamate receptor antagonists, useful for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, alzheimer's disease, cognitive disorders and memory deficits. Other treatable indications are restricted brain function due to the following reasons: bypass surgery or transplantation, cerebral insufficiency, spinal cord injury, head injury, hypoxia induced by pregnancy, cardiac arrest and hypoglycemia. Other treatable indications are chronic and acute pain, Huntington's chorea, ALS, AIDS-induced dementia, eye damage, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments and diseases which lead to glutamate dysfunction, such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia, depression, colon carcinoma, sleep disorders, circadian rhythm disorders and gliomas.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparation may be administered orally, for example in the form of: tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formula (I) and their pharmaceutically acceptable salts may be processed with pharmaceutically inert, inorganic or organic carriers used in the manufacture of pharmaceutical preparations. As such carriers, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be employed for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance, however, in the case of soft gelatin capsules, no carriers are generally required. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. For aqueous injection solutions of water-soluble salts of compounds of formula (I), adjuvants such as alcohols, polyols, glycerol, vegetable oils, and the like may be employed, but are generally not required. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for regulating the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

As mentioned above, medicaments containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as well as a process for the manufacture of such medicaments, which process comprises bringing one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof and one or more other therapeutically valuable substances, if desired, into a galenical form together with one or more therapeutically inert carriers.

The dosage can vary within wide limits and, of course, in special cases it should be adapted to the individual requirements. In general, an effective dose for oral or parenteral administration is 0.01-20 mg/kg/day, preferably 0.1-10 mg/kg/day for all indications mentioned. Thus, for an adult having a body weight of 70kg, the daily dose is 0.7-1400mg per day, preferably 7-700mg per day.

The invention also relates to the use of compounds of formula (I) and their pharmaceutically acceptable salts for the manufacture of medicaments, in particular for the control or prevention of the various acute and/or chronic neurological disorders mentioned above.

The compounds of the present invention are class II mGlu receptor antagonists. The compound exhibits an activity of 0.250. mu.M or less, usually 0.100. mu.M or less, preferably 0.010. mu.M or less, as measured in the following assay. Certain specific Ki values for certain preferred compounds are described in the table below.

[³H]Binding of LY354740 to Glu 2-transfected CHO cell membranes

Transfection and cell culture

The cDNA encoding the rat mGlu2 receptor protein in pBluescript II was subcloned into the eukaryotic expression vector pcDNA I-amp obtained from Invitrogen Ltd (Paisley, UK). According to Chen&The vector construct (pcD1mGR2) was co-transfected into CHO cells together with a psvNeo plasmid encoding a neomycin resistance gene by a modified calcium phosphate method as described by Okayama (1988). The cells were stored in Dulbecco's modified Eagle's medium containing reduced L-glutamine (final concentration of 1mM), 36mg/L L-proline and 10% dialyzed fetal bovine serum obtained from Gibco-Invitrogen; the medium was supplemented with 500. mu.M α -methyl-4-carboxyphenylglycine (MCPG). The screening was carried out in the presence of G-418 (final concentration 300. mu.g/ml). Reverse transcription of 5. mu.g total RNA followed by the use of mGlu2 receptor specific primers 5'-atcactgcttgggtttctggcactg-3' and 5'-agcatcactgtgggtggcataggagc-3' at 60mM Tris HCl (pH 10) (containing 15mM (NH) ₄)₂SO₄、2mM MgCl₂25 units/ml Taq polymerase) for 30 cycles of PCR differential cloning, wherein the PCR reaction conditions are as follows: annealing at 60 deg.C for 1 minExtension was carried out at 72 ℃ for 30 seconds and denaturation was carried out at 95 ℃ for 1 minute.

Membrane preparation

The cultured cells were harvested, washed 3 times with cold PBS, and frozen at-80 ℃. The pellet was suspended in cold 20mM HEPES-NaOH buffer containing 10mM EDTA (pH 7.4) and homogenized with polytron (Kinematica, AG, Littau, Switzerland) at 10000rpm for 10 seconds. After centrifugation at 4 ℃ for 30 minutes, the pellet was washed 1 time with cold 20mM HEPES-NaOH buffer containing 10mM EDTA (pH 7.4). After a second centrifugation at 4 ℃ for 30 minutes, the pellet was resuspended in cold 20mM HEPES-NaOH buffer containing 0.1mM EDTA (pH 7.4). Protein content was determined using the Micro BCA method from Pierce-Perbio (Rockford, IL, USA) using bovine serum albumin as a standard.

[³H]Binding to LY354740

After thawing, the cell membranes were suspended in cold medium containing 2mM MgCl₂(pH 7.4) 50mM Tris-HCl buffer (binding buffer). In this assay, the final concentration of cell membranes was 25. mu.g protein/ml. Contacting a cell membrane with 10nM [ alpha ] peptide in the presence of various concentrations of a test compound at room temperature ³H]LY354740 was incubated together for 1 hour for inhibition experiments. After incubation, the cell membranes were filtered onto Whatmann GF/B glass fiber filters or onto GF/B Unifilter plates and washed 5 times with cold binding buffer. Nonspecific binding was determined in the presence of 10. mu.M (2S, 2 'R, 3' R) -2- (2 '3' -dicarboxylcyclopropyl) glycine (DCG IV, Tocris, Ellisville, Mo USA). The filters were transferred to plastic vials containing 10ml Ultima-gold scintillation fluid from Perkin-Elmer (boston, MA, USA) and the radioactivity was determined by measuring liquid scintillation using a Tri-Carb 2500TR counter (Packard, zurich, switzerland). For the 96-Unifilter plate, after addition of Microscint40 scintillation fluid (Perkin Elmer, Boston MA), radioactivity was measured using TopCount NXT (Packard).

Data analysis

Using a four parameter logarithmic equation and a Hill normFitting the inhibition curve to obtain IC₅₀The value is obtained.

Detailed Description

Example A.1

2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine

1)4- (4-chloro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl trifluoroacetate, commercially available 4-chloro-acetophenone and urea. Pale yellow solid (60%) was obtained. MS (EI)274.1[ (M) ⁺]；mp 200℃。

2) The title compound was prepared according to general procedure I using 4- (4-chloro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one (6.96g, 25.3mmol) and phosphorus oxychloride (80 mL). An off-white solid was obtained (7.35g, 99%). MS (EI)292.0[ (M)⁺]；mp 108℃。

Example A.2

2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

1) 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl trifluoroacetate, commercially available 4-trifluoromethyl-acetophenone and urea. A white solid was obtained (57%). MS (ISP)309.0[ (M + H)⁺]；mp 136℃。

2) The title compound was prepared according to general procedure I using 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -1H-pyrimidin-2-one (8.72g, 28.3mmol) and phosphorus oxychloride (80 mL). Light brown solid (9.13g, 98%) was obtained. MS (EI)326.0[ (M)⁺]；mp 71.5℃。

Example A.3

4- (4-chloro-phenyl) -2-iodo-6-trifluoromethyl-pyrimidine

According to general procedure I, 2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine is used (practice)Example A.1) (1.0g, 3.41mmol) the title compound was prepared. A pale green solid was obtained (1.27g, 97%). MS (ISP)385.0[ (M + H)⁺]；mp 73℃。

Example A.4

2-iodo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure I using 2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.2) (1.31g, 4.01 mmol). Pale yellow solid (1.62g, 97%) was obtained. MS (ISP)419.1[ (M + H) ⁺]；mp 96℃。

Example A.5

2-chloro-4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

1)4- (4-chloro-phenyl) -6-difluoromethyl-1H-pyrimidin-2-one: this compound was prepared according to general procedure I using ethyl difluoroacetate obtained commercially, 4-trifluoromethyl-acetophenone obtained commercially and urea. A white solid was obtained (49%). MS (EI)290.2[ (M)⁺]；mp 210℃。

2) The title compound was prepared according to general procedure I using 4- (4-chloro-phenyl) -6-difluoromethyl-1H-pyrimidin-2-one (5.09g, 17.5mmol) and phosphorus oxychloride (55 mL). Light brown solid was obtained (5.11g, 94%). MS (EI)308.1[ (M)⁺]；mp 63℃。

Example A.6

2-chloro-4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

1)4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl trifluoroacetate, commercially available 3-fluoro-4-trifluoromethyl-acetophenone and urea. A white solid was obtained (56%). MS (EI)326.1[ (M)⁺]；mp 150℃。

2) According to general procedure I, 4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one (4.08g, 12.5 mmo) is usedl) and phosphorus oxychloride (40 mL). A yellow solid was obtained (4.26g, 99%). MS (EI)344.0[ (M)⁺]；mp 41℃。

Example A.7

2-chloro-4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine

1)4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl trifluoroacetate, commercially available 3, 4-dichloro-acetophenone and urea. A white solid was obtained (38%). MS (EI)308.0[ (M)⁺]；mp 180℃。

2) The title compound was prepared according to general procedure I using 4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one (5.72g, 18.5mmol) and phosphorus oxychloride (60 mL). A white solid was obtained (6.04g, 99%). MS (EI)326.0[ (M)⁺]；mp 82℃。

Example A.8

2-chloro-4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine

1)4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl trifluoroacetate, commercially available 4-chloro-3-methyl-acetophenone and urea. A white solid (42%) was obtained. MS (EI)288.1[ (M)⁺]；mp 201℃。

2) The title compound was prepared according to general procedure I using 4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one (9.07g, 31.4mmol) and phosphorus oxychloride (100 mL). A white solid was obtained (8.68g, 99%). MS (EI)306.1[ (M)⁺]；mp 90℃。

Example A.9

4-difluoromethyl-2-iodo-6- (4-trifluoromethyl-phenyl) -pyrimidine

This object was prepared according to general procedure I using 2-chloro-4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example A.5) (0.5g, 1.62mmol)A compound is provided. A green solid (0.43g, 66%) was obtained. MS (ISP)399.0[ (M-H)^-]；mp 85℃。

Example A.10

2-chloro-4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

1)4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one: according to general procedure I, ethyl trifluoroacetate, 3-ethoxy-4-trifluoromethyl-acetophenone [ CAS No. 851263-21-3 ] obtained commercially was used]And urea. An off-white solid was obtained (54%). MS (EI)352.1[ (M)⁺]；mp 217℃。

2) The title compound was prepared according to general procedure I using 4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one (3.74g, 10.6mmol) and phosphorus oxychloride (35 mL). A light brown solid was obtained. MS (EI)370.0[ (M)⁺]；mp 89℃。

Example A.11

2-chloro-4- (4-chloro-phenyl) -6-methyl-pyrimidine

1)4- (4-chloro-phenyl) -6-methyl-1H-pyrimidin-2-one: this compound was prepared according to the method of general procedure I, step 2, using 1- (4-chloro-phenyl) -butane-1, 3-dione and urea. A pale red solid was obtained (85%). MS (ISP)221.1[ (M + H)⁺]；mp 236-239℃。

2) The title compound was prepared according to the method of general procedure I, step 3, using 4- (4-chloro-phenyl) -6-methyl-1H-pyrimidin-2-one (11.0g, 50.0mmol) and phosphorus oxychloride (20 mL). An off-white solid was obtained (6.8g, 57%). MS (ISP)239.0[ (M + H) ⁺]；mp 116-117℃。

Example A.12

2-chloro-4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

1) 6-methyl-4- (4-trifluoromethyl-phenyl) -1H-pyrimidin-2-one: the procedure is according to general procedure I, step 2, using 1- (4-trifluoromethyl-phenyl) -butane-1, 3-bisKetones and ureas. Obtained as a pale yellow solid (14%). MS (ISP)255.3[ (M + H)⁺]；mp 250-252℃。

2) The title compound was prepared according to the method of general procedure I, step 3, using 6-methyl-4- (4-trifluoromethyl-phenyl) -1H-pyrimidin-2-one (5.1g, 20.0mmol) and phosphorus oxychloride (10 mL). Light brown solid was obtained (4.1g, 75%). MS (ISP)273.1[ (M + H)⁺]；mp 82-83℃。

Example A.13

2-chloro-4- (4-chloro-phenyl) -6-cyclopropyl-pyrimidine

1)2, 4-dichloro-6- (4-chloro-phenyl) -pyrimidine: 2, 4, 6-trichloropyrimidine (10.1g, 55mmol), 4-chlorophenylboronic acid (8.6g, 55mmol), sodium carbonate (18.1g, 171mmol), palladium acetate (0.61g, 2.7mmol) and triphenylphosphine (1.44g, 5.5mmol) in dimethoxyethane (0.5L)/H₂The mixture in O (0.1L) was heated at 80 ℃ for 18 h. The cooled mixture was poured into ice water and the product was extracted with ether. The organic layer was washed with brine, dried and evaporated. The crude product was purified by trituration with ether/dichloromethane (9: 1) to give 2, 4-dichloro-6- (4-chloro-phenyl) -pyrimidine as an off-white solid (5.0g, 35%). mp130-132 deg.C.

2) To a solution of 2, 4-dichloro-6- (4-chloro-phenyl) -pyrimidine (2.6g, 10.0mmol) and tetrakis (triphenylphosphine) palladium (0.69g, 0.6mmol) in THF (10mL) at 20 ℃ was added a 0.25M solution of zinc cyclopropylchloride/THF (120mL, 30 mmol; prepared freshly by stirring 60mL of 0.5M cyclopropylmagnesium bromide/THF and 60mL of 0.5M zinc chloride/THF at 0 ℃ for 1h, followed by 20 ℃ for 1 h), the mixture was refluxed under argon for 3 h. Slowly add saturated NH at 0 deg.C₄After a Cl solution (20mL), the mixture was partitioned between AcOEt and 10% sodium chloride solution. Drying the organic layer (Na)₂SO₄) And evaporated in vacuo. The residue was purified by silica gel chromatography using AcOEt/cyclohexane (1: 19v/v) as eluent to give 2-chloro-4- (4-chloro-phenyl) -6-cyclopropyl-pyrimidine (1.12g, 42%) as a pale yellow solid. MS (ISP)265.1[ (M + H)⁺]；mp 70-72℃。

Example A.14

2-chloro-4- (4-chloro-phenyl) -pyrimidine

1) 2, 4-dichloropyrimidine (3.1g, 20mmol), 4-chlorophenylboronic acid (3.0g, 20mmol) and tetrakis (triphenylphosphine) palladium (0.69g, 0.6mmol) in dimethoxyethane (200 mL)/saturated Na₂CO₃The mixture in solution (34mL) was heated at 80 ℃ for 20 h. The cooled mixture was poured into ice water and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate/cyclohexane (1: 2, v/v) as eluent to give the title compound (1.82g, 40%) as a white solid. NMR (DMSO-d) ₆)δ7.67(d，2H，J＝7Hz)，8.19(d，2H，J＝5Hz)，8.23(d，2H，J＝7Hz)，8.86(d，2H，J＝5Hz)ppm；mp 290-292℃。

Example A.15

2-methanesulfonyl-4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine

1) 2-methylsulfanyl-4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine: this compound was prepared according to general procedure I, step 1 and step 2 (thiourea route, scheme a), using ethyl trifluoroacetate, 3-trifluoromethyl-acetophenone and S-methylthiourea sulfate, obtained commercially. A white solid was obtained (98%). MS (ISP)339.0[ (M + H)⁺]。

2) The title compound was prepared according to general procedure I, step 3 (thiourea route), using 2-methylsulfanyl-4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine (1.88g, 6mmol) and m-CPBA (3.365g, 11 mmol). A white solid was obtained (1.8g, 87%). MS (ISP)370.9[ (M + H)⁺]。

Example A.16

2-chloro-6- (4-chloro-phenyl) -4-trifluoromethyl-pyridine

1)6- (4-chloro-phenyl) -2-oxo-4-trifluoromethyl-1, 2-dihydro-pyridine-3-carbonitrile: according to general procedure I, step 1 and procedure Ia, step 1, usingThe compound was prepared from commercial ethyl trifluoroacetate, commercial 4-chloro-acetophenone and commercial cyanoacetamide. A yellow solid was obtained (82%). MS (ISP)299.1[ (M + H)⁺]And 301[ (M +2+ H)⁺]；mp 287℃。

2)6- (4-chloro-phenyl) -4-trifluoromethyl-1H-pyridin-2-one: according to general procedure Ia, step 2, scheme a, 6- (4-chloro-phenyl) -2-oxo-4-trifluoromethyl-1, 2-dihydro-pyridine-3-carbonitrile (26.68g, 89mmol) and 85% H ₂SO₄The compound is prepared in aqueous solution. White solid (22.28g, 91%) was obtained. MS (ISN)272.1[ (M-H)^-]And 274.0[ (M +2-H)^-]；mp 220-221℃。

3) The title compound was prepared according to the general procedure for the preparation of chloride Ia to d using 6- (4-chloro-phenyl) -4-trifluoromethyl-1H-pyridin-2-one (10.0g, 37mmol) and phosphorus oxychloride (16.75mL, 183 mmol). Light brown solid was obtained (10.14g, 95%). MS (ISP)292.1[ (M + H)⁺]，294[(M+2+H)⁺]And 296[ (M +4+ H)⁺]。

Example A.17

2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine

1) 2-oxo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -1, 2-dihydro-pyridine-3-carbonitrile: this compound was prepared according to general procedure I, step 1, and procedure Ia, step 1, using ethyl trifluoroacetate obtained commercially, 4-trifluoromethyl-acetophenone obtained commercially, and cyanoacetamide obtained commercially. Obtained as a pale yellow solid (69%). MS (ISN)331[ (M-H)^-]；mp 197℃。

2) 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one: this compound was prepared according to general procedure Ia, step 2, scheme b, using 2-oxo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -1, 2-dihydro-pyridine-3-carbonitrile (42g, 126mmol) and 48% HBr in aqueous propionic acid. A white solid was obtained (52.98g, 88%). MS (ISP)308.3[ (M + H) ⁺]；mp 203-204℃。

3) According to the preparative chlorinationGeneral procedure Ia to d the title compound was prepared using 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (51.5g, 168mmol) and phosphorus oxychloride (50 mL). An off-white solid was obtained (53.4g, 98%). MS (ISN)384.1[ (M + OAc)^-]，386.0[(M+2+OAc)^-]；mp 39-40℃。

Example A.18

2-bromo-6- (4-chloro-phenyl) -4-trifluoromethyl-pyridine

The title compound was prepared according to general procedure Ia to d for the preparation of the bromide using 6- (4-chloro-phenyl) -4-trifluoromethyl-1H-pyridin-2-one (example A.16 step 2) (7.38g, 27mmol) and phosphorus oxybromide (25g, 87 mmol). A brown solid (8.92g, 98%) was obtained. MS (EI)334.8[ (M)⁺]，336.7[(M+2)⁺]，338.8[(M+4)⁺]And 339.8[ (M +6)⁺]；mp 51-53℃。

Example A.19

2-bromo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure Ia to d for the preparation of the bromide using 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (example A.17 step 2) (15g, 49mmol) and phosphoryl bromide (42g, 146 mmol). A brown solid (18g, quant.) was obtained. MS (EI)368.9[ (M)⁺]And 370.8[ (M +2)⁺]；mp 35-37℃。

Example A.20

6- (4-chloro-phenyl) -2-iodo-4-trifluoromethyl-pyridine

The title compound was prepared according to general procedure Ia to d for the preparation of iodides using 2-chloro-6- (4-chloro-phenyl) -4-trifluoromethyl-pyridine (example a.16) (4.97g, 17 mmol). A brown solid was obtained (5.39g, 79%). MS (ISP)384.0[ (M + H) ⁺]And 386[ (M +2+ H)⁺]。

Example A.21

2-iodo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedures Ia to d for the preparation of iodides using 2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example a.17) (37.12g, 114 mmol). Pale yellow solid (33.37g, 70%) was obtained. MS (ISP)418.0[ (M + H)⁺]。

Example A.22

2-bromo-6- (4-chloro-phenyl) -4-methyl-pyridine

1)6- (4-chloro-phenyl) -4-methyl-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile: this compound was prepared according to general procedure Ia, step 1, scheme b, using ethyl acetate, obtained from commercial sources, 4-chloro-acetophenone, obtained from commercial sources, and malononitrile, obtained from commercial sources. A yellow solid (56%) was obtained. MS (ISP)245.5[ (M + H)⁺]And 247[ (M +2+ H)⁺]。

2)6- (4-chloro-phenyl) -4-methyl-1H-pyridin-2-one: according to general procedure Ia, step 2, scheme a, 6- (4-chloro-phenyl) -4-methyl-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (7.26g, 30mmol) and 85% H₂SO₄The compound was prepared in aqueous solution at 180 ℃. A white solid was obtained (4.66g, 72%). MS (ISP)220.1[ (M + H)⁺]And 222[ (M +2+ H)⁺]；mp 220-221℃。

3) The title compound was prepared according to general procedures Ia to d for the preparation of the bromides using a solution of 6- (4-chloro-phenyl) -4-methyl-1H-pyridin-2-one (1.1g, 5mmol) and phosphoryl bromide (4.63g, 16mmol) in toluene (9.5 mL). A light brown solid was obtained (1.0g, quant., purity 74%). MS (ISP)282.0[ (M + H) ⁺]，284.0[(M+2+H)⁺]And 286.0[ (M +4+ H)⁺]。

Example A.23

2-chloro-4-methyl-6- (4-trifluoromethyl-phenyl) -pyridine

Raw materials: (E) -1- (4-trifluoromethyl-phenyl) -but-2-en-1-one [ CAS number 201164-24-1]

4-iodotrifluorotoluene (obtained commercially at-40 ℃ C. within 5 minutes: (11.76mL, 80mmol) in THF (70mL) was added isopropyl magnesium chloride (2M in THF, 41.2mL, 88mmol) maintaining the internal temperature below-20 deg.C and stirring was continued at-20 to 0 deg.C for 40 min. Adding ZnCl₂(1M in THF, 88mL, 88mmol), the cooling bath was removed and replaced with a water bath, and the mixture was warmed to 23 ℃ and stirred at 23 ℃ for 45min to give a pale yellow suspension. Pd (PPh) was added dropwise at 23 ℃₃)₄(924mg, 1 mol%) and trans-butenoyl chloride (90%, 9.38mL, 88mmol) (exothermic reaction (!) the internal temperature was maintained at-35 ℃ by cooling through a water bath and stirring was continued for 1h at 23 ℃. Ice cold 0.5N HCl was poured in, extracted with EtOAc and saturated NaHCO₃The solution was washed with brine and dried over magnesium sulfate. Removal of the solvent in vacuo afforded a red oil which was purified by chromatography using heptane to heptane: TBME (9: 1) gave (E) -1- (4-trifluoromethyl-phenyl) -but-2-en-1-one as a yellow liquid (18.37g, quant., 93% purity).

1) 4-methyl-6- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one: following general procedure Ib, step 1, the above-described (E) -1- (4-trifluoromethyl-phenyl) -but-2-en-1-one (18.35g, ca. 80mmol), 1-ethoxycarbonylmethyl-pyridinium bromide available commercially [ CAS No. 17282-40-5]The compound was prepared (21.57g, 88mmol) and ammonium acetate (30.71g, 398mmol) in ethanol (80 mL). A pale red solid was obtained (11.43g, 57%). MS (ISN)252.1[ (M-H)^-]。

2) 2-chloro-4-methyl-6- (4-trifluoromethyl-phenyl) -pyridine: this compound was prepared according to the general procedure for the preparation of chloride Ia to d using 4-methyl-6- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (13.64g, 54mmol) and phosphorus oxychloride (14.8mL, 162 mmol). A brown solid was obtained (13.77g, 94%). MS (ISP)272.2[ (M + H)⁺]And 274.0[ (M +2+ H)⁺]。

Example A.24

2-chloro-4-cyclopropyl-6- (4-trifluoromethyl-phenyl) -pyridine

Raw materials: (E) -3-cyclopropyl-1- (4-trifluoromethyl-phenyl) -propenone

Step a) [ 2-oxo-2- (4-trifluoromethyl-phenyl) -ethyl]Dimethyl phosphonate CAS number 51638-15-4]: to a solution of commercial dimethyl methylphosphonate (26.8mL, 247mmol) in THF (500mL) was added n-BuLi (1.6M in hexane) (153.1mL, 245mmol) maintaining the internal temperature below-65 ℃. Stirring was continued for 15min, then a solution of commercial methyl 4- (trifluoromethyl) benzoate (25.0g, 122mmol) in THF (70mL) was added, maintaining the temperature below-70 ℃. The mixture was stirred at-78 ℃ for a further 30min and then warmed to 0 ℃. The mixture was quenched by addition of 1N HCl saturated with solid sodium chloride, extracted with TBME and dried over magnesium sulfate. The solvent was removed in vacuo to give a pale yellow oil, and the dimethyl methylphosphonate was removed by Kugelrohr distillation (0.94mbar) at 120 ℃ to give [ 2-oxo-2- (4-trifluoromethyl-phenyl) -ethyl ]Dimethyl phosphonate as a pale yellow liquid (35.1g, 97%). MS (ISN)295.3[ (M-H)^-]。

Step b) (E) -3-cyclopropyl-1- (4-trifluoromethyl-phenyl) -propenone: the [ 2-oxo-2- (4-trifluoromethyl-phenyl) -ethyl prepared above is reacted with]A mixture of dimethyl phosphonate (11.85g, 40mmol), cyclopropanecarboxaldehyde (2.99mL, 40mmol) and cesium carbonate (13.68g, 42mmol) in dioxane (80mL) and water (1mL) was stirred at 70 ℃ for 30 min. Cooled to 23 ℃, 1N HCl was added until pH 1, extracted with TBME, and the organic layer was saturated NaHCO₃The solution was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to give a yellow oil which was purified by silica gel column chromatography eluting with heptane/EtOAc 2: 1 to give (E) -3-cyclopropyl-1- (4-trifluoromethyl-phenyl) -propenone as a yellow solid (7.38g, 77%). MS (EI)240.0[ (M)⁺]；mp 47-52℃。

1) 4-cyclopropyl-6- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one: following general procedure Ib, step 1, using (E) -1- (4-trifluoromethyl-phenyl) -but-2-en-1-one (2.642g, 11mmol), 1-ethoxycarbonylmethyl-pyridinium bromide obtained commercially [ CAS number 17282-40-5](3.249g, 13mmol) and ammonium acetate (4.24g, 55mmol) in ethanol (20 mL). Light brown solid (0.91g, 30%) was obtained. MS (ISP)280.1[ (M + H) ⁺]。

2) 2-chloro-4-cyclopropyl-6- (4-trifluoromethyl-phenyl) -pyridine: this compound was prepared according to the general procedure for the preparation of chloride Ia to d using 4-cyclopropyl-6- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (0.9g, 3.2mmol) and phosphorus oxychloride (1.0mL, 11 mmol). An off-white solid was obtained (530g, 55%). MS (ISP)298.2[ (M + H)⁺]And 300[ (M +2+ H)⁺]；mp 89-93℃。

Example A.25

2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyridine

1)4- (4-chloro-phenyl) -5-cyano-2-hydroxy-6-oxo-2-trifluoromethyl-piperidine-3-carboxylic acid ethyl ester: this compound was prepared according to general procedure Id step 1 using a solution of 4-chlorobenzaldehyde (28.3g, 201mmol) obtained commercially, cyanoacetamide (17.3g, 206mmol) obtained commercially, ethyl 4, 4, 4-trifluoroacetoacetate (31.0mL, 210mmol) obtained commercially and piperidine (4mL, 0.2eq.) in EtOH (250 mL). A yellow foam (80.57g, quant.) was obtained. MS (ISN)389.1[ (M-H)^-]And 391[ (M +2-H)^-]。

2)4- (4-chloro-phenyl) -5-cyano-6-oxo-2-trifluoromethyl-1, 6-dihydro-pyridine-3-carboxylic acid ethyl ester: this compound was prepared according to general procedure Id step 2, using ethyl 4- (4-chloro-phenyl) -5-cyano-2-hydroxy-6-oxo-2-trifluoromethyl-piperidine-3-carboxylate (80.5g, 200mmol) and thionyl chloride (90mL, 1241 mmol). A brown solid was obtained (46.14g, 63%). MS (ISN)369.1[ (M-H) ^-]And 371.0[ (M +2-H)^-]。

3)4- (4-chloro-phenyl) -6-trifluoromethyl-1H-pyridin-2-one: this compound was prepared according to general procedure Id step 3, using a solution of 4- (4-chloro-phenyl) -5-cyano-6-oxo-2-trifluoromethyl-1, 6-dihydro-pyridine-3-carboxylic acid ethyl ester (45.0g, 121mmol) and 48% hydrobromic acid (400mL) in acetic acid (250mL) at 140 ℃ for 11 days. A light brown solid (29.43g, 89%, 85% purity) was obtained. MS (ISN)272.2[ (M-H)^-]And 274.1[ (M +2-H)^-]。

4) According to the general procedure for preparing chlorides Ia to d, 4- (4-chloro-phenyl)-6-trifluoromethyl-1H-pyridin-2-one (29.5g, 108mmol) and phosphoryl chloride (49.2mL, 539mmol) to prepare the title compound. Light brown solid was obtained (19.7g, 62%). MS (ISP)292.1[ (M + H)⁺]，294[(M+2+H)⁺]And 296[ (M +4+ H)⁺]。

Example A.26

2-chloro-6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine

1) 5-cyano-2-hydroxy-6-oxo-2-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -piperidine-3-carboxylic acid ethyl ester: this compound was prepared according to general procedure Id step 1 using a solution of 4-trifluoromethylbenzaldehyde obtained commercially (28.9mL, 200mmol), cyanoacetamide obtained commercially (17.5g, 208mmol), ethyl 4, 4, 4-trifluoroacetoacetate obtained commercially (30.5mL, 207mmol) and piperidine (4mL, 0.2eq.) in EtOH (100 mL). A yellow foam (90.44g, 98%, 92% purity) was obtained. MS (ISN)423.1[ (M-H) ^-]。

2) 5-cyano-6-oxo-2-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -1, 6-dihydro-pyridine-3-carboxylic acid ethyl ester: this compound was prepared according to general procedure Id step 2, using 5-cyano-2-hydroxy-6-oxo-2-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -piperidine-3-carboxylic acid ethyl ester (94.12g, ca. 210mmol) and thionyl chloride (95mL, 1305 mmol). A brown solid (70.98g, 81%) was obtained. MS (ISN)403.1[ (M-H)^-]。

3) 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one: this compound was prepared according to general procedure Id step 3, using a solution of 5-cyano-6-oxo-2-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -1, 6-dihydro-pyridine-3-carboxylic acid ethyl ester (70.9g, 175mmol) and 48% hydrobromic acid (400mL) in acetic acid (250mL) at 140 ℃ for 12 days. A brown solid (23.7g, 44%, 84% purity) was obtained. MS (ISN)306.2[ (M-H)^-]。

4) The title compound was prepared according to the general procedure for the preparation of chloride Ia to d using 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (23.7g, 77mmol) and phosphorus oxychloride (35.2mL, 386 mmol). An off-white solid was obtained(16.5g，66％)。MS(ISP)326.1[(M+H)⁺]And 328[ (M +2+ H)⁺]。

Example A.27

2-chloro-4- (4-chloro-phenyl) -6-methyl-pyridine

1)4- (4-chloro-phenyl) -6-methyl-1H-pyridin-2-one [ CAS No. 24452-07-1 ]: according to general procedure Ib, step 1, 4- (4-chloro-phenyl) -but-3-en-2-one [ CAS No. 3160-40-5, obtained commercially](44.15g, 244mmol), 1-ethoxycarbonylmethyl-pyridinium bromide available commercially [ CAS No. 17282-40-5](66.17g, 269mmol) and ammonium acetate (100g, 1297mmol) in EtOH (300 mL). A yellow solid (52.61g, 98%, 96% purity) was obtained. MS (ISP)220.2[ (M + H)⁺]And 222[ (M +2+ H)⁺]；mp 212℃。

2) The title compound was prepared according to general procedure Ia to d for the preparation of the chloride, using 4- (4-chloro-phenyl) -6-methyl-1H-pyridin-2-one (15g, 68mmol) and phosphorus oxychloride (31.1mL, 341 mmol). A brown solid (12.3g, 75%) was obtained. MS (ISP)238.1[ (M + H)⁺]，240[(M+2+H)⁺]And 242[ (M +4+ H)⁺]。

Example A.28

2-bromo-4- (4-chloro-phenyl) -6-methyl-pyridine [ CAS No. 23148-57-4]

The title compound was prepared according to general procedure Ia to d for the preparation of the bromide using 4- (4-chloro-phenyl) -6-methyl-1H-pyridin-2-one (example A.27 step 1) (4.00g, 18.2mmol) and phosphorus oxybromide (15.66g, 54.6 mmol). Light brown solid was obtained (2.95g, 57%). MS (ISP)282[ (M + H)⁺]，284[(M+2+H)⁺]And 286[ (M +4+ H)⁺]；mp 92℃。

Example A.29

4- (4-chloro-phenyl) -2-iodo-6-methyl-pyridine

The targeting was prepared according to general procedure Ia to d for the preparation of iodides, using 2-chloro-4- (4-chloro-phenyl) -6-methyl-pyridine (example A.27) (10.0g, 42mmol) A compound (I) is provided. White solid (9.4g, 68%) was obtained. MS (ISP)329.9[ (M + H)⁺]And 331[ (M +2+ H)⁺]。

Example A.30

2-chloro-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine [ CAS No. 697739-23-4]

1) 6-methyl-4- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one: according to general procedure Ib, step 1, using commercially available 4- (4-trifluoromethyl-phenyl) -but-3-en-2-one [ CAS No. 80992-93-4](47.64g, 222mmol), 1-ethoxycarbonylmethyl-pyridinium bromide available commercially [ CAS number 17282-40-5]This compound was prepared (60.21g, 245mmol) and ammonium acetate (85.7g, 1112mmol) in EtOH (275 mL). An off-white solid was obtained (48.79g, 87%). MS (ISP)254.2[ (M + H)⁺]。

2) The title compound was prepared according to general procedure Ia to d for the preparation of the chloride, using 6-methyl-4- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (20g, 79mmol) and phosphorus oxychloride (36.0mL, 395 mmol). An off-white solid was obtained (17.35g, 81%). NMR (DMSO-d)₆)δ7.71(s，1H)，7.73(s，1H)，7.88(d，2H，J＝8.1Hz)，8.05(d，2H，J＝8.1Hz)ppm。

Example A.31

2-iodo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure Ia to d for the preparation of iodides using 2-chloro-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.30) (2.72g, 10 mmol). Pale yellow solid (3.42g, 94%) was obtained. MS (ISP)364.0[ (M + H) ⁺]；mp 87-91℃。

Alternatively, the title compound was prepared according to general procedure Ia to d for the preparation of iodides using a solution of 2-bromo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example A.48) (101.0g, 320mmol), sodium iodide (91.04g, 608mmol), copper (I) iodide (2.89g, 5m0 l%) and N, N' -dimethylethylenediamine (3.31mL, 11 mol%) in dioxane (304 mL). Pale yellow solid (112.5g, 100%) was obtained. MS (ISP)364.0[(M+H)⁺]；mp 91-93℃。

Example A.32

Trifluoro-methanesulfonic acid 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester

The title compound was prepared according to general procedure Ia to d for the preparation of the triflate salt using 6-methyl-4- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (example a.30 step 1) (20.0g, 79 mmol). An off-white solid was obtained (28.13g, 92%). MS (ISP)386.0[ (M + H)⁺]。

Example A.33

2-chloro-6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridine

Raw materials: (E) -1-cyclopropyl-3- (4-trifluoromethyl-phenyl) -propenone [ CAS No. 72881-74-4]

To a solution of commercial 4-trifluoromethylbenzaldehyde (20.6mL, 150mmol) and commercial cyclopropylmethyl ketone (14.1mL, 150mmol) in MeOH (30mL) was added NaOMe solution (5.4M in MeOH, 5.55mL, 30mmol) (slightly exothermic reaction) and the mixture was stirred at 23 ℃ for 16 h. Poured into ice, acidified with solid sodium chloride saturated 1N HCl (150mL), extracted with TBME and dried over magnesium sulfate. The solvent was removed in vacuo to give a yellow semisolid (35.47g, quant.) which was used without further purification. MS (EI)240.2[ (M) ⁺]。

1) 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one: following general procedure Ib, step 1, the above-described (E) -1-cyclopropyl-3- (4-trifluoromethyl-phenyl) -propenone [ CAS No. 72881-74-4](35.09g, 146mmol), 1-ethoxycarbonylmethyl-pyridinium bromide available commercially [ CAS No. 17282-40-5](43.14g, 175mmol) and ammonium acetate (56.3g, 730mmol) in EtOH (350 mL). A pale red solid was obtained (30.17g, 74%). MS (ISP)280.3[ (M + H)⁺]。

2) According to the general procedure Ia to d for the preparation of the chloride, 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (5.0g,18mmol) and phosphorus oxychloride (8.2mL, 90 mmol). An off-white solid was obtained (4.73g, 88%). MS (ISP)298.2[ (M + H)⁺]And 300[ (M +2+ H)⁺]。

Example A.34

Trifluoro-methanesulfonic acid 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester

The title compound was prepared according to general procedure Ia to d for the preparation of the triflate salt using 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (example a.33 step 1) (10.0g, 36 mmol). An orange oil (13.85g, 94%) was obtained. MS (ISP)412.2[ (M + H)⁺]。

Example A.35

4- (3-ethoxy-4-trifluoromethyl-phenyl) -2-iodo-6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure I using 2-chloro-4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.10) (0.74g, 2.0 mmol). A green solid (0.92g, 100%) was obtained. MS (ISP)461.0[ (M-H)^-]；mp 81.5℃。

Example A.36

4- (3, 4-dichloro-phenyl) -2-iodo-6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure I using 2-chloro-4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.7) (0.5g, 1.53 mmol). An off-white solid was obtained (0.24g, 38%). MS (EI)417.9[ (M)⁺]；mp 85℃。

Example A.37

4- (4-chloro-3-methyl-phenyl) -2-iodo-6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure I using 2-chloro-4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.8) (4.9g, mmol). A pale grey solid was obtained (0.99g, 51%). MS (EI)397.9[ (M)⁺]；mp 88.5℃。

Example A.38

2-chloro-4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

1)4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one: according to general procedure I, ethyl trifluoroacetate, 3-methyl-4-trifluoromethyl-acetophenone [ CAS No. 851262-60-7 ] obtained commercially was employed](7.26g, 24.3mmol) and urea. White solid (5.42g, 69%) was obtained. MS (EI)322.1[ (M) ⁺]；mp 182℃。

2) The title compound was prepared according to general procedure I using 4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one (4.31g, 13.4mmol) and phosphorus oxychloride (40 mL). Pale yellow solid (4.47g, 98%) was obtained. MS (EI)340.1[ (M)⁺]；mp 53℃。

Example A.39

2-chloro-4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidine

1)6- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl]-4-trifluoromethyl-1H-pyrimidin-2-one: according to general procedure I, ethyl trifluoroacetate, 3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-acetophenone [ CAS number 851264-00-1 ] obtained commercially was employed]And urea. An off-white solid was obtained (3.89g, 58%). MS (ISN)405.2[ (M-H)^-]；mp 228℃。

2) According to general procedure I, 6- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl]-4-trifluoromethyl-1H-pyrimidin-2-one (3.74g, 9.21mmol) and phosphorus oxychloride (30mL) to prepare the title compound. A brown solid was obtained (3.75g, 96%). MS (EI)424.0[ (M)⁺]；mp 44℃。

Example A.40

2-chloro-4- (3-methyl-4-trifluoromethyl-phenyl) -6-methyl-pyrimidine

1)4-(3-methyl-4-trifluoromethyl-phenyl) -6-methyl-1H-pyrimidin-2-one: according to general procedure I, ethyl acetate, 3-methyl-4-trifluoromethyl-acetophenone [ CAS No. 851262-60-7 ] obtained commercially was employed ](5g, 24.7mmol) and urea. Pale yellow solid (1.84g, 28%) was obtained. MS (EI)268.2[ (M)⁺]；mp 202℃(dec.)。

2) The title compound was prepared according to general procedure I using 4- (3-methyl-4-trifluoromethyl-phenyl) -6-methyl-1H-pyrimidin-2-one (1.73g, 6.45mmol) and phosphorus oxychloride (20 mL). A brown solid was obtained (1.4g, 76%). MS (EI)286.1[ (M)⁺]；mp 101℃。

Example A.41

2-chloro-4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine

1)4- (3, 4-dichloro-phenyl) -6-methyl-1H-pyrimidin-2-one: this compound was prepared according to general procedure I using ethyl acetate, 3, 4-dichloro-acetophenone (5g, 26.4mmol) and urea, obtained commercially. Pale yellow solid (2.64g, 40%) was obtained. MS (EI)254.1[ (M)⁺]；mp277℃(dec.)。

2) The title compound was prepared according to general procedure I using 4- (3, 4-dichloro-phenyl) -6-methyl-1H-pyrimidin-2-one (2.51g, 9.84mmol) and phosphorus oxychloride (35 mL). A brown solid (1.55g, 58%) was obtained. MS (EI)272.1[ (M)⁺]；mp 123℃(dec.)。

Example A.42

2-chloro-4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine

1) 6-trifluoromethyl-4- (3-trifluoromethyl-phenyl) -1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl trifluoroacetate, commercially available 3-trifluoromethyl-acetophenone and urea. A white solid was obtained (7.95g, 53%). MS (ISP)309.0[ (M + H) ⁺]；mp 167℃。

2) According to general procedure I, 6-trifluoromethyl-4- (3-trifluoromethyl-phenyl) -1H-pyrimidin-2-one (7.85g, 25.5 mmo) is usedl) and phosphorus oxychloride (85mL) were used to prepare the title compound. A yellow solid was obtained (5.33g, 64%). MS (EI)326.1[ (M)⁺]；mp 65℃。

Example A.43

2-chloro-4-isopropyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

1) 6-isopropyl-4- (3-trifluoromethyl-phenyl) -1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl isopropylacetate, commercially available 3-trifluoromethyl-acetophenone and urea. White solid (5.28g, 42%) was obtained. MS (ISP)283.4[ (M + H)⁺]；mp234℃(dec.)。

2) The title compound was prepared according to general procedure I using 6-isopropyl-4- (3-trifluoromethyl-phenyl) -1H-pyrimidin-2-one (5.13g, 18.2mmol) and phosphorus oxychloride (61 mL). A pale yellow oil was obtained (3.54g, 65%). MS (ISP)301.1[ (M + H)⁺]。

Example A.44

2-chloro-4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidine

1)4- (3-chloro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl trifluoroacetate, commercially available 3-chloro-acetophenone and urea. An off-white solid was obtained (4.94g, 56%). MS (ISP)275.0[ (M + H)⁺]；mp 195℃。

2) The title compound was prepared according to general procedure I using 4- (3-chloro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one (2.44g, 8.88mmol) and phosphorus oxychloride (25 mL). A white solid was obtained (1.62g, 62%). MS (EI)292.0[ (M) ⁺]；mp 89.5℃。

Example A.45

2-chloro-4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidine

1)4- (4-fluoro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one: according to general procedure I, using commercially available ethyl trifluoroacetate, commercially available 4-fluoro-benzeneEthanones and ureas. A white solid was obtained (15.5g, 82%). MS (ISP)259.1[ (M + H)⁺]；mp 213℃。

2) The title compound was prepared according to general procedure I, using 4- (4-fluoro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one (15.5g, 0.06mol) and phosphorus oxychloride (155 mL). Pale yellow solid (16.5g, 99%) was obtained. MS (EI)276.1[ (M)⁺]；mp 67℃。

Example A.46

2-chloro-4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidine

1)4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl trifluoroacetate, commercially available 3, 4-difluoro-acetophenone and urea. White solid (14.7g, 84%) was obtained. MS (ISP)277.0[ (M + H)⁺]；mp 171℃。

2) The title compound was prepared according to general procedure I using 4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one (14.7g, 0.053mol) and phosphorus oxychloride (148 mL). Light brown solid (15.6g, 99%) was obtained. MS (EI)294.0[ (M)⁺]；mp 53℃。

Example A.47

2-chloro-4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidine

1)4- (4-chloro-3-methyl-phenyl) -6-methyl-1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl acetate, commercially available 4-chloro-3-methyl-acetophenone (25g, 0.15mol) and urea. An off-white solid was obtained (9.78g, 28%). MS (ISN)233.3[ (M-H)^-]；mp255℃(dec.)。

2) The title compound was prepared according to general procedure I using 4- (4-chloro-3-methyl-phenyl) -6-methyl-1H-pyrimidin-2-one (9.78g, 41.7mmol) and phosphorus oxychloride (98 mL). An off-white solid was obtained (7.38g, 70%). MS (ISP)253.1[ (M + H)⁺]；mp 131℃。

Example A.48

2-bromo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to the general procedure Ia to d for the preparation of the bromide using 6-methyl-4- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (example A.30 step 1) (118.1g, 466.4mmol) and phosphorus oxybromide (267.4g, 933 mmol). An off-white solid was obtained (109.67g, 74%). MS (ISP)316.0[ (M + H)⁺]And 318.0[ (M +2+ H)⁺]；mp 74-76℃。

Example A.49

2-iodo-6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedures Ia to d for the preparation of iodides using 2-chloro-6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.26) (10.0g, 30.7 mmol). A white solid was obtained (6.6g, a mixture of 41% starting material and 59% product). MS (ISP)418.0[ (M + H) ⁺]。

Example A.50

4- (4-chloro-phenyl) -2-iodo-6-trifluoromethyl-pyridine

The title compound was prepared according to general procedure Ia to d for the preparation of iodides using 2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyridine (example a.25) (10.0g, 34.2 mmol). White solid (5.9g, 55% product, 45% starting material) and mother liquor (9g, 35% product) were obtained. MS (ISP)384.0[ (M + H)⁺]And 386[ (M +2+ H)⁺]。

Example A.51

2-chloro-4- (3, 4-dichloro-phenyl) -6-methyl-pyridine

1) (E) -4- (3, 4-dichloro-phenyl) -but-3-en-2-one [ CAS No. 55420-70-7]: to an ice-cold mixture of commercial 3, 4-dichlorobenzaldehyde (22.5g, 119mmol) and dimethyl 2-oxopropylphosphonate (25g, 143mmol) was added dropwise K₂CO₃A solution of (32.9g, 238mmol) in water (30.0mL) was continued at 5 ℃ for 15 min. Mixing the mixturePouring saturated NaHCO₃The solution was extracted 2 times with TBME and the organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to give crude (E) -4- (3, 4-dichloro-phenyl) -but-3-en-2-one (26.7g, 104%) as a pale yellow solid, which was used without further purification. MS (ISP)215.2[ (M + H)⁺]，217.1[(M+2+H)⁺]And 219[ (M +4+ H)⁺]。

2)4- (3, 4-dichloro-phenyl) -6-methyl-1H-pyridin-2-one: following general procedure Ib, step 1, the above-described (E) -4- (3, 4-dichloro-phenyl) -but-3-en-2-one (26.7g, 124mmol), 1-ethoxycarbonylmethyl-pyridinium bromide available commercially [ CAS number 17282-40-5 ]The compound was prepared (33.6g, 137mmol) and ammonium acetate (47.8g, 621mmol) in EtOH (150 mL). Light brown solid (25.4g, 81%) was obtained. MS (ISP)254.1[ (M + H)⁺]，256.2[(M+2+H)⁺]And 258.0[ (M +4+ H)⁺]。

3) The title compound was prepared according to general procedure Ia to d for the preparation of the chloride using 4- (3, 4-dichloro-phenyl) -6-methyl-1H-pyridin-2-one (25.4g, 100mmol) and phosphorus oxychloride (45.6mL, 500mmol) as described above. An off-white solid was obtained (23.7g, 87%). MS (ISP)272.1[ (M + H)⁺]，274.0[(M+2+H)⁺]，276.0[(M+4+H)⁺]And 278.0[ (M +6+ H)⁺]。

Example A.52

4- (3, 4-dichloro-phenyl) -2-iodo-6-methyl-pyridine

The title compound was prepared according to general procedure Ia to d for the preparation of iodides using 2-chloro-4- (3, 4-dichloro-phenyl) -6-methyl-pyridine (example a.51) (20.0g, 73.4 mmol). A white solid (17.2g, 80% product, 20% starting material) and a second crop of product (6.0g, 60% product) were obtained. MS (ISP)364.0[ (M + H)⁺]，366[(M+2+H)⁺]And 368[ (M +4+ H)⁺]。

Example A.53

2-chloro-6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridine

1) (E) -1- (4-trifluoromethyl-phenyl) -pent-1-en-3-one [ CAS number 863970-08-5]: to 4- (trifluoromethyl) benzaldehyde (2.74mL, 20mmol) and 2-butanone (8.97mL, 100mmol) in EtOH (20mL) and H₂O (0.8mL) mixture Ba (OH) was added₂·H₂O (100mg, 2.6 mol%) and the mixture was refluxed for 1 h. Pouring into ice water, acidifying with 1N HCl to pH 1, extracting with TBME, and extracting the organic layer with saturated NaHCO ₃The solution was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo to give crude (E) -1- (4-trifluoromethyl-phenyl) -pent-1-en-3-one as a yellow semisolid (4.65g, 102%) which was used without further purification.

