PYRIDYL COMPOUND SUITABLE FOR THE TREATMENT OF METABOLIC

DISORDERS

Field

The present description relates to a compound of Formula 1, a pharmaceutical composition comprising the same, and a process for its preparation. Although sufficient for other uses, the compound of Formula 1 and the pharmaceutical composition comprising the same are suitable for treating metabolic disorders, such as those treatable by administering an insulin sensitizer. Background

A metabolic disorder is a disorder or defect of metabolism that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, water or nucleic acids. Diabetes is a metabolic disorder that affects the ability to produce or use insulin, in an individual. Blood glucose levels are higher than normal for individuals with diabetes. There are two main types of diabetes: type 1 and type 2. In type 1 diabetes, the pancreas does not produce insulin. Type 1 diabetes is generally diagnosed in childhood and hence, known as juvenile diabetes. This type accounts for about 5 % of people with diabetes. In type 2 diabetes, there are two possible defects: i) pancreas does not produce enough insulin; and ii) the tissues are unable to use insulin properly, and the resulting condition is called as insulin resistance. Type 2 diabetes is a chronic metabolic disease characterized by insulin resistance, hyperglycemia and hyperinsulinema. It represents about 95 % of the human population with diabetes. Diabetic patients are also at an increased risk of developing cardiovascular disease due to risk factors such as dyslipidemia, obesity, hypertension and glucose intolerance. Uncontrolled diabetes is the leading cause of blindness, renal failure, non-traumatic limb amputation and premature cardiovascular mortality.

Traditional therapies for type 2 diabetes involve use of synthetic compounds such as sulfonylureas, biguanides and oc-glucosidase inhibitors. All these compounds have limited efficacy and tolerability. Further, these compounds also induce side effects such as hypoglycemia and gastro intestinal (GI) disturbances. Side effects have been associated with some PPARy agonists, like rosiglitazone, insulin sensitizers that has been associated with increased risks of heart disease. Considering the drawbacks associated with the existing drugs, there is a need to provide/develop new synthetic compounds as drugs for the treatment of metabolic disorders. Detailed description

In some embodiment d of Formula 1,

Formula 1

wherein,

A is selected from (Ci-C6)alkyl, (C3-Ce)cycloalkyl, -0(Ci-C6)alkyl, (C6-Cio)aryl, and nitrogen-heteroaryl;

B is O or C(O); or B is absent and X bonds to A; X is N or CR _a ;

Ri and R ₂ are hydrogen or Ri and R ₂ together form a (C2-C3)alkylene bridge;

R3 is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halogen, cyano, and amino;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ or -C(0)NHR ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R7 is (C6-Cio)aryl or nitrogen-heteroaryl; and

R _a is selected from hydrogen, hydroxyl, and cyano;

n is the integer 1 or 2;

wherein,

(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

-0(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, and halogen, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Cr Ce)alkoxy, halogen, amino, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted; heteroaryl is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

A. Definitions

Listed below are definitions, which apply to the terms as they are used throughout the specification and the appended claims (unless they are otherwise limited in specific instances), either individually or as part of a larger group.

It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound, which does not readily undergo transformation such as by rearrangement, cyclization, elimination, etc.

As used herein, the term "(Ci-C6)alkyl" or "alkyl" refers to a saturated aliphatic group, including straight or branched-chain alkyl group containing from 1 to 6 carbon atoms. Suitable examples of alkyl groups containing from 1 to 6 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2- dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl or tert-butyl. Unless otherwise stated, the "(Ci-C6)alkyl" or "alkyl" is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl. In some embodiments, the "(Ci-C6)alkyl" or "alkyl" is unsubstituted or the "(Ci-C6)alkyl" or "alkyl" is substituted by one, two, three, four, or five substituents.

A "(C2-C3) alkylene bridge" or an "alkylene bridge" refers to a straight or branched divalent hydrocarbon bridge linking two different carbons of the same ring structure, consisting solely of carbon and hydrogen, containing no unsaturation and having two to three carbon atoms. The alkylene bridge links any two carbons within a ring structure. One example of alkylene bridge is an ethylene bridge.

The term "-0(Ci-C ₆ )alkyl", "(Ci-C ₆ )alkoxy" or "alkoxy" refers to a (Ci-C ₆ )alkyl or alkyl group as defined herein attached via oxygen linkage to the rest of the molecule. Representative examples of "-0(Ci-C6)alkyl", "(Ci-C6)alkoxy" or "alkoxy" include, but are not limited to, methoxy, ethoxy or propoxy. Unless otherwise stated, the "-0(Ci-C6)alkyl", "(Ci-C6)alkoxy" or "alkoxy" is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, and halogen. In some embodiments, "-0(Ci-C6)alkyl", "(Ci-C6)alkoxy" or "alkoxy" is unsubstituted or "-0(Ci- C6)alkyl", "(Ci-C6)alkoxy" or "alkoxy" is substituted by one, two, three, four, or five substituents.

The term "(C3-C6)cycloalkyl" or "cycloalkyl" refers to a saturated mono-, or bi-cyclic ring system containing a three to six carbon atoms. Examples of cycloalkyl rings containing three to six carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Furthermore, unless stated otherwise, the term "(C3-C6)cycloalkyl" or "cycloalkyl" is unsubstituted or substituted by one or more identical or different substituents selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, amino, halogen, (C6-Cio)aryl, and heterocyclyl. In some embodiments, the "(C3-C6)cycloalkyl" or "cycloalkyl" is unsubstituted or the "(C3-C6)cycloalkyl" or "cycloalkyl" is substituted by one, two, three, four, or five substituents.

As used herein, the term "(C6-Ci ₀ )aryl" or "aryl" refers to a monocyclic or polycyclic hydrocarbon group having from six to ten ring members, the ring members being carbon atoms, in which at least one carbocyclic ring is present which has an aromatic conjugated π electron system. Examples of aryl residues include phenyl and naphthyl. Unless stated otherwise, "(C6-Cio)aryl" or "aryl", for example phenyl or naphthyl, is unsubstituted or substituted by one or more of the same or different substituents selected from halogen, (Ci- Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, cyano, amino, (C ₆ - Cio)aryl, heterocyclyl and C(0)OH. In some embodiments, the "(C6-Cio)aryl" or "aryl" is unsubstituted or the "(C6-Cio)aryl" or "aryl" is substituted by one, two, three, four, or five substituents.

The term "heteroatom" refers to nitrogen (N), oxygen (O) and sulfur (S). It should be noted that any heteroatom with unsatisfied valences is assumed to have a hydrogen atom to satisfy the valency.

The term "heterocyclyl" refers to a saturated, partially unsaturated or aromatic, monocyclic or polycyclic ring system containing three to ten ring atoms, of which one or two are identical or different heteroatoms selected from nitrogen, oxygen and sulfur and the remaining ring atoms are carbon atoms. In some embodiments, the nitrogen or sulfur atom(s) are independently oxidized or the nitrogen atom(s) is independently quaternized. The ring heteroatoms are present in any desired number and in any position with respect to each other provided that the resulting heterocyclic system is stable. The heterocyclyl group may, for example, have one or two oxygen atoms and/or one or two sulfur atoms and/or one or two nitrogen atoms in the ring. Suitable examples of monocyclic heterocyclyl groups are pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, azepinyl, and diazepinyl.

Polycyclic heterocyclyl groups can include two fused rings (bicyclic), at least one of the rings has at least one heteroatom. Exemplary bicyclic heterocyclic groups include benzoxazolyl, quinolyl, isoquinolyl, indolyl, isoindolyl, and benzofurazanyl.

Polycyclic heterocyclyl groups can include two fused rings which contain one or two bridgehead carbon atoms. In some embodiments, the bicyclic heterocyclic groups containing two bridgehead carbon atoms include 2,6-diaza-bicyclo[2.2.2]octane, 3,8- diazabicyclo[3.2.1]octane, and 3,6-diaza-bicyclo[3.2.2] nonane.

Heterocyclyl includes saturated heterocyclic ring systems, which do not contain any double bonds within the rings, as well as unsaturated heterocyclic ring systems which contain from one to six double bonds within the rings provided that the resulting ring system is stable. Unsaturated rings may be non-aromatic or aromatic.

Aromatic heterocyclyl groups are also be referred to as "heteroaryls." The term "heteroaryl" refers to a "nitrogen-heteroaryl" herein but is broader. "Heteroaryl" refers to an unsaturated monocyclic or bicyclic heterocyclic ring system having from five to ten ring member atoms, in which at least one ring is present which has an aromatic conjugated π electron system; the ring member atoms include one or two heteroatoms selected from nitrogen, oxygen, and sulfur and the remaining ring members are carbon atoms, wherein the sulfur or nitrogen heteroatom(s) are independently optionally oxidized, and the nitrogen heteroatom(s) are independently optionally quaternized. Examples of heteroaryl include furan, thiophene, oxazole, isooxazole, thiazole, isothiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, benzoxazole, quinoline, isoquinoline, indole, isoindole and benzofuran.

Unless stated otherwise, the heterocyclyl group is unsubstituted or substituted with from one to five, identical or different, substituents for the ring carbon and ring nitrogen atoms selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, amino, (C6-Cio)aryl, heterocyclyl, and C(0)OH. The substituents can be present at one or more positions provided that a stable molecule results. In some embodiments, the heterocyclyl is unsubstituted or the heterocyclyl is substituted by one, two, three, four, or five substituents. The term "nitrogen-heteroaryl" as used herein refers to an unsaturated monocyclic or bicyclic heterocyclic ring system having from five to ten ring member atoms, in which at least one ring is present which has an aromatic conjugated π electron system; the ring member atoms include one or two nitrogen heteroatoms and the remaining ring members are carbon atoms, wherein the nitrogen heteroatom(s) are independently optionally oxidized, and the nitrogen heteroatom(s) are independently optionally quaternized. The ring member atoms include from four to nine carbon atoms. Any suitable ring position of the nitrogen-heteroaryl moiety can be covalently linked to the defined chemical structure. Examples of nitrogen- heteroaryl include pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, and pyridazine, quinoline and isoquinoline.

Unless otherwise stated, "nitrogen-heteroaryl" is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (Cs-Cio)aryl, heterocyclyl, and C(0)OH. In some embodiments, the "nitrogen-heteroaryl" is unsubstituted or the "nitrogen- heteroaryl" is substituted by one, two, three, four or five substituents.

The term "halogen" or "halo" unless otherwise stated refers to fluorine, chlorine, bromine, and iodine atoms. Two or more atoms of "halogen" or "halo" can be the same or different.

The term "halo(Ci-C ₆ )alkyl" or "haloalkyl" refers to a "(Ci-C ₆ )alkyl" or "alkyl" as defined herein in which one or more of the hydrogen atoms of the alkyl group are substituted with one or more of the same or different halogen atoms. A monohaloalkyl, for example, has a chlorine, bromine, iodine or fluorine atom. Dihaloalkyls and polyhaloalkyls have two or more of the same or different halogen atoms. Examples of halo(Ci-C6)alkyl or haloalkyl include but are not limited to chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl and the like. In some embodiments, the "halo(Ci-C6)alkyl" or "haloalkyl" are perhaloalkyls having n-carbon atoms and (2n+l)-halogen atoms (n=l-6).

The term "halo(Ci-C6)alkoxy" or "haloalkoxy" refers to a (Ci-C6)alkoxy or alkoxy as defined herein wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more same or different halogen atoms. Representative examples of haloalkoxy groups include but not limited to difluoromethoxy (OCHF ₂ ), trifluoromethoxy (OCF ₃ ) or trifluorethoxy (OCH ₂ CF ₃ ). The term "amino" refers to the group NR _x R _y in which R _x and R _y are independently selected from hydrogen, (Ci-C6)alkyl, t-butoxy carbonyl, and (C6-Cio)aryl.