2) 6-ethyl-4- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one: following general procedure Ib, step 1, the above-described (E) -1- (4-trifluoromethyl-phenyl) -pent-1-en-3-one (4.65g, 20.4mmol), 1-ethoxycarbonylmethyl-pyridinium bromide obtained commercially [ CAS number 17282-40-5]This compound was prepared (5.52g, 22.4mmol) and ammonium acetate (7.85g, 102mmol) in EtOH (25 mL). A white solid was obtained (1.15g, 21%, additional 3.6g, 66% light brown residue). MS (ISP)268.3[ (M + H)⁺]。

3) The title compound was prepared according to general procedure Ia to d for the preparation of the chloride using 6-ethyl-4- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (4.6g, 17.2mmol) and phosphorus oxychloride (7.85mL, 86.1mmol) as described above. Pale yellow solid (2.2g, 44%) was obtained. MS (ISP)286.1[ (M + H)⁺]And 288.0[ (M +2+ H)⁺]。

Example A.54

2-Ethyl-6-iodo-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedures Ia to d for the preparation of iodides using 2-chloro-6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.53) (2.2g, 7.7 mmol). A light brown solid was obtained (2.1g, 62% product, 38% starting material). MS (ISP)378.0[ (M + H) ⁺]。

Example A.55

Trifluoro-methanesulfonic acid 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester

The title compound was prepared according to general procedure Ia to d for the preparation of the triflate salt using 4-methyl-6- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (example A.23 step 1) (6.33g, 25mmol) and trifluoromethanesulfonic anhydride (5.0mL, 30 mmol). An off-white solid was obtained (1.61g, 17%). MS (ISP)386.0[ (M + H)⁺]。

Example A.56

Trifluoro-methanesulfonic acid 4-benzo [1, 3] dioxol-5-yl-6-methyl-pyridin-2-yl ester

1) 4-benzo [1, 3]]dioxol-5-yl-6-methyl-1H-pyridin-2-one: according to general procedure Ib, step 1, using 3, 4- (methylenedioxy) benzylideneacetone (25g, 131.4mmol) obtained commercially, 1-ethoxycarbonylmethyl-pyridinium bromide [ CAS No. 17282-40-5 ] obtained commercially]This compound was prepared (35.58g, 144.6mmol) and ammonium acetate (50.7g, 657mmol) in EtOH (150 mL). A brown solid (1.2g, 4%) was obtained. MS (ISP)230.1[ (M + H)⁺]。

2) According to the general procedures Ia to d for the preparation of the triflates, the above-mentioned 4-benzo [1, 3] are used]dioxol-5-yl-6-methyl-1H-pyridin-2-one (1.2g, 5.23mmol) and trifluoromethanesulfonic anhydride (1.04mL, 6.28mmol) the title compound was prepared. Light brown solid (1.13g, 60%) was obtained. MS (ISP)362.1[ (M + H) ⁺]。

Example A.57

2-bromo-4-methyl-6- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure Ia to d for the preparation of the bromide using 4-methyl-6- (4-trifluoromethyl-phenyl) -1H-pyridin-2-one (example A.23 step 1) (25.32g, 100mmol) and phosphoryl bromide (86.0g, 300 mmol). Pale yellow solid (29.27g, 93%) was obtained. MS (ISP)316.0[ (M + H)⁺]And 318.0[ (M +2+ H)⁺]。

Example A.58

2-iodo-4-methyl-6- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedures Ia to d for the preparation of iodides using a solution of 2-bromo-4-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example A.57) (29.0g, 92mmol), sodium iodide (27.5g, 183mmol), copper (I) iodide (0.874g, 5 mol%) and N, N' -dimethylethylenediamine (1.3mL, 10 mol%) in dioxane (150 mL). Pale yellow solid (32.72g, 98%) was obtained. MS (ISP)364.2[ (M + H)⁺]。

Example A.59

Trifluoro-methanesulfonic acid 4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl-pyridin-2-yl ester

1) 5-methoxy-2-nitro-4-trifluoromethyl-phenylamine [ CAS No. 473537-32-5]: commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (30.0g, 125mmol) was dissolved in DMSO (250mL) and MeOH (125mL), followed by the addition of potassium hydroxide (85%, 18.1g, 274mmol) and the resulting dark red solution was stirred at 23 ℃ for 7 days. The mixture was poured into 1N HCl (350mL) and water (1500mL), the suspension was stirred for 1h, then the precipitate was filtered, washed with cold water, and the crystals were dried in air at 60 ℃ overnight to give 5-methoxy-2-nitro-4-trifluoromethyl-phenylamine (28.98g, 98%) as a yellow solid. MS (ISN)235.1[ (M-H) ^-]；mp 56℃。

2) 1-bromo-5-methoxy-2-nitro-4-trifluoromethyl-benzene: 5-methoxy-2-nitro-4-trifluoromethyl-phenylamine (28.9g, 122mmol) prepared above was added portionwise to rapidly stirred tert-butyl nitrite (24.4mL, 206mmol) and CuBr at 65 deg.C₂(41.0g, 184mmol) in MeCN (200 mL). After the addition was complete, stirring was continued for 1h at 65 ℃. The reaction mixture was cooled to room temperature and poured into 1N HCl (300mL), extracted twice with TBME, the organic layer washed with brine, dried over magnesium sulfate, filtered and evaporated to give a brown oil which crystallized to give 1-bromo-5-methoxy-2-nitro-4-trifluoromethyl-benzene (36.34g, 99%) as a light brown solid which was used without further purification.

3) 5-methoxy-2-nitro-4-trifluoromethyl-benzonitrile: a mixture of 1-bromo-5-methoxy-2-nitro-4-trifluoromethyl-benzene (17.1g, 57mmol) prepared above and CuCN (5.36g, 60mmol) in NMP (60mL) was heated to 150 ℃ and stirred under argon for 30 min. The mixture was cooled to room temperature and poured into 1N HCl, extracted with TBME, washed with brine, dried over magnesium sulfate, filtered and evaporated to give crude 5-methoxy-2-nitro-4-trifluoromethyl-benzonitrile (14.76g, 105%) as a brown solid which was used directly in the next step. MS (ISP)264.1[ (M + NH) ₄ ⁺)⁺]。

4) 2-amino-5-methoxy-4-trifluoromethyl-benzonitrile: iron powder (14.7g, 263mol) was added in small portions to a stirred suspension of finely divided 5-methoxy-2-nitro-4-trifluoromethyl-benzonitrile (14.53g, 59mmol) prepared above in MeOH (75mL) and HCl 37% (100 mL). The internal temperature was maintained between 40 and 60 ℃ by means of a water bath. The resulting brown solution was stirred at 50 ℃ for 1 h. The mixture was poured into ice-cold water (200 mL). The precipitated solid was filtered, washed with water, dissolved in boiling EtOH (140mL), activated carbon (3 spoons) was added and the mixture was refluxed for 30 min. The hot solution was filtered and EtOH evaporated to give 2-amino-5-methoxy-4-trifluoromethyl-benzonitrile (7.35g, 58%) as a brown solid, which was used without further purification. MS (ISP)217.2[ (M + H)⁺)⁺]。

5) 3-methoxy-4-trifluoromethyl-benzonitrile [ CAS No. 447-93-8 ]]: 2-amino-5-methoxy-4-trifluoromethyl-benzonitrile (7.08g, 33mmol) prepared above was dissolved in DMF (75mL) heated to 95 deg.C, and isoamyl nitrite (6.75mL, 49mmol) was then slowly added dropwise using a syringe while the reaction temperature was raised to 106 deg.C (exothermic reaction). The reaction mixture was stirred at 95 ℃ for a further 15min, then cooled to room temperature, extracted with water and TBME, the organic layer dried over magnesium sulphate, filtered and the solvent evaporated. Purification by vacuum distillation at 1.6mbar and 120 ℃ gave a pale yellow liquid which still contained isoamyl alcohol and DMF which was then purified by flash chromatography eluting with n-heptane and ethyl acetate to give 3-methyl Oxy-4-trifluoromethyl-benzonitrile (4.0g, 61%) was a colorless liquid. MS (EI)201.1[ M ]⁺]。

6) 3-methoxy-4-trifluoromethyl-benzaldehyde: DIBAH (20% in toluene, ca. 1.2M, 17.7 mL; 22mmol) was added dropwise to a solution of 3-methoxy-4-trifluoromethyl-benzonitrile (3.95g, 20mmol) prepared above in toluene (60mL) at-10 deg.C, maintaining the temperature below-5 deg.C. Stirring is continued for 1h at-5 ℃ to 0 ℃. Poured into 2M HCl, diluted with EtOAc, shaken vigorously for 3min, brine added, shaken again, the phases separated, the organic layer dried over sodium sulfate, filtered and evaporated completely to give 3-methoxy-4-trifluoromethyl-benzaldehyde (3.76g, 91%) as a pale yellow liquid which can be used without further purification. MS (EI)204.2[ M ]⁺]。

5) (E) -4- (3-methoxy-4-trifluoromethyl-phenyl) -but-3-en-2-one: a mixture of 3-methoxy-4-trifluoromethyl-benzaldehyde (3.76g, 18mmol) prepared as described above and dimethyl 2-oxopropylphosphonate (3.2mL, 22mmol) obtained commercially was cooled to 0 deg.C and K was added₂CO₃(5.09g, 37mmol) of water (20mL) and the mixture was stirred at 0 ℃ for 2 h. Pouring saturated NaHCO₃-sol, extracted 2 times with EtOAc, washed with brine, dried over sodium sulfate, filtered and evaporated completely to give (E) -4- (3-methoxy-4-trifluoromethyl-phenyl) -but-3-en-2-one (4.06g, 90%) as a pale yellow solid, which can be used without further purification. MS (EI)244.2[ M ] ⁺]。

6)4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl-1H-pyridin-2-one: according to general procedure Ib, step 1, the above-prepared (E) -4- (3-methoxy-4-trifluoromethyl-phenyl) -but-3-en-2-one (4.03g, 16.5mmol), 1-ethoxycarbonylmethyl-pyridinium bromide obtained commercially [ CAS No. 17282-40-5 [ ]]This compound was prepared (4.47g, 18.1mmol) and ammonium acetate (6.36g, 82.5mmol) in EtOH (20 mL). A yellow solid was obtained (3.6g, 77%). MS (ISP)284.1[ (M + H)⁺]。

7) According to the general procedures Ia to d for the preparation of the triflates, the above-mentioned 4- (3-methoxy-4-trifluoromethyl-phenyl group is used) -6-methyl-1H-pyridin-2-one (2.66g, 9.0mmol) and trifluoromethanesulfonic anhydride (1.9mL, 10.8mmol) the title compound was prepared. A white solid was obtained (3.25g, 83%). MS (ISN)474.1[ (M + OAc)^-)^-]。

Example A.60

2-chloro-4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

1)4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl trifluoroacetate, commercially available 2-fluoro-4-trifluoromethyl-acetophenone and urea. A white solid was obtained (9.95g, 90%). MS (ISP)327.1[ (M + H)⁺]；mp 132.5℃。

2) The title compound was prepared according to general procedure I, using 4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one (9.84g, 0.03mol) and phosphorus oxychloride (50 ml). Pale yellow solid (9.99g, 96%) was obtained. MS (ISN)341.2[ (M-H) ^-]；mp 47℃。

Example A.61

2-chloro-4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine

1)4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one: this compound was prepared according to general procedure I using commercially available ethyl trifluoroacetate, commercially available 2, 4-dichloro-acetophenone and urea. A white solid was obtained (10.3g, 90%). MS (ISP)309.1[ (M + H)⁺]；mp 164℃。

2) The title compound was prepared according to general procedure I, using 4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-1H-pyrimidin-2-one (10.2g, 0.033mol) and phosphorus oxychloride (50 ml). Pale yellow solid (10.6g, 98%) was obtained. MS (ISP)327.0[ (M + H)⁺]；mp 69.5℃。

Example A.62

Trifluoro-methanesulfonic acid 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ester

The title compound was prepared according to the general procedure Ia to d for the preparation of the triflate salt using a solution of 6-methyl-4- (4-trifluoromethyl-phenyl) -1H-pyrimidin-2-one (example A.12, step 1) (3.0g, 12mmol), triflic anhydride (2.4ml, 14mmol) and diisopropylethylamine (4.1ml, 24mmol) in DCM (24 ml). A brown solid was obtained (4.42g, 97%). MS (ISP)387.1[ (M + H)⁺]；mp 74.5℃。

Example A.63

Trifluoro-methanesulfonic acid 6-methyl-4- (4-trifluoromethoxy-phenyl) -pyridin-2-yl ester

1) (E) -4- (4-trifluoromethoxy-phenyl) -but-3-en-2-one: 4-trifluoromethoxy-benzaldehyde [ CAS No. 659-28-9 ] obtained commercially ]A mixture of (20g, 95mmol, 95% purity) and dimethyl 2-oxopropylphosphonate (16.5mL, 114mmol) obtained commercially was cooled to 0 deg.C and K was added₂CO₃(26.17g, 189mmol) of water (100mL) and the mixture was stirred at 0 ℃ for 2 h. Pouring saturated NaHCO₃The solution was extracted 2 times with EtOAc, washed with brine, dried over sodium sulfate, filtered and evaporated completely to give (E) -4- (4-trifluoromethoxy-phenyl) -but-3-en-2-one (19.35g, 69%, 77% purity) as a pale yellow liquid which was used without further purification. MS (ISP)231.1[ (M + H)⁺]。

2) 6-methyl-4- (4-trifluoromethoxy-phenyl) -1H-pyridin-2-one: following general procedure Ib, step 1, using (E) -4- (4-trifluoromethoxy-phenyl) -but-3-en-2-one (19.0g, 64mmol, 77% purity) obtained above, 1-ethoxycarbonylmethyl-pyridinium bromide from commercial origin [ CAS number 17282-40-5]This compound was prepared (17.3g, 70mmol) and ammonium acetate (24.6g, 319mmol) in EtOH (80 mL). Pale yellow solid (13.56g, 79%) was obtained. MS (ISP)270.3[ (M + H)⁺]。

3) The title compound was prepared according to general procedures Ia to d for the preparation of the triflate salt using 6-methyl-4- (4-trifluoromethoxy-phenyl) -1H-pyridin-2-one (3.23g, 12mmol) as described above, diisopropylethylamine (4.1mL, 24mmol) and trifluoromethanesulfonic anhydride (2.4mL, 14mmol) A compound is provided. A light brown oil was obtained (4.47g, 93%). MS (ISP)402.2[ (M + H)⁺]。

Example A.64

Trifluoro-methanesulfonic acid 6-methyl-4- (3-methyl-4-trifluoromethyl-phenyl) -pyridin-2-yl ester

1) 3-methyl-4-trifluoromethyl-benzaldehyde: to a solution of 3-methyl-4-trifluoromethyl-benzonitrile [ CAS No. 871571-28-7] (9.2g, 49.7mmol) in toluene (130ml) at-10 ℃ was added dropwise diisobutylaluminum hydride (20% in toluene, about 1.2M, 44.8ml, 54.2mmol) maintaining the internal temperature below-5 ℃ and stirring was continued at-5 ℃ to 0 ℃ for 1 h. Poured into 2M HCl, diluted with ethyl acetate, shaken vigorously for 3min, brine added, shaken again, the layers separated, the organic layer dried over sodium sulfate, filtered and evaporated completely. The crude product was filtered through a small silica gel column eluting with ethyl acetate to give 3-methyl-4-trifluoromethyl-benzaldehyde (9.1g, 97%) as a pale yellow liquid.

2) (E) -4- (3-methyl-4-trifluoromethyl-phenyl) -but-3-en-2-one: a mixture of the above 3-methyl-4-trifluoromethyl-benzaldehyde (9.1g, 48.3mmol) and dimethyl 2-oxopropylphosphonate (8.46mL, 58.0mmol) obtained commercially was cooled to 0 deg.C and K was added₂CO₃(13.37g, 96.7mmol) of water (16mL) and the mixture was stirred at 0 ℃ for 2 h. Pouring saturated NaHCO ₃The solution was extracted with EtOAc, washed with brine and dried over sodium sulfate, filtered and evaporated completely to give (E) -4- (3-methyl-4-trifluoromethyl-phenyl) -but-3-en-2-one (12.7g, 115%, about 80% purity) as a pale yellow liquid which was used without further purification. MS (ISP)229.2[ (M + H)⁺]。

3) 6-methyl-4- (3-methyl-4-trifluoromethyl-phenyl) -1H-pyridin-2-one: following general procedure Ib, step 1, using (E) -4- (3-methyl-4-trifluoromethyl-phenyl) -but-3-en-2-one (12.7g, 55.7mmol, about 80% purity) obtained commercially as 1-ethoxycarbonylmethyl-pyridinium bromide [ CAS No. 17282-40-5]This compound was prepared (15.07g, 61.2mmol) and ammonium acetate (21.45g, 278mmol) in EtOH (60 mL).An off-white solid was obtained (10.35g, 70%). MS (ISP)268.2[ (M + H)⁺]。

4) The title compound was prepared according to general procedures Ia to d for the preparation of the triflate salt using 6-methyl-4- (3-methyl-4-trifluoromethyl-phenyl) -1H-pyridin-2-one (3.5g, 13.1mmol) as described above, pyridine (50mL) and trifluoromethanesulfonic anhydride (2.59mL, 15.7 mmol). Pale yellow oil (5.1g, 98%) was obtained. MS (ISP)400.0[ (M + H)⁺]。

Example A.65

2-bromo-6- (tetrahydro-pyran-2-yloxymethyl) -4- (4-trifluoromethyl-phenyl) -pyridine

1) 2-bromo-6-bromomethyl-4- (4-trifluoromethyl-phenyl) -pyridine: CCl of 2-bromo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example A.48) (34g, 64.5mmol, 60% purity), N-bromosuccinimide (11.5g, 64.5mmol) and dibenzoyl peroxide (1.04g, 5 mol%) (product of reaction was obtained₄(200ml) the mixture was irradiated with 500W agrolamp and refluxed for 8 h. Cooling to room temperature, filtering the succinimide with CH₂Cl₂Washing and complete evaporation gave a brown oil (43g, NMR showed a mixture of starting material, product and dibromo starting material) which could be used directly in the next step (HPLC purity about 24%).

2) Acetic acid 6-bromo-4- (4-trifluoromethyl-phenyl) -pyridin-2-ylmethyl ester: a mixture of crude 2-bromo-6-bromomethyl-4- (4-trifluoromethyl-phenyl) -pyridine (43g, 24% pure, 26.1mmol) and sodium acetate (4.29g, 52.3mmol) in acetic acid (100ml) was refluxed for 3 h. Cooled to room temperature, extracted with water and AcOEt and the organic layer with saturated NaHCO₃Washing, drying over sodium sulfate, filtration and complete evaporation gave the crude product, which was purified by silica gel column chromatography using n-heptane/AcOEt to give acetic acid 6-bromo-4- (4-trifluoromethyl-phenyl) -pyridin-2-ylmethyl ester (6.05g, 49%, purity 80%) as a light brown solid. MS (ISP)374.1[ (M + H) ⁺]。

3) [ 6-bromo-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-methanol: to the above acetic acid 6-bromo-4- (4-trifluoromethyl-phenyl) at 23 deg.C-pyridin-2-ylmethyl ester (5.0g, 13.4mmol, 80% purity) in methanol (10ml) was added a catalytic amount of sodium methoxide solution (0.4ml, 2.16mmol) (pH about 9) and the mixture was stirred at 23 ℃ for 30 min. Poured into acetic acid, extracted 2 times with AcOEt and saturated NaHCO₃The solution was washed, dried over sodium sulfate, filtered and evaporated completely to give the crude product which was purified by silica gel column chromatography eluting with n-heptane/AcOEt to give [ 6-bromo-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]Methanol (4.2g, 95%, purity 81%) as a white solid. MS (ISP)334.1[ (M + H)⁺]。

4) To the above [ 6-bromo-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl at 23 ℃ was added]Methanol (4.2g, 95%, 81% purity) and 3, 4-dihydro-2H-pyran (1.4ml, 15.4mmol) in DCM (20ml) with the addition of a catalytic amount of p-TsOH. H₂O (10mg), and the mixture was stirred at 23 ℃ for 18 h. Then 3, 4-dihydro-2H-pyran (0.7ml, 7.68mmol) was added again and stirring was continued at 23 ℃ for 2H. The entire reaction mixture was directly purified by silica gel column chromatography eluting with n-heptane/AcOEt to give the title compound (4.59g, 100%, 93% purity) as a pale yellow oil. MS (ISP)418.2[ (M + H) ⁺]。

Synthesis of nitriles

General procedure II

Scheme a: a stirred mixture of compound V, VI, XXIV or XXV (1eq), potassium cyanide (2eq) and bis-triphenylphosphine-palladium chloride (0.02eq.) in an organic solvent such as DMF was heated at reflux for about 1h, cooled, poured into water and extracted 2 times with ethyl acetate. The combined organic layers are washed with brine and dried (e.g., MgSO)₄) And evaporated. The crude product is further purified by flash chromatography on silica gel (e.g., ethyl acetate/heptane) and crystallized (e.g., diethyl ether/hexane) to provide the compound of formula VII.

Scheme b: the stirred mixture of compound of formula VI or XXIV (1eq.) and copper (I) cyanide (1.03-1.1eq.) is heated in a mixture of organic solvents (e.g. DMF, DMA or NMP) under argon atmosphere at 130 ℃ and 150 ℃ for 2-16h, cooled, diluted with water, filtered, the solid is dissolved in ethyl acetate, extracted with ethyl acetate and water/ammonia (1: 1), the organic layer is washed with saturated NaCl solution, dried over magnesium sulphate, filtered and the solvent is evaporated. The crude product is purified by flash chromatography on silica gel (e.g., heptane: ethyl acetate) to provide the compound of formula VII.

Example B.1

4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carbonitrile

The title compound was prepared according to general procedure II, scheme a, using 2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.1) (1.8g, 6.14 mmol). Light brown solid was obtained (1.16g, 67%). MS (EI)283.1[ (M) ⁺]；mp 123.5℃。

Example B.2

4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carbonitrile

The title compound was prepared according to general procedure II, scheme a, using 2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.2) (3.0g, 9.18 mmol). A pale orange solid was obtained (1.96g, 67%). MS (EI)317.1[ (M)⁺]；mp 70℃。

Example B.3

4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carbonitrile

The title compound was prepared according to general procedure II, scheme a, using 2-chloro-4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.5) (1.0g, 3.24 mmol). A pale red liquid (0.58g, 60%) was obtained. MS (ISP)298.1[ (M-H)^-]。

Example B.4

4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carbonitrile

The title compound was prepared according to general procedure II, scheme a, using 2-chloro-4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.10) (1.0g, 2.70 mmol). An orange solid (0.7g, 72%) was obtained. MS (ISN)361.2[ (M-H)^-]；mp 110.5℃。

Example B.5

6- (4-chloro-phenyl) -4-trifluoromethyl-pyridine-2-carbonitrile

The title compound was prepared according to general procedure II, scheme b, using 2-bromo-6- (4-chloro-phenyl) -4-trifluoromethyl-pyridine (example a.18) (6.0g, 18 mmol). A brown solid was obtained (3.67g, 74%). MS (EI)281.9[ (M) ⁺]And 284.0[ (M +2)⁺]；mp 71-74℃。

Example B.6

4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine-2-carbonitrile

The title compound was prepared according to general procedure II, scheme b, using 2-bromo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example a.19) (3.7g, 10 mmol). A green solid was obtained (2.46g, 78%). MS (EI)316.1[ (M)⁺]；mp 97-100℃。

Example B.7

4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carbonitrile

The title compound was prepared according to general procedure II using 2-chloro-4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.7) (2.0g, 6.11 mmol). An orange solid was obtained (1.69g, 87%). MS (ISP)319.1[ (M + H)⁺]；mp 153.5℃。

Example B.8

4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carbonitrile

The title compound was prepared according to general procedure II using 2-chloro-4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.8) (1.5g, 4.88 mmol).Pale yellow solid (0.92g, 63%) was obtained. MS (ISN)296.2[ (M-H)^-]；mp 159.5℃。

Example B.9

4- (4-chloro-phenyl) -6-methyl-pyrimidine-2-carbonitrile

The title compound was prepared according to general procedure II using 2-chloro-4- (4-chloro-phenyl) -6-methyl-pyrimidine (example a.11) (1.0g, 4.18 mmol). An orange solid was obtained (0.68g, 71%). MS (ISN)228.1[ (M-H) ^-]；mp 145℃。

Example B.10

6-methyl-4- (4-trifluoromethyl-phenyl) -pyrimidine-2-carbonitrile

The title compound was prepared according to general procedure II using 2-chloro-4-methyl-6- (4-trifluoro-phenyl) -pyrimidine (example a.12) (1.0g, 3.67 mmol). A brown solid (0.66g, 68%) was obtained. MS (ISN)262.1[ (M-H)^-]；mp 102℃。

Example B.11

4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carbonitrile

The title compound was prepared according to general procedure II using 2-chloro-4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.38) (0.2g, 0.59 mmol). Pale yellow solid (0.17g, 88%) was obtained. MS (EI)331.1[ (M)⁺]；mp 82.5℃。

Example B.12

6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine-2-carbonitrile

The title compound was prepared according to general procedure II, scheme b, using 2-iodo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.31) (2.32g, 6.4 mmol). White solid (1.28g, 76%) was obtained. MS (ISP)263.0[ (M + H)⁺]。

Example B.13

N-tert-butyl-3- (6-cyano-pyridin-2-yl) -benzenesulfonamide

The title compound was prepared according to general procedure II, scheme b, using 3- (6-bromo-pyridin-2-yl) -N-tert-butyl-benzenesulfonamide (example F.6 step 1) (3.12g, 8 mmol). A light brown oil was obtained (1.05g, 39%). MS (ISP)316.1[ (M + H) ⁺]。

Synthesis of N-hydroxy-amidines

Example C.1

4- (4-chloro-phenyl) -N-hydroxy-6-trifluoromethyl-pyrimidine-2-carboxamidine

A stirred mixture of 4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carbonitrile (example B.1) (0.5g, 1.76mmol), hydroxylamine hydrochloride (0.45g, 6.48mol) and sodium carbonate (0.37g, 3.53m0l) in water (10mL) and ethanol (10mL) was heated at reflux for 2 h. The ethanol was partially removed and the mixture was stirred at room temperature for 1 h. The precipitate was collected by filtration, washed with water and dried to give the title compound (0.53g, 94%) as a light brown solid. MS (ISP)316.9[ (M + H)⁺]；mp 243℃。

Example C.2

N-hydroxy-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxamidine

A stirred mixture of 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carbonitrile (example B.2) (1.0g, 3.15mmol), hydroxylamine hydrochloride (0.81g, 11.7mol) and sodium carbonate (0.67g, 6.32mol) in water (15mL) and ethanol (15mL) was heated at reflux for 2 h. The ethanol was partially removed and the mixture was stirred at room temperature for 0.5 h. The precipitate was collected by filtration, washed with water and dried to give the title compound (1.08g, 98%) as a light brown solid. MS (ISP)351.1[ (M + H)⁺]；mp 224℃。

Example C.3

6-amino-N-hydroxy-nicotinamidine (nicotinamididine)

Stirring of commercially available 2-amino-5-cyano-pyridine [ CAS No. 4214-73-7]A mixture of (5.0g, 42mmol), hydroxylamine hydrochloride (17.5g, 0.25mol) and sodium carbonate (31.1g, 0.29mol) in water (95mL) and ethanol (21mL) was heated at reflux for 6 h. The reaction mixture was poured into water (150mL) and extracted with ethyl acetate (4X 100 mL). The combined organic layers were washed with brine (150mL) and dried (MgSO)₄) And evaporated. The crude product was purified by silica gel column chromatography (ethyl acetate/MeOH/NH)₄OH 4: 1: 0.5) and crystallization (ethyl acetate/MeOH/hexane) afforded 6-amino-nicotinamide (1.39g) and the title compound (1.42g, 22%) as an off-white solid MS (EI)152.1[ (M)⁺]；mp 300℃。

Example C.4

2-amino-N-hydroxy-pyrimidine-5-carboxamidines

Stirring of commercially available 2-amino-5-cyano-pyrimidines [ CAS No. 1753-48-6)]A mixture of (1.39g, 11.6mmol), hydroxylamine hydrochloride (1.61g, 23.2mol) and potassium carbonate (4.8g, 34.7mol) in ethanol (57mL) was heated at reflux for 3 h. The reaction mixture was evaporated and purified by silica gel column chromatography (dichloromethane/MeOH 9: 1) to give the title compound (1.28g, 72%) as an off-white solid. MS (EI)153.1[ (M)⁺]；mp 218℃。

Example C.5

2-amino-N-hydroxy-pyridine-4-carboxamidine

Stirring of commercially available 2-amino-4-cyano-pyridine [ CAS No. 42182-27-4 ]A mixture of (1.0g, 8.39mmol), hydroxylamine hydrochloride (1.17g, 16.8mmol) and sodium carbonate (0.89g, 8.39mol) in water (8mL) and ethanol (16mL) was heated at reflux for 3 h. The reaction mixture was evaporated, water (10mL) was added and the mixture was stirred at room temperature for 1 h. The precipitate was collected by filtration to give the title compound (0.87g, 68%) as an off-white solid. MS (EI)152.0[ (M)⁺]；mp 188℃。

Example C.6

6- (4-chloro-phenyl) -N-hydroxy-4-trifluoromethyl-pyridine-2-carboxamidine

A mixture of 6- (4-chloro-phenyl) -4-trifluoromethyl-pyridine-2-carbonitrile (example B.5) (3.6g, 13mmol), hydroxylamine hydrochloride (3.275g, 47mmol) and sodium carbonate (2.7g, 47mmol) in EtOH (60ml) and water (60ml) was stirred under argon at 100 ℃ for 4 h. EtOH was evaporated and the mixture was diluted with water and stirred at 0 ℃ for 1 h. The crude product was filtered and dried in HV to give the pure title compound as a pale yellow solid (3.54g, 88%). MS (ISP)316.1[ (M + H)⁺]And 318[ (M +2+ H)⁺]；mp 180-186℃。

Example C.7

6- (3-tert-Butylsulfamoyl-phenyl) -N-hydroxy-pyridine-2-carboxamidine

A mixture of N-tert-butyl-3- (6-cyano-pyridin-2-yl) -benzenesulfonamide (example B.13) (1.03g, 3.27mmol), hydroxylamine hydrochloride (794mg, 11.4mmol) and sodium carbonate (692mg, 6.53mmol) in EtOH (20ml) and water (20ml) was stirred under argon at 100 ℃ for 2 h. EtOH was evaporated and the mixture was diluted with water and stirred at 0 ℃ for 1 h. The crude product was filtered and dried in HV to give the pure title compound as a white solid (850mg, 75%). MS (ISP)349.3[ (M + H) ⁺]。

Synthesis of carboxylic acids

General procedure III

A stirred solution of compound VII (1eq) in a 1: 1 mixture of 37% hydrochloric acid and an organic solvent (e.g. dioxane) or in 50% aqueous sulfuric acid is heated at reflux for about 2-18h, cooled, poured into water and extracted 3 times with diethyl ether. The combined organic layers are washed with brine and dried (e.g., MgSO)₄) And evaporated. The crude product is crystallized intoOne-step purification (e.g., diethyl ether/hexanes) affords the compound of formula IX.

Example D.1

4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid

The title compound was prepared according to general procedure I using 6- (4-chloro-phenyl) -4-trifluoromethyl-pyrimidine-2-carbonitrile (example b.1) (0.35g, 1.23 mmol). Pale yellow solid (0.31g, 83%) was obtained. MS (EI)302.0[ (M)⁺]；mp 133℃。

Example D.2

4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxylic acid

The title compound was prepared according to general procedure I using 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carbonitrile (example b.2) (0.83g, 2.62 mmol). Pale yellow solid (0.70g, 80%) was obtained. MS (ISN)335.3[ (M-H)^-]；mp 154.5℃。

Example D.3

4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxylic acid

The title compound was prepared according to general procedure I using 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carbonitrile (example b.3) (0.20g, 0.67 mmol). An off-white solid was obtained (0.14g, 66%). MS (ISN)317.1[ (M-H) ^-]；mp 163.5℃。

Example D.4

4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid

The title compound was prepared according to general procedure I using 4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carbonitrile (example b.4) (0.66g, 1.83 mmol). Pale yellow solid (0.55g, 79%) was obtained. MS (ISN)379.3[ (M)⁺]；mp 120℃。

Example D.5

6- (4-chloro-phenyl) -4-trifluoromethyl-pyridine-2-carboxylic acid

The title compound was prepared according to general procedure I using 6- (4-chloro-phenyl) -4-trifluoromethyl-pyridine-2-carbonitrile (example b.5) (0.53g, 1.88 mmol). A white solid was obtained (0.484g, 87%). MS (ISN)300.1[ (M-H)^-]And 302.0[ (M +2-H)^-]；mp＞250℃。

Example D.6

4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid

The title compound was prepared according to general procedure I using 6- (3, 4-dichloro-phenyl) -4-trifluoromethyl-pyrimidine-2-carbonitrile (example B.7) (1.61g, 5.06 mmol). A yellow solid was obtained (1.25g, 73%). MS (ISN)335.3[ (M-H)^-]；mp 126℃。

Example D.7

4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid

The title compound was prepared according to general procedure I using 6- (4-chloro-3-methyl-phenyl) -4-trifluoromethyl-pyrimidine-2-carbonitrile (example B.8) (0.89g, 2.99 mmol). Pale yellow solid (0.85g, 90%) was obtained. MS (ISN)315.3[ (M-H) ^-]；mp 127℃。

Example D.8

4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxylic acid

The title compound was prepared according to general procedure I using 6-methyl-4- (4-trifluoromethyl-phenyl) -pyrimidine-2-carbonitrile (example b.10) (0.56g, 2.13 mmol). Pale yellow oil (0.29g, 48%) was obtained. MS (ISN)281.1[ (M-H)^-]。

Example D.9

4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid

According to general procedure I, 4- (3-methyl-4-trifluoromethyl-benzene is usedYl) -6-trifluoromethyl-pyrimidine-2-carbonitrile (example B.11) (0.164g, 0.5mmol) the title compound was prepared. A white solid was obtained (0.13g, 73%). MS (ISN)351.1[ (M + H)⁺]；mp 130℃。

Example D.10

4- (4-chloro-phenyl) -6-methyl-pyrimidine-2-carboxylic acid

The title compound was prepared according to general procedure I using 4- (4-chloro-phenyl) -6-methyl-pyrimidine-2-carbonitrile (example b.9) (0.58g, 2.53 mmol). An orange solid (0.15g, 24%) was obtained. MS (ISN)247.3[ (M-H)^-]；mp 105.5℃。

Example D.11

6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine-2-carboxylic acid

The title compound was prepared according to general procedure I using 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine-2-carbonitrile (example b.12) (0.60g, 2.29 mmol). White solid (0.291g, 45%) was obtained. MS (ISN)280.3[ (M-H) ^-]。

Example D.12

4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine-2-carboxylic acid

The title compound was prepared according to general procedure I using 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine-2-carbonitrile (example b.6) (0.60g, 2.0 mmol). An off-white solid was obtained (0.272g, 43%). MS (ISN)334.3[ (M-H)^-]。

Synthesis of bromo-and chloro-derivatives (coupling partners)

General procedure IVa (C, N ligation)

Under stirring, a compound of the formula V, VI, XXIV, XXV or XXVIII (1eq)A mixture of the substance, pyrrole, pyrazole or imidazole derivative (1.5eq) and potassium carbonate or sodium hydride (1eq) in an organic solvent (e.g.DMF or NMP) is heated at 130-150 ℃ until analysis (e.g.thin layer chromatography or HPLC) shows complete conversion of the compound of formula VI, cooled, poured into water and extracted 3 times with ethyl acetate. The combined organic layers were washed 2 times with brine and dried (e.g., MgSO)₄) And evaporated. The crude product is further purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (e.g., ethyl acetate/hexane) to provide the compound of formula X.

General procedure IVb (C, C connection A-Suzuki coupling)

To a mixture of a compound of formula V, VI, XXIV or XXV (1eq.) with a boronic acid derivative (1.1eq.) and tetrakis (triphenylphosphine) palladium (0.03eq.) in an organic solvent (e.g. 1, 2-dimethoxy-ethane) at room temperature under stirring is added 1M sodium carbonate solution (2.5eq.) and the reaction mixture is heated at 80-90 ℃ for about 23h, cooled, poured into ice water and extracted 2 times with ethyl acetate. The combined organic layers were washed 2 times with brine and dried (e.g., MgSO) ₄) And evaporated. The crude product is further purified by silica gel flash chromatography (ethyl acetate/heptane) and crystallized (e.g., dichloromethane/hexane) to provide the compound of formula X.

General procedure IVc (C, C connection B-Negishi coupling)

Scheme a: to a stirred solution of the coupling partner (iodide or bromide) (1eq.) in an organic solvent (e.g., THF) at-65 deg.C was added isopropyl magnesium chloride or bromide (1-2M in THF, 1.05-1.1eq.), the mixture was stirred at-45-0 deg.C for about 45min, and zinc chloride or bromide (1M in THF, 1.1-1.3eq.) was added. The reaction mixture was stirred at room temperature for about 45min, the compound of formula V, VI, XXIV or XXV (1eq.) and tetrakis (triphenylphosphine) palladium (0.01-0.03eq.) were added, the reaction mixture was stirred at 50 ℃ for 1-16h, cooled and ice-cold saturated NaHCO was poured in₃The solution was extracted 2 times with ethyl acetate. The combined organic layers are washed with brine and dried (e.g., MgSO)₄) And evaporated. The crude product is further purified by silica gel column chromatography (toluene) to afford the compound of formula X.

Scheme b: to a stirred solution of a compound of formula VI or XXIV (1eq.) in an organic solvent such as THF at-65 to-40 deg.C is added isopropyl magnesium chloride or bromide (1-2M in THF, 1.05 to 1.1eq.), the mixture is stirred at-45 to-10 deg.C for about 45min, and zinc chloride or bromide (1M in THF, 1.1 to 1.3eq.) is added. The reaction mixture was stirred at room temperature for about 45min, the coupling partner (bromide, iodide or triflate) (1-3eq.) and tetrakis (triphenylphosphine) palladium (0.01-0.03eq.) were added, the reaction mixture was stirred at 50 ℃ for 1-16h, cooled, and ice-cold saturated NaHCO was poured in ₃The solution was extracted 2 times with ethyl acetate. The combined organic layers are washed with brine and dried (e.g., MgSO)₄) And evaporated. The crude product is further purified by silica gel column chromatography (toluene) to afford the compound of formula X.

Example E.1

2- (4-bromo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.2) (0.98g, 3.0mmol) and commercially available 4-bromo-imidazole (0.66g, 4.50 mmol). White solid (0.78g, 59%) was obtained. MS (EI)438.0[ (M)⁺]；mp184.5℃。

Example E.2

2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.1) (1.17g, 4.0mmol) and commercially available 4-bromo-imidazole (0.88g, 6.0 mmol). An off-white solid was obtained (1.23g, 76%). MS (EI)404.0[ (M)⁺]；mp 247℃。

Example E.3

2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

According to general procedure IVb, 2-chloro is employedThe title compound was prepared from (4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.2) (0.65g, 2.0mmol) and commercial 3-bromo-phenylboronic acid (0.44g, 2.20 mmol). A white solid was obtained (0.66g, 73%). MS (EI)446.0[ (M) ⁺]；mp134℃。

Example E.4

2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.1) (0.59g, 2.0mmol) and commercially available 3-bromo-phenylboronic acid (0.44g, 2.20 mmol). White solid (0.71g, 86%) was obtained. MS (EI)413.9[ (M)⁺]；mp 146℃。

Example E.5

4- (4-chloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-trifluoromethyl-pyrimidine

According to general procedure IVc scheme a, 4- (4-chloro-phenyl) -2-iodo-6-trifluoromethyl-pyrimidine (example A.3) (1.21g, 3.15mmol) and commercially available 2-chloro-4-iodo-pyridine [ CAS No.153034-86-7 ]](765mg, 3.2mmol) the title compound was prepared. Pale yellow solid (0.53g, 45%) was obtained. MS (ISP)369.8[ (M + H)⁺]；mp 151℃。

Example E.6

2- (2-chloro-pyridin-4-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

According to general procedure IVc scheme a, 2-iodo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example A.4) (1.47g, 3.52mmol) and commercially available 2-chloro-4-iodo-pyridine [ CAS No.153034-86-7 ]](860mg 3.6mmol) the title compound was prepared. Pale yellow solid (0.70g, 49%) was obtained. MS (ISP)404.1[ (M + H)⁺]；mp 144.5℃。

Example E.7

2- (4-bromo-imidazol-1-yl) -4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.5) (1.0g, 3.24mmol) and commercially available 4-bromo-imidazole (0.71g, 4.86 mmol). Light brown solid (0.98g, 72%) was obtained. MS (ISP)420.9[ (M + H)⁺]；mp 147℃。

Example E.8

2- (3-bromo-phenyl) -4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.5) (0.5g, 1.62mmol) and commercially available 3-bromo-phenylboronic acid (0.42g, 2.20 mmol). White solid (0.54g, 78%) was obtained. MS (EI)430.0[ (M)⁺]；mp98.5℃。

Example E.9

2- (4-bromo-imidazol-1-yl) -4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.10) (0.5g, 1.35mmol) and commercially available 4-bromo-imidazole (0.30g, 2.02 mmol). A white solid was obtained (0.47g, 72%). MS (ISP)483.0[ (M + H)⁺]；mp 147.5℃。

Example E.10

2- (2-chloro-pyridin-4-yl) -4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

According to general procedure IVc scheme a, 2-iodo-4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example A.9) (0.43g, 1.07mmol) and commercially available 2-chloro-4-iodo-pyridine [ CAS No.153034-86-7 ]](263mg, 1.1mmol) the title compound was prepared. An off-white solid was obtained (0.20g, 48%). MS (ISP)386.0[ (M + H)⁺]；mp 143.5℃。

Example E.11

2- (4-bromo-pyrazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.2) (0.98g, 3.0mmol) and commercially available 4-bromo-pyrazole (0.66g, 4.50 mmol). A white solid was obtained (0.83g, 59%). MS (ISP)437.0[ (M + H)⁺]；mp175.5℃。

Example E.12

2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -6-methyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-chloro-phenyl) -6-methyl-pyrimidine (example a.11) (1.91g, 8.0mmol) and commercially available 4-bromo-imidazole (1.76g, 12.0 mmol). Light brown solid (2.76g, 98%) was obtained. MS (ISP)349.1[ (M + H)⁺]；mp176-178℃。

Example E.13

2- (4-bromo-imidazol-1-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.12) (2.73g, 10.0mmol) and commercially available 4-bromo-imidazole (2.21g, 15.0 mmol). Light brown solid was obtained (3.20g, 84%). MS (ISP)383.0[ (M + H) ⁺]；mp 166-168℃。

Example E.14

2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -6-cyclopropyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-chloro-phenyl) -6-cyclopropyl-pyrimidine (example a.13) (0.80g, 3.0mmol) and commercially available 4-bromo-imidazole (0.66g, 4.50 mmol). A white solid was obtained (0.71g, 63%). MS (ISP)375.1[ (M + H)⁺]。

Example E.15

2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-chloro-phenyl) -pyrimidine (example a.14) (0.90g, 4.0mmol) and commercially available 4-bromo-imidazole (0.88g, 6.0 mmol). White solid (1.09g, 81%) was obtained. MS (ISP)335.1[ (M + H)⁺]；mp 166-168℃。

Example E.16

2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-methanesulfonyl-4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine (example a.15) (1.1g, 3mmol) and commercially available 4-iodo-imidazole (0.70g, 4 mmol). A white solid was obtained (0.96g, 66%). MS (ISP)485.2[ (M + H)⁺]。

Example E.17

2-cyclopropyl-6- (4-iodo-imidazol-1-yl) -4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVa using 2-chloro-6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.33) (1.0g, 3mmol) and 4-iodo-imidazole obtained commercially (0.782g, 4 mmol). A yellow solid (1.44g, 93%) was obtained. MS (ISP)456.2[ (M + H) ⁺]。

Example E.18

2- (4-iodo-imidazol-1-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVa using 2-chloro-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.30) (1.0g, 3.7mmol) and 4-iodo-imidazole obtained commercially (0.857g, 4.4 mmol). A yellow solid (0.98g, 62%) was obtained. MS (ISP)430.2[ (M + H)⁺]。

Example E.19

2- (4-chloro-phenyl) -6- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-pyridine

The title compound was prepared according to general procedure IVa using 2-chloro-6- (4-chloro-phenyl) -4-trifluoromethyl-pyridine (example a.16) (10.14g, 35mmol) and commercially available 4-iodo-imidazole (8.081g, 42 mmol). White solid (2.80g, 18%) was obtained. MS (ISP)450.0[ (M + H)⁺]And 452[ (M +2+ H)⁺]。

Example E.20

2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVb using 2-bromo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example a.19) (3.0g, 8mmol) and 3-bromo-phenylboronic acid obtained commercially (1.954g, 10 mmol). An orange oil (3.28g, 91%) was obtained. MS (ISP)446.0[ (M + H)⁺]And 448.0[ (M +2+ H)⁺]。

Example E.21

2- (3-bromo-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVb using trifluoro-methanesulfonic acid 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester (example a.32) (1.0g, 2.6mmol) and commercially available 3-bromo-phenylboronic acid (0.573g, 2.85 mmol). An off-white solid was obtained (1.00g, 98%). MS (ISP)392.0[ (M + H)⁺]And 394.0[ (M +2+ H)⁺]。

Example E.22

2- (3-bromo-phenyl) -6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVb using trifluoro-methanesulfonic acid 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester (example a.34) (1.0g, 2.43mmol) and commercially available 3-bromo-phenylboronic acid (0.573g, 2.85 mmol). A white solid was obtained (0.91g, 89%). MS (ISP)418.1[ (M + H)⁺]And 420.1[ (M +2+ H)⁺]。

Example E.23

2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVa using 2-bromo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example a.19) (2.22g, 6mmol) and commercially available 4-iodo-imidazole (1.28g, 6.6 mmol). A white solid (2.70g, 86%, 92% purity) was obtained. MS (ISP)484.2[ (M + H)⁺]。