The term "N-oxide" as used herein refers to the oxide of the nitrogen atom of a nitrogen-heteroaryl or heterocycle. N-oxide can be formed in presence of an oxidizing agent for example peroxide such as m-chloro-perbenzoic acid or hydrogen peroxide.

The term "stereoisomer" is a general term used for all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).

The term "tautomer" refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.

The term "pharmaceutically acceptable salt" refers to a product obtained by reaction of the compound of Formula 1 with a suitable acid or a base.

As used herein, the term "solvate" or "pharmaceutically acceptable solvate" describes a complex wherein the compound is coordinated with a proportional amount of a solvent molecule. Specific solvates, wherein the solvent is water, are referred to as hydrates. In some embodiments, the "pharmaceutically acceptable solvate" is a pharmaceutically acceptable hydrate.

The term "isosteres" refer to the molecules or ions with the same number of atoms and/or the same number of valence electrons. This definition also includes groups that produce compounds that can sometimes have similar biological activities. Some evidence for the validity of this notion was the observation that some pairs, such as benzene and thiophene, thiophene and furan, and even benzene and pyridine, exhibited similarities in many physical and chemical properties.

Within the context of the present invention, the term "prodrugs" includes simple prodrugs of the compounds of Formula 1 , for example esters, amides and other simple derivatives. The term "prodrug" refers to compounds that are drug precursors, which following administration, release the drug in vivo via a chemical or physiological process e.g., a prodrug on being brought to the physiological pH or through an enzyme action is converted to the desired drug form.

The compounds can be crystallized in different forms. The term "polymorph" refers to a specific crystalline form of a compound which differs only in the arrangement and/or conformation of the molecule in the crystal lattice. Polymorphs of a compound have different physical and chemical properties

The term "isotopic forms" refers to all isotopically labeled forms of compounds of Formula 1, wherein one or more atoms of compounds of Formula 1 are enriched by their respective isotopes. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as ² H and ³ H, carbon such as ^U C, ¹³ C and ¹⁴ C, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as ¹⁵ 0, ¹⁷ 0 and

18 O, chlorine such as 36 CI, fluorine such as 18 F and sulphur such as 35 S.

The term, "therapeutically effective amount" refers to an amount of compound or composition comprising, e.g., a compound of Formula 1, sufficient to significantly induce a positive modification in the condition to be regulated or treated, but low enough to avoid undue or severe side effects within the scope of sound medical judgment. The therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated/prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized.

As used herein, the terms "treatment" "treat" and "therapy" refer to alleviate, slow the progression, attenuation or cure of existing disease or condition (e.g., diabetes). Treatment also includes treating the symptoms of the disease or condition. "Prevent", as used herein, refers to delaying, slowing, inhibiting, reducing or ameliorating the onset of diabetes.

The term "pharmaceutically acceptable" as used herein means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.

The term "pharmaceutically acceptable medium" refers to a composition comprising at least one ingredient selected from carriers, diluents, and excipients, wherein the "pharmaceutically acceptable medium" is pharmaceutically acceptable.

The term "metabolic disorder" as used herein refers to a disease, disorder or a condition characterized by an alteration in the normal metabolism of carbohydrates, lipids, proteins, water or nucleic acids.

The term "mammal" used herein refers to warm-blooded vertebrate animals of the class Mammalia, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young. The term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig as well as human.

B. Other Embodiments

In some embodiments, the compound is a compound of Formula 1, wherein,

A is selected from (Ci-C6)alkyl, (C ₃ -C6)cycloalkyl, -0(Ci-C6)alkyl, (X C^aryl, and nitrogen-heteroaryl;

B is O or C(O); or B is absent and X bonds to A;

X is N or CR _a ;

Ri and R ₂ are hydrogen or optionally Ri and R ₂ together form a (C ₂ -C3)alkylene bridge; R3 is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halogen, cyano, and amino;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ or -C(0)NHR ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R7 is (C6-Cio)aryl or nitrogen-heteroaryl; and

R _a is selected from hydrogen, hydroxy or cyano;

n is the integer 1 or 2;

wherein,

(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

-0(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, and halogen, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-

Ce)alkoxy, halogen, amino, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Ci ₀ )aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted; or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is selected from (C3-C6)cycloalkyl, (C6-Cio)aryl, and nitrogen-heteroaryl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R3 is selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halogen, and cyano;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R ₇ is (C6-Cio)aryl;

n is the integer 1 ;

wherein,

(Ci-Ce)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci-

Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Ci ₀ )aryl, and heterocyclyl, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-

Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is selected from (C ₃ -C6)cycloalkyl, (C6-Ci ₀ )aryl, and nitrogen-heteroaryl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, and cyano; R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R7 is selected from 4-methylphenyl, 4-isopropylphenyl, 3-fluoro-4-methylphenyl, 4-fluoro-2- methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2- fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-4- fluorophenyl, 4-cyanophenyl, phenyl-4-carboxylic acid [phenyl-4-C(0)OH], and biphenyl [phenyl-4-phenyl] ;

n is the integer 1 ;

wherein,

(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is 3-methoxyphenyl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen; R ₃ is chlorine;

R ₄ is hydrogen;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen;

R7 is selected from 3-fluoro-4-methylphenyl, 4-trifluoromethylphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-chloro- 4-fluorophenyl, 2-chloro-4-triflurormethyl, 3-chloro-4-fluorophenyl, phenyl-4-carboxylic acid [phenyl-4-C(0)OH] , and biphenyl [phenyl-4-phenyl] ;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is 3-trifluoromethylphenyl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is cyano;

R ₄ is hydrogen;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen;

R ₇ is selected from 4-trifluoromethylphenyl, 2,4-difluorophenyl, 3,4-dimethoxyphenyl, and 2,4-dichlorophenyl; n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is 3-chlorophenyl;

B is absent;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is (Ci-Ce)alkyl or cyano;

R ₄ is hydrogen or methyl;

R5 is -S(0) ₂ R ₇ ;R6 is hydrogen or methyl;R ₇ is selected from 3-trifluoromethylphenyl, 2,5- dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, and 3- chloro-4-fluorophenyl; n is the integer 1 ;

wherein,

(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is 4-methoxyphenyl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is cyano;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R ₆ is hydrogen or methyl;

R ₇ is selected from 4-fluoro-2-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoro methyl phenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-trifluoro methoxy phenyl, and biphenyl [phenyl-4-phenyl] ;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is 2,4-dimethoxyphenyl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is chlorine;

R ₄ is hydrogen;

R ₅ is -S(0) ₂ R ₇ ;

R ₆ is hydrogen;

R ₇ is selected from 3-trifluoromethylphenyl, 2,5-dimethoxyphenyl, 2,4-difluorophenyl, and 2,4-dichlorophenyl; n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is unsubstituted phenyl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is chlorine;

R ₄ is hydrogen;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen;

R ₇ is selected from 2,4-difluorophenyl, 3-chloro-4-fluorophenyl, and 3,4-dimethoxyphenyl; n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is a (C3-C6)cycloalkyl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is cyano;

R ₄ is hydrogen;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen;

R7 is 3-chloro-4-fluorophenyl;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is nitrogen-heteroaryl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen; R ₃ is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, and cyano;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R7 is selected from 4-methylphenyl, 4-isopropylphenyl, 3-fluoro-4-methylphenyl, 4-fluoro-2- methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-methoxyphenyl, 4-methoxy phenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-di methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-fluorophenyl, 3-fluoro phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2- fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-4- fluorophenyl, 4-cyanophenyl, phenyl-4-carboxylic acid [phenyl-4-C(0)OH], and biphenyl [phenyl-4-phenyl] ;

n is the integer 1;

wherein,

(Ci-Ce)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (Cs-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein, A is pyridin-2-yl; B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is trifluoromethyl or chlorine;

R ₄ is hydrogen or methyl;

R5 is -S(0)2R?;R6 is hydrogen or methyl; R ₇ is selected from 4-cyanophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-methoxy phenyl, 3,4-dimethoxyphenyl, and 3,5-dimethoxyphenyl;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is 4-(trifluoromethyl)pyridin-2-yl; B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R3 is cyano;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R ₇ is 2,4-difluorophenyl;

n is the integer 1;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is 6-mo holino-4-(trifluoromethyl)pyridin-2-yl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is cyano;

R ₄ is methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is methyl;

R ₇ is 2,4-difluorophenyl or 3,4-dimethoxyphenyl;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is pyrimidin-2-yl;

B is absent and X bonds to A;

X is N; Ri and R ₂ are hydrogen;

R3 is cyano or chlorine;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R7 is selected from 4-cyanophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, and biphenyl [phenyl-4- phenyl];

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is (C ₆ -Cio)aryl;

B is absent and X bonds to A;

X is CR _a ;

Ri and R ₂ are hydrogen;

R ₃ is halogen or cyano;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R7 IS (C6-Cio)aryl or nitrogen-heteroaryl;

R _a is hydroxy or cyano;

n is the integer 1 ;

wherein,

(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is phenyl;

B is absent and X bonds to A;

X is CR _a ;

Ri and R ₂ are hydrogen;

R3 is chlorine or cyano;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R ₇ is selected from 4-methylphenyl, 4-isopropylphenyl, 3-fluoro-4-methylphenyl, 4-fluoro-2- methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-methoxyphenyl, 4-methoxy phenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-di methoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4- difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4- chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4- chlorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-4-fluorophenyl, 4-cyanophenyl, phenyl-4- carboxylic acid [phenyl-4-C(0)OH] , and biphenyl [phenyl-4-phenyl] ;

R _a is hydroxy;

n is the integer 1 ;

wherein,

phenyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is 4-chlorophenyl;

B is absent and X bonds to A; X is CR _a ;

Ri and R2 are hydrogen;

R ₃ is chlorine or cyano;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R ₇ is selected from 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-chloro-4- trifluoromethylphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-chlorophenyl, 3-fluoro- 4-methoxyphenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-4- fluorophenyl, and 2,4-dichlorophenyl;

R _a is hydroxy;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is 4-chloro-3-trifluoromethylphenyl;

B is absent and X bonds to A;

X is CR _a ;

Ri and R ₂ are hydrogen;

R3 is chlorine or cyano;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R ₇ is selected from 3-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 3- chloro-4-fluorophenyl, and 2,4-dichlorophenyl;

R _a is hydroxy;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is an unsubstituted phenyl;

B is absent and X bonds to A;

X is CR _a ;

Ri and R ₂ are hydrogen; R ₃ is chlorine or cyano;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R7 is selected from 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-chloro-4- trifluoromethylphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2- chloro-4-fluorophenyl, 3-chloro-4-fluorophenyl, 2,4-dichlorophenyl, and 3,4-dichlorophenyl; R _a is hydroxy;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is an unsubstituted phenyl; B is absent and X bonds to A;

X is CR _a ;

Ri and R ₂ are hydrogen;

R ₃ is chlorine or cyano;

R ₄ is hydrogen or methyl;

R5 is -S(0)2R?;R6 is hydrogen or methyl;

R ₇ is selected from quinolin-8-yl, phenyl, 4-methylphenyl, 4-isopropylphenyl, 3-fluoro-4- methylphenyl, 4-fluoro-2-methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2- fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-4- fluorophenyl, 4-cyanophenyl, phenyl-4-carboxylic acid [phenyl-4-C(0)OH], and biphenyl [phenyl-4-phenyl] ;

R _a is hydroxy or cyano;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is an unsubstituted phenyl; B is absent and X bonds to A;

X is CR _a ;