Example E.24

5 '-bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3' ] bipyridinyl

According to general procedure IVb, trifluoro-methanesulfonic acid 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester (example A.32) (2.0g, 5.2mmol) and commercially available 3-bromo-pyridine-boronic acid [ CAS No. 452972-09-07](alternatively prepared according to Tetrahedron 2002, 58(17), 3323 or Synthesis2003, (7), 1035, using 3, 5-dibromopyridine available from commercial sources) (1.152g, 5.7 mmol). A white solid was obtained (1.70g, 83%). MS (ISP)393.0[ (M + H)⁺]And 395.0[ (M +2+ H)⁺]。

Example E.25

5 '-bromo-6-cyclopropyl-4- (4-trifluoromethyl-phenyl) - [2, 3' ] bipyridinyl

According to general procedure IVb, trifluoro-methanesulfonic acid 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester (example A.34) (2.0g, 4.86mmol) and 3-bromo-pyridine-boronic acid, obtained commercially [ CAS No. 452972-09-07 [ ]](alternatively prepared according to Tetrahedron 2002, 58(17), 3323 or Synthesis2003, (7), 1035, using 3, 5-dibromopyridine available from commercial sources) (1.079g, 5.34 mmol). A white solid was obtained (1.55g, 76%). MS (ISP)419.1[ (M + H)⁺]And 421.0[ (M +2+ H)⁺]。

Example E.26

6 '-bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

According to general procedure IVc scheme b, 2-iodo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example A.31) (1.09g, 3.0mmol), i-PrMgBr/ZnBr ₂And commercial 2, 6-dibromopyridine (2.13g, 9mmol) were used to prepare the title compound. Pale yellow solid (0.826g, 70%) was obtained. MS (ISP)393.0[ (M + H)⁺]And 394.8[ (M +2+ H)⁺]。

Example E.27

2 '-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl

According to general procedure IVc scheme a, 2-bromo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example A.19) (1.11g, 3.0mmol), 2-chloro-4-iodo-pyridine obtained commercially [ CAS No.153034-86-7 ]](740mg, 3.1mmol) and i-PrMgCl/ZnCl₂The target compound is prepared. A white solid (0.601g, 50%) was obtained. MS (ISP)403.3[ (M + H)⁺]And 405.2[ (M +2+ H)⁺]。

Example E.28

2 '-chloro-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl

According to general procedure IVc scheme a, trifluoro-methanesulfonic acid 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester (example A.32) (3.0g, 7.8mmol), 2-chloro-4-iodo-pyridine obtained commercially [ CAS No.153034-86-7 [ ]](1.92g, 8.0mmol) and i-PrMgCl/ZnCl₂The target compound is prepared. A white solid was obtained (1.50g, 55%). MS (ISP)349.2[ (M + H)⁺]And 351[ (M +2+ H)⁺]。

Example E.29

2 '-chloro-6-cyclopropyl-4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl

According to general procedure IVc scheme a, using trifluoro-methanesulfonic acid 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester (example A.34) (2.7g, 7.0mmol), obtained fromCommercial 2-chloro-4-iodo-pyridine [ CAS No.153034-86-7 ]](1.62g, 6.8mmol) and i-PrMgCl/ZnCl₂The target compound is prepared. A white solid (0.75g, 30%) was obtained. MS (ISP)375.2[ (M + H)⁺]And 377.1[ (M +2+ H)⁺]。

Example E.30

4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyridine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-chloro-phenyl) -6-methyl-pyridine (example a.27) (2.3g, 10mmol) and commercially available 4-iodo-imidazole (2.248g, 12 mmol). An off-white solid was obtained (2.1g, 55%). MS (ISP)396.0[ (M + H)⁺]。

Example E.31

5 '-bromo-4- (4-chloro-phenyl) -6-methyl- [2, 3' ] bipyridinyl

According to general method IVb, 4- (4-chloro-phenyl) -2-iodo-6-methyl-pyridine (example A.29) (2.15g, 6.5mmol) and 3-bromo-pyridine-boronic acid, obtained commercially [ CAS No. 452972-09-07 ]](alternatively the title compound was prepared according to Tetrahedron 2002, 58(17), 3323 or Synthesis2003, (7), 1035, using commercially available 3, 5-dibromopyridine) (1.448g, 7.1 mmol). A white solid was obtained (1.35g, 57%). MS (ISP)358.9[ (M + H) ⁺]，360.9[(M+2+H)⁺]And 363.0[ (M +4+ H)⁺]。

Example E.32

2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-methyl-pyridine

The title compound was prepared according to general procedure IVb using 4- (4-chloro-phenyl) -2-iodo-6-methyl-pyridine (example a.29) (1.5g, 5mmol) and commercially available 3-bromo-phenylboronic acid (1.005g, 5 mmol). A white solid (0.15g, 8.4%) was obtained. MS (ISP)358.0[ (M + H)⁺]，360.0[(M+2+H)⁺]And 362.2[ (M +4+ H)⁺]。

Example E.33

2- (2-chloro-pyridin-4-yl) -4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVc using 4- (3-ethoxy-4-trifluoromethyl-phenyl) -2-iodo-6-trifluoromethyl-pyrimidine (example a.35) (0.99g, 2.14 mmol). Pale yellow solid (0.35g, 36%) was obtained. MS (EI)447.1[ (M)⁺]；mp 145.5℃。

Example E.34

2- (3-bromo-phenyl) -4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.10) (0.25g, 0.67mmol) and commercially available 3-bromo-phenylboronic acid (0.17g, 0.85 mmol). Pale yellow solid (0.32g, 97%) was obtained. MS (EI)492.0[ (M)⁺]；mp 108℃。

Example E.35

2- (4-bromo-imidazol-1-yl) -4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.6) (0.50g, 1.45mmol) and commercially available 4-bromo-imidazole (0.32g, 2.18 mmol). A white solid was obtained (0.34g, 51%). MS (EI)455.1[ (M)⁺]；mp 164.5℃。

Example E.36

2- (3-bromo-phenyl) -4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.6) (0.50g, 1.45mmol) and commercially available 3-bromo-phenylboronic acid (0.38g, 1.89 mmol). A white solid was obtained (0.31g, 46%). MS (EI)464.0, 466.0[ (M)⁺]；mp 111℃。

Example E.37

2- (3-bromo-phenyl) -4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.7) (0.50g, 1.53mmol) and commercially available 3-bromo-phenylboronic acid (0.40g, 1.99 mmol). Pale yellow oil (0.71g, 83%) was obtained. MS (EI)447.7[ (M)⁺]。

Example E.38

2- (2-chloro-pyridin-4-yl) -4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVc using 4- (3, 4-dichloro-phenyl) -2-iodo-6-trifluoromethyl-pyrimidine (example a.36) (1.11g, 2.65 mmol). Pale yellow solid (0.47g, 44%) was obtained. MS (ISP)406.1[ (M + H) ⁺]；mp 184.5℃。

Example E.39

2- (4-bromo-imidazol-1-yl) -4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.7) (0.50g, 1.53mmol) and commercially available 4-bromo-imidazole (0.34g, 2.31 mmol). A white solid was obtained (0.38g, 57%). MS (ISP)439.0[ (M + H)⁺]；mp225.5℃。

Example E.40

2- (4-bromo-imidazol-1-yl) -4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-dichloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.8) (0.50g, 1.63mmol) and commercially available 4-bromo-imidazole (0.36g, 2.45 mmol). A white solid was obtained (0.52g, 76%). MS (ISP)419.0[ (M + H)⁺]；mp 229.5℃。

Example E.41

2- (3-bromo-phenyl) -4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (4-dichloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.8) (0.50g, 1.63mmol) and commercially available 3-bromo-phenylboronic acid (0.425g, 2.12 mmol). White solid (0.34g, 49%) was obtained. MS (ISN)426.2[ (M-H)^-]；mp 95.5℃。

Example E.42

2 '-chloro-6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyrimidinyl

The title compound was prepared according to general procedure IVc using 2-iodo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.4) (1.0g, 2.39mmol) and 2, 4-dichloro-pyrimidine (0.356g, 2.39 mmol). An off-white solid was obtained (0.49g, 50%). MS (EI)404.1[ (M)⁺]；mp 152℃。

Example E.43

4- (4-chloro-3-methyl-phenyl) -2- (2-chloro-pyridin-4-yl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVc using 4- (4-chloro-3-methyl-phenyl) -2-iodo-6-trifluoromethyl-pyrimidine (example a.37) (0.94g, 2.36 mmol). An off-white solid was obtained (0.49g, 54%). MS (ISP)384.1[ (M + H)⁺]；mp 143℃。

Example E.44

2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-methyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (4-chloro-phenyl) -6-methyl-pyrimidine (example a.11) (1.0g, 4.18mmol) and 3-bromo-phenylboronic acid obtained commercially (1.09g, 5.43 mmol). An off-white solid was obtained (0.5g, 33%). MS (ISP)361.0[ (M + H)⁺]；mp 123℃。

Example E.45

4- (4-chloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-methyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (4-chloro-phenyl) -6-methyl-pyrimidine (example a.11) (0.24g, 1.0mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.21g, 1.3 mmol). Pale yellow solid (0.23g, 73%) was obtained. MS (ISP)316.1[ (M + H) ⁺]；mp 175℃。

Example E.46

2- (2-chloro-pyridin-4-yl) -4- (4-trifluoromethyl-phenyl) -6-methyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.12) (0.27g, 1.0mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.21g, 1.3 mmol). An off-white solid was obtained (0.175g, 50%). MS (ISP)350.4[ (M + H)⁺]；mp 147℃。

Example E.47

2- (3-bromo-phenyl) -4- (4-trifluoromethyl-phenyl) -6-methyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.12) (0.5g, 1.83mmol) and commercially available 3-bromo-phenylboronic acid (0.48g, 2.39 mmol). An off-white solid was obtained (0.11g, 15%). MS (ISP)395.0[ (M + H)⁺]；mp 102.5℃。

Example E.48

2- (4-bromo-imidazol-1-yl) -4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidine (example a.38) (0.68g, 2.0mmol) and commercially available 4-bromo-imidazole (0.44g, 3.0 mmol). An off-white solid was obtained (0.79g, 88%). MS (ISP)452.9[ (M + H)⁺]；mp 191℃。

Example E.49

2- (3-bromo-phenyl) -4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidine (example a.38) (0.68g, 2.0mmol) and commercially available 3-bromo-phenylboronic acid (0.44g, 2.20 mmol). A white solid (0.23g, 25%) was obtained. MS (EI)462.1[ (M)⁺]；mp 102.5℃。

Example E.50

2- (2-chloro-pyridin-4-yl) -4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidine (example a.38) (0.68g, 2.0mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.35g, 2.2 mmol). An off-white solid was obtained (0.33g, 39%). MS (ISP)418.3[ (M + H)⁺]；mp 105.5℃。

Example E.51

2- (4-bromo-imidazol-1-yl) -4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (3-methyl-4-trifluoromethyl-phenyl) -6-methyl-pyrimidine (example a.40) (0.40g, 1.4mmol) and commercially available 4-bromo-imidazole (0.31g, 2.1 mmol). Light brown solid was obtained (0.54g, 97%). MS (ISP)399.0[ (M + H)⁺]；mp 157.5℃。

Example E.52

2- (2-chloro-pyridin-4-yl) -4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidine

According to general procedure IVb, 2-chloro-4- (3-methyl-4-trifluoromethyl-phenyl) -6-methyl-pyrimidine (example a.40) (0.401g, 1.4mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.286g,1.82mmol) to prepare the title compound. Light brown solid (0.11g, 22%) was obtained. MS (ISP)364.1[ (M + H)⁺]；mp 92℃。

Example E.53

2- (3-bromo-phenyl) -4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (3-methyl-4-trifluoromethyl-phenyl) -6-methyl-pyrimidine (example a.40) (0.401g, 1.4mmol) and commercially available 3-bromo-phenylboronic acid (0.366g, 1.82 mmol). Pale yellow oil (0.13g, 23%) was obtained. MS (ISP)409.2[ (M + H)⁺]。

Example E.54

2- (4-bromo-imidazol-1-yl) -4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidine

According to general procedure IVa, 2-chloro-4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl]The title compound was prepared from-6-trifluoromethyl-pyrimidine (example a.39) (0.85g, 2.0mmol) and commercial 4-bromo-imidazole (0.44g, 3.0 mmol). Pale yellow solid (0.83g, 78%) was obtained. MS (ISP)535.0[ (M + H)⁺]；mp 159℃。

Example E.55

2- (3-bromo-phenyl) -4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidine

According to general procedure IVb, 2-chloro-4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl is used]The title compound was prepared from-6-trifluoromethyl-pyrimidine (example a.39) (0.85g, 2.0mmol) and commercial 3-bromo-phenylboronic acid (0.44g, 2.19 mmol). An off-white solid was obtained (0.97g, 80%). MS (EI)544.1[ (M)⁺]；mp 122℃。

Example E.56

2- (2-chloro-pyridin-4-yl) -4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidine

According to general procedure IVb, 2-chloro-4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl is used]The title compound was prepared from-6-trifluoromethyl-pyrimidine (example a.39) (0.85g, 2.0mmol) and commercial 2-chloro-pyridine-4-boronic acid (0.35g, 2.22 mmol). An off-white solid was obtained (0.71g, 70%). MS (EI)501.1[ (M)⁺]；mp 138℃。

Example E.57

2- (4-bromo-imidazol-1-yl) -4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine (example a.42) (0.65g, 2.0mmol) and commercially available 4-bromo-imidazole (0.44g, 3.0 mmol). Pale yellow solid was obtained (0.64g, 73%). MS (ISP)439.1[ (M + H)⁺]；mp 158.5℃。

Example E.58

2- (3-bromo-phenyl) -4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine (example a.42) (0.65g, 2.0mmol) and 0.44g, 2.2mmol) of commercially available 3-bromo-phenylboronic acid. A white solid (0.43g, 48%) was obtained. MS (EI)448.0[ (M)⁺]；mp102.5℃。

Example E.59

2- (2-chloro-pyridin-4-yl) -4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine (example a.42) (0.65g, 2.0mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.35g, 2.22 mmol). An off-white solid was obtained (0.59g, 73%). MS (ISP)404.0[ (M + H)⁺]；mp 147℃。

Example E.60

2- (4-bromo-2-methyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.2) (0.65g, 2.0mmol) and commercially available 4-bromo-2-methyl-imidazole (0.48g, 3.0 mmol). Light brown solid was obtained (0.73g, 81%). MS (ISP)451.0[ (M + H)⁺]；mp 174℃。

Example E.61

2- (4-bromo-imidazol-1-yl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine (example a.41) (0.4g, 1.46mmol) and commercially available 4-bromo-imidazole (0.32g, 2.18 mmol). Light brown solid was obtained (0.33g, 59%). MS (ISP)385.0[ (M + H)⁺]；mp219.5℃。

Example E.62

2- (3-bromo-phenyl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine (example a.41) (0.4g, 0.5mmol) and commercially available 3-bromo-phenylboronic acid (0.38g, 1.89 mmol). An orange solid (0.23g, 40%) was obtained. MS (ISP)394.9[ (M + H)⁺]；mp132.5℃。

Example E.63

2- (2-chloro-pyridin-4-yl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine (example a.41) (0.4g, 1.46mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.3g, 1.9 mmol). Light brown solid (0.15g, 29%) was obtained. MS (ISP)350.2[ (M + H)⁺]；mp 155℃。

Example E.64

2- (4-bromo-2-methyl-imidazol-1-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.12) (0.4g, 1.47mmol) and commercially available 4-bromo-2-methyl-imidazole (0.35g, 2.17 mmol). Light brown solid (0.41g, 70%) was obtained. MS (ISP)399.0[ (M + H) ⁺]；mp 180℃。

Example E.65

2- (3-chloro- [1, 2, 4] triazol-1-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

According to general procedure IVa, 2-chloro-4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example A.12) (0.4g, 1.47mmol) and 3-chloro-1H- [1, 2, 4] obtained commercially]Triazole (0.22g, 2.17mmol) prepared the title compound. A yellow solid (0.36g, 72%) was obtained. MS (ISP)340.0[ (M + H)⁺]；mp 137.5℃。

Example E.66

2- (4-bromo-imidazol-1-yl) -4-isopropyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4-isopropyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.43) (0.4g, 1.33mmol) and commercially available 4-bromo-imidazole (0.29g, 2.0 mmol). An off-white solid was obtained (0.5g, 91%). MS (ISP)413.1[ (M + H)⁺]；mp 185℃。

Example E.67

2- (4-iodo-5-methyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.2) (0.33g, 1.0mmol) and commercially available 4-iodo-5-methyl-imidazole (0.25g, 1.2 mmol). An off-white solid (0.43g, 8) was obtained5％)。MS(ISP)498.8[(M+H)⁺]；mp 202℃。

Example E.68

2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.2) (1.31g, 4.0mmol) and commercially available 4-iodo-imidazole (0.85g, 4.4 mmol). A pink solid was obtained (1.88g, 97%). MS (ISP)485.3[ (M + H)⁺]；mp 194℃。

Example E.69

4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-chloro-phenyl) -6-methyl-pyrimidine (example a.11) (1.67g, 7.0mmol) and 4-iodo-imidazole obtained commercially (2.04g, 10.5 mmol). Pale yellow solid (1.97g, 71%) was obtained. MS (ISP)397.1[ (M + H)⁺]；mp184℃。

Example E.70

4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.1) (1.76g, 6.0mmol) and commercially available 4-iodo-imidazole (1.28g, 6.6 mmol). An off-white product was obtained (2.59g, 96%). MS (ISP)451.0[ (M + H)⁺]；mp258℃。

Example E.71

2- (4-iodo-imidazol-1-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example a.12) (2.34g, 8.58mmol) and commercially available 4-iodo-imidazole (2.50g, 12.9 mmol). A light brown solid was obtained (2.67) g，72％)。MS(ISP)431.1[(M+H)⁺]；mp 167℃。

Example E.72

4- (3-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.44) (3.12g, 10.6mmol) and commercially available 4-iodo-imidazole (2.27g, 11.7 mmol). An off-white solid was obtained (4.0g, 83%). MS (ISP)451.0[ (M + H)⁺]；mp202℃。

Example E.73

2- (4-iodo-imidazol-1-yl) -4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidine (example a.38) (2.04g, 6.0mmol) and commercially available 4-iodo-imidazole (1.28g, 6.6 mmol). An off-white solid was obtained (2.83g, 95%). MS (ISP)499.3[ (M + H)⁺]；mp 190℃。

Example E.74

4- (3, 4-dichloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.7) (1.97g, 6.0mmol) and commercially available 4-iodo-imidazole (1.28g, 6.6 mmol). An off-white solid was obtained (2.67g, 92%). MS (ISP)485.1[ (M + H)⁺]；mp223℃。

Example E.75

4- (3, 4-dichloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine

This was prepared according to general procedure IVa using 2-chloro-4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine (example a.41) (3.83g, 14.0mmol) and commercially available 4-iodo-imidazole (4.07g, 21.0mmol)A target compound. A brown solid (1.41g, 24%) was obtained. MS (ISP)431.0[ (M + H)⁺]；mp224.5℃。

Example E.76

4- (4-chloro-3-methyl-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidine (example a.47) (3.5g, 13.8mmol) and commercially available 4-iodo-imidazole (2.95g, 15.2 mmol). An off-white solid was obtained (2.67g, 92%). MS (ISP)485.1[ (M + H)⁺]；mp 223℃。

Example E.77

2- (3-bromo-phenyl) -4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidine (example a.47) (3.84g, 15.2mmol) and commercially available 3-bromo-phenylboronic acid (3.2g, 15.9 mmol). White solid (2.87g, 51%) was obtained. MS (ISP)375.1[ (M + H)⁺]；mp 108℃。

Example E.78

4- (3, 4-difluoro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidine (example a.46) (1.50g, 5.1mmol) and commercially available 4-iodo-imidazole (1.48g, 7.63 mmol). A pale red solid was obtained (2.23g, 97%). MS (ISP)452.9[ (M + H) ⁺]；mp 206℃。

Example E.79

4- (4-fluoro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

Following general procedure IVa, using 2-chloro-4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidine (example a.45) (1.5g, 5.4mmol) and 4-iodo-imidazole obtained commercially (1.58g, 8).15mmol) to prepare the title compound. A white solid was obtained (2.23g, 95%). MS (ISP)435.0[ (M + H)⁺]；mp 235℃。

Example E.80

2- (4-bromo-thiazol-2-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVc scheme b using 2-iodo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.31) (4.0g, 9.36mmol) and commercially available 2, 4-dibromo-thiazole (2.53g, 10.41 mmol). Pale yellow solid (1.22g, 31%) was obtained. MS (ISP)399.1[ (M + H)⁺]And 401.1[ (M +2+ H)⁺]。

Example E.81

2- (3-bromo-phenyl) -6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVb using a mixture of 2-chloro-6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.26) (65%), 2-iodo-6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.49) (35%) (5.5g, 4.62mmol) and 3-bromo-phenylboronic acid obtained commercially (1.02g, 5.1 mmol). A white solid was obtained (1.43g, 69%). MS (ISP)446.0[ (M + H) ⁺]And 448[ (M +2+ H)⁺]。

Example E.82

2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-trifluoromethyl-pyridine

The title compound was prepared according to general procedure IVb using 4- (4-chloro-phenyl) -2-iodo-6-trifluoromethyl-pyridine (example a.50) (9g, about 35% purity, about 8.2mmol) and commercially available 3-bromo-phenylboronic acid (1.80g, 9 mmol). A white solid was obtained (1.7g, 50%). MS (ISP)412.0[ (M + H)⁺]，414.1[(M+2+H)⁺]And 416.1[ (M +4+ H)⁺]。

Example E.83

2-chloro-4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidine

The title compound was prepared according to general procedure IVc scheme b using 2-iodo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.31) (10.89g, 30mmol) and commercially available 2, 4-dichloropyrimidine (4.47g, 30 mmol). An off-white solid was obtained (7.2g, 68%). MS (ISP)350.2[ (M + H)⁺]And 352[ (M +2+ H)⁺]。

Example E.84

4- (3, 4-dichloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyridine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (3, 4-dichloro-phenyl) -6-methyl-pyridine (example a.51) (3.5g, 12.8mmol) and commercially available 4-iodo-imidazole (2.99g, 15.4 mmol). A pale grey solid was obtained (0.90g, 16%). MS (ISP)430.0[ (M + H)⁺]，432.1[(M+2+H)⁺]And 434.0[ (M +4+ H) ⁺]。

Example E.85

2- (3-bromo-phenyl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyridine

The title compound was prepared according to general procedure IVb using 4- (3, 4-dichloro-phenyl) -2-iodo-6-methyl-pyridine (example a.52) (5.5g, about 60% purity, about 9mmol) and commercially available 3-bromo-phenylboronic acid (1.82g, 9.1 mmol). A white solid was obtained (1.3g, 36%). MS (ISP)391.9[ (M + H)⁺]，394.0[(M+2+H)⁺]，396.0[(M+4+H)⁺]And 398.0[ (M +6+ H)⁺]。

Example E.86

2- (5-bromo-thiophen-2-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVb using 2-iodo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.31) (1.00g, 2.75mmol) and commercially available 5-bromothiophene-2-boronic acid (0.570g, 2.75 mmol). Pale yellow solid (0.480g, 43%) was obtained. MS (ISP)398.0[ (M + H)⁺]And 400.0[ (M +2+ H)⁺]。

Example E.87

2- (5-bromo-thiophen-2-yl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyridine

The title compound was prepared according to general procedure IVb using 4- (3, 4-dichloro-phenyl) -2-iodo-6-methyl-pyridine (example a.52) (1.0g, about 80% purity, about 2.75mmol) and commercially available 5-bromothiophene-2-boronic acid (0.568g, 2.75 mmol). An off-white solid was obtained (0.480g, 46%). MS (ISP)397.9[ (M + H) ⁺]，400.0[(M+2+H)⁺]，402.1[(M+4+H)⁺]And 404.2[ (M +6+ H)⁺]。

Example E.88

2- (4-bromo-thiophen-2-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine the title compound was prepared according to general procedure IVc scheme b using 2-iodo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.31) (4.0g, 9.36mmol) and 2, 4-dibromothiophene (2.518g, 10.41mmol) obtained commercially. A white solid was obtained (2.12g, 54%). MS (ISP)398.0[ (M + H)⁺]And 400.0[ (M +2+ H)⁺]。

Example E.89

2- (3-bromo-phenyl) -6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVb using 4- (3, 4-dichloro-phenyl) -2-iodo-6-methyl-pyridine (example a.54) (2.1g, about 62% purity, about 3.45mmol) and commercially available 3-bromo-phenylboronic acid (0.693g, 3.45 mmol). A pale yellow oil was obtained (1.0g, 71%). MS (ISP)406.2[ (M + H)⁺]And 408.2[ (M +2+ H)⁺]。

Example E.90

2- (3-bromo-phenyl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyridine

According to general method Iba, using trifluoro-methanesulfonic acid 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester (example A.55) (1.6g, 4.15mmol) andthe title compound was prepared from commercial 3-bromobenzeneboronic acid (0.751g, 3.74 mmol). A pale yellow oil was obtained (1.39g, 85%). MS (ISP)392.0[ (M + H) ⁺]And 394.1[ (M +2+ H)⁺]。

Example E.91

4-benzo [1, 3] dioxol-5-yl-2- (3-bromo-phenyl) -6-methyl-pyridine

The title compound was prepared according to general procedure IVb using trifluoro-methanesulfonic acid 4-benzo [1, 3} dioxol-5-yl-6-methyl-pyridin-2-yl ester (example A.56) (1.1g, 3.04mmol) and 3-bromobenzeneboronic acid obtained commercially (0.611g, 3.04 mmol). A colourless gum was obtained (0.44g, 39%). MS (ISP)368.0[ (M + H)⁺]And 370.0[ (M +2+ H)⁺]。

Example E.92

2- (3-chloro- [1, 2, 4] triazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVa using 2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example a.17) (1.628g, 5.0mmol) and 3-chloro-1H- (1, 2, 4) triazole obtained commercially (0.776g, 7 mmol). A white solid was obtained (1.651g, 84%). MS (ISP)393.1[ (M + H)⁺]And 395[ (M +2+ H)⁺]。

Example E.93

2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVa using 2-chloro-6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.26) (2.0g, 6.14mmol) and commercially available 4-iodo-imidazole (1.31g, 6.75 mmol). White solid (1.90g, 82%) was obtained. MS (ISP)484.1[ (M + H) ⁺]。

Example E.94

2 '-chloro-4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl

The title compound was prepared according to general procedure IVb using 2-iodo-4-methyl-6- (4-trifluoromethyl-phenyl) -pyridine (example a.58) (5.45g, 15mmol) and commercially available 2-chloropyridine boronic acid (2.48g, 15.75 mmol). An off-white solid was obtained (3.82g, 73%). MS (ISP)349.2[ (M + H)⁺]And 351[ (M +2+ H)⁺]。

Example E.95

2- (4-chloro-phenyl) -6- (4-iodo-imidazol-1-yl) -4-methyl-pyridine

The title compound was prepared according to general procedure IVa using 2-bromo-6- (4-chloro-phenyl) -4-methyl-pyridine (example a.22) (0.94g, 3.0mmol) and 4-iodo-imidazole obtained commercially (0.71g, 3.3 mmol). A yellow gum (0.213g, 18%) was obtained. MS (ISP)396.0[ (M + H)⁺]。

Example E.96

6 '-bromo-4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

According to Tetrahedron Letters 1996, 37(15), 2537 and general procedure IVc, scheme b, 2-iodo-4-methyl-6- (4-trifluoromethyl-phenyl) -pyridine (example A.58) (5.81g, 16mmol), n-BuLi/ZnBr₂And commercial 2, 6-dibromopyridine (5.31g, 22.4mmol) were used to prepare the title compound. White solid (2.34g, 37%) was obtained. MS (ISP)393.0[ (M + H) ⁺]And 395.0[ (M +2+ H)⁺]。

Example E.97

2-chloro-4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidine

According to general procedure IVc scheme b, 2-iodo-4-methyl-6- (4-trifluoromethyl-phenyl) -pyridine (example A.58) (2.55g, 7.0mmol), i-PrMgCl/ZnCl are employed₂And commercial 2, 4-dichloropyrimidine (1.08g, 7.21mmol) was used to prepare the title compound. Light brown solid was obtained (0.896g, 37%). MS (ISP)350.3[ (M + H)⁺]And 352[ (M +2+ H)⁺]。

Example E.98

2 '-iodo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl

According to the general procedures Ia to d for the preparation of iodides, 2 '-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridine (example E.27) (0.403g, 1.0mmol) prepared the title compound. An off-white solid was obtained (0.436g, 88%). MS (ISP)495.1[ (M + H)⁺]。

Example E.99

2 '-chloro-4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4' ] bipyridinyl

The title compound was prepared according to general procedure IVb using trifluoro-methanesulfonic acid 4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl-pyridin-2-yl ester (example a.59) (2.0g, 5.0mmol) and commercially available 2-chloropyridineboronic acid (0.758g, 5.0 mmol). An off-white solid was obtained (1.50g, 82%). MS (ISP)379.2[ (M + H) ⁺]And 381[ (M +2+ H)⁺]。

Example E.100

2- (6-bromo-pyridin-2-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

According to Tetrahedron Letters 1996, 37(15), 2537 and general procedure IVc, scheme b, 2-iodo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example A.4) (0.900g, 2.15mmol), n-BuLi/ZnBr₂And commercial 2, 6-dibromopyridine (0.510g, 2.15mmol) was used to prepare the title compound. A yellow oil (0.658g, 60%, 88% purity) was obtained. MS (ISP)447.8[ (M + H)⁺]And 450.0[ (M +2+ H)⁺]。

Example E.101

2- (3-bromo-phenyl) -4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidine

According to general procedure IVb, 2-chloro-4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidine (example A.46) (1.50g, 5.1 mm) is usedol) and 3-bromo-phenylboronic acid (123g, 6.12mmol) obtained commercially. A white solid was obtained (1.23g, 58%). MS (EI)416.0[ (M)⁺]；mp103℃。

Example E.102

2- (3-bromo-phenyl) -4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidine (example a.45) (1.50g, 5.42mmol) and commercially available 3-bromo-phenylboronic acid (1.31g, 6.52 mmol). A white solid was obtained (1.17g, 54%). MS (EI)395.9, 397.9[ (M) ⁺]；mp 111℃。

Example E.103

2- (2-chloro-pyridin-4-yl) -4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-6- (4-fluoro-phenyl) -4-trifluoromethyl-pyrimidine (example a.45) (1.5g, 5.42mmol) and commercially available 2-chloro-pyridine-4-boronic acid (1.02g, 6.48 mmol). Light brown solid (0.49g, 26%) was obtained. MS (ISP)354.2[ (M + H)⁺]；mp 138.5℃。

Example E.104

2- (2-chloro-pyridin-4-yl) -4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-6- (3, 4-difluoro-phenyl) -4-trifluoromethyl-pyrimidine (example a.46) (1.5g, 5.09mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.96g, 6.1 mmol). Light brown solid (0.51g, 27%) was obtained. MS (ISP)372.0[ (M + H)⁺]；mp 151.5℃。

Example E.105

2- (3-bromo-phenyl) -4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

According to general procedure IVb, 2-chloro-4- (2-fluoro-4-trifluoromethyl-benzene is usedThe title compound was prepared from yl) -6-trifluoromethyl-pyrimidine (example a.60) (1.50g, 4.35mmol) and commercial 3-bromo-phenylboronic acid (0.96g, 4.78 mmol). A white solid was obtained (1.23g, 61%). MS (EI)466.0[ (M)⁺]；mp 109℃。

Example E.106

2- (3-bromo-phenyl) -4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (2, 4-dichloro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.61) (1.50g, 4.58mmol) and commercially available 3-bromo-phenylboronic acid (1.01g, 5.03 mmol). A white solid was obtained (1.26g, 61%). MS (EI)447.9[ (M)⁺]；mp 124.5℃。

Example E.107

2- (2-chloro-pyridin-4-yl) -4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.61) (1.50g, 4.35mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.75g, 4.8 mmol). A pale red solid was obtained (0.64g, 35%). MS (ISP)422.0[ (M + H)⁺]；mp 146℃。

Example E.108

The title compound was prepared according to general procedure IVc using 2-chloro-4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.10) (0.99g, 2.14 mmol). Pale yellow solid (0.35g, 36%) was obtained. MS (EI)447.1[ (M)⁺]；mp 145.5℃。

Example E.109

The title compound was prepared according to general procedure IVb using 2-chloro-4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.6) (1.79g, 5.19mmol) and commercially available 3-bromo-phenylboronic acid (1.15g, 5.73 mmol). A white solid (0.94g, 39%) was obtained. MS (EI)464.0, 466.0[ (M) ⁺]；mp 111℃。

Example F.1

N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulphonamide

Butyllithium (1.6M in hexanes, 131mL, 0.21mol) was added dropwise at-78 ℃ to a stirred solution of commercial 5-bromo-N-tert-butyl-thiophene-2-sulfonamide (16.9g, 56.7mmol) and commercial triisopropyl borate (39.4g, 0.21mol) in THF (500mL) with the temperature not exceeding-65 ℃. The mixture was stirred at-78 ℃ for 3h, followed by addition of water (500mL) at-20 ℃. The layers were separated and the aqueous layer was extracted with ether (4X 200mL) followed by the addition of 2N HCl (120 mL). The acidic aqueous layer was extracted with ethyl acetate (3X 200mL), the combined organic layers were dried (MgSO) and evaporated to give a light brown gum (12.3g, 83%) which was dissolved in toluene (400 mL). Pinacol (16.6g, 0.14mol) and p-toluenesulfonic acid (0.27g, 1.41mmol) were added, and the reaction mixture was heated at reflux for 3h and evaporated to give a light brown oil. Hexane (50mL) was added and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with hexane and dried to give the title compound as an off-white solid (9.3g, 57%). MS (EI)345.2[ (M)⁺]；mp 127℃。

Example F.2

3-sulfamoyl-phenylboronic acid

Step 1) to a stirred solution of methyl diethanolamide 3-bromobenzoate (5g, 17.6mmol) in THF (150mL) at-78 deg.C over 3 minutes was added n-BuLi (1.6M in hexanes, 11.0mL, 17.6mmol) dropwise and the mixture was stirred at-78 deg.C for 15min, then charged with gaseous sulfur dioxide (about 7.5g, 117mmol) causing immediate precipitation with the internal temperature raised to 40 deg.C. The mixture was warmed to room temperature and stirred for 1 h. The precipitated lithium sulfinate was isolated by filtration under nitrogen, washed with THF and dried over HV to give a white solid (5.1g, 95% purity, 100% yield) (according to bioorg. Med. chem.2005, 13, 2305-2312).

Step 2) N-chlorosuccinimide (1.015g, 7.6mmol) was added to 3- (6-methyl- [1, 3, 6, 2 ] prepared above]Dioxaazaborolan-2-yl) -lithium benzenesulfonate (2g, 7.27mmol) in CH₂Cl₂(14mL) of the suspension, the mixture was stirred at room temperature for 2 h. 25% ammonium hydroxide solution (1.09mL, 14.5mmol) was added and the mixture was stirred at room temperature for a further 2h and then evaporated completely to give the title compound as an off-white solid (1.38g, 94%) (according to bioorg. Med. chem.2005, 13, 2305-. MS (ISP)200.4[ (M-H)^-]。

Example F.3

3-sulfamoyl-pyridine-5-boronic acid

Step 1) 3-bromopyridine-5-boronic acid [ CAS No. 452972-09-7 ]]A mixture of (10g, 50mmol) and N-methyldiethanolamine (5.9g, 50mmol) in toluene (50mL) was stirred at 23 ℃ for 24h, then evaporated completely and triturated with heptane to give 2- (5-bromo-pyridin-3-yl) -6-methyl- [1, 3, 6, 2]Dioxazaborolane (14.1g, 100%) as an off-white solid. MS (ISP)285.0[ (M + H)⁺]。

Step 2) to a stirred solution of the above 2- (5-bromo-pyridin-3-yl) -6-methyl- [1, 3, 6, 2] dioxazaborolane (5g, 17.6mmol) in THF (150mL) at-78 deg.C over 3 minutes was added dropwise n-BuLi (1.6M in hexanes, 11.0mL, 17.6mmol) and the mixture was stirred at-78 deg.C for 15 minutes

min, then gaseous sulfur dioxide (about 7.5g, 117mmol) was bubbled in, precipitation occurred immediately and the internal temperature increased by 40 ℃. The mixture was warmed to room temperature and stirred for 1 h. The precipitated lithium sulfinate was isolated by filtration under nitrogen, washed with THF and dried over HV to give a white solid (5.5g, 88% purity, 100% yield) (according to bioorg. Med. chem.2005, 13, 2305-2312).

Step 3) N-chlorosuccinimide (0.937g, 7.01mmol) was added to 5- (6-methyl- [1, 3, 6, 2] prepared above]Dioxaazaborolan-2-yl) -pyridine-3-sulfinic acid lithium (2g, 7.24mmol) in CH ₂Cl₂(14mL) of the suspension, the mixture was stirred at room temperature for 2 h. 25% ammonium hydroxide solution (1.00mL, 13.4mmol) was added and the mixture was stirred at room temperature for a further 2h and then evaporated completely to give the title compound as an off-white solid (1.28g, 88%) (according to bioorg. Med. chem.2005, 13, 2305-. MS (ISP)201.4[ (M-H)^-]。

Example F.4

3- (2, 2-dimethyl-propoxysulfonyl) -phenylboronic acid

Step 1) 3-bromo-benzenesulfonic acid 2, 2-dimethyl-propyl ester: commercial 3-bromobenzenesulfonyl chloride (10g, 39mmol) and 2, 2-dimethyl-1-propanol (5.18g, 59mmol) were cooled to 10 ℃ followed by the addition of pyridine (6.3mL, 78mmol) and the mixture was stirred at 23 ℃ for 18 h. The reaction mixture was extracted with ethyl acetate and citric acid (5%), and the ethyl acetate layer was saturated NaHCO₃The solution was washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to give 2, 2-dimethyl-propyl 3-bromo-benzenesulfonate (11.48g, 96%) as an off-white solid, which was used without further purification.

Step 2) to a solution of 2, 2-dimethyl-propyl 3-bromo-benzenesulfonate (9.83g, 32mmol) and triisopropyl borate (13.4mL, 58mmol) in THF (45mL) prepared above at-78 deg.C was added n-BuLi (1.6M in hexane, 20mL, 32mmol) maintaining the internal temperature below-65 deg.C. Stirring was continued for 1h at-78 deg.C, then more n-BuLi (4.0mL, 6.4mmol) was added and stirring continued for 30min at-78 deg.C. The reaction mixture was taken up in 1M H ₂SO₄The solution (40mL) was quenched and allowed to warm rapidly (water bath) to about 20 ℃ with stirring for 10 min. Diluted with EtOAc, the layers were separated, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to afford the title compound as a white solid (9.00g, 103%). MS (ISN)271.4[ (M-H)^-]。

Example F.5

2- (2, 5-dimethyl-pyrrol-1-yl) -pyridine-4-boronic acid

Step 1) 4-bromo-2- (2, 5-dimethyl-pyrrol-1-yl) -pyridine: to a solution of commercial 2-amino-4-bromopyridine (3.254g, 19mmol) and acetyl-methyl-acetone (2.5mL, 21mmol) in toluene (40mL) was added p-toluenesulfonic acid monohydrate (36mg, 1 mol%) and refluxed for 1 hour, then a dean Stark trap was installed and refluxed for 1 hour. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and saturated NaHCO₃The solution was extracted 3 times, the organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to give a brown liquid which was purified by silica gel column chromatography using n-heptane and ethyl acetate to give 4-bromo-2- (2, 5-dimethyl-pyrrol-1-yl) -pyridine (2.30g, 50%) as a yellow liquid. MS (ISP)251.1[ (M + H)⁺]And 253.0[ (M +2+ H)⁺]。

Step 2) to a solution of 4-bromo-2- (2, 5-dimethyl-pyrrol-1-yl) -pyridine (1.95g, 7.77mmol) prepared above and triisopropyl borate (2.68mL, 11.6mmol) in THF (40mL) at-78 deg.C was added n-BuLi (1.6M in hexane, 4.85mL, 7.77mmol) maintaining the internal temperature below-65 deg.C. Stirring was continued at-78 deg.C for 1h, then more triisopropyl borate (2.68mL, 11.6mmol) and n-BuLi (4.85mL, 7.77mmol) were added and stirring continued at-78 deg.C for 1 h. The reaction mixture was taken up in 1M NaH ₂PO₄The solution was quenched and allowed to warm rapidly (water bath) to about 20 ℃ and stir for 10 min. Diluted with EtOAc, the layers were separated, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to give the title compound as a yellow foam (2.1g, 100%, 80% purity), which was used without further purification. MS (ISN)215.3[ (M-H)^-]。

Example F.6

N-tert-butyl-3- (6-tributylstannyl-pyridin-2-yl) -benzenesulfonamide

Step 1)3- (6-bromo-pyridin-2-yl) -N-tert-butyl-benzenesulfonamide: at 90 ℃ under argonA mixture of 3- (tert-butylsulfamoyl) -phenylboronic acid (5.142g, 20mmol) obtained from commerce, 2, 6-dibromopyridine (14.2g, 60mmol) obtained from commerce and Pd (PPh3)4(1.156g, 5 mol%) in DME (80ml) and aqueous sodium carbonate (1M, 40ml, 40mmol) was stirred for 18h at ambient temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated. The crude product was purified by flash chromatography eluting with N-heptane/ethyl acetate to give 3- (6-bromo-pyridin-2-yl) -N-tert-butyl-benzenesulfonamide (6.60g, 89%) as a yellow solid. MS (ISP)369.1[ (M + H)⁺]And 371.0[ (M +2+ H)⁺]。

Step 2) 3- (6-bromo-pyridin-2-yl) -N-tert-butyl-benzenesulfonamide (4.6g, 12mmol) above, hexabutylditin (9.9ml, 19mmol) and Pd (PPh) ₃)₄A mixture (144mg, 1 mol%) in toluene (135ml) was stirred at 80 ℃ for 18 h. The solvent was evaporated and the crude product was purified directly by flash chromatography eluting with n-heptane/ethyl acetate to give the title compound (1.66g, 23%) as a yellow oil. MS (ISP)580.7[ (M + H)⁺]。

Example F.7

6- (3-tert-Butylsulfamoyl-phenyl) -pyridine-2-carboxamidine acetate

To a mixture of 6- (3-tert-butylsulfamoyl-phenyl) -N-hydroxy-pyridine-2-carboxamidine (example C.7) (830mg, 2.38mmol) in acetic acid (10ml) was added acetic anhydride (0.34ml, 3.57mmol) at 23 ℃, the mixture was stirred at 23 ℃ for 10min, then 10% palladium on charcoal (84mg, 0.79mmol) was added and the mixture was hydrogenated (1bar hydrogen) at 23 ℃ for 24 h. The catalyst was filtered, washed with acetic acid and the solvent evaporated to give the title compound (1.38g, 148%, containing excess acetic acid) as a pale yellow oil which was used without further purification (cf. synth. Commun.1996, 26(23), 4351). MS (ISP)333.1[ (M + H)⁺]。

Example G.1

2- (4-tributylstannyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

To a stirred solution of 2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.68) (0.48g, 1.0mmol) in THF (5mL) at 0 ℃ was added isopropyl-magnesium chloride lithium chloride (1M in THF, 1.22mL, 1.22 mmol). The reaction mixture was stirred at 0 ℃ for 15min, tributyltin chloride (0.43g, 1.33mmol) was added, the reaction mixture was stirred at room temperature for 16h, saturated ammonium chloride solution (30mL) was poured in, and extraction was performed with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine (30mL) and dried (MgSO) ₄) And evaporated. The crude product was further purified by silica gel flash chromatography (ethyl acetate/heptane) to afford the title compound (0.27g, 42%) as a pale yellow oil. MS (ISP)649.2[ (M + H)⁺]。

Example G.2

4- (4-chloro-phenyl) -2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

To a stirred solution of 4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.70) (0.45g, 1.0mmol) in THF (5mL) at 0 ℃ was added isopropyl-magnesium chloride lithium chloride (1M in THF, 1.22mL, 1.22 mmol). The reaction mixture was stirred at 0 ℃ for 15min, tributyltin chloride (0.43g, 1.33mmol) was added, the reaction mixture was stirred at room temperature for 16h, saturated ammonium chloride solution (30mL) was poured in, and extraction was performed with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine (30mL) and dried (MgSO)₄) And evaporated. The crude product was further purified by silica gel flash chromatography (ethyl acetate/heptane) to afford the title compound (0.29g, 47%) as a pale yellow oil. MS (ISP)615.3[ (M + H)⁺]。

Example G.3

4- (4-chloro-phenyl) -6-methyl-2- (4-tributylstannyl-imidazol-1-yl) -pyrimidine

To a stirred solution of 4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine (example e.69) (0.40g, 1.0mmol) in THF (7mL) at 0 ℃ was added isopropyl-magnesium chloride lithium chloride (1M in THF), 1.22mL, 1.22 mmol). The reaction mixture was stirred at 0 ℃ for 15min, tributyltin chloride (0.43g, 1.33mmol) was added, the reaction mixture was stirred at room temperature for 5h, saturated ammonium chloride solution (30mL) was poured and extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine (30mL) and dried (MgSO)₄) And evaporated. The crude product was further purified by silica gel flash chromatography (ethyl acetate/heptane) to afford the title compound (0.47g, 84%) as a pale yellow oil. MS (ISP)561.2[ (M + H)⁺]。

Example G.4

4- (3, 4-dichloro-phenyl) -6-methyl-2- (4-tributylstannyl-imidazol-1-yl) -pyrimidine

To a stirred solution of 4- (3, 4-dichloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine (example e.75) (0.43g, 1.0mmol) in THF (7mL) at 0 ℃ was added isopropyl-magnesium chloride lithium chloride (1M in THF, 1.22mL, 1.22 mmol). The reaction mixture was stirred at 0 ℃ for 15min, tributyltin chloride (0.43g, 1.33mmol) was added, the reaction mixture was stirred at room temperature for 5h, saturated ammonium chloride solution (30mL) was poured and extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine (30mL) and dried (MgSO)₄) And evaporated. The crude product was further purified by silica gel flash chromatography (ethyl acetate/heptane) to afford the title compound (0.55g, 92%) as a pale yellow oil. MS (ISP)593.2[ (M + H) ⁺]。

Example G.5

4-methyl-2- (4-tributylstannyl-imidazol-1-yl) -6- (4-trifluoromethyl-phenyl) -pyrimidine

To a stirred solution of 2- (4-iodo-imidazol-1-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.71) (0.43g, 1.0mmol) in THF (7mL) at 0 ℃ was added isopropyl-magnesium chloride lithium chloride (1M in THF, 1.22mL, 1.22 mmol). The reaction mixture was stirred at 0 ℃ for 15min, tributyltin chloride (0.43g, 1.33mmol) was added, the reaction mixture was stirred at room temperature for 5h, saturated ammonium chloride solution (30mL) was poured in, extracted with ethyl acetate (2X 50)mL). The combined organic layers were washed with brine (30mL) and dried (MgSO)₄) And evaporated. The crude product was further purified by silica gel flash chromatography (ethyl acetate/heptane) to afford the title compound (0.55g, 93%) as a pale yellow oil. MS (ISP)595.3[ (M + H)⁺]。

Example G.6

4- (3, 4-dichloro-phenyl) -2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