Ri and R ₂ are hydrogen;

R3 is chlorine;

R ₄ is hydrogen;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen;

R7 is selected from 4-isopropylphenyl, 4-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 3- chloro-4-fluorophenyl, and 2,4-dichlorophenyl;

R _a is cyano;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is an unsubstituted phenyl;

B is absent and X bonds to A;

X is CR _a ;

Ri and R ₂ are hydrogen;

R ₃ is cyano;

R ₄ is methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is methyl;

R ₇ is selected from 3-trifluoromethylphenyl, 2,4-difluorophenyl, 3,4-dimethoxyphenyl, 2- chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluoro-phenyl, and 2,4- dichlorophenyl;

R _a is cyano;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is an unsubstituted phenyl;

B is absent and X bonds to A;

X is CR _a ;

Ri and R ₂ are hydrogen; R ₃ is chlorine or cyano;

R4 is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R7 is nitrogen-heteroaryl;

R _a is hydroxy or cyano;

n is the integer 1 ;

wherein,

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is an unsubstituted phenyl;

B is absent and X bonds to A;

X is CR _a ;

Ri and R ₂ are hydrogen;

R3 is chlorine or cyano;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R ₇ is quinolin-8-yl;

R _a is cyano;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is selected from (C3-C6)cycloalkyl, -0(Ci-C6)alkyl, (C6-Cio)aryl, and nitrogen-heteroaryl; B is C(O); or B is absent and X bonds to A;

X is N or CR _a ;

Ri and R ₂ are hydrogen or optionally Ri and R ₂ together form a. (C ₂ -C3)alkylene bridge; R ₃ is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halogen, cyano, and amino;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -C(0)NHR ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R ₇ is (C6-Cio)aryl;

R _a is hydroxy;

n is the integer 1 ;

wherein,

(Ci-Ce)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

-0(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, and halogen, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is (C ₆ -Cio)aryl;

B is absent and X bonds to A;

X is CR _a ;

Ri and R ₂ are hydrogen;

R ₃ is halogen or cyano;

R ₄ is hydrogen or methyl; R ₅ is -C(0)NHR ₇ ;

R6 is hydrogen or methyl;

R ₇ is (C ₆ -Cio)aryl;

R _a is hydroxy;

n is the integer 1 ;

wherein,

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is selected from cyclohexyl, phenyl or pyrimidin-2-yl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is cyano;

R ₄ is hydrogen or methyl;

R ₅ is -C(0)NHR ₇ ;

R6 is hydrogen or methyl;

R ₇ is selected from 2,4-difluorophenyl, 3-chlorophenyl, 2-chlorophenyl, and 2, 4- dimethoxyphenyl;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is pyrimidin-2-yl;

B is absent or X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is cyano; R ₄ is hydrogen or methyl;

R ₅ is -C(0)NHR ₇ ;

R6 is hydrogen or methyl;

R7 is 2,4-difluorophenyl;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is -0(Ci-C ₆ )alkyl;

B is C(O);

X is N;

Ri and R ₂ are hydrogen;

R ₃ is cyano;

R ₄ is hydrogen or methyl;

R ₅ is -C(0)NHR ₇ ;

R ₆ is hydrogen or methyl;

R ₇ is (C ₆ -Cio)aryl;

n is the integer 1 ;

wherein,

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

-0(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, and halogen, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is (Ci-C ₆ )alkyl;

B is absent and X bonds to A;

X is N; Ri and R ₂ together form an alkylene bridge containing two bridgehead carbon atoms;

R ₃ is cyano;

R ₄ is hydrogen or methyl;

R ₅ is -C(0)NHR ₇ ;

R6 is hydrogen or methyl;

R ₇ is (C6-Cio)aryl;

n is the integer 1 ;

wherein,

(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, amino, t- butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Ci ₀ )aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is nitrogen-heteroaryl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is halogen or cyano;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R7 is (C6-Cio)aryl or nitrogen-heteroaryl;

n is the integer 2;

wherein,

(Ci-Ce)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is nitrogen-heteroaryl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is halogen or cyano;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R ₇ is selected from quinolin-8-yl, 4-methylphenyl, 4-isopropylphenyl, 3-fluoro-4- methylphenyl, 4-fluoro-2-methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2- fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-4- fluorophenyl, 4-cyanophenyl, phenyl-4-carboxylic acid [phenyl-4-C(0)OH] or biphenyl [phenyl-4-phenyl] ;

n is the integer 2;

wherein, (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is 5-trifluoromethyl-pyridin-2-yl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is halogen or cyano;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R ₇ is selected from 3-chloro-4-methylphenyl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 2-fluoromethyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2-chloro-4- fluoromethylphenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 2,4- dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chlorophenyl, and 4- chlorophenyl; n is the integer 2;

wherein,

(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein, A is 4-trifluoromethylpyrimidin-2-yl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R3 is halogen or cyano;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R ₇ is 4-isopropylphenyl, 4-fluoro-2-methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoro methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2,4-difluorophenyl, 2,3,4- trifluorophenyl, 2-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-4-methoxy phenyl, 3-methoxyphenyl, 2,5-dimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4- chlorophenyl, 4-fluoro-3-chlorophenyl, 2,4-dichlorophenyl, and 3,4-dichlorophenyl;

n is the integer 2;

wherein,

(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, halogen, alkoxy, halo(Ci-C6)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is nitrogen-heteroaryl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ are hydrogen;

R ₃ is halogen or cyano;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or (Ci-Ce)alkyl;

R ₇ is nitrogen-heteroaryl;

n is the integer 2;

wherein, (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted; or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N-oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is (Ci-C ₆ )alkyl;

B is absent and X bonds to A;

X is N;

Ri and R ₂ together form an alkylene bridge containing two bridgehead carbon atoms;

R ₃ is halogen or cyano;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R7 is (C6-Cio)aryl or nitrogen-heteroaryl;

n is the integer 1 ;

wherein,

(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Ci ₀ )aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is methyl;

B is absent and X bonds to A;

X is N;

Ri and R2 together form an alkylene bridge containing two bridgehead carbon atoms;

R ₃ is halogen or cyano;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R ₇ is selected from 4-isopropylphenyl, 4-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, and

3,4-dimethoxyphenyl;

n is the integer 1 ;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1, wherein,

A is selected from (Ci-C6)alkyl, (C3-C6)cycloalkyl, and (C6-Cio)aryl;

B is C(O);

X is N;

Ri and R ₂ are hydrogen;

R3 is selected from (Ci-C6)alkyl, halogen or cyano;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R7 IS (C6-Cio)aryl or nitrogen-heteroaryl ;

n is the integer 1 ;

wherein,

(Ci-Ce)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is compound of Formula 1,

wherein,

A is selected from (Ci-C6)alkyl, (C ₃ -C6)cycloalkyl, and (C6-Ci ₀ )aryl;

B is C(O);

X is N;

Ri and R ₂ are hydrogen;

R ₃ is selected from (Ci-C6)alkyl, halogen or cyano;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or (Ci-C6)alkyl;

R ₇ is selected from 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, and 3-trifluoromethylphenyl; n is the integer 1 ;

wherein,

(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Ci ₀ )aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted; or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is (C ₆ -Cio)aryl;

B is O;

X is CR _a ;

Ri and R2 are hydrogen;

R ₃ is cyano;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R6 is hydrogen or methyl;

R ₇ is (C ₆ -Cio)aryl;

R _a is hydrogen;

n is the integer 1;

wherein,

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

In some embodiments, the compound is a compound of Formula 1,

wherein,

A is (C ₆ -Cio)aryl;

B is O;

X is CR _a ;

Ri and R ₂ are hydrogen;

R ₃ is cyano;

R ₄ is hydrogen or methyl;

R ₅ is -S(0) ₂ R ₇ ;

R ₆ is hydrogen or methyl;

R ₇ is (C ₆ -Cio)aryl;

R _a is hydrogen; n is the integer 2;

wherein,

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

Representative compounds of Formula 1 encompassed in accordance with the present invention include but not limited to:

N-(5-Chloro-6-(4-cyano-4-phenylpiperidin-l-yl)pyridin-3-yl)- 4-isopropylbenzene sulfonamide;

N-(5-Cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2,4-dimethylpy ridin-3-yl)-3- (trifluoromethyl)benzenesulfonamide;

N-(5-Chloro-6-(4-cyano-4-phenylpiperidin- 1 -yl)pyridin-3-yl)-4-(trifluoromethyl) benzenesulf onamide ;

N-(5-Cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2,4-dimethylpy ridin-3-yl)-2,4- difluorobenzenesulf onamide ;

3-Chloro-N-(5-chloro-6-(4-cyano-4-phenylpiperidin-l-yl)pyrid in-3-yl)-4- fluorobenzenesulfonamide;

2- Chloro-N-(5-cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2,4-dim ethylpyridin-3-yl)-4- fluorobenzenesulf onamide;

3- Chloro-N-(5-cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2,4-dim ethylpyridin-3-yl)-4- fluorobenzenesulf onamide;

2,4-Dichloro-N-(5-chloro-6-(4-cyano-4-phenylpiperidin-l-yl)p yridin-3- yl)benzenesulf onamide ;

2,4-Dichloro-N-(5-cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2 ,4-dimethylpyridin-3- yl)benzenesulf onamide ;

N-(5-Chloro-6-(4-cyano-4-phenylpiperidin-l-yl)pyridin-3-yl)- 2,4-dimethoxy- benzenesulf onamide;

N-(5-Cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2,4-dimethylpy ridin-3-yl)-3,4- dimethoxybenzenesulfonamide ;

N-(5-Chloro-6-(4-cyano-4-phenylpiperidin-l-yl)pyridin-3-yl)q uinoline-8-sulf onamide; N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyano-2, 4-dimethylpyridin-3-yl)-

2- (trifluoromethyl)benzenesulfonamide;

3,4-Dichloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-y l)-5-cyano-2,4- dimethylpyridin-3-yl)benzenesulfonamide;

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)-2,4-dimethyl pyridin-3-yl)-2- (trifluoromethyl)benzenesulfonamide;

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)-2,4-dimethyl pyridin-3-yl)-3- (trifluoromethyl)benzenesulfonamide;

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyano-2, 4-dimethylpyridin-3-yl)-

3- (trifluoromethyl)benzenesulfonamide;

2-Chloro-N-(5-cyano-6-(4-hydroxy-4^henylpiperidin-l-yl)-2,4- dimethylpyridin-3-yl)-4 (trifluoromethyl)benzenesulfonamide;

2- Chloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-5-c yano-2,4- dimethylpyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide;

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)pyridin-3- yl)-2,4- difluorobenzenesulf onamide ;

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyanopyr idin-3-yl)-2,4- difluorobenzenesulf onamide ;

N-(5-Chloro-6-(4-hydroxy-4-phenylpiperidin-l-yl)pyridin-3-yl )-2,4- difluorobenzenesulf onamide ;

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)-2,4-dimethyl pyridin-3-yl)-2,4- difluorobenzenesulf onamide ;

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyano-2, 4-dimethylpyridin-3-yl)- 2,4-difluorobenzenesulf onamide;

4- Chloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-5-c yanopyridin-3-yl)-2- fluorobenzenesulf onamide;

3- Chloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-5-c yanopyridin-3-yl)-4- fluorobenzenesulf onamide;

3-Chloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-5 -cyano-2,4- dimethylpyridin-3-yl)-4-fluorobenzenesulfonamide;

2-Chloro-N-(5-cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)-2,4 -dimethylpyridin-3-yl)-4 fluorobenzenesulf onamide;

2-Chloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-5 -cyano-2,4- dimethylpyridin-3-yl)-4-fluorobenzenesulfonamide; 3-Chloro-N-(5-cyano-6-(4-hydroxy-4^henylpiperidin-l-yl)-2,4- dimethylpyridin-3-yl) fluorobenzenesulfonamide;

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyanopyr idin-3-yl)-3-fluoro-4- methoxybenzenesulf onamide ;

2,4-Dichloro-N-(5-cyano-6-(4-hydroxy-4^henylpiperidin-l-y l)-2,4-dimethylpyridin-3- yl)benzenesulf onamide ;

2,4-Dichloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-y l)-5-cyano-2,4- dimethylpyridin-3-yl)benzenesulf onamide;

3,4-Dichloro-N-(5-cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl) -2,4-dimethylpyridin-3- yl)benzenesulf onamide;

N-(5-Chloro-6-(4-hydroxy-4-phenylpiperidin-l-yl)pyridin-3-yl )-2,4- dimethoxybenzenesulfonamide ;

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)pyridin-3-yl) -2,4- dimethoxybenzenesulfonamide ;

N-(5-Chloro-6-(4-hydroxy-4-phenylpiperidin-l-yl)pyridin-3 -yl)-3,4- dimethoxybenzenesulfonamide ;

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)pyridin-3-yl) -3,4- dimethoxybenzenesulfonamide ;

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyanopyr idin-3-yl)-3,4- dimethoxybenzenesulfonamide;

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)-2,4-dimethyl pyridin-3-yl)-3,4- dimethoxybenzenesulfonamide ;

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyano-2, 4-dimethylpyridin-3-yl)- 3,4-dimethoxybenzenesulfonamide;

N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypip eridin-l-yl)-5-cyanopyridin- 3-yl)-2,4-difluorobenzenesulf onamide;

3-Chloro-N-(6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydr oxypiperidin-l-yl)-5- cyanopyridin-3-yl)-4-fluorobenzenesulf onamide;

N-(5-Chloro-6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydr oxypiperidin-l-yl)pyridin- 3-yl)-3-(trifluoromethyl)benzenesulf onamide;

N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperi din-l-yl)-5-cyanopyridin- 3-yl)-3-(trifluoromethyl)benzenesulf onamide;

N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperi din-l-yl)-5-cyano-2,4- dimethylpyridin-3-yl)-3-(trifluoromethyl)benzenesulf onamide; N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperi din-l-yl)-5-cyanopyridin- 3-yl)-3,4-dimethoxybenzenesulfonamide;

N-(5-Chloro-6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydr oxypiperidin-l-yl)pyridin- 3-yl)-2,4-difluorobenzenesulfonamide;

N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypip eridin-l-yl)-5-cyano-2,4- dimethylpyridin-3-yl)-2,4-difluorobenzenesulfonamide;

3-Chloro-N-(5-chloro-6-(4-(4-chloro-3-(trifluoromethyl)pheny l)-4-hydroxypiperidin-l- yl)pyridin-3 -yl)-4-fluorobenzenesulf onamide ;

N-(5-Chloro-6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydr oxypiperidin-l-yl)pyridin- 3-yl)-3 ,4-dimethoxybenzenesulf onamide ;

2,4-Dichloro-N-(5-chloro-6-(4-(4-chloro-3-(trifluoromethyl)p henyl)-4-hydroxypiperidin- 1 -yl)pyridin-3-yl)benzenesulf onamide ;

3-Chloro-N-(6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydr oxypiperidin-l-yl)-5- cyano-2,4-dimethylpyridin-3-yl)-4-fluorobenzenesulf onamide;

2,4-Dichloro-N-(6-(4-(4-chloro-3-(trifluoromethyl)phenyl) -4-hydroxypiperidin-l-yl)-5- cyanopyridin-3-yl)benzenesulfonamide;

2,4-Dichloro-N-(6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4- hydroxypiperidin-l-yl)-5- cyano-2,4-dimethylpyridin-3-yl)benzenesulf onamide;

N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperi din-l-yl)-5-cyano-2,4- dimethylpyridin-3-yl)-3,4-dimethoxybenzenesulfonamide;

3-Chloro-N-(5-cyano-6-(4-cyclohexylpiperazin-l-yl)pyridin-3- yl)-4-fluorobenzene sulfonamide;

N-(5-Chloro-6-(4-phenylpiperazin-l-yl)pyridin-3-yl)-2,4-difl uorobenzene sulfonamide; 3-Chloro-N-(5-chloro-6-(4-phenylpiperazin-l-yl)pyridin-3-yl) -4-fluorobenzene sulfonamide;

N-(5-Chloro-6-(4-phenylpiperazin-l-yl)pyridin-3-yl)-3,4-dime thoxybenzene sulfonamide;

N-(5-Cyano-6-(4-(3-(trifluoromethyl)phenyl)piperazin-l-yl)py ridin-3-yl)-4- (trifluoromethyl)benzenesulf onamide;

N-(5-Cyano-6-(4-(3-(trifluoromethyl)phenyl)piperazin-l-yl )pyridin-3-yl)-2,4- difluorobenzenesulf onamide ;

2,4-Dichloro-N-(5-cyano-6-(4-(3-(trifluoromethyl)phenyl)pipe razin-l-yl)pyridin-3- yl)benzenesulf onamide ; N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-cyano-2,4-dimethyl pyridin-3-yl)-3- (trifluoromethyl)benzenesulfonamide;

N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-cyano-2,4-dimethyl pyridin-3-yl)-2,4- difluorobenzenesulf onamide ;

3-Chloro-N-(6-(4-(3-chlorophenyl)piperazin-l-yl)-5-cyano- 2,4-dimethylpyridin-3-yl)-4- fluorobenzenesulf onamide;

2,4-Dichloro-N-(6-(4-(3-chlorophenyl)piperazin-l-yl)-5-cyano -2,4-dimethylpyridin-3- yl)benzenesulf onamide ;

N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-methylpyridin-3-yl )-2,5- dimethoxybenzenesulfonamide;

N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-cyano-2,4-dimethyl pyridin-3-yl)-2,5- dimethoxybenzenesulfonamide ;

N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-methylpyridin-3-yl )-3,4- dimethoxybenzenesulfonamide ;

N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-cyano-2,4-dimet hylpyridin-3-yl)-3,4- dimethoxybenzenesulfonamide ;

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-3-fluoro-4- methylbenzenesulf onamide ;

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-4- (trifluoromethyl)benzenesulf onamide ;

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-4-

(trifluoromethyl)benzenesulf onamide hydrochloride ;

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-4-

(trifluoromethyl)benzenesulf onamide hydrobromide ;

2-Chloro-N-(5-chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl )pyridin-3-yl)-4-

(trilluoromethyl)benzenesulf onamide;

4-(N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin- 3-yl)sulfamoyl)benzoic acid;

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-2,4- dilluorobenzenesulf onamide;

3-Chloro-N-(5-chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)py ridin-3-yl)-4- lluorobenzenesulf onamide,

2,4-Dichloro-N-(5-chloro-6-(4-(3-methoxyphenyl)piperazin-l-y l)pyridin-3- yl)benzenesulf onamide ; 3,4-Dichloro-N-(5-chloro-6-(4-(3-methoxyphenyl)piperazin-l-y l)pyridin-3- yl)benzenesulf onamide ;

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-2,5- dimethoxybenzenesulfonamide ;

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin- 3-yl)-3,4- dimethoxybenzenesulfonamide ;

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-[l,l'-biphenyl]-4- sulf onamide;

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dimethy lpyridin-3-yl)-3- (trifluoromethyl)benzenesulf onamide ;

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dimethy lpyridin-3-yl)-4- (trifluoromethyl)benzenesulf onamide;

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)pyridin-3-yl )-4-fluoro-2- methylbenzenesulf onamide ;

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)pyridin-3 -yl)-2,4- difluorobenzenesulf onamide ;

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dimethy lpyridin-3-yl)-2,4- difluorobenzenesulf onamide ;

2,4-Dichloro-N-(5-cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl )pyridin-3- yl)benzenesulf onamide;

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)pyridin-3-yl )-3,4- dimethoxybenzenesulfonamide ;

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dimethy lpyridin-3-yl)-3,4- dimethoxybenzenesulfonamide ;

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)pyridin-3 -yl)-4- (trifluoromethoxy)benzenesulf onamide;

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dimethy lpyridin-3-yl)-4- (trifluoromethoxy)benzenesulf onamide;

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dimethy lpyridin-3-yl)-[l,l'- biphenyl]-4-sulf onamide;

N-(5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin -3-yl)-3- (trifluoromethyl)benzenesulf onamide;

N-(5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin -3-yl)-2,4- difluorobenzenesulf onamide ; 2,4-Dichloro-N-(5-chloro-6-(4-(2,4-dimethoxyphenyl)piperazin -l-yl)pyridin-3- yl)benzenesulf onamide ;

N-(5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin -3-yl)-2,5- dimethoxybenzenesulfonamide ;

N-(5-Chloro-6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-y l)-4-cyanobenzene sulfonamide;

2,4-Difluoro-N-(6-(4-(pyridin-2-yl)piperazin-l-yl)-5-(triflu oromethyl)pyridin-3- yl)benzenesulf onamide ;

2,4-Dichloro-N-(5-chloro-6-(4-(pyridin-2-yl)piperazin-l-yl)p yridin-3- yl)benzenesulf onamide;

2.4- Dichloro-N-(6-(4-(pyridin-2-yl)piperazin-l-yl)-5-(trifluorom ethyl)pyridin-3-yl) benzenesulf onamide ;

N-(5-Chloro-6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-yl)- 4-methoxy

benzenesulf onamide ;

N-(5-Chloro-6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-y l)-3,4-dimethoxy

benzenesulf onamide ;

3.5- Dimethoxy-N-(6-(4-(pyridin-2-yl)piperazin-l-yl)-5-(trifluoro methyl)pyridin-3- yl)benzenesulf onamide ;

3,4-Dimethoxy-N-(6-(4-(pyridin-2-yl)piperazin-l-yl)-5-(trifl uoromethyl) pyridin-3-yl) benzene sulfonamide;

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyridin-2-y l)piperazin-l-yl)pyridin-3- yl)-2,4-difluorobenzenesulf onamide;

N-(5-Cyano-2,4-dimethyl-6-(4-(6-mo holino-4-(trifluoromethyl)pyridin-2-yl)piperazin- l-yl)pyridin-3-yl)-2,4-difluorobenzenesulf onamide;

N-(5-Cyano-2,4-dimethyl-6-(4-(6-mo holino-4-(trifluoromethyl)pyridin-2-yl)piperazin- 1 -yl)pyridin-3-yl)-3 ,4-dimethoxybenzenesulf onamide ;

N-(5-Chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-yl )-4-cyanobenzene sulfonamide;

N-(5-Chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-yl )-4-fluorobenzene sulfonamide;

N-(5-Cyano-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-yl) -2,4-difluorobenzene sulfonamide;

N-(5-Cyano-2-methyl-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyri din-3-yl)-2,4- difluorobenzene sulfonamide; 2,4-Dichloro-N-(5-chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl )pyridin-3- yl)benzenesulf onamide ;

2,4-Dichloro-N-(5-cyano-2-methyl-6-(4-(pyrimidin-2-yl)pipera zin-l-yl)pyridin-3- yl)benzenesulf onamide ;

3,4-Dichloro-N-(5-cyano-2-methyl-6-(4-(pyrimidin-2-yl)pip erazin-l-yl)pyridin -3- yl)benzenesulf onamide ;

N-(5-Cyano-2-methyl-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyri din-3-yl)-2,4- dimethoxybenzenesulfonamide ;

N-(5-Chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-yl )-3,4-dimethoxy benzenesulf onamide;