To a stirred solution of 4- (3, 4-dichloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.74) (1.46g, 3.0mmol) in THF (21mL) at 0 ℃ was added isopropyl-magnesium chloride lithium chloride (1M in THF, 3.6mL, 3.6 mmol). The reaction mixture was stirred at 0 ℃ for 15min, tributyltin chloride (1.27g, 3.9mmol) was added, the reaction mixture was stirred at room temperature for 16h, saturated ammonium chloride solution (70mL) was poured and extracted with ethyl acetate (2X 100 mL). The combined organic layers were washed with brine (70mL) and dried (MgSO) ₄) And evaporated. The crude product was further purified by flash chromatography on an alumina column (ethyl acetate/heptane) to afford the title compound (0.47g, 24%) as a pale yellow oil. MS (ISP)649.2[ (M + H)⁺]。

Example G.7

4- (3-methyl-4-trifluoromethyl-phenyl) -2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

To a stirred solution of 2- (4-iodo-imidazol-1-yl) -6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidine (example e.73) (1.49g, 3.0mmol) in THF (21mL) at 0 ℃ was added isopropyl-magnesium chloride lithium chloride (1M in THF, 3.6mL, 3.6 mmol). The reaction mixture was stirred at 0 ℃ for 15min, tributyltin chloride (1.27g, 3.9mmol) was added, the reaction mixture was stirred at room temperature for 16h, saturated ammonium chloride solution (70mL) was poured and extracted with ethyl acetate (2X 100 mL). The combined organic layers were washed with brine (70mL) and dried (MgSO)₄) And evaporated. The crude product was further purified by flash chromatography on an alumina column (ethyl acetate)Ester/heptane) to give the title compound (0.33g, 17%) as a light brown oil. MS (ISP)663.3[ (M + H)⁺]。

Example G.8

4- (4-chloro-3-methyl-phenyl) -6-methyl-2- (4-tributylstannyl-imidazol-1-yl) -pyrimidine

To a stirred solution of 4- (4-chloro-3-methyl-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine (example e.76) (1.03g, 2.51mmol) in THF (20mL) at 0 ℃ was added isopropyl-magnesium chloride lithium chloride (1M in THF, 3.05mL, 3.05 mmol). The reaction mixture was stirred at 0 ℃ for 15min, tributyltin chloride (1.14g, 3.5mmol) was added, the reaction mixture was stirred at room temperature for 15h, saturated ammonium chloride solution (30mL) was poured and extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine (30mL) and dried (MgSO)₄) And evaporated. The crude product was further purified by flash chromatography on an alumina column (ethyl acetate/heptane) to afford the title compound (1.19g, 83%) as a yellow oil. MS (ISP)575.3[ (M + H)⁺]。

Example G.9

3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenylboronic acid

To a solution of 2- (3-bromo-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example E.21) (4.00g, 10.2mmol) and triisopropyl borate (2.23g, 11.8mmol) in THF (60mL) at-78 deg.C was added n-BuLi (1.6M in hexane, 6.50mL, 10.4mmol) maintaining the internal temperature below-65 deg.C. Stirring was continued at-78 deg.C for 45min, and triisopropyl borate (1.11g, 5.9mmol) and n-BuLi (1.6M in hexane, 3.25mL, 5.2mmol) were added again and stirring was continued at-78 deg.C for 30 min. Adding 1M saturated NaH ₂PO₄·2H₂The O solution, saturated with solid sodium chloride, was extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to give the title compound as a yellow solid (4.39g, 96%). MS (ISP)358.2[ (M + H)⁺]；mp 140℃(dec.)。

Example G.10

3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenylboronic acid

To a solution of 2- (3-bromo-phenyl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyridine (example e.90) (1.23g, 3.13mmol) in TBME (80mL) at-78 ℃ was added n-BuLi (1.6M hexane solution, 3.2mL, 5.0mmol), maintaining the internal temperature below-60 ℃ (about 3min), stirring was continued at-78 ℃ for 25min, triisopropyl borate (1.5mL, 6.27mmol) was added rapidly, allowing the internal temperature to rise to-60 ℃ and stirring continued at-78 ℃ for 20 min. The mixture was purified by adding 1M NaH₂PO₄·2H₂The O solution was quenched, the cooling bath was removed, and the mixture was warmed to 0 ℃ and stirred at 0 ℃ for 10 min. Dilute with EtOAc and brine, extract 3 times with EtOAc, and pass the combined organic layers over Na₂SO₄And (5) drying. The solvent was removed in vacuo to give the title compound as a pale brown foam (1.20g, 70.5%, purity: 65.8%), which was used without further purification. MS (ISP)358.2[ (M + H)⁺]。

Example G.11

2- (4-tributylstannyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine

To a solution of 2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example e.23) (4.83g, 10mmol) in THF (50mL) at 0 ℃ was added i-PrMgCl LiCl (1M in THF, 11mL, 11mmol) quickly and the mixture was stirred at 0 ℃ for 15 min. Then adding Bu₃SnCl (3.25mL, 12mmol), the cooling bath was removed and the mixture was stirred at 23 ℃ for 14 h. Pouring saturated NH₄Cl solution, extracted with EtOAc, washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to give a brown oil which was purified by flash column chromatography on silica eluting with heptane/EtOAc 4: 1 to give a yellow oil (4.42g, 62%, ca. 90% pure). MS (ISP)647.3[ (M + H)⁺]。

Example G.12

2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine

To a solution of 2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.93) (1.2g, 2.48mmol) in THF (15mL) at 0 ℃ was added i-PrMgCl LiCl (1M in THF, 3.0mL, 3.0mmol) quickly and the mixture was stirred at 0 ℃ for 15 min. Then adding Bu₃SnCl (0.94mL, 3.48mmol), the cooling bath was removed and the mixture was stirred at 23 ℃ for 48 h. Pouring saturated NH₄The Cl solution was extracted with EtOAc, washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to give a brown oil which was purified by alumina (neutral) column chromatography eluting with heptane/dichloromethane to give a yellow oil (1.7g, 106%, about 90% pure). MS (ISP)648.3[ (M + H) ⁺]。

Example G.13

4- (3, 4-difluoro-phenyl) -2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

To a stirred solution of 4- (3, 4-dichloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.78) (0.9g, 2.0mmol) in THF (14ml) at 0 ℃ was added isopropyl-magnesium chloride lithium chloride (1M in THF, 2.44ml, 2.44 mmol). The reaction mixture was stirred at 0 ℃ for 15min, tributyltin chloride (0.87g, 2.67mmol) was added, the reaction mixture was stirred at room temperature for 16h, saturated ammonium chloride solution (30ml) was poured in, and extraction was performed with ethyl acetate (2X 50 ml). The combined organic layers were washed with brine (30ml) and dried (MgSO)₄) And evaporated. The crude product was further purified by silica gel flash chromatography (ethyl acetate/heptane) to afford the title compound (0.42g, 34%) as a pale yellow oil. MS (ISP)616.9[ (M + H)⁺]。

Example G.14

4- (4-fluoro-phenyl) -2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

To a stirred solution of 4- (4-fluoro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example E.79) (0.87g, 2.0mmol) in THF (0 deg.C.) (14ml) was added isopropyl-magnesium chloride lithium chloride (1M in THF, 2.44ml, 2.44 mmol). The reaction mixture was stirred at 0 ℃ for 15min, tributyltin chloride (0.87g, 2.67mmol) was added, the reaction mixture was stirred at room temperature for 16h, saturated ammonium chloride solution (30ml) was poured in, and extraction was performed with ethyl acetate (2X 50 ml). The combined organic layers were washed with brine (30ml) and dried (MgSO) ₄) And evaporated. The crude product was further purified by silica gel flash chromatography (ethyl acetate/heptane) to afford the title compound (0.69g, 58%) as a pale yellow oil. MS (ISP)598.7[ (M + H)⁺]。

Example H.1

2-chloro-thiazole-5-sulfonic acid tert-butylamide

To a stirred saturated NaHCO solution obtained from commercial tert-butylamine (5.03g, 68.8mmol) at 0 deg.C (ice water bath)₃To the solution (35mL) and ethyl acetate (17mL) was added 2-chloro-thiazole-5-sulfonyl chloride solution [ CAS No. 88917-11-7](5.0g, 22.9 mmol). The reaction mixture was stirred at room temperature for 2h, and extracted by the addition of ethyl acetate (50 mL). The aqueous layer was extracted again with ethyl acetate (50 mL). The combined organic layers were washed with 2N HCl solution (40mL) and brine (40mL) and dried (MgSO 4)₄) And evaporated to give the title compound (4.9g, 84%) as a yellow solid. MS (ISN)253.1[ (M-H)^-]，mp 75℃。

Example H.2

5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1, 1-dimethyl-ethyl) -amide

To a solution of commercial 2-amino-2-methyl-1-propanol (478mg, 5mmol) and Et3N (0.75mL, 5mmol) in THF (50mL) at 0 deg.C was added 5-bromo-pyridine-3-sulfonyl chloride [ CAS No. 65001-21-0 ] in portions]According to J.org.chem.1989, 54(2), 389) (1.28g, 5mmol), the mixture is stirred at 23 ℃ for 1 h. The reaction was worked up by neutralization with 5% citric acid, extracted with EtOAc and saturated NaHCO ₃The solution and brine were washed, dried over sodium sulfate, filtered and concentrated to give a light brown solid which was triturated with heptane/ether to purify the title compound as a white solid (1.25g, 8)2％)。MS(ISP)309.2[(M+H)⁺]，311.1[(M+2+H)⁺]；mp 112℃。

Example H.3

3-bromo-N-methoxy-benzenesulfonamides

To commercial methoxyamine hydrochloride (1.96g, 23.4mmol) and 2MNa at 0 deg.C₂CO₃A solution (20mL, 40mmol) in THF (100mL) was added dropwise in portions to a commercial 3-bromobenzenesulfonyl chloride (2.5g, 9.8mmol) and the mixture was stirred at 23 ℃ for 18 h. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated to give a light brown solid which was refluxed with a solution of 1M NaOH (10mL) in dioxane (10mL) for 30min to cleave the disulfonylated product. Cool to room temperature, dilute with water, extract with EtOAc, wash the organic layer with brine, and dry over sodium sulfate. Removal of the solvent in vacuo afforded a light brown solid which was purified by trituration with heptane/ether to afford the title compound as a pale yellow solid (1.30g, 50%). MS (ISN)264.0[ (M-H)^-]And 266.0[ (M +2-H)^-]。

Example H.4

3-bromo-N- (2-hydroxy-1, 1-dimethyl-ethyl) -benzenesulfonamide

To a solution of commercial 2-amino-2-methyl-1-propanol (8.91g, 100mmol) in dioxane (20mL) at 5 deg.C was added commercial 3-bromobenzenesulfonyl chloride (2.88mL, 20mmol) and the mixture was stirred vigorously for 1h at 23 deg.C. 1N HCl was poured in, diluted with EtOAc, the phases were separated and the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to afford the title compound as a white solid (5.47g, 89%). MS (ISN)306.1[ (M-H) ^-]And 308.2[ (M +2-H)^-]；mp138℃。

Example H.5

2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide

To a stirred saturated NaHC obtained from commercial tert-butylamine (3.76mL, 35.5mmol) at 0 deg.C (ice bath)O₃To the solution (30mL) and ethyl acetate (50mL) was added 2-chloro-4-methyl-thiazole-5-sulfonyl chloride [ CAS No. 292138-59-1, commercially available](5.0g, 21.5mmol) of the resulting solution. The reaction mixture was stirred at room temperature for 16h, followed by extraction with ethyl acetate (50 mL). The aqueous layer was extracted again with ethyl acetate (50 mL). The combined organic layers were washed with 2N HCl solution (40mL) and brine (40mL) and dried (MgSO₄) And evaporated to give the title compound (4.57g, 79%) as a yellow solid. MS (ISN)267.3[ (M-H)^-]。

Example I.1

3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonyl chloride hydrochloride

1) Preparation of 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] according to general method VI using 2- (2-chloro-pyridin-4-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.6) (1.0g, 2.5mmol) and 3- (2, 2-dimethyl-propoxysulfonyl) -phenylboronic acid (example F.4) (1.09g, 4.0mmol)]-pyridin-2-yl } -benzenesulfonic acid 2, 2-dimethyl-propyl ester. An off-white solid was obtained (1.28g, 86%). MS (ISP)595.7[ (M + H) ⁺]；mp 168.5℃。

2) Stirring 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonic acid 2, 2-dimethyl-propyl ester (1.27g, 2.13mmol), 37% HCl (12.5ml) and dioxane (12.5ml) mixture was heated at reflux for 19h and evaporated to dryness. Diethyl ether (50ml) was added to the crude product and the mixture was stirred at room temperature for 1 h. The precipitate was collected by filtration and dried to give 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonate salt as a white solid (1.08g, 90%). MS (ISN)524.0[ (M-H)^-]；mp 407℃(dec.)。

3) Stirring 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonic acid hydrochloride (0.14g, 0.25mmol), thionyl chloride (2ml) and N, N-dimethylformamide (1 drop) were heated at reflux for 2h and evaporated to dryness to give the title compound as a light solidYellow solid (0.145, 100%) it was used without further purification. MS (EI)543.1[ (M)⁺]；mp171℃。

Example I.2

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonyl chloride

To 3- [6 '-methyl-4' - (4-trifluoromethyl-phenyl) - [2, 2 'at 23 deg.C']Bipyridin-6-yl]Suspension of benzenesulfonic acid (example 345) (2.0g, 4.25mmol) in DMF (20mL) was added thionyl chloride (1.54mL, 21.25mmol), the mixture was stirred at 23 ℃ for 2h, then SOCl was added again ₂(1.54mL, 21.25mmol) and the mixture was stirred at 23 ℃ for 1 h. Diluted with EtOAc and poured into ice-cold, half-saturated NaHCO₃In the solution, the phases were separated and the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to give the title compound as an off-white solid (2.0g, 98%), which was used without further purification. MS (ISP)489.2[ (M + H)⁺]And 491.1[ (M +2+ H)⁺]。

Example I.3

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonyl chloride

1) Preparation of 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl using 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.3) (1.35g, 3.02mmol) and 3- (2, 2-dimethyl-propoxysulfonyl) -phenylboronic acid (example F.4) (1.31g, 4.81mmol) according to general method VI]-biphenyl-3-sulfonic acid 2, 2-dimethyl-propyl ester. A white solid was obtained (1.43g, 80%). MS (ISP)594.6[ (M + H)⁺]；mp 157℃。

2) Stirring 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]A mixture of 2, 2-dimethyl-propyl (biphenyl-3-sulfonate) (1.42g, 2.39mmol), 2M sodium propoxide solution (3ml, 6mmol), 2- (diethylamino) -ethanethiol (0.37g, 2.75mmol) and dioxane (15ml) was heated at reflux for 24h and evaporated. Adding water (40ml), mixing The material was extracted with ethyl acetate (2X 50 ml). The combined organic layers were washed with water (50 ml). The aqueous layers were combined, acidified with 2N HCl and extracted with ethyl acetate (2X 50 ml). The two organic layers were combined, washed with brine (50ml), dried (MgSO)₄) And evaporated to give crude 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]Biphenyl-3-sulfonic acid as a brown solid (0.91g, 51%). Thionyl chloride (20ml) and DMF (4 drops) were added and the mixture was stirred under heating at reflux for 4h, evaporated and purified by silica gel flash chromatography (ethyl acetate/heptane) to give the title compound as a light brown solid (0.43g, 33%). MS (ISP)542.2[ (M)⁺]；mp176℃。

Examples of the Compounds of formula I according to the invention

Example 1

4- (4-chloro-phenyl) -2-imidazol-1-yl-6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.1) (0.15g, 0.5mmol) and imidazole obtained commercially (0.034g, 0.5 mmol). An off-white solid was obtained (0.063g, 39%). MS (EI)324.1[ (M)⁺]；mp 175℃。

Example 2

3- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-5-yl } -benzenesulfonamides

The title compound was prepared according to general procedure VI using 4- (4-chloro-phenyl) -N-hydroxy-6-trifluoromethyl-pyrimidine-2-carboxamidine (example c.1) (0.16g, 0.5mmol) and 3-sulfamoyl-benzoic acid obtained commercially (0.1g, 0.5 mmol). A white solid was obtained (0.1g, 43%). MS (ISP)482.1[ (M + H) ⁺]；mp 273℃。

Example 3

2-imidazol-1-yl-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.2) (0.16g, 0.5mmol) and imidazole obtained commercially (0.034g, 0.5 mmol). A white solid (0.07g, 39%) was obtained. MS (EI)358.0[ (M)⁺]；mp 162℃。

Example 4

2-pyrrol-1-yl-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.2) (0.16g, 0.5mmol) and commercial pyrrole (0.067g, 1.0 mmol). An off-white solid was obtained (0.04g, 22%). MS (EI)357.0[ (M)⁺]；mp 120.5℃。

Example 5

2- (4-pyridin-3-yl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

According to general procedure IVa, 2-chloro-4- (4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example A.2) (0.16g, 0.5mmol) and 3- (1H-imidazol-4-yl) -pyridine obtained commercially [ CAS number. 51746-85-1](0.073g, 0.5mmol) the title compound was prepared. Light brown solid (0.11g, 49%) was obtained. MS (ISP)436.1[ (M)⁺]；mp 200.5℃。

Example 6

4- (4-chloro-phenyl) -2-pyrrol-1-yl-6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example a.1) (0.15g, 0.5mmol) and commercial pyrrole (0.067g, 1.0 mmol). Light brown solid was obtained (0.12g, 74%). MS (EI)323.1[ (M)⁺]；mp 128.5℃。

Example 7

4- (4-chloro-phenyl) -2- (4-pyridin-3-yl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

According to general procedure IVa, 2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example A.1) (0.15g, 0.5mmol) and 3- (1H-imidazol-4-yl) -pyridine obtained commercially [ CAS number 51746-85-1](0.073g, 0.5mmol) the title compound was prepared. Light brown solid (0.09g, 45%) was obtained. MS (EI)401.1[ (M)⁺]；mp 228℃。

Example 8

4- {5- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general method V using 2-amino-N-hydroxy-pyridine-4-carboxamidine (example c.5) (0.11g, 0.75mmol) and 4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example d.1) (0.15g, 0.5 mmol). An off-white solid was obtained (0.018g, 9%). MS (ISP)419.0[ (M + H)⁺]；mp 223.5℃。

Example 9

5- {5- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure V using 6-amino-N-hydroxy-nicotinamidine (example c.3) (0.15g, 1.0mmol) and 4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example d.1) (0.15g, 0.5 mmol). Light brown solid (0.05g, 24%) was obtained. MS (ISP)419.0[ (M + H) ⁺]；mp 211℃。

Example 10

3- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-5-yl } -benzenesulfonamides

The title compound was prepared according to general procedure V using N-hydroxy-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxamidine (example c.2) (0.176g, 0.5mmol) and 3-sulfamoyl-benzoic acid obtained commercially (0.1g, 0.5 mmol). An off-white solid was obtained (0.11g, 42%). MS (ISN)514.1[ (M-H)^-]；mp 205℃。

Example 11

5- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure V using 6-amino-N-hydroxy-nicotinamidine (example c.3) (0.15g, 1.0mmol) and 4- (4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example d.2) (0.17g, 0.5 mmol). Pale yellow solid (0.13g, 24%) was obtained. MS (ISP)453.1[ (M + H)⁺]；mp 218.5℃。

Example 12

4- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure V using 2-amino-N-hydroxy-pyridine-4-carboxamidine (example c.5) (0.11g, 0.75mmol) and 4- (4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example d.2) (0.17g, 0.5 mmol). An off-white solid was obtained (0.13g, 57%). MS (ISP)453.1[ (M + H) ⁺]；mp 223.5℃。

Example 13

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.1) (0.44g, 1.0mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.22g, 1.0 mmol). A yellow solid (0.031g, 7%) was obtained. MS (ISP)451.0[ (M + H)⁺]；mp 286℃。

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine hydrochloride (1: 2)

The salt was prepared by treating the base with MeOH-HCl and ether. A pale yellow solid was obtained. mp305 ℃.

Example 14

5- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example e.2) (0.40g, 1.0mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.22g, 1.0 mmol). A yellow solid (0.095g, 23%) was obtained. MS (ISP)417.3[ (M + H) ⁺]；mp 254℃。

5- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine hydrochloride (1: 2)

The salt was prepared by treating the base with MeOH-HCl and ether. Obtained as a white solid. mp314 ℃.

Example 15

4- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-4-sulfamoyl-benzamidine [ CAS No. 4476-10-2]The title compound was prepared (0.16g, 0.75mmol) and 4- (4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.2) (0.17g, 0.5 mmol). White solid (0.026g, 10%) was obtained. MS (ISN)514.2[ (M-H)^-]；mp 302℃。

Example 16

3- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-3-sulfamoyl-benzamidine [ CAS number 9000-88-7]The title compound was prepared (0.16g, 0.75mmol) and 4- (4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.2) (0.17g, 0.5 mmol). White solid (0.099g, 38%) was obtained. MS (ISN)514.1[ (M-H)^-]；mp 204℃。

Example 17

4- {5- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-4-sulfamoyl-benzamidine [ CAS No. 4476-10-2 ]The title compound was prepared (0.16g, 0.75mmol) and 4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15g, 0.5 mmol). A white solid was obtained (0.038g, 16%). MS (ISN)480.1[ (M-H)^-]；mp 289.5℃。

Example 18

3- {5- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzeneSulfonamides

According to general procedure V, N-hydroxy-3-sulfamoyl-benzamidine [ CAS number 9000-88-7]The title compound was prepared (0.16g, 0.75mmol) and 4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.17g, 0.5 mmol). A white solid was obtained (0.18g, 75%). MS (ISN)480.1[ (M-H)^-]；mp 231℃。

Example 19

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-pyrazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-pyrazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.11) (0.44g, 1.0mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.22g, 1.0 mmol). A yellow solid (0.027g, 6%) was obtained. MS (ISP)451.1[ (M + H)⁺]；mp 206℃。

Example 20

5- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ]-[1，2，4]Oxadiazol-3-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure V using 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example c.4) (0.115g, 0.75mmol) and 4- (4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example d.2) (0.17g, 0.5 mmol). A white solid was obtained (0.14g, 62%). MS (EI)453.1[ (M)⁺]；mp 216℃。

Example 21

5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-5-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure V using N-hydroxy-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxamidine (example c.2) (0.176g, 0.5mmol) and commercially available 6-amino-nicotinic acid (0.07g, 0.5 mmol). An off-white solid was obtained (0.055g, 24%). MS (ISP)453.1[ (M + H)⁺]；mp 205℃。

Example 22

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-5-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 4- (4-chloro-phenyl) -N-hydroxy-6-trifluoromethyl-pyrimidine-2-carboxamidine (example c.1) (0.16g, 0.5mmol) and commercially available 6-amino-nicotinic acid (0.07g, 0.5 mmol). An off-white solid was obtained (0.059g, 28%). MS (ISP)418.9[ (M + H)⁺]；mp 191℃。

Example 23

5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ]-[1，2，4]Oxadiazol-5-yl } -thiophene-2-sulfonamides

According to general method V, N-hydroxy-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxamidine (example C.2) (0.176g, 0.5mmol) and commercially available 2-sulfamoyl-thiophene-5-carboxylic acid [ CAS number 7353-87-9](0.104g, 0.5mmol) the title compound was prepared. Pale yellow solid (0.12g, 46%) was obtained. MS (ISN)520.1[ (M-H)^-]；mp 258.5℃。

Example 24

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-5-yl } -thiophene-2-sulfonamides

Following general procedure VI, using 4- (4-chloro-phenyl) -N-hydroxy-6-trifluoromethyl-pyrimidine-2-carboxamidine (example C.1) (0.16g, 0.5mmol) and commercially available 2-sulfamoyl-thiophene-5-carboxylic acid [ CAS number. 7353-87-9](104mg, 0.5mmol) the title compound was prepared. Pale yellow solid (0.085g, 35%) was obtained. MS (ISN)486.1[ (M-H)^-]；mp 236.5℃。

Example 25

4- (4-chloro-phenyl) -2- (4-pyridin-4-yl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine

According to general procedure IVa, 2-chloro-4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example A.1) (0.15g, 0.5mmol) and 4- (1H-imidazol-4-yl) -pyridine [ CAS number 51746-87-3](0.073g, 0.5mmol) the title compound was prepared. A pale red solid was obtained (0.15g, 76%). MS (ISP)402.3[ (M + H) ⁺]；mp 269℃。

Example 26

5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl) phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.3) (0.22g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.14g, 0.65mmol) obtained commercially. An off-white solid was obtained (0.124g, 54%). MS (ISP)461.1[ (M + H)⁺]；mp 205℃。

Example 27

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

According to general method VI, 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example E.4) (0.21g, 0.5mmol) and commercially available 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxy-pyrimidine are employedHeteroborolan-2-yl) pyridine (0.14g, 0.65mmol) to prepare the title compound. An off-white solid was obtained (0.14g, 66%). MS (ISP)427.0[ (M + H)⁺]；mp 171℃。

Example 28

4- (4-chloro-phenyl) -2- (3-pyridin-4-yl- [1, 2, 4]Oxadiazol-5-yl) -6-trifluoromethyl-pyrimidine

According to general procedure V, N-hydroxy-4-pyridinecarboxamidine [ CAS No. 1594-57-6 ] obtained commercially is used]The title compound was prepared (0.103g, 0.75mmol) and 4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15g, 0.5 mmol). Pale yellow solid (0.088g, 44%) was obtained. MS (ISP)404.1[ (M + H) ⁺]；mp 187.5℃。

Example 29

4- (4-chloro-phenyl) -2- (3-pyridin-3-yl- [1, 2, 4]Oxadiazol-5-yl) -6-trifluoromethyl-pyrimidine

Following general procedure V, the available N-hydroxy-3-pyridinecarboxamidine [ CAS No. 1594-58-7 ] was used]The title compound was prepared (0.103g, 0.75mmol) and 4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15g, 0.5 mmol). A yellow solid (0.092g, 46%) was obtained. MS (ISP)404.4[ (M + H)⁺]；mp 168.5℃。

Example 30

4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine

Prepared according to general method VI using 4- (4-chloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-trifluoromethyl-pyrimidine (example E.5) (0.185g, 0.5mmol) and commercially available 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.14g, 0.65mmol)The target compound. Pale yellow solid (0.18g, 85%) was obtained. MS (ISP)428.0[ (M + H)⁺]；mp 227℃。

Example 31

4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine

The title compound was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.6) (0.202g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). Pale yellow solid (0.18g, 80%) was obtained. MS (ISP)462.0[ (M + H) ⁺]；mp 226℃。

Example 32

5- {1- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.7) (0.21g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.64 mmol). A yellow solid (0.031g, 7%) was obtained. MS (ISP)433.3[ (M + H)⁺]；mp 253.5℃。

5- {1- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine hydrochloride (1: 2)

The salt was prepared by treating the base with MeOH-HCl and ether. An off-white solid was obtained. mp298.5 ℃.

Example 33

2- (3-pyridin-3-yl-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

According to general method VI, 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine is used (example)E.3) (0.22g, 0.5mmol) and 3-pyridineboronic acid (0.08g, 0.65mmol) obtained commercially. White solid (0.154g, 69%) was obtained. MS (ISP)446.3[ (M + H)⁺]；mp 194℃。

Example 34

4- (4-chloro-phenyl) -2- (3-pyridin-3-yl-phenyl) -6-trifluoromethyl-pyrimidine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example E.4) (0.21g, 0.5mmol) and commercially available 3-pyridineboronic acid (0.08g, 0.65 mmol). A white solid was obtained (0.12g, 57%). MS (ISP)412.3[ (M + H)⁺]；mp 162℃。

Example 35

4- {5- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-4-sulfamoyl-benzamidine [ CAS No. 4476-10-2]The title compound was prepared (0.16g, 0.75mmol) and 6-difluoromethyl-4- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxylic acid (example D.3) (0.16g, 0.5 mmol). White solid (0.096g, 39%) was obtained. MS (ISP)498.3[ (M + H)⁺]；mp 307℃。

Example 36

5- {5- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general method V using 6-amino-N-hydroxy-nicotinamidine (example c.3) (0.15g, 1.0mmol) and 6-difluoromethyl-4- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxylic acid (example d.3) (0.16g, 0.5 mmol). To obtain a pale yellow solid (0.066g，30％)。MS(ISP)435.1[(M+H)⁺]；mp 219℃。

Example 37

2-pyridin-3-yl-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.2) (0.33g, 1.0mmol) and 3-pyridineboronic acid obtained commercially (0.184g, 1.5 mmol). Pale yellow solid (0.03g, 8%) was obtained. MS (ISP)370.1[ (M + H) ⁺]；mp 134℃。

Example 38

4-difluoromethyl-2-pyridin-4-yl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (4-difluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.5) (0.31g, 1.0mmol) and commercially available 4-pyridineboronic acid (0.184g, 1.5 mmol). A pale red solid was obtained (0.086g, 24%). MS (ISP)352.3[ (M + H)⁺]；mp 132.5℃。

Example 39

2-pyridin-4-yl-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure IVb using 2-chloro-4- (4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example a.2) (0.33g, 1.0mmol) and commercially available 4-pyridineboronic acid (0.184g, 1.5 mmol). A pale red solid was obtained (0.034g, 9%). MS (ISP)370.0[ (M + H)⁺]；mp 153.5℃。

Example 40

3- {5- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-3-sulfamoyl-benzamidine [ CAS number 9000-88-7]The title compound was prepared (0.16g, 0.75mmol) and 6-difluoromethyl-4- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxylic acid (example D.3) (0.16g, 0.5 mmol). A white solid was obtained (0.12g, 49%). MS (ISP)498.3[ (M + H)⁺]；mp 217.5℃。

EXAMPLE 41

5- {3- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.8) (0.22g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). An off-white solid was obtained (0.035g, 16%). MS (ISP)443.3[ (M + H)⁺]；mp 191℃。

Example 42

2- [3- (2, 6-dimethyl-pyridin-4-yl) -phenyl ] -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

According to general procedure IVc, 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.3) (0.45g, 1.0mmol) and 2, 6-dimethyl-4-iodo-pyridine [ CAS No. 22282-67-3](0.23g, 1.0mmol) the title compound was prepared. Pale yellow solid (0.057g, 12%) was obtained. MS (ISP)474.2[ (M + H)⁺]；mp 159℃。

Example 43

5- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -6-methyl-pyrimidine (example e.12) (0.14g, 0.4mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.088g, 0.4 mmol). Pale yellow solid (0.045) was obtained g，31％)。MS(ISP)363.1[(M+H)⁺]；mp 206-208℃。

Example 44

4- (4-chloro-phenyl) -6-methyl-2- (4-pyridin-3-yl-imidazol-1-yl) -pyrimidine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -6-methyl-pyrimidine (example e.12) (0.14g, 0.4mmol) and 3-pyridyl-boronic acid obtained commercially (0.049g, 0.4 mmol). Pale yellow solid (0.027g, 19%) was obtained. MS (ISN)346.1[ (M-H)^-]；mp 179-181℃。

Example 45

5- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -6-methyl-pyrimidine (example e.12) (0.28g, 0.8mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.18g, 0.8 mmol). An off-white solid was obtained (0.04g, 13%). MS (ISP)364.0[ (M + H)⁺]；mp 264-266℃。

Example 46

5- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.13) (0.31g, 0.8mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.18g, 0.8 mmol). An off-white solid was obtained (0.08g, 26%). MS (ISP)397.3[ (M + H) ⁺]；mp 230-232℃。

Example 47

5- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.13) (0.31g, 0.8mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.18g, 0.8 mmol). White solid (0.093g, 29%) was obtained. MS (ISP)398.0[ (M + H)⁺]；mp 267-269℃。

Example 48

4-methyl-2- (4-pyridin-3-yl-imidazol-1-yl) -6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.13) (0.31g, 0.8mmol) and 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.16g, 0.8 mmol). An off-white solid was obtained (0.012g, 4%). MS (ISP)382.3[ (M + H)⁺]；mp 208-210℃。

Example 49

5- {1- [4- (4-chloro-phenyl) -6-cyclopropyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -6-cyclopropyl-pyrimidine (example e.14) (0.30g, 0.8mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.18g, 0.8 mmol). An off-white solid was obtained (0.08g, 26%). MS (ISP)389.3[ (M + H) ⁺]；mp 220-222℃。

Example 50

4- (4-chloro-phenyl) -6-cyclopropyl-2- (4-pyridin-3-yl-imidazol-1-yl) -pyrimidine

According to general method VI, 2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -6-cyclopropyl-pyrimidine (example E.14) (0.15g, 0.4mmol) and 3- (4, 4, 5, 5-tetramethyl), obtained commercially-1, 3, 2-dioxaborolan-2-yl) pyridine (0.08g, 0.4mmol) to prepare the title compound. An off-white solid was obtained (0.015g, 10%). MS (ISP)374.0[ (M + H)⁺]；mp 180-182℃。

Example 51

5- {1- [4- (4-chloro-phenyl) -6-cyclopropyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -6-cyclopropyl-pyrimidine (example e.14) (0.30g, 0.8mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.18g, 0.8 mmol). White solid (0.093g, 37%) was obtained. MS (ISP)390.3[ (M + H)⁺]；mp 238-240℃。

Example 52

5- {1- [4- (4-chloro-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (4-chloro-phenyl) -pyrimidine (example e.15) (0.27g, 0.8mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.18g, 0.8 mmol). Obtained as a pale yellow solid (0.083g, 30%). MS (ISP)349.3[ (M + H) ⁺]；mp 188-190℃。

Example 53

5- {1- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine (example e.16) (0.90g, 1.86mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.491g, 2.23 mmol). A yellow solid (0.290g, 34%) was obtained. MS (ISP)451.1[ (M + H)⁺]；mp 262℃。

Example 54

5- {1- [ 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2-cyclopropyl-6- (4-iodo-imidazol-1-yl) -4- (4-trifluoromethyl-phenyl) -pyridine (example e.17) (1.0g, 2.2mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.628g, 2.85 mmol). An off-white solid was obtained (0.180g, 46%). MS (ISP)422.2[ (M + H)⁺]；mp233-235℃。

Example 55

2-imidazol-1-yl-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine

In the preparation of example e.18, the title compound was obtained as a by-product. White solid (0.08g, 21%) was obtained. MS (ISP)304.1[ (M + H) ⁺]；mp 158-160℃。

Example 56

5- {1- [6- (4-chloro-phenyl) -4-trifluoromethyl-pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-chloro-phenyl) -6- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-pyridine (example e.19) (1.35g, 3.0mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.792g, 3.6 mmol). Pale yellow solid (0.750g, 60%) was obtained. MS (ISP)416.3[ (M + H)⁺]And 418[ (M +2+ H)⁺]；mp 196℃(dec.)。

5- {1- [6- (4-chloro-phenyl) -4-trifluoromethyl-pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine hydrochloride (1: 2)

The salt was prepared by treating the base with MeOH-HCl and ether. As a white solid. mp > 255 ℃.

Example 57

2- (4-chloro-phenyl) -6- (4-pyridin-3-yl-imidazol-1-yl) -4-trifluoromethyl-pyridine

The title compound was prepared according to general procedure VI using 2- (4-chloro-phenyl) -6- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-pyridine (example e.19) (0.45g, 1.0mmol) and 3-pyridineboronic acid obtained commercially (0.32g, 2.6 mmol). A white solid was obtained (0.011g, 3%). MS (ISP)401.2[ (M + H)⁺]And 403[ (M +2+ H)⁺]。

Example 58

5- {1- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.18) (0.33g, 0.77mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.203g, 0.92 mmol). An off-white solid was obtained (0.100g, 33%). MS (ISP)396.1[ (M + H)⁺]；mp224-226℃。

Example 59

2- (3-pyridin-3-yl-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example e.20) (0.525g, 1.0mmol) and 3-pyridineboronic acid obtained commercially (0.16g, 1.3 mmol). A white solid was obtained (0.083g, 19%). MS (ISP)445.2[ (M + H)⁺]；mp 164-166℃。

Example 60

5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridin-2-ylamine

According to general method VI, 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example E.20) (0.525g, 1.0mmol) and commercially available2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.286g, 1.3mmol) the title compound was prepared. A white solid was obtained (0.10g, 22%). MS (ISP)460.2[ (M + H) ⁺]；mp 170-172℃。

Example 61

2-methyl-6- (3-pyridin-3-yl-phenyl) -4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.21) (0.392g, 1.00mmol) and 3-pyridineboronic acid obtained commercially (0.122g, 0.99 mmol). A white solid was obtained (0.080g, 27%). MS (ISP)391.1[ (M + H)⁺]；mp 89-106℃。

Example 62

5- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.21) (0.300g, 0.77mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.219g, 1.0 mmol). A white foam (0.15g, 48%) was obtained. MS (ISP)406.2[ (M + H)⁺]；mp 68-90℃。

Example 63

2-cyclopropyl-6- (3-pyridin-3-yl-phenyl) -4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.22) (0.392g, 0.72mmol) and 3-pyridineboronic acid obtained commercially (0.115g, 0.93 mmol). A white solid (0.120g, 40%) was obtained. MS (ISP)417.3[ (M + H) ⁺]；mp 100-104℃。

Example 64

5- {3- [ 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -6-cyclopropyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.22) (0.30g, 0.55mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.219g, 0.94 mmol). An off-white solid was obtained (0.250g, 80%). MS (ISP)432.3[ (M + H)⁺]；mp130-135℃。

Example 65

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example e.23) (0.525g, 1.09mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.286g, 1.3 mmol). A yellow solid (0.148g, 33%) was obtained. MS (ISP)450.2[ (M + H)⁺]；mp 245-247℃。

Example 66

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example e.23) (0.525g, 1.09mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.287g, 1.3 mmol). A yellow solid (0.100g, 24%) was obtained. MS (ISP)451.1[ (M) ⁺]；mp＞250℃。

Example 67

6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3'; 5', 3 "] terpyridin-6" -ylamine

According to the general procedure VI, the process,with 5 '-bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3']The title compound was prepared from bipyridine (example E.24) (0.15g, 0.38mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.092g, 0.42 mmol). A white solid was obtained (0.085g, 54%). MS (ISP)407.2[ (M + H)⁺]；mp 161-177℃。

Example 68

5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3 '] bipyridinyl-5' -yl ] -pyrimidin-2-ylamine

According to general method VI, 5 '-bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3']The title compound was prepared from bipyridine (example E.24) (0.15g, 0.38mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (0.093g, 0.42mm ol) obtained commercially. White solid was obtained (0.035g, 22%). MS (ISP)408.3[ (M + H)⁺]；mp 248-252℃。

Example 69

6-cyclopropyl-4- (4-trifluoromethyl-phenyl) - [2, 3'; 5', 3 "] terpyridin-6" -ylamine

According to general method VI, 5 ' -bromo-6-cyclopropyl-4- (4-trifluoromethyl-phenyl) - [2, 3 ' is employed ' ]The title compound was prepared from bipyridine (example E.25) (0.15g, 0.36mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.087g, 0.40 mmol). A white solid was obtained (0.080g, 51%). MS (ISP)433.3[ (M + H)⁺]；mp 207-209℃。

Example 70

5- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine

According to general method VI, 2- (3-bromo-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example E.21) (0.150g, 0.39mmol) and commercially available 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxanBoroacyclopentane-2-yl) pyrimidine (0.093g, 0.42mmol) the title compound was prepared. A white solid was obtained (0.10g, 64%). MS (ISP)407.3[ (M + H)⁺]；mp 215-217℃。

Example 71

6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2'; 6', 3 "] terpyridin-6" -ylamine

According to general method VI, 6 ' -bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2 ' is employed ']The title compound was prepared from bipyridine (example E.26) (0.150g, 0.38mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.092g, 0.42 mmol). A white solid was obtained (0.080g, 51%). MS (ISP)407.3[ (M + H) ⁺]；mp 208-211℃。

Example 72

5- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -pyrimidin-2-ylamine

According to general method VI, 6 ' -bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2 ' is employed ']The title compound was prepared from bipyridine (example E.26) (0.150g, 0.38mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (0.092g, 0.42 mmol). A white solid was obtained (0.080g, 57%). MS (ISP)407.3[ (M + H)⁺]；mp 219-222℃。

Example 73

4- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

According to general method VI, 6 ' -bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2 ' is employed ']Bipyridine (example E.26) (0.150g, 0.38mmol) and 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ] obtained commercially]Dioxaborolan-2-yl) -benzenesulfonamide [ CAS number. 214360-51-7(0.142g, 0.42mmol) the title compound was prepared. A white solid was obtained (0.070g, 44%). MS (ISP)470.0[ (M + H)⁺]；mp 215-227℃。

Example 74

4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4'; 2', 3 "] terpyridin-6" -ylamine

According to general method VI, 2 ' -chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ' ]The title compound was prepared from bipyridine (example E.27) (0.286g, 0.75mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.234g, 1.2 mmol). A yellow solid was obtained (0.343g, 97%). MS (ISP)461.3[ (M + H)⁺]；mp194-196℃。

Example 75

6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4'; 2', 3 "] terpyridin-6" -ylamine

According to general method VI, 2 ' -chloro-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']The title compound was prepared from bipyridine (example E.28) (0.300g, 0.86mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.246g, 1.26 mmol). A white solid (0.140g, 40%) was obtained. MS (ISP)407.2[ (M + H)⁺]；mp 172-190℃。

Example 76

5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -pyrimidin-2-ylamine

According to general method VI, 2 ' -chloro-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']The title compound was prepared from bipyridine (example E.28) (0.300g, 0.86mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (0.247g, 1.26 mmol). A white solid (0.110g, 31%) was obtained. MS (ISP)408.3[ (M + H) ⁺]；mp＞245℃。

Example 77

6-cyclopropyl-4- (4-trifluoromethyl-phenyl) - [2, 4'; 2', 3 "] terpyridin-6" -ylamine

According to general method VI, 2 ' -chloro-6-cyclopropyl-4- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']The title compound was prepared from bipyridine (example E.29) (0.300g, 0.80mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.229g, 1.17 mmol). A white solid was obtained (0.060g, 17%). MS (ISP)433.1[ (M + H)⁺]；mp 172-174℃。

Example 78

5- [ 6-cyclopropyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -pyrimidin-2-ylamine

According to general method VI, 2 ' -chloro-6-cyclopropyl-4- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']The title compound was prepared from bipyridine (example E.29) (0.300g, 0.80mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (0.230g, 1.17 mmol). A white solid was obtained (0.100g, 28%). MS (ISP)434.1[ (M + H)⁺]；mp 242-245℃。

Example 79

2-methyl-6- (3-pyridin-4-yl-phenyl) -4- (4-trifluoromethyl-phenyl) -pyridine

According to general method VI, trifluoro-methanesulfonic acid 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester (example A.32) (0.250g, 0.65mmol) and 3-pyridin-4-yl-phenylboronic acid [ CAS No. 337536-25-1 ](0.143g, 0.71mmol) the title compound was prepared. A white solid (0.101g, 40%) was obtained. MS (ISP)391.1[ (M + H)⁺]；mp 143-147℃。

Example 80

5- {1- [4- (4-chloro-phenyl) -6-methyl-pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

According to general method VI, 4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyridine (example E.30) (0.200g, 0.51mmol) andthe title compound was prepared from commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.122g, 0.62 mmol). White solid was obtained (0.035g, 19%). MS (ISP)362.3[ (M + H)⁺]And 364[ (M +2+ H)⁺]；mp 230-233℃。

Example 81

4- (4-chloro-phenyl) -6-methyl- [2, 3'; 5', 3 "] terpyridin-6" -ylamine

According to general method VI, 5 '-bromo-4- (4-chloro-phenyl) -6-methyl- [2, 3']The title compound was prepared from bipyridine (example E.31) (0.600g, 1.6mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.404g, 1.8 mmol). A white solid was obtained (0.180g, 29%). MS (ISP)373.2[ (M + H)⁺]And 375[ (M +2+ H)⁺]；mp188-192℃。

Example 82

5- {3- [4- (4-chloro-phenyl) -6-methyl-pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-methyl-pyridine (example e.32) (0.075g, 0.20mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.051g, 0.2 mmol). White solid was obtained (0.035g, 45%). MS (ISP)373.2[ (M + H)⁺]And 375[ (M +2+ H)⁺]；mp197-199℃。

Example 83

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide

Following general procedure VI, using 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example E.20) (0.223g, 0.5mmol) and 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -benzenesulfonamide obtained commercially [ CAS No. 486422-08-6](0.283g, 1.0mmol) to prepare theA target compound. Light brown solid (0.125g, 43%) was obtained. MS (ISP)523.3[ (M + H)⁺]；mp 176-179℃。

Example 84

4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3' ] bipyridinyl

The title compound was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-trifluoromethyl-pyrimidine (example e.5) (0.185g, 0.5mmol) and 3-pyridineboronic acid obtained commercially (0.08g, 0.65 mmol). A white solid was obtained (0.018g, 9%). MS (ISP)413.1[ (M + H) ⁺]；mp 226℃。

Example 85

4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3' ] bipyridinyl

The title compound was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.6) (0.202g, 0.5mmol) and commercially available 3-pyridineboronic acid (0.08g, 0.65 mmol). A white solid was obtained (0.013g, 6%). MS (ISP)447.0[ (M + H)⁺]；mp 247℃。

Example 86

4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 4' ] bipyridinyl

The title compound was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-trifluoromethyl-pyrimidine (example e.5) (0.185g, 0.5mmol) and commercially available 4-pyridineboronic acid (0.08g, 0.65 mmol). Pale yellow solid (0.06g, 29%) was obtained. MS (ISP)413.0[ (M + H)⁺]；mp 193℃。

Example 87

5- {1- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

According to general method VI, 2- (4-bromo) is used-imidazol-1-yl) -4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example E.9) (0.24g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65mmol) the title compound was prepared. A yellow solid (0.038g, 15%) was obtained. MS (ISP)495.3[ (M + H) ⁺]；mp 266.5℃。

Example 88

4- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine

The title compound was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.10) (0.19g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). Pale yellow solid was obtained (0.021g, 9%). MS (ISP)444.4[ (M + H)⁺]；mp 210℃。

Example 89

4- {5- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-4-sulfamoyl-benzamidine [ CAS No. 4476-10-2]The title compound was prepared (0.16g, 0.75mmol) and 4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.4) (0.19g, 0.5 mmol). Pale yellow solid (0.114g, 41%) was obtained. MS (ISP)560.2[ (M + H)⁺]；mp 250.5℃。

Example 90

5- {5- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure V using 6-amino-N-hydroxy-nicotinamidine (example c.3) (0.15g, 1.0mmol) and 4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example d.4) (0.19g, 0.5 mmol). Pale yellow solid (0.076g, 31%) was obtained. MS (ISP)497.3[ (M + H) ⁺]；mp 216℃。

Example 91

3- {5- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-3-sulfamoyl-benzamidine [ CAS number 9000-88-7]The title compound was prepared (0.16g, 0.75mmol) and 4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.4) (0.19g, 0.5 mmol). A white solid was obtained (0.05g, 18%). MS (ISP)560.0[ (M + H)⁺]；mp 227℃。

Example 92

4- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine

The title compound was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.33) (0.224g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). Pale yellow solid (0.155g, 61%) was obtained. MS (ISP)506.1[ (M + H)⁺]；mp 222℃。

Example 93

5- {3- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.34) (0.25g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). An off-white solid was obtained (0.157g, 62%). MS (ISP)505.3[ (M + H) ⁺]；mp 208℃。

Example 94

5- {1- [4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example 35) (0.23g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). A yellow solid was obtained (0.065g, 28%). MS (ISP)469.2[ (M + H)⁺]；mp 309℃。