N-(5-Cyano-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-yl) -3,4-dimethoxy

benzenesulf onamide ;

N-(5-Cyano-2-methyl-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyri din-3-yl)-[l,l'-biphenyl]- 4- sulfonamide;

3-Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(5 -(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)pyridin-3-yl)-4-methylbenzenesulf onamide;

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazep an-l-yl)pyridin-3-yl)-3- (trifluoromethyl)benzenesulf onamide;

N-(5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diaze pan-l-yl)pyridin-3-yl)-4- (trifluoromethyl)benzenesulf onamide ;

N-(5-Cyano-2,4-dimethyl-6-(4-(5-(trifluoromethyl)pyridin-2-y l)piperazin-l-yl)pyridin-3- yl)-3-(trifluoromethyl)benzenesulfonamide;

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazep an-l-yl)pyridin-3-yl)-4- (trifluoromethyl)benzenesulf onamide;

N-(5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-di azepan-l-yl)pyridin-3-yl)-2- fluorobenzenesulf onamide;

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazep an-l-yl)pyridin-3-yl)-2,4- difluorobenzenesulf onamide ;

N-(5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diaze pan-l-yl)pyridin-3-yl)-2,4- difluorobenzenesulf onamide;

N-(5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diaze pan-l-yl)pyridin-3-yl)-2,6- difluorobenzenesulf onamide ;

2-Chloro-N-(5-chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)- l,4-diazepan-l-yl)pyridin-3- yl)-4-fluorobenzenesulfonamide ; 3-Chloro-N-(5-cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l ,4-diazepan-l-yl)pyridin-3 yl)-4-fluorobenzenesulfonamide ;

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazep an-l-yl)pyridin-3-yl)-3- fluoro-4-methoxybenzenesulfonamide;

3-Chloro-N-(5-chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)- l,4-diazepan-l-yl)pyridin-3 yl)benzenesulf onamide ;

3- Chloro-N-(5-cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4 -diazepan-l-yl)pyridin-3 yl)benzenesulf onamide ;

4- Chloro-N-(5-chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l, 4-diazepan-l-yl)pyridin-3 yl)benzenesulf onamide ;

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazep an-l-yl)pyridin-3-yl)-2,5- dimethoxybenzenesulfonamide ;

N-(5-Cyano-2,4-dimethyl-6-(4-(5-(trifluoromethyl)pyridin-2-y l)piperazin-l-yl)pyridin-3 yl)-2,5-dimethoxybenzenesulfonamide;

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazep an-l-yl)pyridin-3-yl)-3,4- dimethoxybenzenesulfonamide ;

N-(5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diaze pan-l-yl)pyridin-3-yl)-3,4- dimethoxybenzenesulfonamide ;

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3 -yl)-4-isopropylbenzenesulfonamide ;

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3 -yl)-4-fluoro-2-methylbenzenesulfonamide ;

N-(5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-dia zepan-l-yl)pyridin-3-yl)-4- fluoro-2-methylbenzenesulf onamide;

3-Chloro-N-(5-chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl )-l,4-diazepan-l- yl)pyridin-3-yl)-4-methylbenzenesulf onamide;

3-Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)py rimidin-2-yl)-l,4- diazepan- 1 -yl)pyridin-3-yl)benzenesulfonamide;

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3-yl)-2-(trifluoromethyl)benzenesulf onamide;

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulf onamide;

N-(5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-dia zepan-l-yl)pyridin-3-yl)-3- (trifluoromethyl)benzenesulf onamide; N-(5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-dia zepan-l-yl)pyridin-3-yl) (trifluoromethyl)benzenesulfonamide;

N-(5-Cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-diaz epan-l-yl)pyridin-3-yl)-3- (trifluoromethyl)benzenesulfonamide;

N-(5-Cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-diaz epan-l-yl)pyridin-3-yl)-4- (trifluoromethyl)benzenesulfonamide;

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide;

N-(5-Cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-diaz epan-l-yl)pyridin-3-yl)- 2,4-difluorobenzenesulfonamide;

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3 -yl)-2,4-difluorobenzenesulfonamide ;

N-(5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-dia zepan-l-yl)pyridin-3-yl)- 2,3,4-trifluorobenzenesulfonamide;

2- Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyri midin-2-yl)-l,4- diazepan- 1 -yl)pyridin-3-yl)-4-fluorobenzenesulfonamide;

3- Chloro-N-(5-cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l ,4-diazepan-l-yl)pyridin 3-yl)-4-fluorobenzenesulfonamide;

N-(5-Cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-diaz epan-l-yl)pyridin-3-yl)-3- fluoro-4-methoxybenzenesulfonamide;

3-Chloro-N-(5-cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl) -l,4-diazepan-l-yl)pyridin 3-yl)benzenesulfonamide;

3-Chloro-N-(5-chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl )-l,4-diazepan-l- yl)pyridin-3 -yl)benzenesulfonamide ;

3- Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyri midin-2-yl)-l,4- diazepan- 1 -yl)pyridin-3-yl)benzenesulfonamide;

4- Chloro-N-(5-chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- l,4-diazepan-l- yl)pyridin-3 -yl)benzenesulfonamide ;

2,4-Dichloro-N-(5-cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3 -yl)benzenesulfonamide ;

2,4-Dichloro-N-(5-chloro-6-(4-(4-(trifluoromethyl)pyrimidin- 2-yl)-l,4-diazepan-l- yl)pyridin-3 -yl)benzenesulfonamide ;

2,4-Dichloro-N-(5-cyano-2,4-dimethyl-6-(4-(4-(trifluoromethy l)pyrimidin-2-yl)-l ,4- diazepan- 1 -yl)pyridin-3-yl)benzenesulfonamide; 3,4-Dichloro-N-(5-cyano-2,4-dimethyl-6-(4-(4-(trifluoromethy l)pyrimidin-2-yl)-l ,4- diazepan- 1 -yl)pyridin-3-yl)benzenesulfonamide,

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3-yl)-3-methoxybenzenesulfonamide;

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidi n-2-yl)-l,4-diazepan-l- yl)pyridin-3-yl)-2,5-dimethoxybenzenesulfonamide;

N-(5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-dia zepan-l-yl)pyridin-3- yl)quinoline-8-sulfonamide;

N-(5-Cyano-2,4-dimethyl-6-(3-methyl-3 , 8-diazabicyclo [3.2.1] octan- 8-yl)pyridin-3-yl)-4- isopropylbenzenesulfonamide;

N-(5-Cyano-2,4-dimethyl-6-(3-methyl-3 , 8-diazabicyclo [3.2.1] octan- 8-yl)pyridin-3-yl)-4- (trifluoromethyl)benzenesulfonamide;

N-(5-Cyano-2,4-dimethyl-6-(3-methyl-3 , 8-diazabicyclo [3.2.1] octan- 8-yl)pyridin-3-yl)-4- fluorobenzenesulfonamide;

N-(5-Cyano-2,4-dimethyl-6-(3-methyl-3 , 8-diazabicyclo [3.2.1] octan- 8-yl)pyridin-3-yl)-

3,4-dimethoxybenzenesulfonamide;

l-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyano pyridin-3-yl)-3-(3- (trifluoromethyl)phenyl)urea ;

l-(5-Cyano-6-(4-phenylpiperazin-l-yl)pyridin-3-yl)-3-(2,4 -dilluoro phenyl)urea;

l-(5-Cyano-2-methyl-6-(4-(pyrimidin-2-yl)piperazin-l-yl)p yridin-3-yl)-3-(2,4- dilluorophenyl)urea;

l-(2-Chlorophenyl)-3-(5-cyano-6-(4-cyclohexylpiperazin-l- yl)pyridin-3-yl)urea;

Ethyl 4-(3-cyano-5-(3-(2,4-dimethoxyphenyl)ureido)pyridin-2-yl)pip erazine-l- carboxylate;

l-(5-Cyano-2,4-dimethyl-6-(3-methyl-3,8-diazabicyclo[3.2. 1]octan-8-yl)pyridin-3-yl)-3- (2,4-dimethoxyphenyl)urea;

tert-Butyl-(3-(4-(3-cyano-5-(2,4-dilluorophenylsulfonamid o)pyridin-2-yl)piperazin-l-yl)- 3-oxopropyl)carbamate;

3-Chloro-N-(5-cyano-6-(4-(cyclohexanecarbonyl)piperazin-l-yl )pyridin-3-yl)-4- lluorobenzenesulfonamide;

N-(5-Cyano-2,4-dimethyl-6-(4-(2-(trifluoromethyl)benzoyl)pip erazin-l-yl)pyridin-3-yl)- 3-(trifluoromethyl)benzenesulfonamide;

N-(5-Cyano-2,4-dimethyl-6-(4-(2-(trifluoromethyl)benzoyl)pip erazin-l-yl)pyridin-3-yl)- 2,4-difluorobenzenesulfonamide; 3-Chloro-N-(5-chloro-6-(4-(2-(trifluoromethyl)benzoyl)pipera zin-l-yl)pyridin-3 fluorobenzenesulfonamide;

3-Chloro-N-(5-cyano-6-(4-(2-(trifluoromethyl)benzoyl)piperaz in-l-yl)pyridin-3-yl)-4- fluorobenzenesulfonamide;

3-Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(2-(trifluoromethyl)be nzoyl) piperazin-1- yl)pyridin-3 -yl)-4-fluorobenzenesulf onamide ;

3-Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(2-(trifluoromethyl)ph enoxy) piperidin-1- yl)pyridin-3 -yl)-4-fluorobenzenesulf onamide ; and

3-Chloro-N-(5-cyano-6-(4-(2-(trifluoromethyl)phenoxy)piperid in-l-yl)pyridin -3-yl)-4- fluorobenzenesulfonamide.

The compounds of the present invention also include all their isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable polymorphs and N-oxides, isosteres and prodrugs thereof.

C. Preparation of the compounds

According to a further aspect of the invention, there is provided a process for the preparation of compounds of Formula 1 ,

wherein,

A is selected from (Ci-C6)alkyl, (C3-C6)cycloalkyl, -0(Ci-C6)alkyl, (C6-Cio)aryl, and nitrogen-heteroaryl ;

B is O or C(O); or B is absent and X bonds to A;

X is N or CR _a ;

Ri and R ₂ are hydrogen or optionally Ri and R ₂ together form a (C2-C3)alkylene bridge;

R ₃ is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halogen, cyano, and amino;

R ₄ is hydrogen or (Ci-C6)alkyl;

R ₅ is -S(0) ₂ R ₇ or -C(0)NHR ₇ ;

R6 is hydrogen or (Ci-Ce)alkyl;

R7 is (C6-Cio)aryl or nitrogen-heteroaryl ; and

R _a is selected from hydrogen, hydroxyl, and cyano;

n is the integer 1 or 2;

wherein, (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, hydroxy, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;

-0(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, and halogen, wherein the substituents are not further substituted;

(C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;

or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.

The compound of Formula 1 is preparable in a number of different ways including using methods well known to those of ordinary skill in the art. A method to prepare the compounds of Formula 1 is illustratable in Scheme 1, but is not limited thereto. It will be appreciated by those of ordinary skill in the art that within certain of the processes described herein, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent to be used in the synthetic steps.

One or more of the reagents, reactants and intermediates used in the following processes are either commercially available or can be prepared according to standard literature procedures known in the art. The starting compounds and the intermediates used for the synthesis of the compounds and the final compounds of the present invention are referred to by the symbols (a), (b), (c), (d), (e), and (f) in Scheme 1 below.