Example 95

N- (5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-yl) -acetamide

Stirring 5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]A solution of (0.314g, 0.7mmol) of (E) -1H-imidazol-4-yl } -pyridin-2-ylamine (example 13) in acetic anhydride (6ml) was heated at 120 ℃ for 1H. Diethyl ether (10ml) was added to the cooled reaction mixture, and the precipitate was collected by filtration and dried to give the title compound as a pale yellow solid (0.29g, 84%). MS (ISP)493.3[ (M + H)⁺]；mp 314℃。

Example 96

5- {3- [4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

According to general procedure VI, 2- (3-bromo-phenyl) -4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl- The title compound was prepared from pyrimidine (example E.36) (0.23g, 0.5mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.14g, 0.65 mmol). Pale yellow solid (0.19g, 79%) was obtained. MS (ISP)479.0[ (M + H)⁺]；mp 212℃。

Example 97

5- {3- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general method VI using 2- (3-bromo-phenyl) -4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example e.37) (0.13g, 0.29mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.083g, 0.38 mmol). An off-white solid was obtained (0.07g, 52%). MS (ISP)461.3[ (M + H)⁺]；mp 179℃。

Example 98

4- {5- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-4-sulfamoyl-benzamidine [ CAS No. 4476-10-2]The title compound was prepared (0.16g, 0.74mmol) and 4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example d.6) (0.17g, 0.50 mmol). Pale yellow solid was obtained (0.042g, 16%). MS (ISP)516.1[ (M + H) ⁺]；mp 302.5℃。

Example 99

3- {5- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to the general method V, N-hydroxy-3-sulfamoyl-benzamidine [ CAS number 9000-88-7]The title compound was prepared (0.16g, 0.74mmol) and 4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example d.6) (0.17g, 0.50 mmol). Pale yellow solid (0.055g, 21%) was obtained. MS (ISP)516.1[ (M + H)⁺]；mp 258℃。

Example 100

5- {5- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure V using 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example c.4) (0.114g, 0.75mmol) and 4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example d.6) (0.17g, 0.5 mmol). Pale yellow solid (0.11g, 49%) was obtained. MS (ISP)453.1[ (M + H)⁺]；mp 227℃。

Example 101

5- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyrimidinyl-2' -yl ] -pyridin-2-ylamine

According to general method VI, 2 ' -chloro-6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']The title compound was prepared from bipyrimidine (example E.42) (g, 0.5mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.14g, 0.65 mmol). Pale yellow solid (0.17g,%) was obtained. MS (ISP)463.1[ (M + H) ⁺]；mp 236.5℃。

Example 102

5- {1- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

According to general procedure VI, 2- (4-bromo-imidazol-1-yl) -4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example E.39) (0.22g, 0.5mmol) and commercially available 2-amino-5- (4, 4, 5, 5-)Tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.14g, 0.65mmol) to prepare the title compound. A yellow solid (0.022g, 10%) was obtained. MS (ISP)451.1[ (M + H)⁺]；mp 282.5℃。

Example 103

4- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine

The title compound was prepared according to general procedure VI using 4- (3, 4-dichloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-trifluoromethyl-pyrimidine (example e.38) (0.20g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). Light brown solid (0.15g, 63%) was obtained. MS (ISP)462.1[ (M + H)⁺]；mp 224.5℃。

Example 104

5- {1- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.40) (0.21g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). A yellow solid (0.096g, 45%) was obtained. MS (ISP)431.2[ (M + H) ⁺]；mp 276℃。

Example 105

5- {3- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.41) (0.21g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). A white solid (0.13g, 60%) was obtained. MS (ISP)441.1[ (M +)H)⁺]；mp 168.5℃。

Example 106

3- {5- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-3-sulfamoyl-benzamidine [ CAS number 9000-88-7]The title compound was prepared (0.16g, 0.74mmol) and 4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.7) (0.16g, 0.50 mmol). A white solid was obtained (0.046g, 19%). MS (ISP)496.2[ (M + H)⁺]；mp 246℃。

Example 107

5- {5- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure V using 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example c.4) (0.114g, 0.75mmol) and 4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example d.7) (0.16g, 0.5 mmol). Pale yellow solid (0.11g, 52%) was obtained. MS (ISP)433.2[ (M + H) ⁺]；mp 199.5℃。

Example 108

4- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine

The title compound was prepared according to general procedure VI using 4- (4-chloro-3-methyl-phenyl) -2- (2-chloro-pyridin-4-yl) -6-trifluoromethyl-pyrimidine (example e.43) (0.19g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). A yellow solid (0.16g, 72%) was obtained. MS (IS)P)442.3[(M+H)⁺]；mp 207℃。

Example 109

5- {3- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-methyl-pyrimidine (example e.44) (0.18g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). A white solid was obtained (0.090g, 48%). MS (ISP)373.0[ (M + H)⁺]；mp 168.5℃。

Example 110

5- {3- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-methyl-pyrimidine (example e.44) (0.18g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.14g, 0.65 mmol). A white solid was obtained (0.055g, 29%). MS (ISP)374.1[ (M + H) ⁺]；mp 228℃。

Example 111

4- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -phenylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.1) (0.22g, 0.5mmol) and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline obtained commercially (0.14g, 0.65 mmol). A brown solid was obtained (0.032g, 14%). MS (ISP)450.1[ (M + H)⁺]；mp 270℃。

Example 112

4- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' ylamine

The title compound was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-methyl-pyrimidine (example e.45) (0.158g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). An off-white solid was obtained (0.032g, 17%). MS (ISP)374.0[ (M + H)⁺]；mp 199℃。

Example 113

4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine

The title compound was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.46) (0.175g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). An off-white solid was obtained (0.021g, 10%). MS (ISP)408.3[ (M + H) ⁺]；mp 232℃。

Example 114

{ 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-4-yl } -methanol

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.3) (0.22g, 0.5mmol) and commercially available 4-hydroxymethyl-phenyl-boronic acid (0.09g, 0.6 mmol). A white solid was obtained (0.199g, 54%). MS (ISP)475.1[ (M + H)⁺]；mp 171℃。

Example 115

5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -pyrimidin-2-ylamine

According to general method VI, 2- (3-bromo-phenyl) -4- (4-trifluoromethyl-phenyl) -6-methyl-pyrimidine (example E.47) (0.175g, 0.5mmol) and commercially available 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxanBoroacyclopentane-2-yl) pyrimidine (0.14g, 0.65mmol) the title compound was prepared. An off-white solid was obtained (0.021g, 10%). MS (ISP)408.3[ (M + H)⁺]；mp 290℃。

Example 116

5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-trifluoromethyl-phenyl) -6-methyl-pyrimidine (example e.47) (0.197g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). An off-white solid was obtained (0.097g, 48%). MS (ISP)407.3[ (M + H) ⁺]；mp 224℃。

Example 117

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-4-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.3) (0.22g, 0.5mmol) and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline obtained commercially (0.13g, 0.59 mmol). Pale yellow solid (0.174g, 76%) was obtained. MS (ISP)460.3[ (M + H)⁺]；mp 186℃。

Example 118

4- {5- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-4-sulfamoyl-benzamidine [ CAS No. 4476-10-2]The title compound was prepared (0.12g, 0.55mmol) and 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxylic acid (example D.8) (0.104g, 0.37 mmol). A white solid was obtained (0.025g, 15%). MS (ISP)462.4[ (M+H)⁺]；mp 326℃。

Example 119

5- {3- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.49) (0.23g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). Pale yellow solid was obtained (0.174g, 73%). MS (ISP)475.1[ (M + H) ⁺]；mp 207℃。

Example 120

5- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.48) (0.23g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). A yellow solid (0.084g, 36%) was obtained. MS (ISP)465.3[ (M + H)⁺]；mp 290℃。

Example 121

4- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine

The title compound was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.50) (0.15g, 0.36mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.103g, 0.47 mmol). Pale yellow solid (0.144g, 84%) was obtained. MS (ISP)476.0[ (M + H)⁺]；mp 223℃。

Example 122

5- {1- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl) 1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidine (example e.51) (0.20g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). Light brown solid (0.034g, 17%) was obtained. MS (ISP)411.0[ (M + H)⁺]；mp 247.5℃。

Example 123

5- {1- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidine (example e.51) (0.20g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.14g, 0.65 mmol). Light brown solid was obtained (0.022g, 11%). MS (ISP)412.4[ (M + H)⁺]；mp 248℃。

Example 124

5- {3- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.49) (0.23g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.14g, 0.65 mmol). An off-white solid was obtained (0.186g, 78%). MS (ISP)476.1[ (M + H) ⁺]；mp 244℃。

Example 125

5- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.48) (0.23g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.14g, 0.65 mmol). A yellow solid (0.168g, 72%) was obtained. MS (ISP)466.1[ (M + H)⁺]；mp 297℃。

Example 126

3- {5- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-3-sulfamoyl-benzamidine [ CAS number 9000-88-7]The title compound was prepared (0.16g, 0.74mmol) and 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxylic acid (example D.8) (0.14g, 0.50 mmol). White solid (0.097g, 42%) was obtained. MS (ISP)462.1[ (M + H)⁺]；mp 240.5℃。

Example 127

5- {5- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure V using 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example c.4) (0.15g, 1.0mmol) and 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine-2-carboxylic acid (example d.8) (0.14g, 0.5 mmol). Obtained as a pale yellow solid (0.075g, 38%). MS (ISP)399.3[ (M + H) ⁺]；mp 216.5℃。

Example 128

4- {5- [4- (3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]IIAzol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-4-sulfamoyl-benzamidine [ CAS No. 4476-10-2]The title compound was prepared (0.14g, 0.65mmol) and 4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.9) (0.175g, 0.5 mmol). A white solid was obtained (0.147g, 56%). MS (ISN)528.3[ (M-H)^-]；mp 261℃。

Example 129

3- {5- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]IIAzol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-3-sulfamoyl-benzamidine [ CAS number 9000-88-7]The title compound was prepared (0.14g, 0.65mmol) and 4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.9) (0.175g, 0.5 mmol). A white solid was obtained (0.15g, 57%). MS (ISN)528.3[ (M-H)^-]；mp 223.5℃。

Example 130

5- {5- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-[1，2，4]IIAzol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure V using 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example c.4) (0.152g, 1.0mmol) and 4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine-2-carboxylic acid (example d.9) (0.175g, 0.5 mmol). An off-white solid was obtained (0.157g, 67%). MS (ISP)467.1[ (M + H) ⁺]；mp 223℃。

Example 131

4- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine

The title compound was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidine (example e.52) (0.11g, 0.27mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.079g, 0.36 mmol). Light brown solid (0.021g, 18%) was obtained. MS (ISP)422.1[ (M + H)⁺]；mp 188℃。

Example 132

5- {3- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidine (example e.53) (0.11g, 0.3mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.087g, 0.4 mmol). Light brown solid was obtained (0.028g, 22%). MS (ISP)421.1[ (M + H)⁺]；mp153℃。

Example 133

5- (3- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } -phenyl) -pyridin-2-ylamine

According to general method VI, 2- (3-bromo-phenyl) -4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl is used ]The title compound was prepared from (e.55) (0.273g, 0.5mmol) 6-trifluoromethyl-pyrimidine (example E.55) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.13g, 0.6mmol) obtained commercially. An off-white solid was obtained (0.20g, 73%). MS (ISP)559.2[ (M + H)⁺]；mp 220℃。

Example 134

5- (1- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } -1H-imidazol-4-yl) -pyridin-2-ylamine

According to general method VI, 2- (4-bromo-imidazol-1-yl) -4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl is used]The title compound was prepared from (E.54) (0.268g, 0.5mmol) 6-trifluoromethyl-pyrimidine (example E.54) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.13g, 0.6mmol) obtained commercially. A yellow solid (0.056g, 20%) was obtained. MS (ISP)549.2[ (M + H)⁺]；mp 285℃。

Example 135

4- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } - [2, 3 '] bipyridinyl-6' -ylamine

According to general method VI, 2- (2-chloro-pyridin-4-yl) -4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl is used]The title compound was prepared from (e.g.. 6) -trifluoromethyl-pyrimidine (example E.56) (0.25g, 0.5mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.13g, 0.6 mmol). Light brown solid was obtained (0.21g, 77%). MS (ISP)560.0[ (M + H) ⁺]；mp 223℃。

Example 136

4- {5- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-4-sulfamoyl-benzamidine [ CAS No. 4476-10-2]The title compound was prepared (0.16g, 0.75mmol) and 4- (4-chloro-phenyl) -6-methyl-pyrimidine-2-carboxylic acid (example D.10) (0.124g, 0.5 mmol). An off-white solid was obtained (0.032g, 15%). MS (ISN)426.1[ (M-H)^-]；mp 297℃。

Example 137

5- {5- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure V using 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example c.4) (0.152g, 1.0mmol) and 4- (4-chloro-phenyl) -6-methyl-pyrimidine-2-carboxylic acid (example d.10) (0.124g, 0.5 mmol). A white solid was obtained (0.024g, 13%). MS (ISP)365.3[ (M + H)⁺]；mp 258℃。

Example 138

5- (3- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } -phenyl) -pyrimidin-2-ylamine

According to general method VI, 2- (3-bromo-phenyl) -4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl is used]The title compound was prepared from (6-trifluoromethyl-pyrimidine (example E.55) (0.273g, 0.5mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (0.14g, 0.65 mmol). An off-white solid was obtained (0.19g, 68%). MS (ISP)560.2[ (M + H) ⁺]；mp 250℃。

Example 139

5- {1- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (3-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.57) (0.22g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.13g, 0.6 mmol). A yellow solid (0.106g, 47%) was obtained. MS (ISP)452.0[ (M + H)⁺]；mp 223℃。

Example 140

5- {3- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine (example e.58) (0.2g, 0.45mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.12g, 0.54 mmol). A yellow solid (0.14g, 68%) was obtained. MS (ISP)461.3[ (M + H)⁺]；mp 162℃。

Example 141

4- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine

The title compound was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine (example e.59) (0.202g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.13g, 0.6 mmol). Pale yellow solid (0.19g, 81%) was obtained. MS (ISP)462.0[ (M + H) ⁺]；mp 196℃。

Example 142

5- { 2-methyl-1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-2-methyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.60) (0.23g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.13g, 0.6 mmol). A yellow solid (0.11g, 47%) was obtained. MS (ISP)465.3[ (M + H)⁺]；mp 285℃。

Example 143

5- { 2-methyl-1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-2-methyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.60) (0.23g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.13g, 0.6 mmol). A yellow solid (0.135g, 58%) was obtained. MS (ISP)466.3[ (M + H)⁺]；mp 286.5℃。

Example 144

5- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine (example e.61) (0.16g, 0.42mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.12g, 0.54 mmol). A yellow solid was obtained (0.043g, 26%). MS (ISP)398.1[ (M + H) ⁺]；mp 255.5℃。

Example 145

5- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine (example e.61) (0.16g, 0.42mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.12g, 0.54 mmol). A yellow solid (0.06g, 36%) was obtained. MS (ISP)397.1[ (M + H)⁺]；mp 213℃。

Example 146

4- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] - [2, 3 '] bipyridinyl-6' -ylamine

According to general method VI, 2- (2-chloro-pyridin-4-yl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine (example E.63) (0.15g, 0.43mmol) andcommercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.12g, 0.54mmol) produced the title compound. A yellow solid (0.11g, 63%) was obtained. MS (ISP)408.4[ (M + H)⁺]；mp 205℃。

Example 147

5- {3- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine (example e.62) (0.2g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.14g, 0.65mmol) obtained commercially. An off-white solid was obtained (0.11g, 54%). MS (ISP)407.4[ (M + H) ⁺]；mp 170.5℃。

Example 148

2- (3-pyridin-4-yl- [1, 2, 4] triazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

According to general procedure IVa, 2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example A.2) (0.16g, 0.5mmol) and 4- (1H- [1, 2, 4 mmol) are used]-triazol-3-yl) -pyridine [ CAS number 14803-99-7](0.075g, 0.51mmol) the title compound was prepared. White solid (0.096g, 44%) was obtained. MS (ISP)437.3[ (M + H)⁺]；mp 248℃。

Example 149

2- (3-pyridin-3-yl- [1, 2, 4] triazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

According to general procedure IVa, 2-chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example A.2) (0.16g, 0.5mmol) and 3- (1H- [1, 2, 4 mmol) are employed]-triazol-3-yl) -pyridine [ CAS No. 23195-63-3](0.075g, 0.51mmol) the title compound was prepared. Light brown solid was obtained (0.095g, 44%). MS (ISP)437.3[ (M + H)⁺]；mp 190℃。

Example 150

5- { 2-methyl-1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-2-methyl-imidazol-1-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.64) (0.2g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). Pale yellow solid (0.11g, 55%) was obtained. MS (ISP)411.0[ (M + H) ⁺]；mp 227.5℃。

Example 151

5- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H- [1, 2, 4] triazol-3-yl } -pyridin-2-ylamine

According to general method VI, 2- (3-chloro- [1, 2, 4)]Triazol-1-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.65) (0.17g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.14g, 0.65mmol) obtained commercially were used to prepare the title compound. Light brown solid was obtained (0.032g, 16%). MS (ISP)398.1[ (M + H)⁺]；mp 244℃。

Example 152

5- {1- [ 4-isopropyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4-isopropyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.66) (0.21g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.14g, 0.65 mmol). Pale yellow solid (0.125g, 59%) was obtained. MS (ISP)425.3[ (M + H)⁺]；mp274.5℃。

Example 153

5- {1- [ 4-isopropyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-imidazol-1-yl) -4-isopropyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.66) (0.21g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.14g, 0.65 mmol). An off-white solid was obtained (0.052g, 24%). MS (ISP)426.1[ (M + H) ⁺]；mp277℃。

Example 154

5- { 5-methyl-1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-iodo-5-methyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.67) (0.25g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.13g, 0.6 mmol). A yellow solid (0.12g, 50%) was obtained. MS (ISP)465.1[ (M + H)⁺]；mp 252℃。

Example 155

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.3) (0.45g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A white solid was obtained (0.48g, 83%). MS (ISP)580.3[ (M + H)⁺]；mp 200℃。

Example 156

N-tert-butyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

According to general method VI, 2- (2-chloro-pyridin-4-yl) -4-trifluoromethyl-6- (4-trifluoro-methyl) Methyl-phenyl) -pyrimidine (example E.6) (0.404g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2mmol) the title compound was prepared. An off-white solid was obtained (0.51g, 88%). MS (ISP)581.3[ (M + H)⁺]；mp 211℃。

Example 157

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

To ice-cooled and stirred 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-Biphenyl-3-sulfonic acid tert-butylamide (example 155) (0.38g, 0.65mmol) in dichloromethane (5mL) TFA (5mL) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as a white solid (0.31g, 90%). MS (ISN)522.3[ (M-H)^-]；mp 267℃。

Example 158

3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To ice-cooled and stirred N-tert-butyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonamide (example 156) (0.4g, 0.69mmol) in dichloromethane (5mL) TFA (5mL) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as an off-white solid (0.31g, 90%). MS (ISN)523.7[ (M-H)^-]；mp 237℃。

Example 159

4- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-4- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.68) (0.48g, 1.0mmol) and 4- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A light brown solid (0.043g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-4- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]To a solution of-1H-imidazol-4-yl } -benzenesulfonamide (0.043g) in dichloromethane (1.5mL) was added TFA (1.5mL), and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (2mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as an off-white solid (0.029g, 6%). MS (ISP)514.3[ (M + H) ⁺]；mp 292℃。

Example 160

3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.68) (0.73g, 1.5mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.46g, 1.8 mmol). A light brown solid (0.128g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.128g) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness, purified by flash chromatography (heptane/ethyl acetate) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solidBody (0.079g, 10%). MS (ISP)514.3[ (M + H)⁺]；mp 198℃。

Example 161

5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.3) (0.45g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.41g, 1.2 mmol). A light brown solid (0.44g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.44g) in dichloromethane (7mL) was added TFA (7mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness, purified by flash chromatography (heptane/ethyl acetate) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as an off-white solid (0.2g, 38%). MS (ISN)528.0[ (M-H)^-]；mp 204℃。

Example 162

5- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide

The title compound was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.6) (0.404g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example f.1) (0.41g, 1.2 mmol). An off-white solid was obtained (0.24g, 41%). MS (ISN)585.2[ (M-H)^-]；mp 237℃。

Example 163

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

1) 5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.68) (0.73g, 1.5mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.62g, 1.8 mmol). A light brown solid (0.43g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]To a solution of-1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.43g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness, purified by flash chromatography (heptane/ethyl acetate) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.062g, 8%). MS (ISN)518.3[ (M-H)^-]；mp 281℃。

Example 164

5- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

To the cooled and stirred 5- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]-pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide (example 162) (0.2g, 0.34mmol) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) to give the title compound as an off-white solid (0.12g, 67%). MS (ISN)529.3[ (M-H)^-]；mp 262℃。

Example 165

3' - [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-trifluoromethyl-phenyl) -6-methyl-pyrimidine (example e.47) (0.39g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A white solid was obtained (0.4g, 76%). MS (ISP)526.3[ (M + H) ⁺]；mp 163℃。

Example 166

3' - [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-methyl-pyrimidine (example e.44) (0.11g, 0.3mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.09g, 0.35 mmol). A light brown solid (0.16g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl group]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.16g) in dichloromethane (3mL) was added TFA (3mL), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as an off-white solid (0.083, 63%). MS (ISP)436.1[ (M + H)⁺]；mp 221℃。

Example 167

3' - [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

To the cooled and stirred 3' - [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]-Biphenyl-3-sulfonic acid tert-butylamide (example 165) (0.3g, 0.57mmol) in dichloromethane (5mL) TFA (5mL) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, and the precipitate was collected by filtrationThe material was washed with water and heptane and dried to give the title compound as a white solid (0.24g, 90%). MS (ISP)570.3[ (M + H)⁺]；mp 224.5℃。

Example 168

3- {4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) N-tert-butyl-3- {4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.46) (0.29g, 0.83mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.26g, 1.0 mmol). A light brown solid (0.23g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]-pyridin-2-yl } -benzenesulfonamide (0.23g) in dichloromethane (4mL) was added TFA (4mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness, purified by flash chromatography (heptane/ethyl acetate) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.081, 21%). MS (ISP)471.5[ (M + H) ⁺]；mp 218.5℃。

Example 169

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonic acid tert-butylamide

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example E.4) (0.414g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example f.1) (0.41g, 1.2 mmol). A white solid (0.22g, 40%) was obtained. MS (ISN)550.2[ (M-H)^-]；mp 197.5℃。

Example 170

5- {4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

1) 5- {4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-trifluoromethyl-pyrimidine (example E.5) (0.37g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.41g, 1.2 mmol). A light brown solid (0.25g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group ]-pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide (0.25g) in dichloromethane (6mL) TFA (6mL) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness, purified by flash chromatography (heptane/ethyl acetate) and crystallized (THF/hexane) to give the title compound as a white solid (0.13g, 26%). MS (ISN)495.2[ (M-H)^-]；mp 290℃。

Example 171

5- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

1) 5- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example E.70) (0.68g, 1.5mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.62g, 1.8 mmol). A light brown solid (0.52g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.52g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (4mL), diethyl ether and heptane. Will be mixed withThe mixture was stirred at rt for 1h, the precipitate collected by filtration, further purified by flash chromatography (heptane/ethyl acetate) and crystallized (THF/hexane) to give the title compound as a pale yellow solid (0.045g, 6%). MS (ISN)484.2[ (M-H)^-]；mp 284℃。

Example 172

5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyrimidine (example E.47) (0.39g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.41g, 1.2 mmol). A pale yellow solid (0.16g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.16g) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (4mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, further purified by flash chromatography (heptane/ethyl acetate) and crystallized (dichloromethane/heptane) to give the title compound as an off-white solid (0.098g, 21%). MS (ISP)476.0[ (M + H) ⁺]；mp225℃。

Example 173

5- {3- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (4-chloro-phenyl) -4-methyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-methyl-pyrimidine (example E.44) (0.36g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.41g, 1.2 mmol). A pale yellow solid (0.14g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (4-chloro-phenyl) -4-methyl-pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.14g) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (4mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, further purified by flash chromatography (heptane/ethyl acetate) and crystallized (dichloromethane/heptane) to give the title compound as an off-white solid (0.087g, 20%). MS (ISP)442.4[ (M + H)⁺]；mp 227℃。

Example 174

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

To the cooled and stirred 5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]-phenyl } -thiophene-2-sulfonic acid tert-butylamide (example 169) (0.175g, 0.32mmol) in dichloromethane (4mL) TFA (5mL) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (4mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as a white solid (0.12g, 75%). MS (ISN)494.1[ (M-H)^-]；mp 226℃。

Example 175

4- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-4- {1- [6- (4-chloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.70) (0.68g, 1.5mmol) and 4- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.46g, 1.8 mmol). A pale yellow solid (0.26g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-4- {1- [6- (4-chloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.26g) in dichloromethane (6mL) was added TFA1 (6mL), and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (3mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as an off-white solid (0.073g, 10%). MS (ISN)478.0[ (M-H)^-]；mp 324℃。

Example 176

1) N-tert-butyl-3- {1- [6- (4-chloro-phenyl) -4-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine (example e.69) (0.40g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.39g, 1.5 mmol). A pale yellow solid (0.103g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {1- [6- (4-chloro-phenyl) -4-methyl-pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.103g) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (3mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as a white solid (0.046g, 11%). MS (ISP)426.0[ (M + H) ⁺]；mp 275℃。

Example 177

3- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-3- {1- [6- (4-chloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.70) (0.68g, 1.5mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.46g, 1.8 mmol). A pale yellow solid (0.34g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {1- [6- (4-chloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.34g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (3mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as an off-white solid (0.24g, 34%). MS (ISN)478.0[ (M-H)^-]；mp 225℃。

Example 178

3' - [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidine (example E.4) (0.41g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A white foam (0.47g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.47g) in dichloromethane (6mL) was added TFA (6mL), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as a white solid (0.31g, 63%). MS (ISN)488.1[ (M-H)^-]；mp 165℃。

Example 179

3- {4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) 3- {4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonic acid tert-butylamide was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-trifluoromethyl-pyrimidine (example E.5) (0.37g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A light brown solid (0.41g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3- {4- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]-pyridin-2-yl } -benzenesulfonic acid tert-butylamide (0.41g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as an off-white solid (0.31g, 63%). MS (ISN)489.1[ (M-H)^-]；mp 182℃。

Example 180

4- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-4- {1- [6- (4-chloro-phenyl) -4-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine (example e.69) (0.40g, 1.0mmol) and 4- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.39g, 1.5 mmol). A light brown solid (0.64g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-4- {1- [6- (4-chloro-phenyl) -4-methyl-pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.64g) in dichloromethane (7mL TFA (7mL) was added, the reaction mixture was stirred at room temperature for 15HaHCO₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as an off-white solid (0.051g, 12%). MS (ISP)426.1[ (M + H) ⁺]；mp 312℃。

Example 181

2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide

1) A stirred mixture of 2- (4-tributylstannyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example G.1) (0.265g, 0.41mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (example H.1) (0.115g, 0.45mmol), tetrakis (triphenyl-phosphine) palladium (0.028g, 0.024mmol) in toluene (5mL) was heated at reflux for 15 h. The mixture was poured into saturated potassium fluoride solution (5mL), water (20mL) was added, and the aqueous layer was extracted with ethyl acetate (2X 30 mL). The combined organic layers were washed with brine (30mL) and dried (MgSO)₄) And evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallized (THF/hexane) to give N-tert-butyl-2- {1-]4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-1H-imidazol-4-yl } -thiazole-5-sulfonamide (0.081) as a light brown solid. Mp 281 ℃.

2) To the cooled and stirred N-tert-butyl-2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]To a solution of (E) -1H-imidazol-4-yl } -thiazole-5-sulfonamide (0.075g) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness, purified by flash chromatography on silica gel (ethyl acetate/hexane) and crystallized (THF/hexane) to give the title compound as a light brown solid (0.037g, 18%). MS (ISN)519.0[ (M-H) ^-]；mp 264℃。

Example 182

2- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide

1) Stirring 4- (4-chloro-phenyl) -2- (4-tributyl)A mixture of stannyl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example G.2) (0.28g, 0.46mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (example H.1) (0.128g, 0.5mmol), tetrakis (triphenyl-phosphine) palladium (0.032g, 0.028mmol) in toluene (5mL) was heated at reflux for 15 h. The mixture was poured into saturated potassium fluoride solution (5mL), water (20mL) was added, and the aqueous layer was extracted with ethyl acetate (2X 30 mL). The combined organic layers were washed with brine (30mL) and dried (MgSO)₄) And evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallized (THF/hexane) to give N-tert-butyl-2- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl } -thiazole-5-sulfonamide (0.094) as a light brown solid. Mp261 ℃.

2) To the cooled and stirred N-tert-butyl-2- {1- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-1H-imidazol-4-yl } -thiazole-5-sulfonamide (0.088g) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness, purified by flash chromatography on silica gel (ethyl acetate/hexane) and crystallized (THF/hexane) to give the title compound as a light brown solid (0.03g, 14%). MS (ISN)485.2[ (M-H) ^-]；mp 263℃。

Example 183

4- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-4- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyrimidine (example e.71) (0.43g, 1.0mmol) and 4- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.39g, 1.5 mmol). A light brown solid (0.2g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-4- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.2g) in dichloromethane (4mL) was addedTFA (4mL), the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (2mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as an off-white solid (0.075g, 16%). MS (ISP)460.1[ (M + H)⁺]；mp 323℃。

Example 184

3- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-3- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyrimidine (example e.71) (0.43g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.39g, 1.5 mmol). A pale yellow solid (0.19g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.19g) in dichloromethane (4mL) was added TFA (4mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (3mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as an off-white solid (0.13g, 28%). MS (ISP)460.2[ (M + H)⁺]；mp 186℃。

Example 185

3- {1- [4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-3- {1- [6- (3-chloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (3-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.72) (0.68g, 1.5mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.46g, 1.8 mmol). A pale yellow solid (0.2g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {1- [6- (3-chloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.2g) in dichloromethane (5mL) was added TFA (5mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (3mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as a white solid (0.1g, 14%). MS (ISP)580.2[ (M + H)⁺]；mp 204.5℃。

Example 186

5- {1- [4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 4- (3-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.72) (0.45g, 1.0mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.26g, 1.2 mmol). A yellow solid (0.27g, 65%) was obtained. MS (ISP)417.2[ (M + H)⁺]；mp 248℃。

Example 187

5- {1- [4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 4- (3-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.72) (0.45g, 1.0mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.26g, 1.2 mmol). A yellow solid (0.27g, 65%) was obtained. MS (ISP)418.1[ (M + H) ⁺]；mp 281℃。

Example 188

5- {1- [4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

1) 5- {1- [4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 4- (3-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example E.72) (0.68g, 1.5mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.62g, 1.8 mmol). A pale yellow solid (0.4g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {1- [4- (3-chloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.4g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness, purified by flash chromatography (heptane/ethyl acetate) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.036g, 5%). MS (ISP)486.2[ (M + H)⁺]；mp 280℃。

Example 189

3- {4- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) 3- {4- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonic acid tert-butylamide was prepared according to general method VI using 4- (4-chloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-methyl-pyrimidine (example E.45) (0.32g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A light brown solid (0.47g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3- {4- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl group]-pyridin-2-yl } -benzenesulfonic acid tert-butylamide (0.47g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate was collected by filtration, washed with water and heptane and dried to give the title compoundCompound as a white solid (0.2, 46%). MS (ISP)437.1[ (M + H)⁺]；mp 224℃。

Example 190

5- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {1- [6- (4-chloro-phenyl) -4-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine (example E.69) (0.40g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.41g, 1.2 mmol). A light brown solid (0.15g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {1- [6- (4-chloro-phenyl) -4-methyl-pyrimidin-2-yl group ]To a solution of (E) -1H-imidazol-4-yl } -thiophene-2-sulfonamide (0.15g) in dichloromethane (4mL) was added TFA (4mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, and the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (ether) afforded the title compound as a light brown solid (0.01g, 2%). MS (ISP)432.3[ (M + H)⁺]；mp 281℃。

Example 191

5- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyrimidine (example E.71) (0.43g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.45g, 1.3 mmol). A pale yellow solid (0.08g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {1- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group ]To a solution of (E) -1H-imidazol-4-yl } -thiophene-2-sulfonamide (0.08g) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (3mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, and the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (ether) afforded the title compound as a white solid (0.014g, 3%). MS (ISP)466.1[ (M + H)⁺]；mp 277℃。

Example 192

5- {4- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

1) 5- {4- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 4- (4-chloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-methyl-pyrimidine (example E.45) (0.22g, 0.7mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.31g, 0.9 mmol). A pale yellow solid (0.12g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {4- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl group]-pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide (0.12g) in dichloromethane (4mL) TFA (4mL) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, and the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (ether) afforded the title compound as a white solid (0.036g, 12%). MS (ISP)443.2[ (M + H)⁺]；mp 232.5℃。

Example 193

3' - [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine (example e.62) (0.39g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A light brown solid (0.54g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl group]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.54g) in dichloromethane (6mL) was added TFA (6mL), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, and the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (ether) afforded the title compound as a white solid (0.16, 34%). MS (ISP)470.1[ (M + H) ⁺]；mp206.5℃。

Example 194

3- {4- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) 3- {4- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonic acid tert-butylamide was prepared according to general procedure VI using 4- (3, 4-dichloro-phenyl) -2- (2-chloro-pyridin-4-yl) -6-methyl-pyrimidine (example E.63) (0.35g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A light brown solid (0.54g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3- {4- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl group]-pyridin-2-yl } -benzenesulfonic acid tert-butylamide (0.54g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15 h. Steaming the mixtureLeft to dry, saturated NaHCO is added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, and the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (ether) afforded the title compound as a white solid (0.175, 37%). MS (ISP)471.2[ (M + H)⁺]；mp 202.5℃。

Example 195

5- {3- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (3, 4-dichloro-phenyl) -4-methyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine (example E.62) (0.39g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.45g, 1.3 mmol). A pale yellow solid (0.39g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (3, 4-dichloro-phenyl) -4-methyl-pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.39g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (4mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, further purified by flash chromatography (heptane/ethyl acetate) and crystallized (dichloromethane/heptane) to give the title compound as a light brown solid (0.054g, 11%). MS (ISP)476.0[ (M + H)⁺]；mp 238℃。

Example 196

5- {4- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

1) 5- {4- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidine (example E.63) (0.35g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.45g, 1.3 mmol). A pale yellow solid (0.22g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {4- [4- (2, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl group]-pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide (0.22g) in dichloromethane (6mL) TFA (6mL) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, and the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) afforded the title compound as a white solid (0.024g, 5%). MS (ISP)477.1[ (M + H)⁺]；mp 267℃。

Example 197

5- {4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

1) 5- {4- [ 6-methyl-4- (4-trifluoro-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -6-methyl-4- (4-trifluoro-phenyl) -pyrimidine (example E.46) (0.35g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.45g, 1.3 mmol). A pale yellow solid (0.21g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {4- [ 6-methyl-4- (4-trifluoro-phenyl) -pyrimidin-2-yl group]-pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide (0.21g) in dichloromethane (3mL) TFA (3mL) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, and the precipitate was collected by filtration, washed with water and heptane and dried. Rapid silica gelFurther purification by chromatography (ethyl acetate/hexane) and crystallization (dichloromethane) afforded the title compound as a white solid (0.073g, 15%). MS (ISP)477.1[ (M + H)⁺]；mp 263.5℃。

Example 198

3- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-3- {1- [6- (3, 4-dichloro-phenyl) -4-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (3, 4-dichloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine (example e.74) (0.37g, 0.86mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.33g, 1.29 mmol). A pale yellow solid (0.23g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {1- [6- (3, 4-dichloro-phenyl) -4-methyl-pyrimidin-2-yl group ]-1H-imidazol-4-yl } -benzenesulfonamide (0.23g) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (3mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as a white solid (0.18g, 46%). MS (ISP)460.1[ (M + H)⁺]；mp 210℃。

Example 199

4- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-4- {1- [6- (3, 4-dichloro-phenyl) -4-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (3, 4-dichloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine (example e.74) (0.37g, 0.86mmol) and commercially available 4- (tert-butylsulfamoyl) -phenylboronic acid (0.33g, 1.29 mmol). A pale yellow solid (0.2g) was obtained which was subsequently deprotected.

2) Is cooled and stirredN-tert-butyl-4- {1- [6- (3, 4-dichloro-phenyl) -4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl } -benzenesulfonamide (0.2g) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (3mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane and dried to give the title compound as a white solid (0.13g, 33%). MS (ISP)460.1[ (M + H)⁺]；mp 282.5℃。

Example 200

2- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide

1) A stirred mixture of 4- (4-chloro-phenyl) -6-methyl-2- (4-tributylstannyl-imidazol-1-yl) -pyrimidine (example G.3) (0.45g, 0.80mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (example H.1) (0.225g, 0.88mmol), tetrakis (triphenyl-phosphine) palladium (0.056g, 0.048mmol) in toluene (10mL) was heated at reflux for 15 h. The mixture was poured into saturated potassium fluoride solution (10mL), water (40mL) was added, and the aqueous layer was extracted with ethyl acetate (2X 60 mL). The combined organic layers were washed with brine (60mL) and dried (MgSO)₄) And evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallized (THF/hexane) to give N-tert-butyl-2- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl } -thiazole-5-sulfonamide (0.1g) as a light brown solid.

2) To the cooled and stirred N-tert-butyl-2- {1- [4- (4-chloro-phenyl) -6-methyl-pyrimidin-2-yl group ]To a solution of-1H-imidazol-4-yl } -thiazole-5-sulfonamide (0.1g) in dichloromethane (2mL) was added TFA (2mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness, purified by flash chromatography on silica gel (ethyl acetate/hexane) and crystallized (dichloromethane) to give the title compound as a light brown solid (0.016g, 5%). MS (ISP)433.2[ (M + H)⁺]；mp 255.5℃。

Example 201

2- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide

1) A stirred mixture of 4- (3, 4-dichloro-phenyl) -6-methyl-2- (4-tributylstannyl-imidazol-1-yl) -pyrimidine (example G.4) (0.55g, 0.93mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (example H.1) (0.26g, 1.0mmol), tetrakis (triphenyl-phosphine) palladium (0.064g, 0.055mmol) in toluene (10mL) was heated at reflux for 15 h. The mixture was poured into saturated potassium fluoride solution (10mL), water (40mL) was added, and the aqueous layer was extracted with ethyl acetate (2X 60 mL). The combined organic layers were washed with brine (60mL) and dried (MgSO)₄) And evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallized (THF/hexane) to give N-tert-butyl-2- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ]-1H-imidazol-4-yl } -thiazole-5-sulfonamide (0.23g) as a light brown solid.

2) To the cooled and stirred N-tert-butyl-2- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl group]To a solution of (E) -1H-imidazol-4-yl } -thiazole-5-sulfonamide (0.23g) in dichloromethane (4mL) was added TFA (4mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness, purified by flash chromatography on silica gel (ethyl acetate/hexane) and crystallized (dichloromethane) to give the title compound as a light brown solid (0.028g, 6%). MS (ISP)467.1[ (M + H)⁺]；mp 230℃。

Example 202

3' - [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example e.37) (0.40g, 0.89mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.275g, 1.07 mmol). A white foam (0.45g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidinePyridin-2-yl]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.45g) in dichloromethane (6mL) was added TFA (6mL), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at rt for 1h, the precipitate collected by filtration, further purified by flash chromatography (heptane/ethyl acetate) and crystallized (THF/hexane) to give the title compound as a white solid (0.34g, 72%). MS (ISN)522.2[ (M-H)^-]；mp 241℃。

Example 203

3- {4- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) 3- {4- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example E.38) (0.4g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A light brown foam (0.41g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3- {4- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]-pyridin-2-yl } -benzenesulfonic acid tert-butylamide (0.41g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, further purified by flash chromatography (heptane/ethyl acetate) and crystallized (THF/hexane) to give the title compound as an off-white solid (0.28g, 54%). MS (ISP)523.1[ (M-H) ^-]；mp 247℃。

Example 204

5- {3- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (3, 4-dichloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example E.37) (0.40g, 0.89mmol) and N-tert-butyl-5- (, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.40g, 1.16 mmol). A white foam (0.45g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (3, 4-dichloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.39g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (4mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, further purified by flash chromatography (heptane/ethyl acetate) and crystallized (THF/hexane) to give the title compound as an off-white solid (0.24g, 51%). MS (ISN)527.9[ (M-H) ^-]；mp 203℃。

Example 205

5- {4- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

1) 5- {4- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example E.38) (0.405g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.45g, 1.3 mmol). A light brown foam (0.41g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {4- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]-pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide (0.41g) in dichloromethane (6mL) TFA (6mL) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (4mL), diethyl ether and heptane. The mixture was cooled to room temperatureStirring for 1h, the precipitate was collected by filtration, further purified by flash chromatography (heptane/ethyl acetate) and crystallized (THF/hexane) to give the title compound as an off-white solid (0.2g, 38%). MS (ISN)528.9[ (M-H) ^-]；mp266℃。

Example 206

3' - [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.49) (0.46g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A white foam (0.52g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.52g) in dichloromethane (6mL) was added TFA (6mL), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallized (dichloromethane/MeOH) to give the title compound as a white solid (0.29g, 54%). MS (ISP)536.2[ (M-H)^-]；mp 205℃。

Example 207

5- {3- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example E.49) (0.46g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.45g, 1.3 mmol). A light brown solid (0.46g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.46g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallized (dichloromethane/MeOH) to give the title compound as an off-white solid (0.21g, 38%). MS (ISN)542.1[ (M-H)^-]；mp 216℃。

Example 208

5- {1- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

1) A stirred mixture of 4- (3, 4-dichloro-phenyl) -2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example G.6) (0.46g, 0.71mmol), 5-bromothiophene-2-N-tert-butylsulfonamide (0.23g, 0.78mmol) obtained commercially, tetrakis (triphenyl-phosphine) palladium (0.049g, 0.042mmol) in toluene (8mL) was heated at reflux for 15h, hexane (10mL) was added and the mixture stirred at room temperature for 1 h. The precipitate was collected by filtration and dried to give 5- {1- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.34g) as a white solid.

2) To the cooled and stirred 5- {1- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.34g) in dichloromethane (6mL) was added TFA (6mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and purified by silica gel column chromatography (dichloromethane/MeOH/NH)₄OH 80: 10: 1) and crystallization (MeOH/ether) afforded the title compound as a pale yellow solid (0.23g, 62%). MS (ISN)520.3[ (M-H)^-]；mp282℃(dec.)。

Example 209

5- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

1) A stirred mixture of 4- (3-methyl-4-trifluoromethyl-phenyl) -2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example G.7) (0.33g, 0.5mmol), 5-bromothiophene-2-N-tert-butylsulfonamide (0.16g, 0.55mmol) obtained from commercial, tetrakis (triphenyl-phosphine) palladium (0.035g, 0.03mmol) in toluene (6mL) was heated at reflux for 15h, heptane (10mL) was added and the mixture stirred at room temperature for 1 h. The precipitate was collected by filtration and dried to give 5- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.24g) as a light yellow solid.

2) To the cooled and stirred 5- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.24g) in dichloromethane (5mL) was added TFA (5mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and purified by silica gel column chromatography (dichloromethane/MeOH/NH)₄OH 80: 10: 1) and crystallization (MeOH/ether) afforded the title compound as a pale yellow solid (0.14g, 52%). MS (ISN)532.3[ (M-H)^-]；mp 260℃。

Example 210

4- (4-chloro-phenyl) -2- [4- (3-methanesulfonyl-phenyl) -imidazol-1-yl ] -6-methyl-pyrimidine

A stirred mixture of 4- (4-chloro-phenyl) -6-methyl-2- (4-tributylstannyl-imidazol-1-yl) -pyrimidine (example G.3) (0.47g, 0.84mmol), 3-bromo-phenylmethylsulfone obtained commercially (0.22g, 0.92mmol), tetrakis (triphenyl-phosphine) palladium (0.058g, 0.05mmol) in toluene (8mL) was heated at reflux for 15 h. Hexane (10mL) was added at room temperature and the mixture was stirred for 1 h. The precipitate was collected by filtration, washed with heptane and dried to give the title compound (0.33g, 92%) as an off-white solidAnd (3) a solid. MS (ISN)423.3[ (M-H)^-]；mp 233℃。

Example 211

4- {1- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-4- {1- [6- (3, 4-dichloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (3, 4-dichloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.74) (0.485g, 1.0mmol) and 4- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A pale yellow solid (0.08g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-4- {1- [6- (3, 4-dichloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.08g) in dichloromethane (2mL) was added TFA (2mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (2.5mL) and MeOH (2.5 mL). The mixture was stirred at room temperature for 30min, and the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to afford the title compound as a white solid (0.058g, 11%). MS (ISN)512.3[ (M-H)^-]；mp 334℃。

Example 212

4- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-4- {1- [6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidine (example e.73) (0.50g, 1.0mmol) and 4- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A pale yellow solid (0.057g) was obtained which was subsequently deprotected.

2) To coolAnd stirring N-tert-butyl-4- {1- [6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl]To a solution of-1H-imidazol-4-yl } -benzenesulfonamide (0.057g) in dichloromethane (2mL) was added TFA (2mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (2.5mL) and MeOH (2.5 mL). The mixture was stirred at room temperature for 30min, and the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to afford the title compound as a white solid (0.038g, 7%). MS (ISN)526.5[ (M-H)^-]；mp 287℃。

Example 213

3- {1- [4- (3-methyl-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-3- {1- [6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidine (example e.73) (0.50g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). An off-white solid (0.118g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {1- [6- (3-methyl-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.128g) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (2.5mL) and MeOH (2.5 mL). The mixture was stirred at room temperature for 30min, and the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to afford the title compound as an off-white solid (0.077g, 15%). MS (ISN)526.4[ (M-H)^-]；mp 180℃。

Example 214

4- (3, 4-dichloro-phenyl) -2- [4- (3-methanesulfonyl-phenyl) -imidazol-1-yl ] -6-methyl-pyrimidine

A stirred mixture of 4- (3, 4-dichloro-phenyl) -6-methyl-2- (4-tributylstannyl-imidazol-1-yl) -pyrimidine (example G.4) (0.45g, 0.76mmol), 3-bromo-phenylmethylsulfone obtained commercially (0.20g, 0.83mmol), tetrakis (triphenyl-phosphine) palladium (0.053g, 0.046mmol) in toluene (8mL) was heated at reflux for 15 h. Heptane (10mL) was added at room temperature and the mixture was stirred for 1 h. The precipitate was collected by filtration, washed with heptane and dried to give the title compound (0.27g, 78%) as an off-white solid. MS (ISP)459.2[ (M + H)⁺]；mp 213℃。

Example 215

3- {1- [4- (3, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-3- {1- [6- (3, 4-dichloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (3, 4-dichloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.74) (0.485g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A pale yellow solid (0.084g) was obtained, which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {1- [6- (3, 4-dichloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.084g) in dichloromethane (2mL) was added TFA (2mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (2.5mL) and MeOH (2.5 mL). The mixture was stirred at room temperature for 30min, and the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to afford the title compound as an off-white solid (0.054g, 10%). MS (ISP)514.2[ (M + H)⁺]；mp 239℃。

Example 216

5- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

1) A stirred mixture of 4- (3, 4-dichloro-phenyl) -6-methyl-2- (4-tributylstannyl-imidazol-1-yl) -pyrimidine (example G.4) (0.45g, 0.76mmol), 5-bromothiophene-2-N-tert-butylsulfonamide (0.25g, 0.84mmol) obtained from commercial, tetrakis (triphenyl-phosphine) palladium (0.053g, 0.046mmol) in toluene (8mL) was heated at reflux for 15h, hexane (10mL) was added and the mixture stirred at room temperature for 1 h. The precipitate was collected by filtration and dried to give 5- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.41g) as a light brown solid.