Throughout the description of the process, the corresponding substituent groups in the various formulae representing starting compounds and intermediates have the same meanings as that for the compound of Formula 1 , unless stated otherwise or the molecule is protected. Scheme 1 , wherein the processes for the preparation of the compounds of Formula 1 are depicted, is given herein below. For ease of reference, the reaction steps depicted in the Scheme 1 are referred to by using general symbols namely la, lb, lc and Id.

The compounds of Formula 1 [corresponds to compound (e) when R5 is S(0)2 7 and compound (f) when R5 is C(0)NHR ₇ ] are preparable by, or in analogy with, standard synthetic methods, and especially according to, or in analogy with, Scheme 1.

Scheme 1

(e) (f)

[Compound of Formula 1 , [Compound of Formula 1 , wherein R ₅ is S0 ₂ R ₇ ] wherein R ₅ is C(0)NHR ₇ ] Step l

As shown in Scheme 1, compound of formula (c), wherein A, B, X, Ri, R2, R3, R ₄ , R6, and n are as defined above, can be prepared by reacting compound of formula (a), (wherein R ₃ , R ₄ , and R6 are as defined above), with a compound of formula (b) (wherein A, B, X, Ri, R ₂ and n are as defined above), in the presence of a solvent such as dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, or acetonitrile, optionally in the presence of a base such as cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, or potassium fluoride (reaction step la).

Step 2

The nitro group of compound of formula (c) is reduced to the corresponding amino group to obtain compound of formula (d), wherein A, B, X, Ri, R ₂ , R _3, R ₄ , R6, and n are as defined above. Reduction of the nitro group may be carried out by using reducing agent such as SnCl ₂ in a solvent such as ethyl acetate; or by using Fe/HCl; or in presence of gaseous hydrogen and a catalyst such as Pd-C, Rh-C, Pt-C; or any suitable method known in the art (reaction step lb).

Step 3

The compound of formula (d) is further converted to the desired compound of formula (e), which corresponds to Formula 1, wherein R5 is SO ₂ R ₇ , A, B, X, Ri, R ₂ , R _3, R ₄ , R6, R ₇ and n are as defined above, by reacting with R ₇ S0 ₂ -halide wherein halide is represented by fluorine, chlorine, bromine or iodine and R ₇ is as defined above, in the presence of pyridine or triethyl amine as a base and a solvent selected from acetonitrile, dichlorome thane, chloroform, carbon tetrachloride, tetrahydrofuran or dioxane (reaction step lc).

Step 4

The compound of formula (d) may also be converted to the desired compound of formula (f), which corresponds to Formula 1, wherein R5 is C(0)NHR ₇ , A, B, X, Ri, R ₂ , R _3, R ₄ , R6, R7 and n are as defined above, by reaction with [R ₇ NC(0)], wherein R ₇ is as defined above, in the presence a solvent selected from benzene, toluene, tetrahydrofuran or dioxane (reaction step Id).

The compound of Formula 1, wherein A, B, X, Ri, R ₂ , R _3, R _4, R5, R6, and n are as defined above may be converted into a pharmaceutically acceptable salt by standard procedures known in the literature.

In some embodiments, the compound of Formula 1 is in an isotopically labeled form of compounds of Formula 1 , wherein one or more atoms of compounds of Formula 1 are enriched in one or more of their respective isotopes. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as ² H and ³ H, carbon such as ^U C, ¹³ C and ¹⁴ C, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as 15 O, 17 O and 18 O, chlorine such as 36 CI, fluorine such as 18 F and sulphur such as ³⁵ S.

Substitution with heavier isotopes, for example, replacing one or more key carbon- hydrogen bonds with carbon-deuterium bond may show certain therapeutic advantages, for example, longer metabolism cycles, improved safety or greater effectiveness.

Isotopically labeled forms of compounds of Formula 1 can be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described above and in the subsequent section on examples by using an appropriate isotopically labeled reagent instead of non-labeled reagent.

In some embodiments, the compound of Formula 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is selected from salts of acidic or basic groups present in compounds of Formula 1. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, or p-toluene sulfonate salts. In some embodiements, the compound of Formula 1 is in the form of a pharmaceutically acceptable salt with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin. Suitable base salts also include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.

I ⁾ . More Embodiments

According to an embodiment there is provided a method for the treatment of metabolic disorders related to insulin resistance or hyperglycemia, including administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 1. In some embodiments, the mammal is a human.

In some embodiments, the method for the treatment of metabolic disorders is related to insulin resistance or hyperglycemia, including type 2 diabetes, obesity, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension, and nonalcoholic fatty liver disease, including administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 1. In some embodiments, the mammal is a human.

According to an embodiment there is provided a method for the treatment of dyslipidemia, including administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 1. In some embodiments, the mammal is a human.

According to an embodiment there is provided a method for the treatment of type 2 diabetes and disorders related thereto, including administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 1. In some embodiments, the mammal is a human.

According to an embodiment the compound of Formula 1, when administered to a mammal in need thereof, is useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia. In some embodiments, the mammal is a human.

According to an embodiment, the compound of Formula 1, when administered to a mammal in need thereof, is useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia, including type 2 diabetes, obesity, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension, and nonalcoholic fatty liver disease. In some embodiments, the mammal is a human.

According to an embodiment, the compound of Formula 1, when administered to a mammal in need thereof, is useful for the treatment of type 2 diabetes. In some embodiments, the mammal is a human.

According to an embodiment, the compound of Formula 1, when administered to a mammal in need thereof, is useful for the treatment of dyslipidemia. In some embodiments, the mammal is a human.

Administering is by any suitable method. In some embodiments, administering is an oral route. In some embodiments, administering is via injection.

In some embodiments, the mammal is human.

According to an embodiment, the compound of Formula 1 is useful for the manufacture of a medicament for the treatment of a metabolic disorder related to insulin resistance or hyperglycemia in a mammal.

While it is possible that compound of Formula 1 is therapeutically administered as the raw chemical, in some embodiments it is preferable to present the active ingredient as a pharmaceutical composition. For example, in some embodiments, the pharmaceutical composition comprises, in pharmaceutically acceptable medium, a compound of Formula 1. In some embodiments, the pharmaceutical composition comprises a compound of Formula 1 or a pharmaceutically acceptable salt or solvate or a prodrug thereof, for example, together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients.

The pharmaceutical composition may be in the forms normally employed, such as tablets, lozenges, capsules, powders, syrups, solutions, suspensions and the like specially formulated for oral, buccal, parenteral, transdermal, inhalation, intranasal, transmucosal, implant, or rectal administration, however oral administration is preferred. For buccal administration, the formulation may take the form of tablets or lozenges formulated in conventional manner. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycolate) or wetting agents, such as sodium lauryl sulfate. The tablets may be coated according to methods well known in the art.

Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydro genated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Additionally, formulations of the present invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use. The formulations according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil, for example), ion exchange resins or as sparingly soluble derivatives as a sparingly soluble salt, for example.

In some embodiments, there is provided a method for manufacture of a medicament comprising a compound of Formula 1, which are useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

It will be appreciated by those of ordinary skill in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02 mg - 5000 mg per day or 1 mg -1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.

The formulations according to the invention may contain between 0.1-99 % of the compound of Formula 1 active ingredient, conveniently from 30-95 % for tablets and capsules and 3-50 % for liquid preparations.

Furthermore, in addition to at least one compound of Formula 1 , as active ingredient, the pharmaceutical compositions may also contain one or more other therapeutically active ingredients, which differ from the compound of Formula 1.

Accordingly, in an embodiment, the further therapeutically active ingredient that can be used in combination with one or more compounds of Formula 1 (as an active ingredient), is selected from one or more of the agents including, but not limited to, insulin, rosiglitazone, pioglitazone, rivoglitazone, simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, tolbutamide, glibenclamide, glipizide, glimepiride, repaglinide, nateglinide, mitiglinide, exenatide, liraglutide, taspoglutide albiglutide, lixisenatide, alogliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin and the like.

The compounds of Formula 1 can be prepared as illustrated by the accompanying working examples. The following examples are set forth to illustrate the synthesis and biological activity of some particular compounds of the present invention and to exemplify general processes. Accordingly, the following Examples section is in no way intended to limit the scope of the invention contemplated herein.

Examples

The following terms/abbreviations are employed in the preparation of intermediates and Examples:

L : Litre vol : Volumes

mL : Millilitre RT : Room Temperature (25±5 °C) μΕ : Microlitre co _{2 :} Carbon dioxide

g : Gram P0C1 ₃ : Phosphorous oxychloride;

mg : Milligram DCM : Dichloromethane

: Microgram DMF : Dimethylformamide

ng : Nanogram DMSO : Dimethyl sulfoxide

mol : Molar Rh-C : Rhodium on carbon

mM : Millimolar THF : Tetrahydrofuran

μΜ : Micromolar EtOAc : Ethyl acetate

nM : Nanomolar HC1 : Hydrochloric acid

w/v : Weight by volume HBr : Hydrobromic acid

v/v : Volume by volume Cs ₂ C0 ₃ : Cesium carbonate

h : Hours NaOH : Sodium hydroxide

min : Minutes Na ₂ S0 ₄ : Sodium sulphate

mmol : Millimole POCI3 : Phosphorous oxychloride

CPM : Counts per minute SnCl ₂ : Stannous chloride

N : Normal Pd-C : Palladium on carbon

Fe : Iron Pt-C : Platinum on carbon

Preparation of intermediates and general procedures:

(A) Preparation of nitro compounds of formula (a)

The intermediates of formula (a) are either commercially available or were prepared by procedures known in the literature, but are not limited to:

(i) 2-Chloro-3-methyl-5-nitropyridine (Sigma Aldrich, India);

(ii) 2-Chloro-3-trifluoromethyl-5-nitropyridine (Sigma Aldrich, India); (iii) 2,3-Dichloro-5-nitropyridine;

(iv) 2-Chloro-5-nitronicotinonitrile;

(v) 2-Chloro-6-methyl-5-nitronicotinonitrile; and

(vi) 2-Chloro-4,6-dimethyl-5-nitronicotinonitrile.

(iii) Synthesis of 2,3-dichloro-5-nitropyridine

Step a: Synthesis of 2-hydroxy-3-chloro-5-nitropyridine

2-Hydroxy-5-nitropyridine (lg, 7.14 mmol) was added portion wise to concentrated HCl (4.5 mL) under constant stirring and was then heated to 50 °C. To this, a solution of sodium chlorate (266 mg, 2.5 mmol) in water (4 mL) was added. The reaction was maintained at the same temperature for 1 h, and then was cooled to 0 °C. The precipitate obtained was filtered, washed with water and dried to obtain 2-hydroxy-3-chloro-5- nitropyridine. Yield: 68.2 %; *H NMR (DMSO-d ₆ ): δ 13.21 (bs, 1H), 8.66 (d, J=2.7Hz, 1H), 8.39 (d, J=2.7Hz, 1H).

Step b: Synthesis of 2,3-dichloro-5-nitropyridine

Quinoline (0.3 mL, 2.34 mmol) was added to POCl ₃ (0.5 mL 4.68 mmol) at 0 °C under nitrogen. To this stirred mixture was added 2-hydroxy-3-chloro-5-nitropyridine (816 mg, 4.68 mmol) obtained in step a. The reaction mixture was heated at 120 °C for 2 h, and was cooled to 0 °C followed by addition of ice-cold water. The precipitate obtained was filtered, washed with water and dried to obtain 2,3-dichloro-5-nitropyridine. Yield: 70.3 %; *H NMR (DMSO-d ₆ ): δ 9.16 (d, J=1.8HZ, 1H), 8.60 (d, J=1.8Hz, 1H); MS (ES): m/z 193 (M+l).