2) To the cooled and stirred 5- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyrimidin-2-yl group]To a solution of-1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.41g) in dichloromethane (5mL) was added TFA (5mL) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (10 mL). The mixture was stirred at room temperature for 30min, and the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (MeOH/ether) to afford the title compound as a light brown solid (0.28g, 79%). MS (ISP)466.1[ (M + H)⁺]；mp 253.5℃。

Example 217

2- [4- (3-methanesulfonyl-phenyl) -imidazol-1-yl ] -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

A stirred mixture of 2- (4-tributylstannyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example g.1) (0.155g, 0.24mmol), 3-bromo-phenylmethylsulfone obtained commercially (0.062g, 0.26mmol), tetrakis (triphenyl-phosphine) palladium (0.017g, 0.015mmol) in toluene (5mL) was heated at reflux for 15 h. Heptane (5mL) was added at room temperature and the mixture was stirred for 1 h. The precipitate was collected by filtration, washed with heptane and dried. Further purification by silica gel flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) afforded the title compound (0.078g, 64%) as a white solid. MS (ISP)512.9[ (M + H) ⁺]；mp 231℃。

Example 218

2- [2- (3-methanesulfonyl-phenyl) -pyridin-4-yl ] -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.6) (0.404g, 1.0mmol) and commercially available 3-methanesulfonyl-phenylboronic acid (0.22g, 1.1 mmol). A white solid was obtained (0.4g, 77%). MS (ISP)524.0[ (M + H)⁺]；mp 238.5℃。

Example 219

2- (3' -methanesulfonyl-biphenyl-3-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.3) (0.45g, 1.0mmol) and commercially available 3-methanesulfonyl-phenylboronic acid (0.22g, 1.1 mmol). White solid (0.45g, 86%) was obtained. MS (ISP)523.0[ (M + H)⁺]；mp 183.5℃。

Example 220

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-ylamine

1) 2- (3' -Nitro-biphenyl-3-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.3) (1.79g, 4.0mmol) and 3-nitro-phenylboronic acid obtained commercially (0.8g, 4.8 mmol). A light grey solid was obtained (1.74g, 89%). MS (EI)489.2[ (M) ⁺]；mp 219℃。

2) To a stirred suspension of 2- (3' -nitro-biphenyl-3-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (1.6g, 3.27mmol) in MeOH (40mL) was added Pd-C (10%, 0.16g) and THF (40mL) at rt. The mixture was stirred at room temperature for 2h under hydrogen, the catalyst was removed by filtration and the resulting solution was evaporated. The crude product is purified by reaction with diethyl etherCrystallization from hexanes further purification afforded the title compound as an off-white solid (1.28g, 85%). MS (ISP)460.2[ (M + H)⁺]；mp 156.5℃。

Example 221

N- { 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-yl } -sulfonamide

To the stirred 3' [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]A solution of-biphenyl-3-ylamine (example 220) (0.46g, 1.0mmol) in dichloromethane (10mL) was added triethylamine (0.42mL) and N-Boc-sulfamoyl chloride (0.8M, 3.75mL, 3.0mmol), and the reaction mixture was stirred at room temperature for 45h, poured into ice water (20mL), and extracted with ethyl acetate (2X 30 mL). The combined organic layers were washed with brine (30mL) and dried (MgSO)₄) And evaporated. Further purification by silica gel flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) gave a white solid (0.3g) which was dissolved in TFA (10mL) and stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (10 mL). The mixture was stirred at room temperature for 30min, and the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/MeOH/hexane) to afford the title compound as a white solid (0.21g, 39%). MS (ISP)539.3[ (M + H)⁺]；mp 174℃。

Example 222

N- {3 ' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-yl } -N ', N ' -dimethyl-sulfonamide

To the stirred 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]To a solution of-biphenyl-3-ylamine (example 220) (0.23g, 0.5mmol) in toluene (5mL) was added triethylamine (0.21mL) and dimethylsulfamoyl chloride (0.14g, 1.0mmol), the reaction mixture was stirred at 70 ℃ for 22h, poured into ice water (20mL), and extracted with ethyl acetate (2X 30 mL). The combined organic layers were washed with brine (30mL) and dried (MgSO)₄) And evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (E)tioh/hexane) to give the title compound (0.104g, 37%) as an off-white solid. MS (ISP)567.3[ (M + H)⁺]；mp 113℃。

Example 223

N- { 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-yl } -methanesulfonamide

To a stirred and cooled (ice bath) solution of 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ]To a solution of-biphenyl-3-ylamine (example 220) (0.23g, 0.5mmol) in dichloromethane (5mL) was added triethylamine (0.21mL) and methanesulfonyl chloride (0.06g, 0.52mmol), the reaction mixture was stirred at room temperature for 1h, and saturated NaHCO was poured in₃The solution (20mL) was extracted with ethyl acetate (2X 30 mL). The combined organic layers were washed with brine (30mL) and dried (MgSO)₄) And evaporated. Further purification by silica gel flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) gave the title compound (0.16g, 72%) as a white solid. MS (ISP)538.0[ (M + H)⁺]；mp 191℃。

Example 224

3- {1- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-3- {1- [6- (4-chloro-3-methyl-phenyl) -4-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (4-chloro-3-methyl-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine (example e.76) (0.41g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A pale grey solid (0.53g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {1- [6- (4-chloro-3-methyl-phenyl) -4-methyl-pyrimidin-2-yl group ]-1H-imidazol-4-yl } -benzenesulfonamide (0.53g) in dichloromethane (5ml) TFA (5ml) was added and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (10ml), diethyl ether and heptane. The mixture was stirred at room temperature for 1h,the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by silica gel flash chromatography (ethyl acetate/heptane) and crystallization (THF/heptane) gave the title compound as a white solid (0.3g, 68%). MS (ISP)440.1[ (M + H)⁺]；mp 219℃(dec.)。

Example 225

5- {1- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

1) A stirred mixture of 4- (4-chloro-3-methyl-phenyl) -6-methyl-2- (4-tributylstannyl-imidazol-1-yl) -pyrimidine (example G.8) (0.59g, 1.03mmol), 5-bromothiophene-2-N-tert-butylsulfonamide (0.34g, 1.13mmol) obtained commercially, tetrakis (triphenyl-phosphine) palladium (0.071g, 0.062mmol) in toluene (8ml) was heated at reflux for 15h, heptane (10ml) was added and the mixture stirred at room temperature for 1 h. The precipitate was collected by filtration and dried to give 5- {1- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.54g) as a white solid.

2) To the cooled and stirred 5- {1- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl group]To a solution of (E) -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.54g) in dichloromethane (5ml) was added TFA (5ml) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (10 ml). The mixture was stirred at room temperature for 30min, and the precipitate was collected by filtration and washed with water. The crude product was further purified by silica gel flash chromatography (ethyl acetate/heptane) and crystallized (THF/ether) to give the title compound as a white solid (0.24g, 52%). MS (ISP)445.9[ (M + H)⁺]；mp 267℃(dec.)。

Example 226

5- {1- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

According to general procedure VI, 4- (4-chloro-3-methyl-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyrimidine (example e.76) (0.41g,1.0mmol) and commercially available 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.26g, 1.2 mmol). A yellow solid was obtained (0.14g, 37%). MS (ISP)377.3[ (M + H)⁺]；mp 202℃(dec.)。

Example 227

2-methyl-6- [3- (4-methyl-imidazol-1-yl) -phenyl ] -4- (4-trifluoromethyl-phenyl) -pyridine

Prepared according to general procedure VI using 2-iodo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example A.31) (400mg, 1.09mmol) and 4-methyl-1- [3- (4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxaborolan-2-yl) -phenyl]-1H-imidazole the target compound is prepared, said imidazole can be prepared in situ by the following scheme: step 1) A mixture of commercial 3-bromophenyl isothiocyanate (10.06g, 47.0mmol) and 2-aminopropionaldehyde dimethyl acetal (5.96mL, 47.0mmol) in EtOH (50mL) was refluxed for 1 h. Evaporation to dryness afforded 1- (3-bromo-phenyl) -3- (2, 2-dimethoxy-1-methyl-ethyl) -thiourea as an off-white solid (15.69g, 100%). Step 2) 1- (3-bromo-phenyl) -3- (2, 2-dimethoxy-1-methyl-ethyl) -thiourea (15.69g, 47mmol) prepared above was taken in H₂A mixture of O (85mL) and 37% HCl (8.5mL) was refluxed for 4.5 h. The oil bath was removed, ice and ice water (total volume 250mL) were added, the precipitate filtered, washed several times with ice water and dried under vacuum at 60 ℃ to give 1- (3-bromo-phenyl) -4-methyl-1H-imidazole-2-thiol as a pale orange solid (8.71g, 69%). Step 3) to the suspension of 1- (3-bromo-phenyl) -4-methyl-1H-imidazole-2-thiol prepared above (6.00g, 22mmol) in acetic acid (20mL) and water (5mL) was added 35% H dropwise over 15 min ₂O₂(13.4mL, 156mmol), maintaining the internal temperature below 60 ℃. Stirring at 23 deg.C for 30min, pouring into ice, adding saturated Na₂SO₃Destruction of excess H by the solution₂O₂The pH was adjusted to pH 9 with 32% NaOH solution, extracted with EtOAc (3X 100mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to give a red oil. Purifying by silica gel column chromatography, eluting with EtOAe to obtain 1- (3-bromo-phenyl) -4-methyl-1H-imidazole as a brown oil (3.80g, 72%). Step 4) 1- (3-bromo-phenyl) -4-methyl-1H-imidazole (0.313g, 1.31mmol), bis (0.364g, 1.438mmol), potassium acetate (0.389g, 3.96mmol) and PdCl prepared as described above₂(PPh₃)₂(0.023g, 3 mol%) of a mixture of DMF was stirred at 100 ℃ for 2 h; then Pd (OAc) is added₂(0.007g, 3 mol%) and dppf (0.018g, 3 mol%) were stirred at 100 ℃ overnight. The solution obtained can be used directly. An off-white solid was obtained (0.140g, 32%). MS (ISP)394.0[ (M + H)⁺]；mp 126-132℃。

Example 228

3' - [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide

The title compound was prepared according to general method VI using 2- (3-bromo-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example E.21) (0.200g, 0.51mmol) and 3-sulfamoyl-phenylboronic acid (example F.2) (0.102g, 0.51 mmol). A white solid (0.120g, 50%) was obtained. MS (ISP)467.1[ (M + H) ⁺]；mp 196℃。

Example 229

5- {3- [4- (4-chloro-phenyl) -6-methyl-pyridin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-methyl-pyridine (example e.32) (0.15g, 0.42mmol) and 2-amino-5- (4, 4.5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.101g, 0.46 mmol). A white solid was obtained (0.045g, 29%). MS (ISP)372.1[ (M + H)⁺]And 374[ (M +2+ H)⁺]；mp76-95℃。

Example 230

5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -pyridin-2-ylamine

According to general method VI, 2- (4-bromo-thiazol-2-yl) -6-methyl is usedThe title compound was prepared from yl-4- (4-trifluoromethyl-phenyl) -pyridine (example E.80) (0.30g, 0.75mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.248g, 1.13 mmol). A pale yellow solid was obtained (0.o40g, 11%). MS (ISP)413.2[ (M + H)⁺]；mp 191℃。

Example 231

5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-thiazol-2-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.80) (0.20g, 0.50mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.133g, 0.60 mmol). A white solid (0.100g, 48%) was obtained. MS (ISP)414.2[ (M + H) ⁺]；mp＞250℃。

Example 232

5- {3- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.81) (0.20g, 0.45mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.109g, 0.49 mmol). A white solid was obtained (0.110g, 53%). MS (ISP)460.2[ (M + H)⁺]；mp 166℃。

Example 233

5- {3- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine

Following general procedure VI, using 2- (3-bromo-phenyl) -6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example E.81) (0.20g, 0.45mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (0) obtained commercially109g, 0.49mmol) to prepare the title compound. Pale yellow solid (0.160g, 77%) was obtained. MS (ISP)461.2[ (M + H)⁺]；mp 260℃。

Example 234

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-trifluoromethyl-pyridine (example e.82) (0.20g, 0.485mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.118g, 0.532 mmol). A white solid was obtained (0.110g, 53%). MS (ISP)427.1[ (M + H) ⁺]And 429[ (M +2+ H)⁺]；mp 239℃。

Example 235

5- {3- [4- (4-chloro-phenyl) -6-trifluoromethyl-pyridin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-phenyl) -6-trifluoromethyl-pyridine (example e.82) (0.30g, 0.727mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.192g, 0.873 mmol). A pale grey solid was obtained (0.200g, 65%). MS (ISP)426.0[ (M + H)⁺]And 428[ (M +2+ H)⁺]；mp 172℃。

Example 236

5- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general method V using 6-amino-N-hydroxy-nicotinamidine (example c.3) (0.113g, 0.53mmol) and 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine-2-carboxylic acid (example d.11) (0.10g, 0.36 mmol). An off-white solid (0.045g, 31%)。MS(ISP)398.1[(M+H)⁺]；mp 163℃。

Example 237

3- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-3-sulfamoyl-benzamidine [ CAS number 9000-88-7]The title compound was prepared (0.115g, 0.53mmol) and 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine-2-carboxylic acid (example D.11) (0.10g, 0.36 mmol). An off-white solid was obtained (0.080g, 49%). MS (ISP)461.0[ (M + H) ⁺]；mp 277℃。

Example 238

5- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-[1，2，4]Oxadiazol-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure V using 6-amino-N-hydroxy-nicotinamidine (example c.3) (0.128g, 0.60mmol) and 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine-2-carboxylic acid (example d.12) (0.135g, 0.403 mmol). Pale yellow solid was obtained (0.022g, 12%). MS (ISP)452.1[ (M + H)⁺]；mp 229℃。

Example 239

5- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -pyridin-2-ylamine

According to general method VI, 2-chloro-4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl is employed]The title compound was prepared from pyrimidine (example E.83) (0.40g, 1.14mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.302g, 1.37mmol) obtained commercially. An off-white solid was obtained (0.050g, 10%). MS (ISP))408.3[(M+H)⁺]；mp 191℃。

Example 240

4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] - [2, 5 '] bipyrimidinyl-2' -ylamine

According to general method VI, 2-chloro-4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl is employed]The title compound was prepared from pyrimidine (example E.83) (0.40g, 1.14mmol) and commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (0.303g, 1.37 mmol). A white solid was obtained (0.050g, 10%). MS (ISP)409.2[ (M + H) ⁺]；mp 264℃。

Example 241

5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-4-yl } -pyridin-2-ylamine

The title compound was prepared according to the following scheme:

step 1) 2-chloro-4- [6- (2, 5-dimethyl-pyrrol-1-yl) -pyridin-3-yl } -pyrimidine: according to general procedure IVc scheme b, 5-bromo-2- (2, 5-dimethyl-pyrrol-1-yl) -pyridine [ CAS number 228710-82-5](2.76g, 11.0mmol) and commercially available 2, 4-dichloropyrimidine (1.49g, 10.0mmol) and n-BuLi, ZnCl₂And Pd (PPh)₃)₄And (4) preparation. A yellow solid was obtained (1.39g, 49%). MS (ISP)285.1[ (M + H)⁺]And 287.1[ (M +2+ H)⁺]。

Step 2)4- [6- (2, 5-dimethyl-pyrrol-1-yl) -pyridin-3-yl]-2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-a pyrimidine: according to general procedure IVc scheme b, the above-described 2-chloro-4- [6- (2, 5-dimethyl-pyrrol-1-yl) -pyridin-3-yl group is used]-pyrimidine (404mg, 1.21mmol) and 2-iodo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.31) (0.5g, 1.17 mmol). An off-white solid was obtained (0.250g, 44%). MS (ISP)486.3[ (M + H)⁺]。

Step 3) in a sealed test tube at 120 ℃ in aqueous NaOH solution (1.5M, 0.86)mL, 1.29mmol) of 1-propanol (2.5mL) was added the above 4- [6- (2, 5-dimethyl-pyrrol-1-yl) -pyridin-3-yl group ]-2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]The target compound was prepared by heating pyrimidine (0.250g, 1.29mmol) and hydroxylamine hydrochloride (259mg, 3.86 mmol). Cool to room temperature, add water, extract 2 times with AcOEt, dry over sodium sulfate, filter and evaporate completely. The crude product was triturated with ether to give the title compound (0.140g, 67%) as an off-white solid. MS (ISP)408.3[ (M + H)⁺]；mp 258℃。

Example 242

3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -benzonitrile

The title compound was prepared according to general procedure VI using trifluoro-methanesulfonic acid 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ester (example a.32) (5.00g, 13mmol) and commercially available 3-cyanophenylboronic acid (1.67g, 14.3 mmol). A white solid was obtained (3.00g, 68%). MS (ISP)339.1[ (M + H)⁺]；mp 140℃。

Example 243

3- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-[1，2，4]Oxadiazol-3-yl } -benzenesulfonamides

According to general procedure V, N-hydroxy-3-sulfamoyl-benzamidine [ CAS number 9000-88-7]The title compound was prepared (0.230g, 1.06mmol) and 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine-2-carboxylic acid (example D.12) (0.30g, 1.00 mmol). A white solid was obtained (0.100g, 22%). MS (ISP)513.2[ (M + H) ⁺]；mp 211℃。

Example 244

3' - [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide

According to general method VI, 2- (3-bromo-phenyl) is used) The title compound was prepared from-6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example E.81) (0.200g, 0.448mmol) and 3-sulfamoyl-phenylboronic acid (example F.2) (0.100g, 0.488 mmol). A white solid was obtained (0.040g, 15%). MS (ISP)523.3[ (M + H)⁺]；mp 187℃。

Example 245

5- {3- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridine-3-sulfonamide

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.81) (0.20g, 0.448mmol) and 3-sulfamoyl-pyridine-5-boronic acid (example f.3) (0.100g, 0.488 mmol). White solid was obtained (0.035g, 15%). MS (ISP)522.2[ (M + H)⁺]；mp 240℃。

Example 246

5- {1- [4- (3, 4-dichloro-phenyl) -6-methyl-pyridin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 4- (3, 4-dichloro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-methyl-pyridine (example e.84) (0.20g, 0.47mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.113g, 0.51 mmol). An off-white solid was obtained (0.035g, 17%). MS (ISP)396.0[ (M + H) ⁺]，398.1[(M+2+H)⁺]And 400[ (M +4+ H)⁺]；mp 245℃。

Example 247

4- (3, 4-dichloro-phenyl) -2-imidazol-1-yl-6-methyl-pyridine

The title compound was prepared according to general procedure IVa using 2-chloro-4- (3, 4-dichloro-phenyl) -6-methyl-pyridine (example a.51) (0.5g, 0.8mmol) and imidazole obtained commercially (0.112g, 1.6 mmol). A white solid was obtained (0.060g, 24%). MS (ISP)304.0[ (M + H)⁺]，306[(M+2+H)⁺]And 308[ (M +4+ H)⁺]；mp 227℃。

Example 248

5- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridine-3-sulfonamide

The title compound was prepared according to general method VI using 2- (3-bromo-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example E.21) (0.200g, 0.51mmol) and 3-sulfamoyl-pyridine-5-boronic acid (example F.3) (0.103g, 0.51 mmol). A white solid was obtained (0.015g, 6%). MS (ISP)470.3[ (M + H)⁺]；mp＞250℃。

Example 249

5- {3- [4- (3, 4-dichloro-phenyl) -6-methyl-pyridin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyridine (example e.85) (0.20g, 0.509mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.123g, 0.56 mmol). An off-white solid was obtained (0.050g, 21%). MS (ISP)4060[ (M + H) ⁺]，408.1[(M+2+H)⁺]And 410[ (M +4+ H)⁺]；mp 99℃(dec.)。

Example 250

5- {3- [4- (3, 4-dichloro-phenyl) -6-methyl-pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyridine (example e.85) (0.20g, 0.509mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.124g, 0.56 mmol). An off-white solid was obtained (0.100g, 48%). MS (ISP)407.2[ (M + H)⁺]，409.1[(M+2+H)⁺]And 411[ (M +4+ H)⁺]；mp 188℃。

Example 251

2-methyl-6-thiazol-2-yl-4- (4-trifluoromethyl-phenyl) -pyridine

The title compound was prepared according to general procedure IVc scheme b using 2-iodo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example a.31) (4.0g, 9.36mmol) and commercially available 2, 4-dibromothiazole (2.53g, 10.4 mmol). By-product was obtained as a pale yellow solid (0.065g, 2%). MS (ISP)321.2[ (M + H)⁺]；mp 103℃。

Example 252

5- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiophen-2-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (5-bromo-thiophen-2-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example E.86) (0.27g, 0.678mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.164g, 0.745 mmol). Light brown solid (0.100g, 35%) was obtained. MS (ISP)412.2[ (M + H) ⁺]；mp196℃。

Example 253

5- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiophen-2-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (5-bromo-thiophen-2-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.86) (0.20g, 0.502mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.124g, 0.552 mmol). A yellow solid (0.045g, 21%) was obtained. MS (ISP)413.2[ (M + H)⁺]；mp＞250℃。

Example 254

5- {5- [4- (3, 4-dichloro-phenyl) -6-methyl-pyridin-2-yl ] -thiophen-2-yl } -pyridin-2-ylamine

According to general method VI, 2- (5-bromo-thiophen-2-yl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyridine (example E.87) (0.25g, 0.626mmol) andthe title compound was prepared from commercial 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.152g, 0.689 mmol). Light brown solid was obtained (0.055g, 21%). MS (ISP)412.1[ (M + H)⁺]，414.2[(M+2+H)⁺]And 416.2[ (M +4+ H)⁺]；mp 180℃。

Example 255

5- {5- [4- (3, 4-dichloro-phenyl) -6-methyl-pyridin-2-yl ] -thiophen-2-yl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (5-bromo-thiophen-2-yl) -4- (3, 4-dichloro-phenyl) -6-methyl-pyridine (example e.87) (0.25g, 0.626mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine obtained commercially (0.152g, 0.689 mmol). A yellow solid was obtained (0.060g, 23%). MS (ISP)413.1[ (M + H) ⁺]，415.2[(M+2+H)⁺]And 417[ (M +4+ H)⁺]；mp 237℃。

Example 256

5- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiophen-3-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (4-bromo-thiophen-2-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.88) (0.20g, 0.5mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.122g, 0.55 mmol). A white solid was obtained (0.115g, 55%). MS (ISP)412.2[ (M + H)⁺]；mp 175℃。

Example 257

5- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridine-3-sulfonic acid (2-hydroxy-1, 1-dimethyl-ethyl) -amide

According to general method VI, 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]Phenylboronic acid (example G.9) (0.20g, 0.56mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1, 1-dimethyl-ethyl) -amide (example H.2) (0.173g, 0.56mmol) the title compound was prepared. A white solid was obtained (0.080g, 26%). MS (ISP)542.2[ (M + H)⁺]；mp 105℃(dec.)。

Example 258

3' - [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid methoxy-amide

According to general method VI, 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ]Phenylboronic acid (example G.9) (0.20g, 0.56mmol) and 3-bromo-N-methoxy-benzenesulfonamide (example H.3) (0.149g, 0.56mmol) the title compound was prepared. A white solid (0.120g, 43%) was obtained. MS (ISP)499.2[ (M + H)⁺]；mp 181℃。

Example 259

3' - [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid (2-hydroxy-1, 1-dimethyl-ethyl) -amide

According to general method VI, 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]The title compound was prepared from phenylboronic acid (example G.9) (0.442g, 1.2mmol) and 3-bromo-N- (2-hydroxy-1, 1-dimethyl-ethyl) -benzenesulfonamide (example H.4) (0.381g, 1.2 mmol). A white solid was obtained (0.150g, 22%). MS (ISP)499.2[ (M + H)⁺]；mp 181℃。

Example 260

5- {3- [ 6-Ethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyrimidin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.89) (0.30g, 0.739mm0l) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (0.180g, 0.813mmol) obtained commercially. A white solid was obtained (0.050g, 16%). MS (ISP)421.1[ (M + H) ⁺]；mp 209℃。

Example 261

N-tert-butyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

According to general method VI, 6 ' -bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2 ' is employed ']The title compound was prepared from bipyridine (example E.26) (0.65g, 1.65mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.468g, 1.82 mmol). White solid (0.10g, 12%) and another off-white solid (0.57g, 66%) were obtained. MS (ISP)526.2[ (M + H)⁺]；mp 183℃。

Example 262

N-tert-butyl-3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -benzenesulfonamide

According to general method VI, 2-chloro-4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl is employed]Pyrimidine (example e.83) (0.5g, 1.432mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid (0.404g, 1.575mmol) obtained commercially. White solid (0.10g, 13%) and another off-white solid (0.48g, 64%) were obtained. MS (ISP)527.2[ (M + H)⁺]；mp218℃。

Example 263

N-tert-butyl-3- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -benzenesulfonamide

The title compound was prepared according to general procedure VI using 2- (4-bromo-thiazol-2-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.80) (0.5g, 1.253mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.354g, 1.378 mmol). White solid (0.10g, 15%) and another off-white solid (0.40g, 60%) were obtained. MS (ISP)532.1[ (M + H) ⁺]；mp196℃。

Example 264

5- {3- [ 6-Ethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.89) (0.30g, 0.739mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.179g, 0.813 mmol). A white solid was obtained (0.050g, 16%). MS (ISP)420.1[ (M + H)⁺]；mp 74℃。

Example 265

3' - [ 6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.89) (0.30g, 0.739mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.209g, 0.813 mmol). White solid (0.10g, 25%) and another off-white solid (0.20g, 50%) were obtained. MS (ISP)539.3[ (M + H)⁺]；mp 169℃。

Example 266

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

To a cooled and stirred mixture of N-tert-butyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ]Bipyridin-6-yl]To a solution of benzenesulfonamide (example 261) (0.570g, 1.085mmol) in dichloromethane (10mL) was added TFA (10mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried to give the title compound as a white solid (0.28g, 55%). MS (ISP)468.2[ (M + H)⁺]；mp 250℃。

Example 267

3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -benzenesulfonamide

To the cooled and stirred N-tert-butyl-3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl group]-Pyrimidin-2-yl } -benzenesulfonamide (example 262) (0.480g, 0.912mmol) in dichloromethane (10mL) was added TFA (10mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried to give the title compound as a white solid (0.25g, 46%). MS (ISP)469.3[ (M + H)⁺]；mp＞250℃。

Example 268

3- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -benzenesulfonamide

To the cooled and stirred N-tert-butyl-3- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl group]-Thiazol-4-yl } -benzenesulfonamide (example 263) (0.40g, 0.753mmol) in dichloromethane (10mL) TFA (10mL) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried to give the title compound as a white solid (0.20g, 56%). MS (ISP)474.1[ (M + H)⁺]；mp＞250℃。

Example 269

3' - [ 6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide

To the cooled and stirred 3' - [ 6-ethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-Biphenyl-3-sulfonic acid tert-butylamide (example 265) (0.40g, 0.742mmol) in dichloromethane (10mL) TFA (10mL) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate was collected by filtration, washed with water and heptane/ether and dried to give the title compound as whiteA colored solid (0.022g, 12%). MS (ISP)481.2[ (M + H) ⁺]。

Example 270

4, 6-difluoro-3' - [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide

According to general method VI, 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]Phenylboronic acid (example G.9) (0.40g, 1.1mmol) and commercial 5-bromo-2, 4-difluoro-benzenesulfonamide (0.635g, 2.3mmol) were used to prepare the title compound. A white solid was obtained (0.150g, 27%). MS (ISP)505.1[ (M + H)⁺]；mp 227℃。

Example 271

5- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -thiophene-2-sulfonamide

According to general method VI, 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]Phenylboronic acid (example G.9) (0.40g, 1.1mmol) and the commercial 5-bromo-thiophene-2-sulfonamide (0.478g, 2.4mmol) prepared the title compound. A white solid was obtained (0.180g, 42%). MS (ISP)475.2[ (M + H)⁺]；mp 215℃。

Example 272

5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -thiophene-2-sulfonic acid tert-butylamide

The title compound was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-methyl-6- (4-trifluoromethyl-phenyl) -pyridine (example e.90) (0.392g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example f.1) (0.380g, 1.1 mmol). A white solid was obtained (0.409g, 77%). MS (ISP)531.3[ (M + H) ⁺]；mp 156℃。

Example 273

5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -thiophene-2-sulfonamide

To the 5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonic acid tert-butylamide (example 272) (0.30g, 0.565mmol) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried to give the title compound as a white solid (0.092g, 34%). MS (ISP)475.1[ (M + H)⁺]；mp 211℃。

Example 274

3' - [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonic acid amide

According to general method VI, 3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl]The title compound was prepared from phenylboronic acid (example G.10) (0.407g, 1.14mmol) and 3-bromobenzenesulfonamide (177mg, 1.14mmol) obtained commercially. A white solid was obtained (0.052g, 10%). MS (ISP)469.4[ (M + H)⁺]；mp 200℃。

Example 275

5- {3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -pyridine-3-sulfonamide

According to general method VI, 3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ]Phenylboronic acid (example G.10) (0.407g, 1.14mmol) and commercial 5-bromo-pyridine-3-sulfonamide (178mg, 1.14mmol) were used to prepare the title compound. A white solid was obtained (0.101g, 19%). MS (ISP)470.3[ (M + H)⁺]；mp 217℃。

Example 276

5- [3- (4-benzo [1, 3] dioxol-5-yl-6-methyl-pyridin-2-yl) -phenyl ] -pyridin-2-ylamine

According to general method VI, 4-benzo [1, 3] is used]Dioxol-5-yl-2- (3-bromo-phenyl) -6-methyl-pyridine (example E.91)(0.150g, 0.407mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.099g, 0.448mmol) obtained commercially. A white solid was obtained (0.100g, 64%). MS (ISP)382.2[ (M + H)⁺]；mp 203℃。

Example 277

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H- [1, 2, 4] triazol-3-yl } -pyridin-2-ylamine

According to general method VI, 2- (3-chloro- [1, 2, 4)]Triazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example E.92) (0.314g, 0.8mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.176g, 0.8mmol) the title compound was prepared. A white solid was obtained (0.027g, 8%). MS (ISP)451.2[ (M + H) ⁺]。

Example 278

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide

The title compound was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example e.23) (0.966g, 2.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example f.1) (0.829g, 2.4 mmol). A white solid (0.158g, 14%) was obtained. MS (ISP)575.2[ (M + H)⁺]。

Example 279

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

To the cooled and stirred 5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (example 278) (0.137g, 0.24mmol) in dichloromethane (3mL) TFA (3mL) was added and the reaction was repeatedThe mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried to give the title compound as a white solid (0.100g, 81%). MS (ISP)519.2[ (M + H) ⁺]。

Example 280

N-tert-butyl-3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

The title compound was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example e.23) (0.483g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.334g, 1.3 mmol). A white solid was obtained (0.126g, 22%). MS (ISP)539.3[ (M + H)⁺]。

Example 281

2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonic acid tert-butylamide

A stirred mixture of 2- (4-tributylstannyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example G.11) (0.575g, 0.76mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (example H.1) (0.227g, 0.85mmol), tetrakis (triphenyl-phosphine) palladium (0.051g, 0.038mmol) in toluene (5mL) was heated at reflux for 4 h. Cooling to room temperature gave some precipitate, which was diluted with toluene (. about.5 mL), placed in a freezer for 30min, heptane (total volume 25mL) was added, the precipitate filtered, washed with toluene/heptane (ca.1: 1, 3X 10mL), and dried in HV to give the title compound as an off-white solid (305mg, 70%). MS (ISP)576.3[ (M + H) ⁺]；mp 236℃。

Example 282

3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H- [1, 2, 4] triazol-3-yl } -benzenesulfonamide

1) Preparation of N-tert-butyl-3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example E.23) (0.393g, 0.81mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.334g, 1.3mmol)]-1H-[1，2，4]Triazol-3-yl } -benzenesulfonamide. A white solid (0.021g, 4%) and another light brown residue (0.090g, 16%) were obtained. MS (ISP)570.2[ (M + H)⁺]。

2) To the cooled and stirred solution of N-tert-butyl-3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] prepared as described above]-1H-[1，2，4]Triazol-3-yl } -benzenesulfonamide (0.090g, 0.16mmol) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate was collected by filtration, washed with water and heptane/ether and dried to give the title compound as a white solid (0.022g, 27%). MS (ISP)514.3[ (M + H) ⁺]。

Example 283

3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

To the cooled and stirred N-tert-butyl-3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (example 280) (0.110g, 0.19mmol) in dichloromethane (3mL) TFA (3mL) was added and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried to give the title compound as a white solid (0.092g, 93%). MS (ISP)513.4[ (M + H)⁺]；mp＞266℃。

Example 284

2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide

To the 2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl group]To a solution of-1H-imidazol-4-yl } -thiazole-5-sulfonic acid tert-butylamide (example 281) (0.160g, 0.28mmol) was added TFA (5mL) and the reaction mixture was stirred at room temperature for 24H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried to give the title compound as an off-white solid (0.124g, 86%). MS (ISP)520.2[ (M + H) ⁺]；mp＞266℃。

Example 285

N-tert-butyl-3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide

According to general method VI, 2 ' -chloro-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']The title compound was prepared from bipyridine (example E.27) (0.403g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.334g, 1.3 mmol). Pale yellow solid was obtained (0.375g, 65%). MS (ISP)580.3[ (M + H)⁺]；mp 196℃。

Example 286

3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide

To a stirred and cooled N-tert-butyl-3- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]To a solution of benzenesulfonamide (example 285) (0.248g, 0.43mmol) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried to give the title compound as a white solid (0.182g, 81%). MS (ISP)524.3[ (M + H)⁺]；mp 227℃(dec.)。

Example 287

N-tert-butyl-3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide

According to general method VI, 2 ' -chloro-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']The title compound was prepared from bipyridine (example E.28) (0.200g, 0.6mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.177g, 0.7 mmol). An off-white solid was obtained (0.286g, 95%). MS (ISP)526.2[ (M + H)⁺]；mp 189℃。

Example 288

N-tert-butyl-3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3 '] bipyridinyl-5' -yl ] -benzenesulfonamide

According to general method VI, 5 '-bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3']The title compound was prepared from bipyridine (example E.24) (0.200g, 0.5mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.157g, 0.6 mmol). An off-white solid was obtained (0.182g, 68%). MS (ISP)526.3[ (M + H)⁺]。

Example 289

3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide

To a stirred and cooled N-tert-butyl-3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]To a suspension of benzenesulfonamide (example 287) (0.239g, 0.455mmol) in dichloromethane (1.5mL) was added TFA (10mL) and the reaction mixture was stirred at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO was added ₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried to give the title compound as a white solid (0.200g, 94%). MS (ISP)470.3[ (M + H)⁺]；mp＞250℃。

Example 290

5- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -pyridine-3-sulfonamide

A stirred mixture of 2- (4-tributylstannyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example g.11) (0.503g, 0.7mmol), 5-bromo-pyridine-3-sulfonamide (0.183g, 0.77mmol) obtained from commercial, tetrakis (triphenyl-phosphine) palladium (0.040g, 0.030mmol) in toluene (5mL) was heated at reflux for 18 h. Cooling to room temperature gave some precipitate, diluting with toluene (-5 mL), adding heptane, filtering the precipitate, washing with toluene/heptane, and drying in HV to give the title compound as a white solid (258mg, 72%). MS (ISP)514.2[ (M + H)⁺]；mp＞250℃。

Example 291

N- (2-hydroxy-1, 1-dimethyl-ethyl) -3- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

A stirred mixture of 2- (4-tributylstannyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example g.11) (0.503g, 0.7mmo1), 3-bromo-N- (2-hydroxy-1, 1-dimethyl-ethyl) -benzenesulfonamide (example H.4) (0.237g, 0.77mmol), tetrakis (triphenyl-phosphine) palladium (0.040g, 0.030mmol) in toluene (5mL) was heated at reflux for 18 h. Cooling to room temperature gave some precipitate, diluting with toluene (. about.5 mL), adding heptane, filtering the precipitate, washing with toluene/heptane, and drying in HV afforded the title compound as a white solid (268mg, 66%). MS (ISP)585.2[ (M + H) ⁺]；mp 150℃(dec.)。

Example 292

4-methyl-2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonic acid tert-butylamide

Stirring of 2- (4-tributylstannyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example G.11) (0.718g, 1.0mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (example G.11)A mixture of example H.5) (0.295g, 1.1mmol), tetrakis (triphenyl-phosphine) palladium (0.058g, 0.044mmol) in toluene (5mL) was heated at reflux for 18 h. Cooling to room temperature gave some precipitate, diluting with toluene (. about.5 mL), adding heptane, filtering the precipitate, washing with toluene/heptane, and drying in HV afforded the title compound as a white solid (384mg, 59%). MS (ISP)590.4[ (M + H)⁺]；mp＞250℃。

Example 293

N-tert-butyl-3- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

The title compound was prepared according to general procedure VI using 2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example e.93) (0.200g, 0.41mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.117g, 0.46 mmol). A white solid (0.120) was obtained

g，51％)。MS(ISP)569.2[(M+H)⁺]。

Example 294

4-methyl-2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide

To the stirred and cooled 4-methyl-2- {1- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl]To a suspension of-1H-imidazol-4-yl } -thiazole-5-sulfonic acid tert-butylamide (example 292) (0.295g, 0.50mmol) in dichloromethane (3mL) was added TFA (3mL) and the reaction mixture was stirred at room temperature for 16H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried to give the title compound as a white solid (0.264g, 99%). MS (ISP)534.2[ (M + H)⁺]；mp 187℃(dec.)。

Example 295

3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3 '] bipyridinyl-5' -yl ] -benzenesulfonamide

To a stirred and cooled N-tert-butyl-3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 3']Bipyridyl-5' -yl]To a suspension of benzenesulfonamide (example 288) (0.150g, 0.29mmol) in dichloromethane (0.9mL) was added TFA (6.3mL) and the reaction mixture was stirred at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried to give the title compound as a white solid (0.130g, 97%). MS (ISP)470.3[ (M + H) ⁺]；mp 235℃(dec.)。

Example 296

3- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

To the stirred and cooled N-tert-butyl-3- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (example 293) (0.110g, 0.19mmol) in dichloromethane (0.69mL) was added TFA (4.3mL) and the reaction mixture was stirred at room temperature for 16H. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5mL), diethyl ether and heptane. The mixture was stirred at rt for 1h, the precipitate collected by filtration, washed with water and heptane/ether and dried, purified by silica gel column chromatography eluting with heptane/EtOAc, triturated with ether to give the title compound as a white solid (0.040g, 40%). MS (ISP)513.2[ (M + H)⁺]；mp＞250℃。

Example 297

N-tert-butyl-3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide

According to general method VI, 2 ' -chloro-4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']The title compound was prepared from bipyridine (example E.94) (0.350g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.283g, 1.1 mmol). White solid (0.426g, 81%) was obtained. MS (ISP)526.2[ (M) +H)⁺]；mp 189℃。

Example 298

N-tert-butyl-3- {1- [6- (4-chloro-phenyl) -4-methyl-pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

The title compound was prepared according to general procedure VI using 2- (4-chloro-phenyl) -6- (4-iodo-imidazol-1-yl) -4-methyl-pyridine (example e.95) (0.198g, 0.5mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.141g, 0.55 mmol). A white solid was obtained (0.028g, 12%). MS (ISP)482.4[ (M + H)⁺]。

Example 299

N-tert-butyl-3- [4 ' -methyl-6 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

According to general method VI, 6 ' -bromo-4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 2 ' is employed ']The title compound was prepared from bipyridine (example E.96) (0.393g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid (0.283g, 1.1mmol) obtained commercially. A white solid was obtained (0.500g, 95%). MS (ISP)526.3[ (M + H)⁺]。

Example 300

4-methyl-2- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonic acid tert-butylamide

A stirred mixture of 2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example G.12) (0.570g, 0.88mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (example H.5) (0.266g, 0.99mmol), tetrakis (triphenyl-phosphine) palladium (0.061g, 0.046mmol) in toluene (6mL) was heated at reflux for 16 h. Cooling to room temperature gave some precipitate, diluting with toluene (. about.5 mL), adding heptane, filtering the precipitate, washing with toluene/heptane, and drying in HV afforded the title compound as a white solid (130mg, 25%). MS (ISP)590.4[ (M + H) ⁺]；mp 260℃。

Example 301

5- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide

A stirred mixture of 2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example g.12) (0.570g, 0.88mmol), tert-butylamide from commercial 5-bromo-thiophene-2-sulfonic acid (0.295g, 0.99mmol), tetrakis (triphenyl-phosphine) palladium (0.061g, 0.046mmol) in toluene (6mL) was heated at reflux for 16 h. Cooling to room temperature gave some precipitate, diluting with toluene (. about.5 mL), adding heptane, filtering the precipitate, washing with toluene/heptane, and drying in HV afforded the title compound as a white solid (290mg, 57%). MS (ISP)575.2[ (M + H)⁺]；mp＞250℃。

Example 302

2- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonic acid tert-butylamide

A stirred mixture of 2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridine (example G.12) (0.570g, 0.88mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (example H.1) (0.265g, 0.99mmol), tetrakis (triphenyl-phosphine) palladium (0.061g, 0.046mmol) in toluene (6mL) was heated at reflux for 16 h. Cooling to room temperature gave some precipitate, diluting with toluene (. about.5 mL), adding heptane, filtering the precipitate, washing with toluene/heptane, and drying in HV afforded the title compound as a white solid (220mg, 43%). MS (ISP)576.3[ (M + H) ⁺]；mp 252℃。

Example 303

5- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -thiophene-2-sulfonic acid tert-butylamide

According to general method VI, 2-chloro-4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl is employed]Pyrimidine (example E.83) (0.3g, 0.858mmol) and N-tert-butylButyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.355g, 1.029mmol) the title compound is prepared. A white solid was obtained (0.220g, 48%). MS (ISP)533.2[ (M + H)⁺]；mp 242℃(dec.)。

Example 304

5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonic acid tert-butylamide

According to general method VI, 2 ' -chloro-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']The title compound was prepared from bipyridine (example E.28) (0.300g, 0.86mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.356g, 1.029 mmol). A white solid (0.110g, 24%) was obtained. MS (ISP)532.1[ (M + H)⁺]；mp 225℃。

Example 305

5- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -thiophene-2-sulfonic acid tert-butylamide

According to general method VI, 6 ' -bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2 ' is employed ']The title compound was prepared from bipyridine (example E.26) (0.300g, 0.763mmol) and N-tert-butyl-5- (4, 45, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.316g, 0.839 mmol). An off-white solid was obtained (0.040g, 10%). MS (ISP)532.1[ (M + H)⁺]；mp 227℃。

Example 306

6-methyl-2 '- (3-nitro-phenyl) -4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl

According to general method VI, 2 ' -chloro-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']The title compound was prepared from bipyridine (example E.28) (5.7g, 16.34mmol) and commercial 3-nitrophenylboronic acid (3.274g, 19.61 mmol). A white solid was obtained(6.6g，92％)。MS(ISP)436.2[(M+H)⁺]；mp 164℃。

Example 307

3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -phenylamine

Mixing 6-methyl-2 '- (3-nitro-phenyl) -4- (4-trifluoromethyl-phenyl) - [2, 4']A mixture of bipyridine (example 306) (6.6g, 15.15mmol) in THF-MeOH 1: 1(300mL) and 10% palladium on charcoal (10 mol%) was hydrogenated (1bar hydrogen) at 23 ℃ for 2 h. The catalyst was filtered off, washed with MeOH, and the filtrate was evaporated completely to give the crude product, which was triturated with ether and dried in HV to give the title compound as a light brown solid (6.0g, 97%). MS (ISP)406.3[ (M + H) ⁺]；mp162℃(dec.)。

Example 308

3- {4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -benzenesulfonamide

1) According to the general procedure, 2-chloro-4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl is employed]Preparation of N-tert-butyl-3- {4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidine (example E.97) (0.350g, 1.0mmol) and commercial 3- (tert-butylsulfamoyl) -phenylboronic acid (0.283g, 1.1mmol)]-pyrimidin-2-yl } -benzenesulfonamide. A white solid was obtained (0.400g, 76%). MS (ISP)527.2[ (M + H)⁺]；mp 218℃。

2) To the N-tert-butyl-3- {4- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl group prepared above]To a solution of-pyrimidin-2-yl } -benzenesulfonamide (0.110g, 0.19mmol) was added TFA (6mL) and the reaction mixture was stirred at 50 ℃ for 2 h. The mixture was evaporated to dryness in EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.235g, 100%). MS (ISP)471.2[ (M + H)⁺]；mp＞250℃。

Example 309

3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide

To N-tert-butyl-3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4' ]Bipyridyl-2' -yl]To a solution of benzenesulfonamide (example 297) (0.110g, 0.19mmol) was added TFA (6mL) and the reaction mixture was stirred at 50 ℃ for 2 h. The mixture was evaporated to dryness in EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.230g, 98%). MS (ISP)470.3[ (M + H)⁺]；mp 238℃。

Example 310

3- [4 ' -methyl-6 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

To N-tert-butyl-3- [4 ' -methyl-6 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]To a solution of benzenesulfonamide (example 299) (0.450g, 0.856mmol) was added TFA (5mL) and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as an off-white solid (0.304g, 76%). MS (ISP)470.3[ (M + H)⁺]；mp 229℃。

Example 311

3- {1- [6- (4-chloro-phenyl) -4-methyl-pyridin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

To N-tert-butyl-3- {1- [6- (4-chloro-phenyl) -4-methyl-pyridin-2-yl ]To a solution of (E) -1H-imidazol-4-yl } -benzenesulfonamide (example 298) (0.028g, 0.058mmol) was added TFA (2mL) and the reaction mixture was stirred at 23 ℃ for 16H. The mixture was evaporated to dryness in EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as an off-white solidBody (0.025g, 101%). MS (ISP)425.1[ (M + H)⁺]And 427[ (M +2+ H)⁺]。

Example 312

4-methyl-2- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide

To 4-methyl-2- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]To a solution of (0.150g, 0.254mmol) of (example 300) of (4-imidazol-1-yl) -thiazole-5-sulfonic acid tert-butylamide was added TFA (5mL) and the reaction mixture was stirred at 23 ℃ for 16H. The mixture was evaporated to dryness in TBME and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.070g, 51%). MS (ISP)534.2[ (M + H)⁺]；mp 170℃(dec.)。

Example 313

2- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiazole-5-sulfonamide

To the 2- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl group]To a solution of (0.150g, 0.260mmol) of (example 302) tert-butylamide-1H-imidazol-4-yl } -thiazole-5-sulfonic acid was added TFA (5mL) and the reaction mixture was stirred at 23 ℃ for 16H. The mixture was evaporated to dryness in TBME and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.120g, 88%). MS (ISP)520.2[ (M + H)⁺]；mp＞250℃。

Example 314

5- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

To the 5- {1- [ 6-trifluoromethyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl group]-1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (example)Example 301) (0.200g, 0.348mm0l) solution TFA (5mL) was added and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in TBME and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.170g, 94%). MS (ISP)519.2[ (M + H)⁺]；mp 237℃(dec.)。

Example 315

5- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -thiophene-2-sulfonamide

To the 5- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl group]-Pyrimidin-2-yl } -thiophene-2-sulfonic acid tert-butylamide (example 303) (0.250g, 0.469mmol) to a solution TFA (5mL) was added and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in TBME and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.200g, 89%). MS (ISP)477.1[ (M + H)⁺]；mp＞250℃。

Example 316

5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonamide

To 5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]To a solution of-thiophene-2-sulfonic acid tert-butylamide (example 304) (0.170g, 0.32mmol) was added TFA (5mL) and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in TBME and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.135g, 88%). MS (ISP)476.2[ (M + H) ⁺]；mp＞250℃。