(iv) Synthesis of 2-chloro-5-nitronicotinonitrile

Step a: Synthesis of 2-hydroxy-nicotinonitrile

Acetic acid (826 mL) was added to 2-chloronicotinonitrile (250 g) and mixture was refluxed for 48 h. The reaction mass was poured in ice-water mixture. The precipitate obtained was filtered washed with water and dried to obtain 2-hydroxy-nicotinonitrile. Yield: 95 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 12.57 (s, 1H), 8.16 (dd, J=3, 6Hz, 1H), 7.80 (dd, J=3, 6Hz, 1H), 6.37 (t, 1H); MS (ES): m/z 121.

Step b: Synthesis of 2-hydroxy-5-nitronicotinonitrile

2-Hydroxy-nicotinonitrile (160 g, 1.33 mol) was dissolved in sulfuric acid (10 volumes) and reaction mixture was cooled to 0 °C in ice bath with stirring. Nitric acid (3 volumes) was added very slowly using dropping funnel. During the addition, temperature was maintained at 0-5 °C. After 2 h of stirring, reaction mixture was poured into crushed ice and water mixture and stirred. Nitro compound was precipitated out, which was filtered and dried to obtain 2-hydroxy-5-nitronicotinonitrile. Yield: 63 %; H NMR (300 MHz, DMSO-d ₆ ): δ 11.34 (bs, 1H), 9.01 (m, J= 3HZ, 1H), 8.71 (m, J= 3 HZ, 1H); MS (ES): m/z 165.

Step c: Synthesis of 2-chloro-5- nitronicotinonitrile

2-Hydroxy-5-nitronicotinonitrile (0.30 mol) was added to a mixture of POCI ₃ (0.45 mol) and quinoline (0.15 mol) at 0 °C. Resultant mixture was heated at 110 °C for 2 h. Water (25 mL) was added and reaction mixture was poured into ice (9 volumes) and extracted with ethyl acetate. Organic layer was separated, dried over Na ₂ S0 ₄ and was concentrated to obtain 2-chloro-5-nitronicotinonitrile. Yield: 79 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.43 (d, J=3Hz, 1H), 8.81 (d, J=3Hz, 1H); MS (ES): m/z 183.5.

(v) Synthesis of 2-chloro-6-methyl-5-nitronicotinonitrile

(Reference: WO2008/101682 A2)

Step a: Synthesis of 2-hydroxy-6-methyl-5-nitronicotinonitrile

Concentrated sulphuric acid (75 mL) was cooled in an ice bath. To it compound, 6- methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (10 g) was added under stirring. To this mixture, mixed acid reagent (freshly prepared from 5.0 mL of concentrated sulphuric acid and 3.4 mL of fuming nitric acid) was added drop-wise over a period of 10 min. Reaction mixture was stirred further for 4 h. The mixture was poured into ice-water mixture. The precipitate obtained was filtrated, washed with water and dried. The precipitate was purified by column chromatography to obtain 6-methyl-5-nitro-2-oxo-l,2-dihydropyridine-3- carbonitrile. Yield: 45 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 12.11 (s, 1H), 6.85 (s, 1H), 2.14 (s, 3H); MS (ES): m/z 180.1 (M+l).

Step b: Synthesis of 2-chloro-6-methyl-5-nitronicotinonitrile

Phosphorus oxychloride (64 mL, 689 mmol) was added to 6-dimethyl-5-nitro-2-oxo- l,2-dihydropyridine-3-carbonitrile (19.5 g, 107 mmol). To this mixture, phosphorus pentachloride (20.81 g, 100 mmol) was added and reaction mixture was heated to 100 °C for 20 h. Reaction mixture was cooled and poured in ice-water mixture. The precipitate obtained was filtered washed with water and dried to obtain 2-chloro-6-methyl-5-nitronicotinonitrile. Yield: 80 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.45 (s, 1H), 2.77 (s, 3H); MS (ES): m z 198.1 (M+l). (vi) Synthesis of 2-chloro-4,6-dimethyl-5-nitronicotinonitrile

Step a: Synthesis of 4,6-dimethyl-5-nitro-2-oxo-l,2-dihydropyridine-3-carbonitril e

Concentrated sulphuric acid (75 mL) was cooled in an ice bath. To it compound, 4,6- dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (10 g) was added under stirring. To this mixture, mixed acid reagent (freshly prepared from 5.0 mL of concentrated sulphuric acid and 3.4 mL of fuming nitric acid) was added drop-wise over a period of 10 min. Reaction mixture was stirred further for 4 h. The mixture was poured into ice-water mixture. The precipitate obtained was filtrated, washed with water and dried. The precipitate was purified by column chromatography to obtain 4,6-dimethyl-5-nitro-2-oxo-l,2-dihydropyridine-3- carbonitrile. Yield: 46 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 12.31 (s, 1H), 2.40(s, 3H), 2.36 (s, 3H); MS (ES): m/z 193.1.

Step b: Synthesis of 2-chloro-4,6-dimethyl-5-nitronicotinonitrile

Phosphorus oxychloride (64 mL, 689 mmol) was added to 4,6-dimethyl-5-nitro-2- oxo-l,2-dihydropyridine-3-carbonitrile (19.3 g, 100 mmol). To this mixture, phosphorus pentachloride (20.81 g, 100 mmol) was added and reaction mixture was heated to 100 °C for 20 h. Reaction mixture was cooled and poured in ice-water mixture. The precipitate obtained was filtered washed with water and dried to obtain 2-chloro-4,6-dimethyl-5- nitronicotinonitrile. Yield: 80 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 2.61 (s, 3H), 2.56 (s, 3H); MS (ES): m/z 211.6.

(B) Amino compounds of formula (b)

The intermediates of formula (b) are commercially available (Sigma Aldrich, India), but are not limited to:

(vii) 4-Phenyl-piperidine-4-carbonitrile;

(viii) 4-Phenyl-piperidin-4-ol;

(ix) 4-(4-Chloro-phenyl)-piperidin-4-ol;

(x) 4-(4-Chloro-3-trifluoromethyl -phenyl)-piperidin-4-ol;

(xi) 1 -Cyclohexyl-piperazine;

(xii) 1 -Phenyl-piperazine ;

(xiii) l-(3-Chloro-phenyl)-piperazine;

(xiv) l-(3-Trifluoromethyl-phenyl)-piperazine;

(XV) 1 -(3 -Methoxy-phenyl)-piperazine ;

(xvi) 1 -(4-Methoxy-phenyl)-piperazine ; (xvii) l-(2,4-Dimethoxy-phenyl)-piperazine;

(xviii) 1 -Pyridin-2-yl-piperazine ;

(xix) l-(4-Trifluoromethyl-pyridin-2-yl)-piperazine;

(XX) 4-(6-Piperazin-l-yl-4-triίluoromethyl-pyridin-2-yl)-mo holine;

(xxi) 2-Piperazin- 1 -yl-pyrimidine ;

(xxii) 1 -(5-Trifluoromethyl-pyridin-2-yl)- [ 1 ,4] diazepane ;

(xxiii) l-(4-Trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane;

(xxiv) 3 -Methyl-3 , 8-diaza-bicyclo[3.2.1 ] octane;

(xxv) Piperazine-l-carboxylic acid ethyl ester;

(xxvi) tert-Butyl (3-oxo-3-(piperazin- l-yl)propyl)carbamate;

(xxvii) Cyclohexyl(piperazin- 1 -yl)methanone;

(xxviii) Piperazine- 1 -yl-(2-trifluoromethyl-phenyl)-methanone ; and

(xxix) 4-(2-Trifluoromethyl-phenoxy)-piperidine. (C) General procedure to prepare nitro compounds of formula (c)

The intermediate of formula (c) was obtained by reacting intermediate of formula (a), with substituted amine of formula (b), as follows:

A substituted amine (compound of formula (b); 1 mmol), was dissoved in dimethylformamide (10 mL). To it, cesium carbonate (1 mmol) was added at room temperature (25 °C). After 30 min, the nitro compound (compound of formula (a); 1 mmol), was added and the stirring was continued further for 18 h. Reaction mixture was concentrated and diluted with water (20 mL). Reaction mixture was extracted with ethyl acetate, dried over sodium sulfate and was concentrated to obtain crude product which was purified by column chromatography (silica gel, ethyl acetate in pet ether) to obtain the nitro compound of formula (c).

(D) General procedure to prepare amino compounds of formula (d)

The intermediate of formula (d) was obtained by reducing the compound of formula (c) as follows:

The compound of formula (c) (1 mmol) was dissolved in ethyl acetate (50 mL) and stannous chloride dihydrate (4 mmol) was added at room temperature (25 °C) and stirring was continued for 18 h. Solvent was removed and chloroform (50 mL) was added. 1 N NaOH solution was added until a clear solution was obtained. Organic layer was separated and reaction mixture was extracted with chloroform. The chloroform layer was washed with brine and water, dried over sodium sulfate and was concentrated to obtain crude product that was further purified by column chromatography (silica gel, methanol in chloroform) to obtain the title compound of formula (d).

Representative compounds of formula (d) prepared by using these procedures (C) and (D), include but are not limited to:

l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbon itrile;

5-Amino-2-(4-cyano-4-phenylpiperidin-l-yl)-4,6-dimethylnicot inonitrile; 5-Amino-2-(4- hydroxy-4-phenylpiperidin- 1 -yl)nicotinonitrile ;

5-Amino-2-(4-hydroxy-4-phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile; 5-Amino-2- (4- (4-chlorophenyl) -4-hydroxypiperidin- 1 -yl)nicotinonitrile ;

5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethylnicotinonitrile; 5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l- yl)nicotinonitrile ;

5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l-yl)-4,6- dimethylnicotinonitrile;

l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidin-4-ol;

l-(5-Amino-3-chloropyridin-2-yl)-4-(4-chloro-3-(trifluoromet hyl)phenyl)piperidin-4-ol; 5-Amino-2-(4-cyclohexylpiperazin- 1 -yl)nicotinonitrile;

5- Chloro-6-(4-phenylpiperazin-l-yl)pyridin-3-amine;

5-Amino-2-(4-(3-(trifluoromethyl)phenyl)piperazin-l-yl)nicot inonitrile;

5 - Amino-2- (4-(3 -chlorophenyl)piperazin- 1 -yl) -4,6 -dimethylnicotinonitrile ;

6- (4-(3-Chlorophenyl)piperazin-l-yl)-5-methylpyridin-3-amine;

5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e;

5-Amino-2-(4-(4-methoxyphenyl)piperazin- 1 -yl)nicotinonitrile;

5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile;

5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin-3- amine;

5- Chloro-6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-amine;

6- (4-(Pyridin-2-yl)piperazin-l-yl)-5-(trifluoromethyl)pyridin- 3-amine;

5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyridin-2-yl)p iperazin-l- yl)nicotinonitrile;

5-Amino-4,6-dimethyl-2-(4-(6-mo holino-4-(trifluoromethyl)pyridin-2-yl) piperazin- 1 - yl)nicotinonitrile ;

5-Chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-amine ;

5-Amino-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotinonitrile; 5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotin onitrile^

5-Amino-4,6-dimethyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile ;

5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile;

5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan -l-yl)pyridin-3-amine; 5-Amino-4,6-dimethyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)- l,4-diazepan-l- yl)nicotinonitrile ;

5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )-l,4-diazepan-l- yl)nicotinonitrile ;

5-Chloro-6-(4-(4-(trifluoromethyl)pyrim

5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile;

5-Amino-4,6-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]o ctan-8-yl)nicotinonitrile;

5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)nic otinonitrile;

5- Amino-2-(4-phenylpiperazin- 1 -yl)nicotinonitrile ;

5- Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin- 1 -yl)nicotinonitrile;