Example 317

5- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -thiophene-2-sulfonamide

To 5- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]To a solution of-thiophene-2-sulfonic acid tert-butylamide (example 305) (0.170g, 0.32mmol) was added TFA (5mL) and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in TBME and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.130g, 85%). MS (ISP)476.2[ (M + H)⁺]；mp 243℃(dec.)。

Example 318

N- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -phenyl } -methanesulfonamide

To stirred and cooled 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]To a solution of-phenylamine (example 307) (0.200g, 0.493mmol) in EtOAc (2mL) and saturated sodium bicarbonate solution (1mL) was added methanesulfonyl chloride (1.0mL, 13.6mmol), and the mixture was stirred at 23 ℃ for 2 h. Diluted with EtOAc, washed with saturated sodium bicarbonate solution and water, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether to afford the title compound as a white solid (0.070g, 29%). MS (ISP)484.4[ (M + H) ⁺]；mp 196℃。

Example 319

5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl-2-yl ] -thiophene-2-sulfonic acid tert-butylamide

According to general method VI, 2 '-iodo-4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4']The title compound was prepared from bipyridine (example E.98) (0.494g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.380g, 1.1 mmol). A white solid was obtained (0.360g,62％)。MS(ISP)586.2[(M+H)⁺]；mp 220℃。

example 320

5- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonic acid tert-butylamide

According to general method VI, 2 ' -chloro-4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']The title compound was prepared from bipyridine (example E.94) (0.349g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.380g, 1.1 mmol). Pale yellow solid (0.267g, 50%) was obtained. MS (ISP)532.1[ (M + H)⁺]；mp 209℃。

Example 321

5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonamide

To 5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) - [2, 4' ]Bipyridyl-2' -yl]To a solution of-thiophene-2-sulfonic acid tert-butylamide (example 319) (0.180g, 0.307mmol) was added TFA (3mL) and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.097g, 60%). MS (ISP)530.2[ (M + H)⁺]；mp 97℃(dec.)。

Example 322

4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -2- (3-nitro-phenyl) -pyrimidine

According to general method VI, 2-chloro-4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl is employed]Pyrimidine (example E.83) (3.6g, 10.29mmol) and 3-nitrophenylboronic acid (2.062g, 12.35mmol) obtained commercially. Light brown solid (2.1g, 46%) was obtained. MS (ISP)437.2[ (M + H)⁺]。

Example 323

5- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonamide

To 5- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]To a solution of-thiophene-2-sulfonic acid tert-butylamide (example 320) (0.240g, 0.45mmol) was added TFA (3mL) and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in EtOAc and saturated NaHCO ₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.215g, 100%). MS (ISP)476.1[ (M + H)⁺]；mp 228℃(dec.)。

Example 324

5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide

The title compound was prepared according to general method VI using 2- (4-bromo-thiazol-2-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example E.80) (0.150g, 0.375mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.143g, 0.413 mmol). A white solid (0.130g, 64%) was obtained. MS (ISP)538.3[ (M + H)⁺]；mp 171℃。

Example 325

5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -thiophene-2-sulfonamide

To the 5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl group]To a solution of (0.100g, 0.186mmol) of-thiazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (example 324) was added TFA (10mL) and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. Removing the solvent in vacuo to obtain a crude product, which is then triturated with diethyl ether To the target compound as a white solid (0.075g, 83%). MS (ISP)482.3[ (M + H)⁺]。

Example 326

3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -phenylamine

Reacting 4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]A mixture of (2- (3-nitro-phenyl) -pyrimidine (example 322) (2.1g, 4.81mmol) in THF-EtOH 1: 1(100mL) and 10% palladium on charcoal (1 mol%) was hydrogenated at 23 deg.C (1bar hydrogen) for 2 h. The catalyst was filtered off, washed with EtOH and the filtrate was evaporated completely to give the crude product, which was purified by column chromatography on silica gel eluting with heptane/EtOAc followed by trituration with ether to give the title compound as an off white solid (1.5g, 76%). MS (ISP)407.4[ (M + H)⁺]；mp 167℃。

Example 327

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -phenylamine

1) According to general method VI, 6 ' -bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2 ' is employed ']Preparation of 6-methyl-6 ' - (3-nitro-phenyl) -4- (4-trifluoromethyl-phenyl) - [2, 2 ' from bipyridine (example E.26) (5.0g, 12.71mmol) and commercial 3-nitrophenylboronic acid (2.547g, 15.26mmol) ']Bipyridine. White solid (3.7g, 66%) was obtained. MS (ISP)436.2[ (M + H) ⁺]。

2) Mixing the prepared 6-methyl-6 '- (3-nitro-phenyl) -4- (4-trifluoromethyl-phenyl) - [2, 2']A mixture of bipyridyl (3.4g, 7.81mmol) in THF-EtOH 1: 1(100mL) and 10% palladium on charcoal (1 mol%) was hydrogenated (1bar hydrogen) at 23 ℃ for 2 h. The catalyst was filtered off, washed with EtOH and the filtrate was evaporated completely to give the crude product, which was purified by silica gel column chromatography eluting with heptane/EtOAc followed by trituration with ether to give the title compound as a white solid (2.55g, 80%). MS (ISP)406.3[ (M + H)⁺]；mp 167℃。

Example 328

4- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -benzenesulfonamide

According to general method VI, 2-chloro-4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl is employed]Pyrimidine (example E.83) (0.150g, 0.381mmol) and (4-aminosulfonylphenyl) boronic acid [ CAS No. 613660-87-0 ] obtained commercially](0.130g, 0.457mmol) the title compound was prepared. A white solid was obtained (0.045g, 25%). MS (ISP)471.1[ (M + H)⁺]。

Example 329

4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide

According to general method VI, 2 ' -chloro-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']Bipyridine (example E.28) (0.150g, 0.430mmol) and (4-aminosulfonylphenyl) boronic acid [ CAS number 613660-87-0 ] obtained commercially ](0.146g, 0.516mmol) the title compound was prepared. A white solid was obtained (0.075g, 37%). MS (ISP)470.3[ (M + H)⁺]。

Example 330

N- (3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -phenyl) -methanesulfonamide

To the stirred and cooled 3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]To a solution of-pyrimidin-2-yl } -phenylamine (example 326) (0.150g, 0.369mmol) in EtOAc (2mL) and saturated sodium bicarbonate solution (1mL) was added methanesulfonyl chloride (1.0mL, 13.6mmol), and the mixture was stirred at 23 ℃ for 2 h. Diluted with EtOAc, washed with saturated sodium bicarbonate solution and water, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether to afford the title compound as a white solid (0.085g, 47%). MS (ISP)485.3[ (M + H)⁺]。

Example 331

N- (3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -phenyl) -acetamide

To the stirred and cooled 3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]To a solution of-pyrimidin-2-yl } -phenylamine (example 326) (0.150g, 0.369mmol) in EtOAc (2mL) and saturated sodium bicarbonate solution (1mL) was added acetyl chloride (0.030mL, 0.406mmol) and the mixture was stirred at 23 ℃ for 1 h. Diluted with EtOAc, washed with saturated sodium bicarbonate solution and water, and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was purified by trituration with ether to give the title compound as a white solid (0.100g, 60%). MS (ISP)449.3[ (M + H) ⁺]。

Example 332

N- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -phenyl } -acetamide

To stirred and cooled 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]To a solution of phenylamine (example 327) (0.400g, 0.986mmol) in EtOAc (4mL) and saturated sodium bicarbonate solution (2mL) was added acetyl chloride (0.080mL, 1.085mmol) and the mixture was stirred at 23 ℃ for 1 h. Diluted with EtOAc, washed with saturated sodium bicarbonate solution and water, and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was purified by trituration with ether to give the title compound as a white solid (0.250g, 57%). MS (ISP)484.2[ (M + H)⁺]。

Example 333

N- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -phenyl } -methanesulfonamide

To stirred and cooled 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]To a solution of phenylamine (example 327) (0.400g, 0.986mmol) in EtOAc (4mL) and saturated sodium bicarbonate solution (2mL) was added methanesulfonyl chloride (1.08mL, 14.7mmol), and the mixture was stirred at 23 ℃ for 2 h. Diluted with EtOAc, washed with saturated sodium bicarbonate solution and water, employing sulfuric acid Sodium dried the organic layer. Removal of the solvent in vacuo afforded the crude product which was purified by column chromatography on silica gel eluting with EtOA followed by trituration with ether to afford the title compound as a white solid (0.090g, 19%). MS (ISP)484.4[ (M + H)⁺]。

Example 334

N- (tert-butoxycarbonyl) -N '- {3- [ 6' -methyl-4 '- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl-6-yl ] -phenyl } -sulfonamide

To a stirred and cooled solution of commercial chlorosulfonyl isocyanate (isocyanate) (0.215mL, 2.47mmol) in methylene chloride (5mL) was added tert-butanol (0.232mL, 2.47mmol) and the mixture was stirred at 0 ℃ for 30 min. Then 3- [6 '-methyl-4' - (4-trifluoromethyl-phenyl) - [2, 2 'is added']Bipyridin-6-yl]Phenylamine (example 327) (0.200g, 0.494mmol) and triethylamine (0.42mL, 2.96mmol), and the mixture was stirred at 23 ℃ for 0.5 h. Diluted with DCM, washed with saturated sodium bicarbonate solution and water and the organic layer dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with heptane/EtOAc/THF, followed by trituration with ether to afford the title compound as an off-white solid (0.100g, 35%). MS (ISP)585.3[ (M + H) ⁺]。

Example 335

N- (tert-butoxycarbonyl) -N' - (3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -phenyl) -sulfonamide

To a stirred and cooled solution of commercial chlorosulfonyl isocyanate (0.215mL, 2.47mmol) in methylene chloride (5mL) was added tert-butanol (0.232mL, 2.47mmol) and the mixture was stirred at 0 ℃ for 30 min. Then 3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl is added]Pyrimidin-2-yl } -phenylamine (example 326) (0.200g, 0.494mmol) and triethylamine (0.42mL, 2.96mmol), and the mixture was stirred at 23 ℃ for 0.5 h. Diluted with DCM, washed with saturated sodium bicarbonate solution and water and the organic layer dried over sodium sulfate. The solvent is removed in vacuo to give the crude product which is passed throughPurification by column chromatography on silica eluting with heptane/EtOAc/THF followed by trituration with ether afforded the title compound as an off-white solid (0.100g, 35%). MS (ISP)586.2[ (M + H)⁺]。

Example 336

N-tert-butyl-3- [4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide

According to general method VI, 2 ' -chloro-4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4 ' is used ']The title compound was prepared from bipyridine (example E.99) (0.378g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.283g, 1.1 mmol). A white solid was obtained (0.390g, 70%). MS (ISP)556.5[ (M + H) ⁺]；mp 189℃。

Example 337

N- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -phenyl } -sulfonamide

To N- (tert-butoxycarbonyl) -N '- {3- [ 6' -methyl-4 '- (4-trifluoromethyl-phenyl) - [2, 2']Bipyridin-6-yl]-phenyl } -sulphonamide (example 334) (0.100g, 0.171mmol) solution TFA (5mL) was added and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.090g, 98%). MS (ISP)485.4[ (M + H)⁺]。

Example 338

N- (3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -phenyl) -sulfonamide

To N- (tert-butoxycarbonyl) -N' - (3- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl)]-pyrimidin-2-yl } -phenyl) -sulfonamide (example 335) (0.100g, 0.171mmol) solution was added to TFA (5mL) and the reaction mixture was stirred at 23 ℃ for 16 h. Steaming the mixtureDried in EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.065g, 78%). MS (ISP)486.3[ (M + H) ⁺]。

Example 339

5- [4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonic acid tert-butylamide

According to general method VI, 2 ' -chloro-4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4 ' is used ']Bipyridine (example E.99) (0.378g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.380g, 1.1 mmol). The title compound was prepared as a white solid (0.142g, 25%). MS (ISP)562.3[ (M + H)⁺]；mp 209℃(dec.)。

Example 340

3- [4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide

To N-tert-butyl-3- [4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4']Bipyridyl-2' -yl]To a solution of benzenesulfonamide (example 336) (0.277g, 0.5mmol) was added TFA (3mL) and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.250g, 100%). MS (ISP)500.2[ (M + H) ⁺]；mp 233℃(dec.)。

Example 341

5- [4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4 '] bipyridinyl-2' -yl ] -thiophene-2-sulfonamide

To 5- [4- (3-methoxy-4-trifluoromethyl-phenyl) -6-methyl- [2, 4']Bipyridyl-2' -yl]To a solution of-thiophene-2-sulfonic acid tert-butylamide (example 339) (0.100g, 0.178mmol) was added TFA (3mL) and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.090g, 100%). MS (ISP)506.2[ (M + H)⁺]；mp 261℃(dec.)。

Example 342

4- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -thiazol-2-ylamine

1) N, N-dimethyl-N' - (4- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-phenyl } -thiazol-2-yl) -carboxamidine: according to general procedure IVc scheme b, 2-iodo-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine (example A.31) (1.5g, 4.13mmol) and N' - [4- (3-bromo-phenyl) -thiazol-2-yl are employed]-N, N-dimethyl-formamidine (1.41g, 4.54mmo1) [ prepared according to the following method: commercial 4- (3-bromo-phenyl) -thiazol-2-ylamine (4g, 15.67mmol) was refluxed with DMF-dimethyl acetal (6.3mL, 47.03mmol) in toluene (10mL) for 1h, then evaporated to dryness to give a white solid (4.8g, 99%) ]And (4) preparation. White solid (0.88g, 46%) was obtained. MS (ISP)467.2[ (M + H)⁺]；mp174℃。

2) The above N, N-dimethyl-N' - (4- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl) is reacted at 50 deg.C]-phenyl } -thiazol-2-yl) -carboxamidine (880mg, 1.886mmol) was treated with 3M HCl (20mL) in THF (20mL) for 16 h. 2N NaOH was added until pH 10, extracted 2 times with EtOAc, and the organic layer was dried over sodium sulfate, filtered and evaporated completely to give the crude product, which was triturated with ether to give the title compound (750mg, 53%) as a white solid. MS (ISP)412.2[ (M + H)⁺]；mp＞250℃。

Example 343

2- [4- (3-methanesulfonyl-phenyl) -imidazol-1-yl ] -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine

A mixture of 2- (4-tributylstannyl-imidazol-1-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridine (example G.11) (0.718g, 1.0mmol), obtained from commercial 3-bromophenyl methyl sulfone (259mg, 1.1mmol), tetrakis (triphenyl-phosphine) palladium (0.058g, 0.050mmol) in toluene (5mL) was heated at reflux for 18 h. Cooling to room temperature gave some precipitate, which was diluted with toluene (. about.5 mL), placed in a freezer for 30min, heptane (total volume 25mL) was added, the precipitate was filtered, washed with toluene/heptane (ca.1: 1, 3X 10mL), purified by silica gel column chromatography eluting with heptane/ethyl acetate, followed by trituration with ether/heptane to give the title compound as a white solid (0.150g, 29%). MS (ISP)512.3[ (M + H) ⁺]。

Example 344

N- (tert-butoxycarbonyl) -N' - (4- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -phenyl } -thiazol-2-yl) -sulfonamide

To a stirred and cooled solution of commercial chlorosulfonyl isocyanate (0.215mL, 2.47mmol) in methylene chloride (5mL) was added tert-butanol (0.232mL, 2.47mmol) and the mixture was stirred at 0 ℃ for 30 min. 4- {3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl is then added]-phenyl } -thiazol-2-ylamine (example 342) (0.100g, 0.243mmol) and triethylamine (0.42mL, 2.96mmol), the mixture was stirred at 23 ℃ for 0.5 h. Diluted with DCM, washed with saturated sodium bicarbonate solution and water and the organic layer dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with heptane/EtOAc/THF, followed by trituration with ether/heptane to afford the title compound as a white solid (0.060g, 42%). MS (ISP)591.3[ (M + H)⁺]；mp 152℃(dec.)。

Example 345

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonic acid

1)3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]-a benzene sulfonic acid 2,2-dimethyl-propyl ester: according to general method VI, 6 ' -bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2 ' is employed ' ]The ester was prepared from bipyridine (example E.26) (7.0g, 17.8mmol) and 3- (2, 2-dimethyl-propoxysulfonyl) -phenylboronic acid (example F.4) (8.159g, 28.5 mmol). An off-white solid was obtained (7.7g, 80%). MS (ISP)541.3[ (M + H)⁺]。

2) The target compound was prepared as follows: mixing the above 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]2, 2-dimethyl-propyl benzenesulfonate (7.7g, 14.24mmol) in 1-propanol (15mL) in sodium propoxide (1.7M solution in n-propanol, 20.95mL, 35.6mmol) and 2- (diethylamino) ethanethiol (2.48mL, 16.38mmol) were refluxed together for 18 h. Cooled to room temperature, water (300mL) was added, 1N HCl (ca. 50mL) was added until pH 3-4, stirred for 10min, the solid was filtered, washed 3 times with water then acetone and dried in HV to give the title compound (5.4g, 81%) as an off-white solid. MS (ISN)469.1[ (M-H)^-]。

Example 346

6-methyl-2 '- [3- (morpholine-4-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl

1)2 '- (3-iodo-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridine: mixing 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]-phenylamine (example 307) (5.0g, 12.58mmol) in CH ₃CN (100mL), then cooled to 0 deg.C, and acetic acid (10mL) and concentrated HCl (5mL followed by NaNO addition₂(903mg, 13.08mmol) in water (2mL) was stirred for 5min, then KI (2.172g, 13.08mmol) in water (3mL) was added and the mixture was heated to 50 ℃ and stirred at 50 ℃ for 30 min. Pouring into saturated sodium bicarbonate solution, extracting with OEtOAc, and extracting the organic layer with brine and a small amount of Na₂SO₃Washing, drying over sodium sulfate, filtration and complete evaporation gave the crude product, which was purified by silica gel column chromatography eluting with n-heptane/EtOAc followed by trituration with ether/heptane to give 2 '- (3-iodo-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']The bipyridine (2.7g,41%) as a white solid. MS (ISP)517.1[ (M + H)⁺]。

2)3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]-benzenesulfonyl chloride: to the stirred mixture of 2 '- (3-iodo-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']To a solution of bipyridine (2.7g, 5.23mmol) in THF (70mL) was added n-BuLi (1.6M in hexanes, 3.27mL, 5.23mmol), and the mixture was stirred at-78 deg.C for 15 min. Gaseous sulfur dioxide (ca. 2.2g, 35mmol) was then passed in to raise the internal temperature by 20 ℃. The mixture was warmed to room temperature and stirred for 1 h. To a mixture of 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4' ]Bipyridyl-2' -yl]Lithium benzenesulfinate MS (ISP)455.2[ (M + H)⁺]To the reaction mixture of (1) was added N-chlorosuccinimide (0.768g, 5.75mmol), and the mixture was stirred at 23 ℃ for 16h to give 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]-benzenesulfonyl chloride solution, which is separated (split) and can be used directly in the next step.

3) The target compound was prepared as follows: mixing the prepared 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]Benzenesulfonyl chloride (ca. 0.2g, 0.41mmol) was treated with excess morpholine in THF (5mL) at 50 ℃ for 16 h. Cool to room temperature, dilute with EtOAc, wash with 1N HCl, and dry the organic layer over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with n-heptane/EtOAc followed by trituration with n-heptane/ether to afford the title compound (0.150g, 68%) as a white solid. MS (ISP)539.9[ (M + H)⁺]；mp 115℃。

Example 347

6-methyl-2 '- [3- (thiomorpholine-4-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl

The target compound was prepared as follows: mixing 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]A solution of-benzenesulfonyl chloride (example 346, step 2) (ca. 0.2g, 0.41mmol) was treated with excess thiomorpholine in THF (5mL) for 16h at 50 deg.C. Cooled to room temperature and diluted with EtOAc The organic layer was washed with 1N HCl and dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with n-heptane/EtOAc followed by trituration with n-heptane/ether to afford the title compound (0.150g, 66%) as a white solid. MS (ISP)555.8[ (M + H)⁺]；mp 156℃(dec.)。

Example 348

N- (2-hydroxy-ethyl) -3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [24 '] bipyridinyl-2' -yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]A solution of benzenesulfonyl chloride (example 346, step 2) (ca. 0.2g, 0.41mmol) was treated with excess ethanolamine in THF (5mL) for 16h at 50 ℃. Cool to room temperature, dilute with EtOAc, wash with 1N HCl, and dry the organic layer over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with n-heptane/EtOAc followed by trituration with n-heptane/ether to afford the title compound (0.045g, 21%) as a white solid. MS (ISP)514.0[ (M + H)⁺]；mp 103℃(dec.)。

Example 349

N- (2-hydroxy-1, 1-dimethyl-ethyl) -3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]A solution of-benzenesulfonyl chloride (example 346, step 2) (ca. 0.2g, 0.41mmol) was treated with an excess of 2-amino-2-methyl-1-propanol in THF (5mL) for 16h at 50 ℃. Cool to room temperature, dilute with EtOAc, wash with 1N HCl, and dry the organic layer over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with n-heptane/EtOAc followed by trituration with n-heptane/ether to afford the title compound (0.035g, 16%) as a white solid. MS (ISP)542.2[ (M + H)⁺]；mp 92℃。

Example 350

6-methyl-2 '- [3- (4-methyl-piperazine-1-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl

The target compound was prepared as follows: mixing 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 4']Bipyridyl-2' -yl]A solution of benzenesulfonyl chloride (example 346, step 2) (ca. 0.2g, 0.41mmol) was treated with excess N-methylpiperazine in THF (5mL) for 16h at 50 ℃. Cool to room temperature, dilute with EtOAc, wash with 1N HCl, and dry the organic layer over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with n-heptane/EtOAc followed by trituration with n-heptane/ether to afford the title compound (0.085g, 37%) as a white solid. MS (ISP)5528[ (M + H) ⁺]；mp 180℃(dec.)。

Example 351

Morpholine-4-sulfonic acid {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -phenyl } -amide

To stirred 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]To a solution of-phenylamine (example 327) (0.200g, 0.5mmol) and triethylamine (0.21mL, 1.5mmol) in dichloromethane (5mL) was added morpholine-4-sulfonyl chloride (0.101mg, 0.55mmol) obtained commercially and the mixture was stirred at 23 ℃ for 30 min. Diluted with DCM, washed with saturated sodium bicarbonate solution and water and the organic layer dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with heptane/EtOAc followed by trituration with heptane/ether to afford the title compound as an off-white solid (0.035g, 13%). MS (ISP)555.2[ (M + H)⁺]；mp 191℃。

Example 352

N, N- (dimethyl) -N '- {3- [ 6' -methyl-4 '- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl-6-yl ] -phenyl } -sulphonamide

To a stirred solution of 3- [6 '-methyl-4' - (4-trifluoromethyl-phenyl) - [2,2′]bipyridin-6-yl]A solution of-phenylamine (example 327) (0.200g, 0.5mmol) and triethylamine (0.21mL, 1.5mmol) in dichloromethane (5mL) was added to commercial dimethylsulfamoyl chloride (0.078mg, 0.55mmol) and the mixture was stirred at 23 ℃ for 30 min. Diluted with DCM, washed with saturated sodium bicarbonate solution and water and the organic layer dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with heptane/EtOAc followed by trituration with heptane/ether to afford the title compound as an off-white solid (0.020g, 8%). MS (ISP)513.0[ (M + H) ⁺]。

Example 353

2- (3' -methanesulfonyl-biphenyl-3-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine

According to general method VI, 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]Phenylboronic acid (example G.9) (0.357g, 1.0mmol) and 3-bromophenylmethyl sulfone (0.235g, 1.0mmol) obtained commercially to prepare the title compound. A white solid was obtained (0.414g, 89%). MS (ISP)468.0[ (M + H)⁺]；mp 110℃(dec.)。

Example 354

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -N-propionyl-benzenesulfonamide

Mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]A mixture of benzenesulfonamide (example 266) (470mg, 1.0mmol) and propionic anhydride (0.77mL, 6mmol) in propionic acid (5mL) was stirred at 150 ℃ for 2 days. Cooled to room temperature, diluted with EtOAc and saturated NaHCO₃The solution was extracted, dried over sodium sulfate, filtered and evaporated completely to give the crude product, which was purified by silica gel column chromatography eluting with n-heptane/ethyl acetate followed by trituration with ether/n-heptane to give the title compound (350mg, 66%) as a white solid. MS (ISP)526.9[ (M + H)⁺]；mp 173℃。

Example 355

2- (3-methanesulfonyl-phenyl) -4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidine

According to general method VI, 2-chloro-4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl is employed]Pyrimidine (example E.83) (0.350g, 1.0mmol) and (3-methylsulfonylphenyl) boronic acid (0.220g, 1.0mmol) obtained commercially. An off-white solid was obtained (0.280g, 59%). MS (ISP)470.1[ (M + H)⁺]；mp 208℃。

Example 356

6 '- (3-methanesulfonyl-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

According to general method VI, 6 ' -bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2 ' is employed ']The title compound was prepared from bipyridine (example E.26) (0.39g, 1.1mmol) and (3-methylsulfonylphenyl) boronic acid obtained commercially (0.218g, 1.0 mmol). A white solid (0.420g, 90%) was obtained. MS (ISP)469.1[ (M + H)⁺]；mp 186℃。

Example 357

6-methyl-6 '- (3-methylsulfanyl-phenyl) -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

According to general method VI, 6 ' -bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2 ' is employed ']The title compound was prepared from bipyridine (example E.26) (0.39g, 1.1mmol) and 3- (methylthio) phenylboronic acid obtained commercially (0.183g, 1.1 mmol). A white solid was obtained (0.150g, 31%). MS (ISP)437.1[ (M + H)⁺]；mp 144℃。

Example 358

6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2'; 6', 4 "] terpyridin-2" -ylamine

1)2 "- (2, 5-dimethyl-pyrrol-1-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2'; 6', 4 ″]Terpyridine: according to general method VI, 6 ' -bromo-6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2 ' is employed ']Bipyridine (example E.26)) (0.39g, 1.1mmol) and 2- (2, 5-dimethyl-pyrrol-1-yl) -pyridine-4-boronic acid (example F.5) (0.295g, 1.1 mmol). A white solid (0.220g, 45%) and another pale brown gum (270mg) were obtained. MS (ISP)485.2[ (M + H)⁺]；mp 175℃。

2) Mixing the above 2 "- (2, 5-dimethyl-pyrrol-1-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2'; 6', 4 ″]A mixture of terpyridine (470mg, 0.969mmol), hydroxylamine hydrochloride (337mg, 4.849mmol), 1.5M NaOH solution (1.62mL, 2.43mmol) in 1-propanol (5mL) was stirred in a sealed tube at 120 ℃ for 3 h. Cooled to room temperature, the reaction mixture was directly applied to silica gel column chromatography eluting with EtOAc followed by trituration with ether/heptane to give the title compound (0.110g, 27%) as a pale yellow solid. MS (ISP)407.3[ (M + H)⁺]；mp 160℃。

Example 359

N- (2-hydroxy-ethyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: from 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.275g, 0.5mmol) was treated with excess ethanolamine in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, washed with 1N HCl and the organic layer dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with n-heptane/EtOAc followed by trituration with n-heptane/ether to afford the title compound (0.110g, 43%) as a white solid. MS (ISP)513.9[ (M + H)⁺]；mp 110℃(dec.)。

Example 360

4- {4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidin-2-yl } -pyridin-2-ylamine

1)2- [2- (2, 5-dimethyl-pyrrol-1-yl) -pyridin-4-yl]-4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-a pyrimidine: according to general method VI, 2-chloro-4- [ 6-methyl-4- (4-trifluoromethyl) is usedPhenyl-pyridin-2-yl]-pyrimidine (example e.83) (0.35g, 1.0mmol) and 2- (2, 5-dimethyl-pyrrol-1-yl) -pyridine-4-boronic acid (example F.5) (0.297g, 1.1mmol) were prepared. A white solid (0.150g, 31%) and another pale brown gum (190mg) were obtained. MS (ISP)486.1[ (M + H)⁺]；mp 177℃。

2) Mixing the above 2- [2- (2, 5-dimethyl-pyrrol-1-yl) -pyridin-4-yl ]-4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]A mixture of pyrimidine (280mg, 0.577mmol), hydroxylamine hydrochloride (200mg, 2.89mmol), 1.5M NaOH solution (0.96mL, 1.44mmol) in 1-propanol (3mL) was stirred in a sealed tube at 120 ℃ for 3 h. Cooled to room temperature, the reaction mixture was directly applied to a silica gel column chromatography eluting with EtOAc followed by trituration with ether/heptane to give the title compound (0.050g, 27%) as an off-white solid. MS (ISP)408.4[ (M + H)⁺]；mp 217℃。

Example 361

3- [ 4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 '] bipyridinyl-2' -yl ] -phenylamine

1) According to general method VI, 2 ' -chloro-4-methyl-6- (4-trifluoromethyl-phenyl) - [2, 4 ' is employed ']Preparation of 4-methyl-2 ' - (3-nitro-phenyl) -6- (4-trifluoromethyl-phenyl) - [2, 4 ' from bipyridine (example E.94) (1.25g, 3.6mmol) and commercial 3-nitrophenylboronic acid (0.718g, 4.3mmol) ']Bipyridine. Light brown solid (1.03g, 66%) was obtained. MS (ISP)436.1[ (M + H)⁺]；mp 91℃。

2) Mixing the prepared 4-methyl-2 '- (3-nitro-phenyl) -6- (4-trifluoromethyl-phenyl) - [2, 4']A mixture of bipyridine (1.12g, 3.0mmol) in THF-MeOH 1: 1(100mL) and 10% palladium on charcoal (1 mol%) was hydrogenated (1bar hydrogen) at 23 deg.C for 2 h. The catalyst was filtered off, washed with MeOH, and the filtrate was evaporated completely to give the crude product, which was purified by trituration with ether to give the title compound as a light brown solid (0.914g, 88%). MS (ISP)406.5[ (M + H) ⁺]；mp 87℃(dec.)。

Example 362

N-tert-butyl-3- {6- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

The title compound was prepared according to general procedure VI using 2- (6-bromo-pyridin-2-yl) -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example e.100) (0.600g, 1.34mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.448g, 1.74 mmol). A pale yellow foam (0.318g, 41%) was obtained. MS (ISP)581.6[ (M + H)⁺]；mp 75℃。

Example 363

N- (2-hydroxy-1, 1-dimethyl-ethyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.228g, 0.47mmol) was treated with an excess of 2-amino-2-methyl-1-propanol in THF (10mL) for 1h at 23 ℃. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with n-heptane/EtOAc followed by trituration with n-heptane/ether to afford the title compound (0.158g, 63%) as a white solid. MS (ISP)541.9[ (M + H) ⁺]；mp 171℃。

Example 364

3- {6- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To N-tert-butyl-3- {6- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonamide (example 362) (0.232g, 0.40mmol) solution was added TFA (3mL) and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was evaporated to dryness in EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. Removing the solvent in vacuo to give a crude product, which is triturated with diethyl ether to give the desired compoundMaterial as a white solid (0.170g, 81%). MS (ISP)524.8[ (M + H)⁺]；mp 244℃(dec.)。

Example 365

N, N-bis- (2- {2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethoxy } -ethyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.258g, 0.528mmol) with bis- [2- [2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethoxy]-ethoxy radical]-ethyl radical]Amine [ CAS number 123852-08-4](0.210g, 0.528mmol) and Et₃A solution of N (0.221mL, 1.58mmol) in THF (5mL) was treated at 23 ℃ for 1 h. Diluted with EtOAc and washed with 5% citric acid, saturated sodium bicarbonate solution +2M Na ₂CO₃The solution was washed with brine, and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc/EtOH to give the title compound (0.158g, 63%) as a yellow oil. MS (ISP)850.5[ (M + H)⁺]。

Example 366

N, N-bis- (2-hydroxy-ethyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.210g, 0.429mmol) was treated with excess diethanolamine in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with n-heptane/ether to afford the title compound (0.120g, 50%) as a white solid. MS (ISP)557.6[ (M + H)⁺]；mp 176℃。

Example 367

N- (2- {2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethoxy } -ethyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.210g, 0.429mmol) with 2- {2- [2- (2-methoxy-ethoxy) -ethoxy]-ethoxy } -ethylamine [ CAS number 85030-56-4](0.089g, 0.429mmol) and Et₃A solution of N (0.180mL, 1.287mmol) in THF (5mL) was treated at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc to give the title compound (0.080g, 28%) as an orange oil, MS (ISP)659.7[ (M + H)⁺]。

Example 368

6 '- [3- (1, 1-dioxo-1. lamda.6-thiomorpholine-4-sulfonyl) -phenyl ] -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.300g, 0.613mmol) was treated with a solution of commercially available thiomorpholine-1, 1-dioxide (0.166g, 1.226mmol) and Et3N (0.260mL, 1.84mmol) in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.170g, 47%) as a white solid. MS (ISP)588.1[ (M + H) ⁺]；mp 230℃(dec.)。

Example 369

6-methyl-6 '- [3- (pyrrolidine-1-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.300g, 0.613mmol) was treated with pyrrolidine (0.131mg, 1.84mmol) in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtCAc followed by trituration with ether/heptane to afford the title compound (0.230g, 71%) as a white solid. MS (ISP)524.3[ (M + H)⁺]；mp 174℃。

Example 370

6-methyl-6 '- [3- (4-methyl-piperazine-1-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.300g, 0.613mmol) was treated with pyrrolidine (0.184mg, 1.84mmol) in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.210g, 62%) as a white solid. MS (ISP)553.3[ (M + H) ⁺]；mp 167℃(dec.)。

Example 371

N- (2-methoxy-ethyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.300g, 0.613mmol) was treated with a solution of commercial 2-methoxyethylamine (0.138mg, 1.84mmol) in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, 5% citric acid, saturated carbonThe sodium hydrogen acid solution and brine were washed, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.200g, 62%) as a white solid. MS (ISP)528.2[ (M + H)⁺]；mp 126℃。

Example 372

N- [2- (2-hydroxy-ethoxy) -ethyl ] -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.300g, 0.613mmol) was treated with a solution obtained from commercial 2- (2-aminoethoxy) ethanol (0.194mg, 1.84mmol) in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.210g, 61%) as a white solid. MS (ISP)558.2[ (M + H) ⁺]；mp 123℃。

Example 373

6-methyl-6 '- [3- (morpholine-4-sulfonyl) -phenyl ] -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.300g, 0.613mmol) was treated with morpholine (0.160mg, 1.84mmol) in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.250g, 75%) as a white solid. MS (ISP)540.3[ (M + H)⁺]；mp 216℃。

Example 374

N-propionyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonamide (example 158) (0.1g, 0.19mmol), propionic anhydride (0.45ml) and propionic acid (2ml) were stirred at 150 ℃ for 40h, and saturated NaHCO was poured in₃The solution (30ml) was extracted with ethyl acetate (2X 50 ml). The combined organic layers were washed with brine (30ml) and dried (MgSO) ₄) And evaporated. The crude product was further purified by silica gel flash chromatography (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to give the title compound (0.086g, 78%) as an off-white solid. MS (ISP)579.2[ (M-H)^-]；mp 144℃。

Example 375

5- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid propionyl-amide

5- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -thiophene-2-sulfonamide (example 164) (0.1g, 0.19mmol), propionic anhydride (0.45ml) and propionic acid (2ml) were stirred at 150 ℃ for 40h, and saturated NaHCO was poured in₃The solution (30ml) was extracted with ethyl acetate (2X 50 ml). The combined organic layers were washed with brine (30ml) and dried (MgSO)₄) And evaporated. The crude product was further purified by silica gel flash chromatography (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to give the title compound (0.074g, 67%) as a light brown solid. MS (ISP)585.3[ (M-H)^-]；mp 257℃。

Example 376

5- {3- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -pyridin-2-ylamine

According to general method VI, 2- (3-bromo-phenyl) -4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidine is used (example EXAMPLE E.77) (0.37g, 1.0mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine from commercial origin (0.24g, 1.2mmol) the title compound was prepared. A white solid was obtained (0.27g, 70%). MS (ISP)387.2[ (M + H)⁺]；mp 158℃(dec.)。

Example 377

4- (3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonyl) -morpholine

To a cooled (ice-water bath and stirred mixture of morpholine (0.063g, 0.72mmol), triethylamine (0.07ml, 0.5mmol) and THF (1ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.14g, 0.24mmol) in THF (2 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/hexane) and crystallized (dichloromethane/hexane) to give the title compound as a white solid (0.13g, 91%). MS (ISP)595.2[ (M + H)⁺]；mp 202℃。

Example 378

5- {1- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 4- (4-fluoro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.79) (0.43g, 1.0mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.26g, 1.2 mmol). Pale yellow solid (0.13g, 33%) was obtained. MS (ISP)401.3[ (M + H) ⁺]；mp 249.5℃。

Example 379

3' - [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [4- (4-chloro-3-methyl-phenyl-6-methyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidine (example e.77) (0.37g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A white foam (0.45g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl group]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.45g) in dichloromethane (6ml) was added TFA (6ml), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5ml), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, and the precipitate was collected by filtration and washed with water and heptane. The crude product was further purified by silica gel flash chromatography (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to afford the title compound as a white solid (0.29g, 65%). MS (ISP)450.1[ (M + H)⁺]；mp 201℃。

Example 380

5- {3- [4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (4-chloro-3-methyl-phenyl) -4-methyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-chloro-3-methyl-phenyl) -6-methyl-pyrimidine (example E.77) (0.37g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.45g, 1.3 mmol). A pale yellow oil (0.405g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (4-chloro-3-methyl-phenyl) -4-methyl-pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.405g) in dichloromethane (6ml) was added TFA (6ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO was added₃Solution (5ml), diethyl ether and heptane. The mixture was stirred at room temperature for 1h, the precipitate collected by filtration, further purified by flash chromatography (heptane/ethyl acetate) and crystallized (ether/heptane) to yieldThe title compound was an off-white solid (0.093g, 20%). MS (ISP)456.1[ (M + H)⁺]；mp 240℃。

Example 381

N- (2-hydroxy-ethyl) -3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To a cooled (ice-water bath) and stirred mixture of ethanolamine (0.066g, 1.08mmol), triethylamine (0.11ml, 0.76mmol) and THF (2ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.21g, 0.36mmol) in THF (3 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/hexane) and crystallized (ether/hexane) to give the title compound as a white solid (0.156g, 76%). MS (ISP)569.2[ (M + H)⁺]；mp 1925℃。

Example 382

N- (2-hydroxy-1, 1-dimethyl-ethyl) -3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To a cooled (ice-water bath) and stirred mixture of 2-amino-2-methyl-1-propanol (0.097g, 1.09mmol), triethylamine (0.11ml, 0.76mmol) and THF (2ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.21g, 0.36mmol) in THF (3 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/hexane) and crystallized (ether/hexane) to give the title compound as a white solid (0.135g, 63%). MS (ISP)597.3[ (M + H) ⁺]；mp221℃。

Example 383

N, N-bis- (2-hydroxy-ethyl) -3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

Cooling (ice water bath) and stirringTo a mixture of diethanolamine (0.114g, 1.08mmol), triethylamine (0.11ml, 0.76mmol) and THF (2ml) was added 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl dropwise]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.21g, 0.36mmol) in THF (3 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/hexane) and crystallized (ether/hexane) to give the title compound as a white solid (0.127g, 57%). MS (ISP)613.2[ (M + H)⁺]；mp 186℃。

Example 384

5- {1- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -pyridin-2-ylamine

The title compound was prepared according to general procedure VI using 4- (3, 4-difluoro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.78) (0.45g, 1.0mmol) and 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine obtained commercially (0.26g, 1.2 mmol). A yellow solid (0.036g, 9%) was obtained. MS (ISP)419.1[ (M + H) ⁺]；mp 232℃。

Example 385

5- {1- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

1) A stirred mixture of 4- (3, 4-difluoro-phenyl) -2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example G.13) (0.21g, 0.34mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.11g, 0.37mmol), tetrakis (triphenyl-phosphine) palladium (0.024g, 0.02mmol) in toluene (3ml) was heated at reflux for 15h, hexane (10ml) was added and the mixture stirred at room temperature for 1 h. The precipitate was collected by filtration and further purified by silica gel flash chromatography (ethyl acetate/heptane) to give 5- {1- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.24g) as a white solid.

2) To cool and stir5- {1- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl]To a solution of (E) -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.24g) in dichloromethane (4ml) was added TFA (4ml) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and poured into 2N NaHCO₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO) ₄) And evaporated. Further purification by flash chromatography on silica gel (MeOH/dichloromethane) and crystallization (dichloromethane/heptane) gave the title compound as a pale yellow solid (0.077g, 46%). MS (ISP)487.9[ (M + H)⁺]；mp 228℃。

Example 386

5- {1- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonamide

1) A mixture of 4- (4-fluoro-phenyl) -2- (4-tributylstannyl-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example G.14) (0.34g, 0.57mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.19g, 0.63mmol), tetrakis (triphenyl-phosphine) palladium (0.039g, 0.033mmol) in toluene (5ml) was heated at reflux for 15h, hexane (10ml) was added and the mixture stirred at room temperature for 1 h. The precipitate was collected by filtration and further purified by silica gel flash chromatography (ethyl acetate/heptane) to give 5- {1- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.37g) as a white solid.

2) To the cooled and stirred 5- {1- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of (E) -1H-imidazol-4-yl } -thiophene-2-sulfonic acid tert-butylamide (0.37g) in dichloromethane (4ml) was added TFA (4ml) and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and poured into 2N naHCO ₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as an off-white solid (0.18g, 67%). MS (ISN)468.0[ (M-H)^-]；mp 244.5℃。

Example 387

3- {1- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-3- {1- [6- (4-fluoro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (4-fluoro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.79) (0.25g, 0.57mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.175g, 0.68 mmol). A pale yellow solid (0.52g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {1- [6- (4-fluoro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]-1H-imidazol-4-yl } -benzenesulfonamide (0.52g) in dichloromethane (4ml) TFA (4ml) was added and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and poured into 2N naHCO₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO) ₄) And evaporated. Further purification by silica gel flash chromatography (dichloromethane/MeOH) and crystallization (ethyl acetate/heptane) afforded the title compound as an off-white solid (0.13g, 48%). MS (ISN)462.0[ (M-H)^-]；mp 260℃。

Example 388

5- {3- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (3, 4-difluoro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidine (example E.101) (0.415g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.414g, 1.2 mmol). A white foam (0.37g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (3, 4)-difluoro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl]To a solution of-phenyl } -thiophene-2-sulfonamide (0.37g) in dichloromethane (6ml) was added TFA (6ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and poured into 2N naHCO₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO) ₄) And evaporated. Further purification by silica gel flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.11g, 22%). MS (ISP)498.1[ (M + H)⁺]；mp 238℃。

Example 389

2- {2- [3- (4-methyl-piperazine-1-sulfonyl) -phenyl ] -pyridin-4-yl } -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

To a cooled (ice-water bath) and stirred mixture of N-methyl-piperazine (0.09g, 0.9mmol), triethylamine (0.09ml, 0.63mmol) and THF (2ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.20g, 0.34mmol) in THF (3 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/hexane) and crystallized (dichloromethane/hexane) to give the title compound as a white solid (0.18g, 88%). MS (ISP)607.6[ (M + H)⁺]；mp 205℃。

Example 390

2- {2- [3- (pyrrolidine-1-sulfonyl) -phenyl ] -pyridin-4-yl } -4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine

To a cooled (ice-water bath) and stirred mixture of pyrrolidine (0.065g, 0.91mmol), triethylamine (0.09ml, 0.63mmol) and THF (2ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.20g, 0.34mmol) in THF (3 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/hexane) and crystallized (dichloromethane/hexane) to give the objective compoundAs a white solid (0.17g, 85%). MS (ISP)578.6[ (M + H)⁺]；mp184℃。

Example 391

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid (2-hydroxy-ethyl) -amide

To a cooled (ice-water bath) and stirred mixture of ethanolamine (0.071g, 1.16mmol), triethylamine (0.06ml, 0.42mmol) and THF (2ml) was added dropwise 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-biphenyl-3-sulfonyl chloride (example I.3) (0.21g, 0.39mmol) in THF (3 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.15g, 69%). MS (ISP)567.7[ (M + H)⁺]；mp 153℃。

Example 392

3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid bis- (2-hydroxy-ethyl) -amide

To a cooled (ice-water bath) and stirred mixture of diethanolamine (0.12g, 1.14mmol), triethylamine (0.06ml, 0.42mmol) and THF (2ml) was added dropwise 3' - [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ]-biphenyl-3-sulfonyl chloride (example I.3) (0.21g, 039mmol) in THF (3 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (ether/hexane) to give the title compound as a white solid (0.125g, 53%). MS (ISP)611.6[ (M + H)⁺]；mp 111.5℃。

Example 393

3' - [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidine (example e.101) (0.415g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A white foam (0.43g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.43g) in dichloromethane (6ml) was added TFA (6ml), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and poured into 2N NaHCO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO) ₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.26g, 53%). MS (ISP)492.1[ (M + H)⁺]；mp 211℃。

Example 394

3' - [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidine (example e.102) (0.40g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A white foam (0.49g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.49g) in dichloromethane (6ml) was added TFA (6ml), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and poured into 2N NaHCO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.37g, 78%). MS (ISP)474.0[ (M + H) ⁺]；mp 208℃。

Example 395

5- {3- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (4-fluoro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidine (example E.102) (0.40g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.414g, 1.2 mmol). An off-white foam (0.37g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (4-fluoro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.37g) in dichloromethane (6ml) was added TFA (6ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and poured into 2N NaHCO₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by silica gel flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) afforded the title compound as a pale yellow solid (0.17g, 35%). MS (ISP)480.0[ (M + H) ⁺]；mp 228.5℃。

Example 396

3- {1- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide

1) N-tert-butyl-3- {1- [6- (3, 4-difluoro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -1H-imidazol-4-yl } -benzenesulfonamide was prepared according to general procedure VI using 4- (3, 4-difluoro-phenyl) -2- (4-iodo-imidazol-1-yl) -6-trifluoromethyl-pyrimidine (example e.78) (0.15g, 0.33mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.103g, 0.4 mmol). A pale yellow solid (0.16g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {1- [6- (3, 4-difluoro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl } -benzenesulfonamide (0.16g) in dichloromethane (4ml) TFA (4ml) was added and the reaction mixture was stirred at room temperature for 15H. The mixture was evaporated to dryness and poured into 2N naHCO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by silica gel flash chromatography (dichloromethane/MeOH) and crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.019g, 12%). MS (ISP)482.1[ (M + H)⁺]；mp 241.5℃。

Example 397

5- {4- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

1) 5- {4- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidine (example E.103) (0.24g, 0.68mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.28g, 0.81 mmol). A light brown solid (0.27g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {4- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]-pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide (0.27g) in dichloromethane (4ml) TFA (4ml) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and poured into 2N naHCO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.16g, 49%). MS (ISP)480.9[ (M + H)⁺]；mp282℃。

Example 398

3- {4- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) 3- {4- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidine (example E.103) (0.24g, 0.68mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.21g, 0.82 mmol). A light brown solid (0.38g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3- {4- [4- (4-fluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]-pyridin-2-yl } -benzenesulfonic acid tert-butylamide (0.38g) in dichloromethane (5ml) TFA (5ml) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and poured into 2N NaHCO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.25g, 78%). MS (ISP)475.0[ (M + H)⁺]；mp 239.5℃。

Example 399

5- {4- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

1) 5- {4- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidine (example E.104) (0.25g, 0.67mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.28g, 0.81 mmol). A pale yellow solid (0.29g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {4- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]-pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide (0.29g) in dichloromethane (4ml) TFA (4ml) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and poured into 2NNaHCO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Purification by crystallization (ethyl acetate/heptane) gave the title compound as a white solid (0.08g, 24%). MS (ISP)499.1[ (M + H)⁺]；mp 281℃。

Example 400

3- {4- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) 3- {4- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidine (example E.104) (0.25g, 0.67mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.21g, 0.82 mmol). A pale yellow solid (0.25g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3- {4- [4- (3, 4-difluoro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group ]-pyridin-2-yl } -benzenesulfonic acid tert-butylamide (0.25g) in dichloromethane (4ml) TFA (4ml) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and poured into 2N NaHCO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.16g, 48%). MS (ISP)492.9[ (M + H)⁺]；mp 233.5℃。

Example 401

N, N-dimethyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To a cooled (ice-water bath) and stirred mixture of dimethylamine solution (60% in water) (0.27ml, 3.21mmol), triethylamine (0.29ml, 2.1mmol) and THF (4ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzeneSulfonyl chloride hydrochloride (example I.1) (0.58g, 1.0mmol) in THF (6 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.5g, 97%). MS (ISP)552.7[ (M + H) ⁺]；mp 225℃。

Example 402

N-methyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To a cooled (ice-water bath) and stirred mixture of methylamine solution (2M in THF) (1.5ml, 3.0mmol), triethylamine (0.29ml, 2.1mmol) and THF (4ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.58g, 1.0mmol) in THF (6 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.46g, 92%). MS (ISP)538.8[ (M + H)⁺]；mp 174℃。

Example 403

N-isobutyl-N-methyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To a cooled (ice-water bath) and stirred mixture of N-methylisobutylamine (0.26g, 3.0mmol), triethylamine (0.29ml, 2.1mmol) and THF (4ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.58g, 1.0mmol) in THF (6 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.45g, 80%). MS (ISP)594.7[ (M + H) ⁺]；mp 144℃。

Example 404

N-methyl-N-propyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To a cooled (ice-water bath) and stirred mixture of N-methylpropylamine (0.23g, 3.0mmol), triethylamine (0.29ml, 2.1mmol) and THF (4ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.58g, 1.0mmol) in THF (6 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.47g, 86%). MS (ISP)580.6[ (M + H)⁺]；mp 144℃。

Example 405

N-benzyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To a cooled (ice-water bath) and stirred mixture of benzylamine (0.32g, 3.0mmol), triethylamine (0.29ml, 2.1mmol) and THF (4ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (058g, 1.0mmol) in THF (6 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.49g, 85%). MS (ISP)614.8[ (M + H) ⁺]；mp 202.5℃。

Example 406

N-phenethyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To a cooled (ice-water bath) and stirred mixture of phenethylamine (0.36g, 3.0mmol), triethylamine (0.29ml, 2.1mmol) and THF (4ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.58g, 1.0mmol) in THF (6 ml). The mixture was stirred at rt for 16 h.The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/. hexane) to give the title compound as a white solid (0.57g, 97%). MS (ISP)628.8[ (M + H)⁺]；mp 201℃。

Example 407

(RS) -1- (3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonyl) -pyrrolidin-3-ol

To a cooled (ice water bath) and stirred mixture of (RS) -3-pyrrolidinol (0.27g, 3.0mmol), triethylamine (0.29ml, 2.1mmol) and THF (4ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.58g, 1.0mmol) in THF (6 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.49g, 88%). MS (ISP)594.6[ (M + H) ⁺]；mp 234℃。

Example 408

N-cyclopropylmethyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To a cooled (ice-water bath) and stirred mixture of cyclopropylmethylamine (0.21g, 2.96mmol), triethylamine (0.28ml, 2.0mmol) and THF (4ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.56g, 0.96mmol) in THF (6 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.51g, 97%). MS (ISP)578.6[ (M + H)⁺]；mp 133.5℃。

Example 409

N-cyclopropyl-3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To a cooled (ice-water bath) and stirred mixture of phenethylamine (0.165g, 3.0mmol), triethylamine (0.28ml, 2.0mmol) and THF (4ml) was added dropwise 3- {4- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonyl chloride hydrochloride (example I.1) (0.56g, 0.96mmol) in THF (6 ml). The mixture was stirred at rt for 16 h. The reaction mixture was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallized (dichloromethane/MeOH/hexane) to give the title compound as a white solid (0.49g, 96%). MS (ISP)564.7[ (M + H) ⁺]；mp 195.5℃。

Example 410

3' - [4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example e.106) (0.45g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). An off-white solid (0.36g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.36g) in dichloromethane (6ml) was added TFA (6ml), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.25g, 48%). MS (ISP)524.2[ (M + H)⁺]；mp 202℃。

Example 411

5- {3- [4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (2, 4-dichloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (2, 4-dichloro-phenyl) -6-trifluoromethyl-pyrimidine (example E.106) (0.45g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.414g, 1.2 mmol). An off-white solid (0.4g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (2, 4-dichloro-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.4g) in dichloromethane (6ml) was added TFA (6ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by silica gel flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) afforded the title compound as an off-white solid (0.13g, 25%). MS (ISP)530.0[ (M + H)⁺]；mp 237.5℃。

Example 412

3' - [4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.105) (0.465g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A pale yellow foam (0.54g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.54g) in dichloromethane (6ml) was added TFA (6ml), and the reaction mixture was stirred at room temperature for 15 h.The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.39g, 72%). MS (ISP)542.1[ (M + H)⁺]；mp 224.5℃。

Example 413

5- {3- [4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (2-fluoro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example E.105) (0.465g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.414g, 1.2 mmol). An off-white solid (0.43g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (2-fluoro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.43g) in dichloromethane (6ml) was added TFA (6ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as an off-white solid (0.23g, 42%). MS (ISP)548.1[ (M + H)⁺]；mp 192℃。

Example 414

5- {4- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

1) 5- {4- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 4- (4-chloro-3-methyl-phenyl) -2- (2-chloro-pyridin-4-yl) -6-trifluoromethyl-pyrimidine (example E.43) (0.14g, 0.36mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.15g, 0.43 mmol). A light brown solid (0.14g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {4- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]-pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide (0.14g) in dichloromethane (4ml) TFA (4ml) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.048g, 26%). MS (ISP)511.1[ (M + H)⁺]；mp 280℃。

Example 415

3- {4- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) 3- {4- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidine (example E.43) (0.14g, 0.36mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.11g, 0.43 mmol). A light brown solid (0.17g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3- {4- [4- (4-chloro-3-methyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group ]-pyridin-2-yl } -benzenesulfonic acid tert-butylamide (0.17g) in dichloromethane (4ml) TFA (4ml) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). Combining the organic layersWashed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as an off-white solid (0.1g, 55%). MS (ISP)505.1, 507.1[ (M + H)⁺]；mp234℃。

Example 416

3' - [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (4-trifluoromethyl-phenyl) -6-methyl-pyrimidine (example e.53) (0.21g, 0.52mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.16g, 0.62 mmol). A pale yellow solid (0.21g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.21g) in dichloromethane (4ml) was added TFA (4ml), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured ₂CO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.17g, 68%). MS (ISP)484.2[ (M + H)⁺]；mp 222.5℃。

Example 417

5- {3- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -6-methyl-4- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidine (example E.53) (0.21g, 0.52mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.21g, 0.62 mmol). A pale yellow solid (0.15g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [ 4-methyl-6- (3-methyl-4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.15g) in dichloromethane (3ml) was added TFA (3ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured ₂CO₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a light brown solid (0.064g, 25%). MS (ISP)490.1[ (M + H)⁺]；mp 242℃。

Example 418

N-tert-butyl-3- {6- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

A stirred mixture of 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl trifluoro-methanesulfonate (example A.62) (0.418g, 1.08mmol), N-tert-butyl-3- (6-tributylvanadyl-pyridin-2-yl) -benzenesulfonamide (example F.6) (0.570g, 0.98mmol), tetrakis (triphenyl-phosphine) palladium (0.057g, 5 mol%) in toluene (5mL) was heated at reflux for 18 h. Cooled to room temperature, extracted with ethyl acetate and water, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the product as a crude which was purified by silica gel column chromatography eluting with n-heptane/ethyl acetate and triturated with ether to afford the title compound as a white solid (260mg, 50%). MS (ISP)527.3[ (M + H)⁺]；mp＞250℃。

Example 419

3- {6- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To N-tert-butyl-3- {6- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonamide (example 418) (0.250g, 0.475 mmo)l) to the solution TFA (3mL) was added and the reaction mixture was stirred at 23 ℃ for 3 h. The mixture was washed with EtOAc and saturated NaHCO₃Partition between solutions, organic layer over MgSO₄And (5) drying. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a white solid (0.223g, 100%). MS (ISP)471.2[ (M + H)⁺]；mp 239℃(dec.)。

Example 420

N- [2- (2-methoxy-ethoxy) -ethyl ] -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) with 2- (2-methoxy-ethoxy) -ethylamine obtained commercially [ CAS number.31576-51-9]A solution of (0.244mg, 2.04mmol) in THF (5mL) was treated at 23 deg.C for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc followed by trituration with ether/heptane to give the title compound (0.160g, 68%) as a pale yellow oil. MS (ISP)572.2[ (M + H) ⁺]。

Example 421

N- {2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethyl } -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) with 2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethanol]-ethylamine [ CAS number 74654-07-2]A solution of (0.334mg, 2.04mmol) in THF (5mL) was treated at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removing the solvent in vacuo to give a crude product which is subjected to silica gel column chromatographyPurification, eluting with EtOAc, followed by trituration with ether/heptane afforded the title compound (0.180g, 71%) as a pale yellow oil. MS (ISP)616.2[ (M + H)⁺]。

Example 422

N-methyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) was treated with a solution of commercial methylamine (2M in THF, 2.05mL, 4.1mmol) in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.130g, 65%) as a white solid. MS (ISP)484.2[ (M + H) ⁺]；mp 176℃。

Example 423

N, N-dimethyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) was treated with a solution of commercial dimethylamine (40% in water, 0.52mL, 4.1mmol) in THF (5mL) for 16h at 23 deg.C. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc followed by trituration with ether/heptane to afford the title compound (0.110g, 54%) as a white foam MS (ISP)498.3[ (M + H)⁺]；mp 155℃。

Example 424

N-cyclopropyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) was treated with a solution of commercially available cyclopropylamine (0.14mL, 2.05mmol) in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.090g, 43%) as a white solid. MS (ISP)510.2[ (M + H) ⁺]；mp 150℃。

Example 425

N-cyclopropyl-N-methyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) N-cyclopropyl-N-methylamine [ CAS No. 5163-20-2, commercially available]A solution of (0.16mL, 2.05mmol) in THF (5mL) was treated at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.110g, 51%) as a white solid. MS (ISP)524.3[ (M + H)⁺]；mp 157℃。

Example 426

6 '- [3- (azetidine-1-sulfonyl) -phenyl ] -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200 g)0.409mmol) was employed with azetidine [ CAS number 503-29-7, available from commercial sources]A solution of (0.14mL, 2.05mmol) in THF (5mL) was treated at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.110g, 53%) as a white solid. MS (ISP)510.2[ (M + H) ⁺]；mp 158℃。

Example 427

1- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonyl } -piperidin-4-ol

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) with commercially available 4-hydroxypiperidine [ CAS No. 5382-16-1 [)]A solution of (0.207g, 2.05mmol) in THF (5mL) was treated at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.130g, 57%) as a white solid. MS (ISP)554.3[ (M + H)⁺]；mp 195℃。

Example 428

1- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonyl } -azetidin-3-ol

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) with 3-hydroxyazetidine hydrochloride [ CAS No. 18621-18-6, obtained commercially ]A solution of (0.224mg, 2.05mmol) and triethylamine (0.57mL, 4.1mmol) in THF (5mL) was treated at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was washed with EtOAcAnd (4) drying by using sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.120g, 55%) as a white solid. MS (ISP)526.3[ (M + H)⁺]；mp 205℃。

Example 429

6 '- [3- (4-methoxy-piperidine-1-sulfonyl) -phenyl ] -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) with commercially available 4-methoxypiperidine [ CAS number 4045-24-3]A solution of (0.236g, 2.05mmol) in THF (5mL) was treated at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.090g, 39%) as a white foam. MS (ISP)568.3[ (M + H) ⁺]；mp 107℃。

Example 430

2- (1- {3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonyl } -piperidin-4-yloxy) -ethanol

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) with 4- (2-hydroxyethoxy) piperidine [ CAS No. 40256-14-2]A solution of (0.297g, 2.05mmol) in THF (5mL) was treated at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.120g, 49%) as a white foam. MS (ISP)598.3[ (M + H)⁺]。

Example 431

N-benzyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) was treated with a solution of commercial benzylamine (0.22mL, 2.05mmol) in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.100g, 49%) as a white solid. MS (ISP)560.2[ (M + H) ⁺]；mp 168℃。

Example 432

N- (4-methoxy-benzyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) was treated with a solution of commercial 4-methoxybenzylamine (0.27mL, 2.05mmol) in THF (5mL) for 16h at 23 ℃. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.130g, 53%) as a white solid. MS (ISP)590.2[ (M + H)⁺]；mp 126℃(dec.)。

Example 433

N- (4-fluoro-benzyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

Preparation of the target CompoundThe following were used: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) was treated with a solution of commercial 4-fluorobenzylamine (0.23mL, 2.05mmol) in THF (5mL) for 16h at 23 deg.C. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.110g, 46%) as a white solid. MS (ISP)578.2[ (M + H) ⁺]；mp 175℃。

Example 434

6-methyl-6 '- {3- [4- (pyridin-4-yloxy) -piperidine-1-sulfonyl ] -phenyl } -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) with 4- (piperidin-4-yloxy) -pyridine [ CAS number 224178-65-8]A solution of (0.365g, 2.05mmol) in THF (5mL) was treated at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.130g, 50%) as a white foam. MS (ISP)631.3[ (M + H)⁺]。

Example 435

6-methyl-6 '- {3- [4- (pyrimidin-2-yloxy) -piperidine-1-sulfonyl ] -phenyl } -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.200g, 0.409mmol) with commercially available 2- (piperidin-4-yloxy) -pyrimidine [ CAS number. 499240-48-1 ]A solution of (0.367g, 2.05mmol) in THF (5mL) was treated at 23 deg.C for 16 h. Dilute with EtOAcAfter washing with 5% citric acid, saturated sodium bicarbonate solution and brine, the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.140g, 54%) as a white foam. MS (ISP)632.3[ (M + H)⁺]；mp134℃(dec.)。

Example 436

N-tert-butyl-3- [6 '-methyl-4' - (4-trifluoromethoxy-phenyl) - [2, 2] bipyridin-6-yl ] -benzenesulfonamide

A stirred mixture of trifluoro-methanesulfonic acid 6-methyl-4- (4-trifluoromethoxy-phenyl) -pyridin-2-yl ester (example A.63) (0.221g, 0.55mmol), N-tert-butyl-3- (6-tributylstannyl-pyridin-2-yl) -benzenesulfonamide (example F.6) (0.290g, 0.50mmol), tetrakis (triphenyl-phosphine) palladium (0.032g, 5 mol%) in toluene (5mL) was heated at reflux for 18 h. Cooled to room temperature, extracted with ethyl acetate and water, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with n-heptane/ethyl acetate to afford the title compound as a white solid (100mg, 34%) after trituration with ether. MS (ISP)542.8[ (M + H) ⁺]；mp 148℃。

Example 437

3- [6 ' -methyl-4 ' - (4-trifluoromethoxy-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

To N-tert-butyl-3- {6- [ 4-methyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonamide (example 436) (0.100g, 0.185mmol) solution was added TFA (3mL) and the reaction mixture was stirred at 23 ℃ for 3 h. The mixture was EtOAc and saturated NaHCO₃Partition between solutions and organic layer over MgSO₄And (5) drying. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as an off-white solid (0.068g, 76%). MS (ISP)486.0[ (M + H)⁺]；mp 231℃(dec.)。

Example 438

N-tert-butyl-3- [6 ' -methyl-4 ' - (3-methyl-4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

A stirred mixture of trifluoro-methanesulfonic acid 6-methyl-4- (3-methyl-4-trifluoromethyl-phenyl) -pyridin-2-yl ester (example A.64) (0.250g, 0.626mmol), N-tert-butyl-3- (6-tributylstannyl-pyridin-2-yl) -benzenesulfonamide (example F.6) (0.363g, 0.626mmol), tetrakis (triphenyl-phosphine) palladium (0.036g, 5 mol%) in toluene (5mL) was heated at reflux for 18 h. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with n-heptane/ethyl acetate to afford the title compound as a white solid (300mg, 88%) after trituration with ether. MS (ISP)539.8[ (M + H) ⁺]；mp 150℃(dec.)。

Example 439

3- [6 ' -hydroxymethyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

1) N-tert-butyl-3- [6 ' - (tetrahydro-pyran-2-yloxymethyl) -4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]-a benzenesulfonamide: a stirred mixture of 2-bromo-6- (tetrahydro-pyran-2-yloxymethyl) -4- (4-trifluoromethyl-phenyl) -pyridine (example A.65) (0.400g, 0.894mmol), N-tert-butyl-3- (6-tributylstannyl-pyridin-2-yl) -benzenesulfonamide (example F.6) (0.518g, 0.894mmol), tetrakis (triphenyl-phosphine) palladium (0.052g, 5 mol%) in toluene (5mL) was heated at reflux for 18 h. After cooling to room temperature, the reaction mixture was directly purified by column chromatography on silica gel eluting with N-heptane/ethyl acetate to give N-tert-butyl-3- [6 ' - (tetrahydro-pyran-2-yloxymethyl) -4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonamide (550mg, 98%) as a pale yellow oil. MS (ISP)626.0[ (M + H)⁺]。

2) To the above N-tert-butyl-3- [6 ' - (tetrahydro-pyran-2-yloxymethyl) -4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]To a solution of benzenesulfonamide (0.550g, 0.88mmol) was added TFA (5mL), and the reaction was mixed The mixture was stirred at 23 ℃ for 18 h. The mixture was poured into 3N NaOH solution (100ml), stirred at 23 ℃ for 15min, then partitioned between EtOAc and water and the organic layer was washed with saturated NaHCO₃The solution was washed and dried over magnesium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as an off-white solid (0.100g, 23%). MS (ISP)486.0[ (M + H)⁺]；mp 213℃(dec.)。

Example 440

3- [6 ' -methyl-4 ' - (3-methyl-4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

To N-tert-butyl-3- [6 ' -methyl-4 ' - (3-methyl-4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]To a solution of benzenesulfonamide (example 438) (0.300g, 0.556mmol) was added TFA (5mL) and the reaction mixture was stirred at 23 ℃ for 16 h. The mixture was washed with EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as an off-white solid (0.090g, 33%). MS (ISP)484.1[ (M + H)⁺]；mp＞250℃。

Example 441

N-tert-butyl-3- {6- [4- (4-cyano-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1)4- (3-oxo-but-1-ynyl) -benzonitrile: to commercially available 4- (3-hydroxy-but-1-ynyl) -benzonitrile [ CAS number 893748-15-7 at 23 deg.C ](380mg, 2.22mmol) in diethyl ether (5ml) was added Jones reagent solution (0.625M CrO)₃8.9ml, 5.55mmol) of sulfuric acid, the mixture is stirred at 23 ℃ for 18 h. 2-propanol (2ml) was added to the reaction mixture, the solution was stirred for a further 10min at 23 ℃ and then the reaction mixture was extracted with ether and water and the organic layer was washed with saturated NaHCO₃The solution was washed, dried over magnesium sulfate, filtered and the solvent was evaporated to give 4- (3-oxo-but-1-ynyl) -benzonitrile (260mg, 69%) as an off-white solid, which was used without further purification.

2) A mixture of 4- (3-oxo-but-1-ynyl) -benzonitrile above (85mg, 0.5mmol), 6- (3-tert-butylsulfamoyl-phenyl) -pyridine-2-carboxamidine acetate (236mg, 0.6mmol) and sodium carbonate (127mg, 1.2mmol) in acetonitrile (2ml) was microwave-irradiated at 120 ℃ for 60 min. The reaction mixture was extracted with ethyl acetate and water, the organic layers were combined, dried over magnesium sulfate, filtered and the solvent was evaporated to give the crude product, which was purified by flash chromatography on silica gel eluting with n-heptane and ethyl acetate to give the title compound (98mg, 41%) as a light brown foam (cf. synlett 2003, (2), 259). MS (ISP)484.2[ (M + H) ⁺]。

Example 442

3- {6- [4- (4-cyano-phenyl) -6-methyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

To N-tert-butyl-3- {6- [4- (4-cyano-phenyl) -6-methyl-pyrimidin-2-yl]-pyridin-2-yl } -benzenesulfonamide (example 441) (0.080g, 0.165mmol) was added TFA (2mL) and the reaction mixture was stirred at 23 ℃ for 3 h. The mixture was washed with EtOAc and saturated NaHCO₃The solution was partitioned between and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo to give the crude product, which was triturated with ether to give the title compound as a pale brown solid (0.047g, 67%). MS (ISP)428.1[ (M + H)⁺]；mp 255℃。

Example 443

N-acetyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

Mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]A mixture of benzenesulfonamide (example 266) (300mg, 0.639mmol) and acetic anhydride (2.42mL, 25.6mmol) in acetic acid (5mL) was stirred at 130 ℃ for 3 days. Cooled to room temperature, diluted with EtOAc and saturated NaHCO₃The solution is extracted, dried over sodium sulfate, filtered and evaporated completely to give the crude product which is purified by silica gel column chromatography eluting with n-heptane/ethyl acetate followed by trituration with diethyl ether/n-heptane to give the title compound Material (290mg, 88%) as a white solid. MS (ISP)512.0[ (M + H)⁺]；mp 244℃。

Example 444

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -N- (tetrahydro-pyran-4-yl) -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.465g, 0.951mmol) 4-aminotetrahydropyran [ CAS number.38041-19-9, commercially available]A solution of (0.192g, 1.9mmol) in THF (5ml) was treated at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.460g, 87%) as an off-white solid. MS (ISP)554.2[ (M + H)⁺]；mp 163℃(dec.)。

Example 445

3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -N- (2, 2, 2-trifluoro-ethyl) -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.465g, 0.951mmol) with 2, 2, 2-trifluoroethylamine [ CAS number. 753-90-2-obtained from commercial ]A solution of (0.15ml, 1.9mmol) and triethylamine (1.33ml, 9.51mmol) in THF (5ml) was treated at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.220g, 46%) as an off-white solid. MS (ISP)552.2[ (M + H)⁺]；mp 198℃。

Example 446

N-ethyl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

The target compound was prepared as follows: mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]Benzenesulfonyl chloride (example I.2) (0.465g, 0.951mmol) was treated with a solution of obtained from commercial ethylamine (2M in THF, 2.38ml, 4.76mmol) and triethylamine (1.33ml, 9.51mmol) in THF (5ml) at 23 ℃ for 16 h. Diluted with EtOAc, washed with 5% citric acid, saturated sodium bicarbonate solution and brine, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with EtOAc, followed by trituration with ether/heptane to afford the title compound (0.260g, 55%) as an off-white solid. MS (ISP)498.3[ (M + H) ⁺]；mp135℃。

Example 447

3' - {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } -biphenyl-3-sulfonic acid amide

1) 3' - {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidine (example E.55) (0.38g, 0.69mmol) and commercially available 3- (tert-butylsulfamoyl) -phenylboronic acid (0.23g, 0.89 mmol). A pale yellow solid (0.45g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl]To a solution of (E) -6-trifluoromethyl-pyrimidin-2-yl } -biphenyl-3-sulfonic acid tert-butylamide (0.45g) in dichloromethane (6ml) was added TFA (6ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and poured into saturated NaHCO₃The solution (20ml) was extracted with ethyl acetate (2X 30 ml). The combined organic layers were washed with brine (20ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (dichloromethane/MeOH `)Hexane) gave the title compound as a white solid (0.25g, 59%). MS (ISP)622.2[ (M + H) ⁺]；mp 188℃。

Example 448

3- (4- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } -pyridin-2-yl) -benzenesulfonamide

1) 3- (4- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidin-2-yl } -pyridin-2-yl) -benzenesulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl ] -6-trifluoromethyl-pyrimidine (example E.56) (0.16g, 0.32mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.11g, 0.41 mmol). A pale yellow solid (0.21g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3- (4- {4- [3- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl]To a solution of-6-trifluoromethyl-pyrimidin-2-yl } -pyridin-2-yl) -benzenesulfonic acid tert-butylamide (021g) in dichloromethane (5ml) was added TFA (5ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and poured into saturated NaHCO₃The solution (20ml) was extracted with ethyl acetate (2X 30 ml). The combined organic layers were washed with brine (20ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (diethyl ether) afforded the title compound as an off-white solid (0.15g, 77%). MS (ISP)623.2[ (M + H) ⁺]；mp 211℃。

Example 449

3- {4- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) N-tert-butyl-3- {4- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidine (example E.59) (0.17g, 0.42mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.14g, 0.54 mmol). An off-white solid (0.22g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {4- [ 4-trifluoromethyl-6- (3-trifluoromethyl-phenyl) -pyrimidin-2-yl group]-pyridin-2-yl } -benzenesulfonamide (0.22g) in dichloromethane (5ml) TFA (5ml) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and poured into saturated NaHCO₃The solution (20ml) was extracted with ethyl acetate (2X 30 ml). The combined organic layers were washed with brine (20ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (diethyl ether) afforded the title compound as an off-white solid (0.14g, 65%). MS (ISP)525.2[ (M + H)⁺]；mp244℃。

Example 450

3- {4- [4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) N-tert-butyl-3- {4- [6- (2-fluoro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -6- (2-fluoro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidine (example E.107) (0.32g, 0.76mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.23g, 0.91 mmol). An off-white solid (0.24g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {4- [6- (2-fluoro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]-pyridin-2-yl } -benzenesulfonamide (0.24g) in dichloromethane (6ml) TFA (6ml) was added and the reaction mixture was stirred at room temperature for 15 h. Evaporating the mixture and pouring it into 2NNa₂CO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (20ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.2g, 49%). MS (ISP)543.1[ (M + H)⁺]；mp210℃。

Example 451

5- {4- [4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (2-fluoro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (2-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example E.107) (0.32g, 0.76mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.314g, 0.91 mmol). An off-white foam (0.37g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (2-fluoro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.37g) in dichloromethane (6ml) was added TFA (6ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by silica gel flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.18g, 43%). MS (ISP)549.1[ (M + H)⁺]；mp 228℃。

Example 452

3- {4- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) N-tert-butyl-3- {4- [6- (3-ethoxy-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -6- (3-ethoxy-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidine (example E.108) (0.185g, 0.41mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.13g, 0.50 mmol). An off-white solid (0.24g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {4- [6- (3-ethoxy-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]-pyridin-2-yl } -benzenesulfonamide (0.24g) in dichloromethane (6ml) TFA (6ml) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and saturated Na was poured in₂CO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.17g, 72%). MS (ISP)569.2[ (M + H)⁺]；mp 223.5℃。

Example 453

5- {4- [4- (3-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (2-ethoxy-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (2-ethoxy-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example E.108) (0.185g, 0.41mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.17g, 0.49 mmol). An off-white foam (0.18g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (2-ethoxy-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.18g) in dichloromethane (6ml) was added TFA (6ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by silica gel flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) afforded the title compound as an off-white solid (0.08g, 34%). MS (ISP)575.1[ (M + H)⁺]；mp 237.5℃。

Example 454

N-butyryl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

Mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]A mixture of-benzenesulfonamide (example 266) (300mg, 0.639mmol) and n-butyric anhydride (1.05mL) was stirred at 150 ℃ for 6 h. Cooled to 80 ℃, diluted with n-heptane, cooled to room temperature overnight, the precipitate filtered, washed with n-heptane, and dried under high vacuum to give the title compound (300mg, 87%) as a white solid. MS (ISP)539.8[ (M + H) ⁺]；mp 188℃。

Example 455

N-isobutyryl-3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

Mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]A mixture of benzenesulfonamide (example 266) (300mg, 0.639mmol) and isobutyric anhydride (1.06mL) was stirred at 150 ℃ for 6 h. Cooled to 80 ℃, diluted with n-heptane, cooled to room temperature overnight, the precipitate filtered, washed with n-heptane, and dried under high vacuum to give the title compound (250mg, 73%) as a white solid. MS (ISP)539.8[ (M + H)⁺]；mp 190℃。

Example 456

3' - [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.8) (0.39g, 0.9mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). An off-white solid (0.51g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [ 4-difluoromethyl-6-(4-trifluoromethyl-phenyl) -pyrimidin-2-yl]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.51g) in dichloromethane (6ml) was added TFA (6ml), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured ₂CO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by silica gel flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.21g, 42%). MS (ISP)506.1[ (M + H)⁺]；mp 204℃。

Example 457

3- {4- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide

1) N-tert-butyl-3- {4- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide was prepared according to general method VI using 2- (2-chloro-pyridin-4-yl) -4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.10) (0.43g, 1.11mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.21 mmol). A light brown solid (0.37g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-3- {4- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]-pyridin-2-yl } -benzenesulfonamide (0.37g) in dichloromethane (5ml) was added TFA (5ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO) ₄) And evaporated. Further purification by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) afforded the title compound as an off-white solid (0.17g, 34%). MS (ISP)507.2[ (M + H)⁺]；mp 233.5℃。

Example 458

5- {4- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonamide

1) 5- {4- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (2-chloro-pyridin-4-yl) -4-difluoromethyl-6- (4-trifluoro-phenyl) -pyrimidine (example E.10) (0.43g, 1.11mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.41g, 1.19 mmol). A pale yellow solid (0.24g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 5- {4- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]-pyridin-2-yl } -thiophene-2-sulfonic acid tert-butylamide (0.24g) in dichloromethane (5ml) TFA (5ml) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO) ₄) And evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) afforded the title compound as a beige solid (0.1g, 20%). MS (ISP)513.3[ (M + H)⁺]；mp 242℃。

Example 459

5- {3- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidine (example E.8) (0.385g, 0.9mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.41g, 1.19 mmol). A pale yellow solid (0.4g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [ 4-difluoromethyl-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yl group]-phenyl radicalTo a solution of the } -thiophene-2-sulfonamide (0.4g) in dichloromethane (7ml) was added TFA (7ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO) ₄) And evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) afforded the title compound as a white solid (0.064g, 13%). MS (ISP)512.3[ (M + H)⁺]；mp 240.5℃。

Example 460

3' - [4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid amide

1) 3' - [4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -biphenyl-3-sulfonic acid tert-butylamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example e.109) (0.465g, 1.0mmol) and 3- (tert-butylsulfamoyl) -phenylboronic acid obtained commercially (0.31g, 1.2 mmol). A pale yellow solid (0.47g) was obtained which was subsequently deprotected.

2) To the cooled and stirred 3' - [4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl group]To a solution of-biphenyl-3-sulfonic acid tert-butylamide (0.47g) in dichloromethane (6ml) was added TFA (6ml), and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (25ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as a white solid (0.27g, 50%). MS (ISP)542.1[ (M + H) ⁺]；mp 227.5℃。

Example 461

5- {3- [4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide

1) N-tert-butyl-5- {3- [6- (3-fluoro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl ] -phenyl } -thiophene-2-sulfonamide was prepared according to general procedure VI using 2- (3-bromo-phenyl) -4- (3-fluoro-4-trifluoromethyl-phenyl) -6-trifluoromethyl-pyrimidine (example E.109) (0.465g, 1.0mmol) and N-tert-butyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiophene-2-sulfonamide (example F.1) (0.414g, 1.2 mmol). An off-white solid (0.32g) was obtained which was subsequently deprotected.

2) To the cooled and stirred N-tert-butyl-5- {3- [6- (3-fluoro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrimidin-2-yl group]To a solution of-phenyl } -thiophene-2-sulfonamide (0.32g) in dichloromethane (6ml) was added TFA (6ml) and the reaction mixture was stirred at room temperature for 15 h. The mixture was evaporated to dryness and 2N Na was poured₂CO₃The solution (20ml) was extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50ml) and dried (MgSO)₄) And evaporated. Further purification by crystallization (ethyl acetate/heptane) afforded the title compound as an off-white solid (0.071g, 13%). MS (ISP)548.0[ (M + H) ⁺]；mp 213.5℃。

Example 462

N- (2-methoxy-acetyl) -3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide

Mixing 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ']Bipyridin-6-yl]A mixture of benzenesulfonamide (example 266) (300mg, 0.639mmol), N-ethyldiisopropylamine (0.22ml, 1.278mmol) and methoxyacetyl chloride (0.067ml, 0.639mmol) in dichloromethane (3ml) was stirred at 23 ℃ for 16 h. Diluting with dichloromethane, washing with water, and passing the organic layer through MgSO₄And (5) drying. Removal of the solvent in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with n-heptane/EtOAc followed by trituration with ether to afford the title compound (46mg, 13%) as a white solid. MS (ISP)542.7[ (M + H)⁺]；mp 188℃。

Formulations of pharmaceutical compositions containing the compounds of the invention:

example I

Tablets having the following composition were prepared in a conventional manner:

example II

example III

Capsules having the following composition were prepared:

the active ingredient having the appropriate particle size, crystalline lactose and microcrystalline cellulose are mixed uniformly, sieved and then mixed with talc and magnesium stearate. The final mixture was filled into hard gelatin capsules of appropriate size.

Claims

1. A compound of formula (Ib):

wherein:

one of X or Y is N, the other is CH, or X and Y are both N;

a is aryl or is 5-or 6-membered heteroaryl, each of which is optionally substituted by C_1-6-alkyl substituted;

b is H, cyano, or

the halogen(s) are selected from the group consisting of,

the nitro group(s),

c optionally substituted by hydroxy_1-6-an alkyl group,

-S-C_1-6-an alkyl group,

-(SO₂)-OH，

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

C_1-6-an alkoxy group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

-(CH₂)_p-C_3-6cycloalkyl, wherein p is 0 or 1,

a 5-or 6-membered heterocycloalkyl group,

NHSO₂-C_1-6-alkyl, and

H、C_3-8-cycloalkyl, aryl, heteroaryl with 5-12 ring atoms and C optionally substituted by one or more substituents selected from the group consisting of_1-6-an alkyl group: halogen, hydroxy, C_3-8-cycloalkyl, aryl, heteroaryl with 5-12 ring atoms and-NR^lR^mWherein R is^lAnd R^mIndependently selected from H and C_1-6-an alkyl group;

or R^jAnd R^kMay form, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclyl group comprising 5 to 12 ring atoms and optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur, wherein the heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 Substituted with a group selected from: halogen, hydroxy, C_1-6-alkyl and C_1-6-a haloalkyl group;

or R²And R³Can together form a dioxo bridge;

R⁴is H or halogen.

2. A compound of formula (Ib) according to claim 1 wherein:

b is H, cyano, or

the halogen(s) are selected from the group consisting of,

the nitro group(s),

c optionally substituted by hydroxy_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group,

-S-C_1-6-an alkyl group,

-(SO₂)-OH，

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

C_1-6-an alkoxy group,

optionally with C_1-6Alkoxy-substituted (CO) C_1-6-an alkyl group,

-(CH₂)_maryl, where m is 1 or 2, aryl being optionally substituted by halogen or C_1-6-alkoxy radicalThe substituent(s) is (are) substituted,

-(CH₂)_p-C_3-6cycloalkyl, wherein p is 0 or 1,

a 5-or 6-membered heterocycloalkyl group,

-(SO₂)-NR^fR^gwherein R is^fAnd R^gTogether with the nitrogen atom to which they are attached form a compound optionally containing a nitrogen, oxygen, sulfur or SO group₂Wherein the 4, 5 or 6 membered heterocycloalkyl ring of the other heteroatom of (a), wherein the 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted with a substituent selected from the group consisting of: hydroxy, C _1-6-alkyl, C optionally substituted by hydroxy_1-6-alkoxy and 5-or 6-membered heteroaryloxy,

NHSO₂-C_1-6-alkyl, and

H、C_3-8cycloalkyl, aryl, heteroaryl having 5 to 12 ring atoms and optionally substituted by one or more groups selected fromRadical substituted C_1-6-an alkyl group: halogen, hydroxy, C_3-8-cycloalkyl, aryl, heteroaryl with 5-12 ring atoms and-NR^lR^mWherein R is^lAnd R^mIndependently selected from H and C_1-6-an alkyl group;

or R^jAnd R^kMay form, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclyl group comprising 5 to 12 ring atoms and optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur, wherein the heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from: halogen, hydroxy, C _1-6-alkyl and C_1-6-a haloalkyl group;

or R²And R³Can together form a dioxo bridge;

R⁴is H or halogen.

3. A compound of formula (Ib) according to claim 2 wherein:

b is H or cyano;

R³is H, halogen, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6-alkyl or C_1-6-a haloalkoxy group;

or R²And R³Can together form a dioxo bridge;

R⁴is H or halogen.

4. A compound of formula (Ib) as claimed in any one of claims 1-3 wherein:

b is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are

Selected from the following groups:

the halogen(s) are selected from the group consisting of,

the nitro group(s),

C_1-6-an alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group,

-S-C_1-6-an alkyl group,

-(SO₂)-OH，

-(SO₂)-C_1-6-an alkyl group,

-(SO₂)-NR^cR^dwherein R is ^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

C_1-6-an alkoxy group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

-(CH₂)_p-C_3-6cycloalkyl, wherein p is 0 or 1,

a 5-or 6-membered heterocycloalkyl group,

-(SO₂)-NR^fR^gwherein R is^fAnd R^gTogether with the nitrogen atom to which they are attached form a compound optionally containing a nitrogen, oxygen, sulfur or SO group₂A 4-, 5-or 6-membered heterocycloalkyl ring of the other heteroatom(s), whereinSaid 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted with a substituent selected from the group consisting of:

NHSO₂-C_1-6-alkyl, and

Or R²And R³Can together form a dioxo bridge;

R⁴is H or halogen.

5. A compound of formula (Ib) as claimed in any one of claims 1 to 4 having the structure of formula (Ib 1):

b, R therein¹、R²、R³And R⁴As defined in claims 1-4.

6. The compound of claim 5 of formula (Ib1), wherein B is unsubstituted aryl or unsubstituted 5-or 6-membered heteroaryl.

7. The compound of claim 6 of formula (Ib1), wherein the compound is selected from:

2-methyl-6- (3-pyridin-3-yl-phenyl) -4- (4-trifluoromethyl-phenyl) -pyridine;

2-methyl-6- (3-pyridin-4-yl-phenyl) -4- (4-trifluoromethyl-phenyl) -pyridine.

8. The compound of claim 5 of formula (Ib1) wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is cyano.

9. A compound of formula (Ib1) according to claim 8, wherein the compound is 3- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -benzonitrile.

10. The compound of claim 5 of formula (Ib1), wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is halogen.

11. The compound of formula (Ib1) of claim 10, wherein the compound is 4, 6-difluoro-3' - [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -biphenyl-3-sulfonamide.

12. The compound of claim 5 of formula (Ib1), wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is C_1-6-an alkyl group.

13. A compound of formula (Ib1) according to claim 12, wherein the compound is 2-methyl-6- [3- (4-methyl-imidazol-1-yl) -phenyl ] -4- (4-trifluoromethyl-phenyl) -pyridine.

14. The compound of claim 5 of formula (Ib1), wherein B isOptionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is NR^aR^bWherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group.

15. The compound of claim 14 of formula (Ib1), wherein the compound is:

16. The compound of claim 5 of formula (Ib1), wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-C_1-6-an alkyl group.

17. The compound of formula (Ib1) according to claim 16, wherein the compound is 2- (3' -methanesulfonyl-biphenyl-3-yl) -6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine.

18. The compound of claim 5 of formula (Ib1), wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO) ₂)-NR^cR^dWherein R is^cAnd R^dIndependently are: h; c optionally substituted by hydroxy_1-6-an alkyl group; c_1-6-a haloalkyl group; c_1-6-an alkoxy group; optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group; - (CH)₂CH₂O)_nCHR^eWherein R is^eIs H or CH₂OH, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; - (CH)₂)_mAryl, where m is 1 or 2, aryl being optionally substituted by halogen or C_1-6-alkoxy substitution; wherein p is 0 or 1- (CH)₂)_p-C_3-6-cycloalkyl or 5 or 6-membered heterocycloalkyl.

19. The compound of formula (Ib1) of claim 18, wherein the compound is selected from:

20. The compound of formula (Ib) of claim 5, having the structure of formula (Ib 11):

b, R therein¹、R²、R³And R⁴As defined in claim 5.

21. The compound of formula (Ib) of claim 1, having the structure of formula (Ib2) below:

b, R therein¹、R²、R³And R⁴As defined in claims 1-4.

22. The compound of claim 21 of formula (Ib2), wherein B is a 5-or 6-membered heteroaryl group which may be selected from: imidazolyl group, [1, 2, 4 ]] Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1, 2, 4 ]]Triazolyl, thiazolyl, pyrimidinyl and thienyl.

23. A compound of formula (Ib2) as claimed in any one of claims 21 or 22 wherein:

B is H or cyano, preferably H;

R¹is C_1-6-alkyl or C_1-6-a haloalkyl group;

R²is halogen or C_1-6-a haloalkyl group;

R⁴is H or halogen.

24. The compound of claim 23 of formula (Ib2), wherein the compound is selected from:

2-imidazol-1-yl-6-methyl-4- (4-trifluoromethyl-phenyl) -pyridine;

4- (3, 4-dichloro-phenyl) -2-imidazol-1-yl-6-methyl-pyridine; and

2-methyl-6-thiazol-2-yl-4- (4-trifluoromethyl-phenyl) -pyridine.

25. A compound of formula (Ib2) as claimed in any one of claims 21 or 22 wherein B is optionally substituted aryl or optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of:

the nitro group(s),

c optionally substituted by hydroxy_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

NR^aR^bwherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group,

-S-C_1-6-an alkyl group,

NHSO₂-C_1-6-an alkyl group,

-(SO₂)-OH，

-(SO₂)-NR^cR^dwherein R is^cAnd R^dIndependently are:

H，

c optionally substituted by hydroxy or halogen_1-6-an alkyl group,

optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

-(CH₂)_p-C_3-6cycloalkyl, wherein p is 0 or 1,

5 or 6-membered heterocycloalkyl, and

R¹is C_1-6-alkyl or C_1-6-a haloalkyl group;

R²is halogen or C_1-6-a haloalkyl group;

R⁴is H or halogen.

26. The compound of formula (Ib2) of claim 25, wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is nitro.

27. The compound of claim 26 of formula (Ib2), wherein the compound is selected from: 6-methyl-2 '- (3-nitro-phenyl) -4- (4-trifluoromethyl-phenyl) - [2, 4' ] bipyridinyl and 4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -2- (3-nitro-phenyl) -pyrimidine.

28. The compound of claim 25 of formula (Ib2), wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is NR ^aR^bWherein R is^aAnd R^bIndependently is H or- (CO) -C_1-6-an alkyl group.

29. The compound of claim 28 of formula (Ib2), wherein the compound is selected from:

4- (4-chloro-phenyl) -6-methyl- [2, 3'; 5', 3 "] terpyridin-6" -ylamine;

5- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-[1，2，4] Oxadiazol-3-yl } -pyridin-2-ylamine;

5- {5- [ 4-trifluoromethyl-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-[1，2，4] Oxadiazol-3-yl } -pyridin-2-ylamine;

30. The compound of claim 25 of formula (Ib2) wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are-S-C _1-6-an alkyl group.

31. The compound of formula (Ib2) of claim 30, wherein the compound is 6-methyl-6 '- (3-methylsulfanyl-phenyl) -4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl.

32. The compound of claim 25 of formula (Ib2), wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituents are S (O)₂-C_1-6-an alkyl group.

33. The compound of claim 32 of formula (Ib2), wherein the compound is selected from:

2- (3-methanesulfonyl-phenyl) -4- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -pyrimidine; and

6 '- (3-methanesulfonyl-phenyl) -6-methyl-4- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl.

34. The compound of claim 25 of formula (Ib2) wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-NR^cR^dWherein R is^cAnd R^dIndependently are: h; c optionally substituted by hydroxy or halogen_1-6-an alkyl group; optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group; - (CH)₂CH₂O)_nCHR^eWherein R is^eIs H or CH₂OH, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; optionally substituted by halogen or C_1-6-alkoxy substituted- (CH)₂)_mAryl, where m is 1 or 2, optionally substituted by halogen, C_1-6Aryl substituted by alkoxy, or- (CH)₂)_p-C_3-6-cycloalkyl, wherein p is 0 or 1; and 5 or 6-membered heterocycloalkyl.

35. The compound of claim 34 of formula (Ib2), wherein the compound is selected from:

3- {5- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-[1，2，4] Oxadiazol-3-yl } -benzenesulfonamide;

5- {2- [ 6-methyl-4- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -thiazol-4-yl } -thiophene-2-sulfonamide;

36. The compound of claim 25 of formula (Ib2) wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is NHSO ₂-C_1-6-an alkyl group.

37. The compound of formula (Ib2) according to claim 36, wherein the compound is selected from:

38. The compound of claim 25 of formula (Ib2) wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is-SO₂-OH。

39. The compound of formula (Ib2) according to claim 38, wherein the compound is 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonic acid.

40. The compound of claim 35 of formula (Ib2) wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is NHSO₂-NR^hRⁱWherein R is^hAnd RⁱIndependently is H, C_1-6-alkyl or- (CO) O-C_1-6-an alkyl group.

41. The compound of claim 40 of formula (Ib2), wherein the compound is selected from:

n, N-dimethyl-N '- {3- [ 6' -methyl-4 '- (4-trifluoromethyl-phenyl) - [2, 2' ] bipyridinyl-6-yl ] -phenyl } -sulfonamide.

42. The compound of claim 25 of formula (Ib2) wherein B is optionally substituted aryl or optionally substituted 5-or 6-membered heteroaryl, wherein the substituent is- (SO)₂)-NR^fR^gWherein R is^fAnd R^gTogether with the nitrogen atom to which they are attached form a compound optionally containing a nitrogen, oxygen, sulfur or SO group₂Wherein the 4, 5 or 6 membered heterocycloalkyl ring of the other heteroatom of (a), wherein the 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted with a substituent selected from the group consisting of: hydroxy, C_1-6-alkyl, C optionally substituted by hydroxy_1-6Alkoxy and heteroaryloxy.

43. The compound of claim 42 of formula (Ib2), wherein the compound is selected from:

44. The compound of claim 1 which is 3- [6 ' -methyl-4 ' - (4-trifluoromethyl-phenyl) - [2, 2 ' ] bipyridinyl-6-yl ] -benzenesulfonamide, and pharmaceutically acceptable salts thereof.

45. A pharmaceutical composition comprising a compound according to any one of claims 1 to 44 for use in the prevention or treatment of a disease or condition in which activation of mGluR2 plays a role or is associated with activation of mGluR 2.

46. The pharmaceutical composition of claim 45, wherein the acute and/or chronic neurological disorder prevented or treated is psychosis, cognitive disorders, memory deficits, colon cancer, sleep disorders, circadian rhythm disorders, and glioma.

47. The pharmaceutical composition of claim 46, wherein the psychosis is schizophrenia.

48. The pharmaceutical composition of claim 46, wherein the cognitive disorder is Alzheimer's disease.

49. Use of a compound according to any one of claims 1 to 44 in the manufacture of a medicament for the prevention or treatment of a disease or condition in which activation of mGluR2 plays a role or is associated with activation of mGluR 2.

50. The use according to claim 49 for the treatment and/or prevention of acute and/or chronic neurological disorders, including psychosis, Alzheimer's disease, cognitive disorders, memory deficits, colon cancer, sleep disorders, disorders of circadian rhythms and glioma.

51. The use of claim 50, wherein the psychosis is schizophrenia.

52. The use of claim 50, wherein the cognitive disorder is Alzheimer's disease.