Ethyl 4-(5-amino-3-cyanopyridin-2-yl)piperazine-l-carboxylate;

teri-Butyl-(3-(4-(5-amino-3-cyanopyridin-2-yl)piperazin-l-yl )-3-oxopropyl)carbamate; 5-Amino-2-(4-(cyclohexanecarbonyl)piperazin-l-yl)nicotinonit rile;

5-Amino-4,6-dimethyl-2-(4-(2-(trifluoromethyl)benzoyl)pipera zin-l-yl)nicotinonitrile; (4-(5-Amino-3-chloropyridin-2-yl)piperazin- 1 -yl)(2-(trifluoromethyl)phenyl) methanone; 5-Amino-2-(4-(2-(trifluoromethyl)benzoyl)piperazin-l-yl)nico tinonitrile;

5-Amino-4,6-dimethyl-2-(4-(2-(trifluoromethyl)phenoxy)piperi din-l-yl)nicotinonitrile; and 5- Amino-2-(4-(2-(trifluoromethyl)phenoxy)piperidin- 1 -yl)nicotinonitrile; (E) General procedure to prepare compounds of formula (e)

(corresponds to compounds of Formula 1, wherein, R5 is S(0)2 ?),

To a stirred solution of amine (compound of formula (d), 1 mmol) in dichlorome thane, pyridine (0.5-2 mmol) was added which was followed by addition of optionally substituted benzenesulfonylchloride (1 mmol) or optionally substituted quinolinesulfonylchloride (1 mmol). The reaction mixture was stirred at room temperature (25 °C). After completion of the reaction, reaction mixture was diluted using dichlorome thane, washed with water, dried over sodium sulfate and was concentrated. The crude product was purified using column chromatography (silica gel) to obtain the desired compound of formula (e). The compounds of examples 1-56, 57-97, 98-119 and 120-167, 168-171 and 178-186 were prepared by this procedure.

It is to be noted that the substituted benzenesulfonylchlorides used herein are commercially available (Sigma Aldrich, India) .

(F) General procedure for preparation of compounds of formula (f)

(corresponds to compounds of Formula 1, wherein R5 is C(0)NHR ₇ )

To a stirred solution of amine (compound of formula (d), 1 mmol) in tetrahydrofuran (10-20 mL), optionally substituted isocynatobenzene (1 mmol) was added. The reaction mixture was stirred at room temperature (25 °C). After completion of reaction, THF was removed and reaction mixture was diluted with water (20 mL). The precipitate obtained was filtered off and washed with pet-ether followed by ethyl acetate and acetone. The precipitate was dried to obtain the desired compound of formula (f).

The compounds of examples 172-177 were prepared by this procedure.

It is to be noted that the substituted isocynatobenzenes used herein are commercially available (Sigma Aldrich, India) .

Example 1

N-(5-Chloro-6-(4-cyano-4-phenylpiperidin-l-yl)pyridin-3-yl)- 4-isopropylbenzene sulfonamide

Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbon itrile was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-phenyl-piperidine-4-carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbon itrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.67 (d, J=2.4Hz, IH), 7.59 (m, 2H), 7.49 (m, 2H), 7.38 (m, IH), 7.08 (d, J=2.4Hz, IH), 5.24 (s, 2H), 3.48 (m, 4H), 3.07 (m, 4H); MS (ES): m/z 312.11.

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-phenylpiperidine-4-carbonitrile with 4-isopropylbenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.75 (s, IH), 7.94 (d, J=2.4Hz, IH), 7.65 (d, J=8.4Hz, 2H), 7.43 (d, J=2.1Hz, IH), 7.36 (t, J=7.2HZ, IH), 7.54 (d, J=7.2Hz, 2H), 7.42 (d, J=4.2Hz, 2H), 7.44 (d, J=1.8Hz, IH), 7.46 (t, J=4.2Hz, IH), 3.7 (m, 2H), 3.4 (m, 2H), 3.1 (m, IH), 3.0 (m, 2H), 2.2 (m, 2H), 1.9 (m, 6H); MS (ES): m/z 496.0. Example 2

N-(5-Cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2,4-dim

methyl) benzenesulfonamide

Step 1 : 5-Amino-2-(4-cyano-4-phenylpiperidin-l-yl)-4,6-dimethylnicot inonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl-piperidine-4- carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-cyano-4- phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 3-(trifluoromethyl)benzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.93 (s, 1H), 8.13 (d, J=8.7Hz, 1H), 8.02 (d, J=8.4Hz, 1H), 7.90 (m, 2H), 7.58 (m, 2H), 7.49 (m, 2H), 7.41 (m, 1H), 4.36 (d, J=14.1Hz, 2H), 3.28 (m, 2H), 2.28 (d, J=14.7Hz, 2H), 2.18 (m, 2H), 2.08 (s, 3H), 1.99 (s, 3H); MS (ES): m/z 540.2 (M+l).

Example 3

N-(5-Chloro-6-(4-cyano-4-phenylpiperidin-l-yl)pyridin-3-yl)- 4-(trifluoromethyl) benzene sulfonamide

Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbon itrile was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-phenyl-piperidine-4-carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

l-(5-Aamino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbo nitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.67 (d, J=2.4Hz, 1H), 7.59 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 7.08 (d, J=2.4Hz, 1H), 5.24 (s, 2H), 3.48 (m, 4H), 3.07 (m, 4H); MS (ES): m/z 312.11.

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-phenylpiperidine-4-carbonitrile with 4-(trifluoromethyl)benzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, 1H), 7.98 (dd, J=8.4, 3.6Hz, 2H), 7.94 (dd, J=6.9, 1.8Hz, 2H), 7.92 (d, J=1.8Hz, 1H), 7.55 (d, J=7.2Hz, 2H), 7.52 (d, J=6.9Hz, 1H), 7.45 (t, J=7.8Hz, 2H), 7.36 (t, J=6.6Hz, 1H), 3.52 (m, 2H), 3.01 (m, 2H), 2.10 (m, 2H), 2.20 (m, 2H); MS (ES): m/z 522. Example 4

N-(5-Cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2,4-dimethylpy ridin-3-yl)-2,4- diiluorobenzene sulfonamide

Step 1 : 5-Amino-2-(4-cyano-4-phenylpiperidin-l-yl)-4,6-dimethylnicot inonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl-piperidine-4- carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-cyano-4- phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 2,4-difluorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.12 (s, 1H), 7.79 (m, 1H), 7.67 (m, 1H), 7.58 (m, 2H), 7.49 (m, 2H), 7.41 (m, 1H), 7.30 (m, 1H), 4.37 (d, J=13.2Hz, 2H), 3.27 (m, 2H), 2.32 (d, J=13.2Hz, 2H), 2.18 (s, 3H), 2.13 (s, 3H), 2.06 (m, 2H); MS (ES): m/z 508.0 (M+l).

Example 5

3-Chloro-N-(5-chloro-6-(4-cyano-4-phenylpiperidin-l-yl)pyrid in-3-yl)-4-fluorobenzene sulfonamide

Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbon itrile was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-phenyl-piperidine-4-carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbon itrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.67 (d, J=2.4Hz, 1H), 7.59 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 7.08 (d, J=2.4Hz, 1H), 5.24 (s, 2H), 3.48 (m, 4H), 3.07 (m, 4H); MS (ES): m/z 312.11.

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-phenylpiperidine-4-carbonitrile with 3-chloro-4-fluorobenzene-l -sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.79 (s, 1H), 7.93 (d, J=2.4Hz, 1H), 7.92 (d, J=7.5Hz, 1H), 7.72 (d, J=2.4Hz, 1H), 7.62 (m, J=9.0Hz, 1H), 7.54 (d, J=5.1Hz, 2H), 7.52 (dd, J=5.0, 5.1Hz, 1H), 7.43 (t, J=7.8Hz, 2H), 7.33 (d, J=7.2Hz, 1H), 3.57 (m, 2H), 3.00 (m, 2H), 2.10 (m, 2H), 2.20 (m, 2H); MS (ES): m/z 505.3 (M+l). Example 6

2- Chloro-N-(5-cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2,4-dim ethylpyridin- benzenesulfonamide

Step 1 : 5-Amino-2-(4-cyano-4-phenylpiperidin-l-y^ was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl-piperidine-4- carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-cyano-4- phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 2-chloro-4-fluorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.00 (s, 1H), 7.89 (dd, J=8.7, 6.0Hz, 1H), 7.82 (dd, J=8.7, 2.4Hz, 1H), 7.57 (m, 2H), 7.49 (m, 2H), 7.44 (m, 2H), 4.37 (d, J=13.2Hz, 2H), 3.27 (m, 2H), 2.32 (d, J=13.5Hz, 2H), 2.16 (s, 3H), 2.13 (m, 2H), 2.10 (s, 3H); MS (ES): m/z 524.1 (M+l).

Example 7

3- Chloro-N-(5-cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2,4-dim ethylpyridin-3-yl)-4-fluoro benzenesulfonamide

Step 1 : 5-Amino-2-(4-cyano-4-phenylpiperidin-l-yl)-4,6-dimethylnicot inonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl-piperidine-4- carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-cyano-4- phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 3-chloro-4-fluorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.88 (s, 1H), 7.87 (m, 1H), 7.69-7.63 (m, 2H), 7.58 (m, 2H), 7.49-7.44 (m, 2H), 7.41 (m, 1H), 4.36 (d, J=13.2Hz, 2H), 3.42 (m, 2H), 2.32 (d, J=12.9Hz, 2H), 2.14 (s, 3H), 2.11 (m, 2H), 2.04 (s, 3H); MS (ES): m/z 524.1 (M+l). Example 8

2,4-Dichloro-N-(5-chloro-6-(4-cyano-4-phenylpiperidin-l-yl)p yridin-3-yl)benzene sulfonamide Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbon itrile was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-phenyl-piperidine-4-carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbon itrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.67 (d, J=2.4Hz, IH), 7.59 (m, 2H), 7.49 (m, 2H), 7.38 (m, IH), 7.08 (d, J=2.4Hz, IH), 5.24 (s, 2H), 3.48 (m, 4H), 3.07 (m, 4H); MS (ES): m/z 312.11.

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-phenylpiperidine-4-carbonitrile with 2,4-dichlorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield; 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 8.02 (d, J=8.7Hz, IH), 8.01 (d, J=1.8Hz, IH), 7.89 (d, J=21.5Hz, IH), 7.62 (dd, J=1.5, 7.8Hz, IH), 7.58 (d, J=1.8Hz, IH), 7.52 (d, J=7.8Hz, 2H), 7.43 (t, J=7.8Hz, 2H), 7.34 (t, J=7.2Hz, IH), 3.57 (m, 2H), 3.00 (m, 2H), 2.10 (m, 2H), 2.20 (m, 2H); MS (ES): m/z 521.0 (M+l).

Example 9

2,4-dichloro-N-(5-cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2 ,4-dimethylpyridin-3-yl) benzene sulfonamide

Step 1 : 5-Amino-2-(4-cyano-4-phenylpiperidin-l-yl)-4,6-dimethylnicot inonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl-piperidine-4- carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-cyano-4- phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 2,4-dichlorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.06 (s, IH), 7.97 (d, J=1.8Hz, IH), 7.83 (d, J=8.4Hz, IH), 7.63 (dd, J=8.7, 1.8Hz, IH), 7.57 (m, 2H), 7.49 (t, J=8.1Hz, 2H), 7.41 (m, IH), 4.37 (d, J=10.2Hz, 2H), 3.27 (m, 2H), 2.32 (d, J=13.2Hz, 2H), 2.17 (s, 3H), 2.13 (m, 2H), 2.10 (s, 3H); MS (ES): m/z 540.1 (M+l).

Example 10

N-(5-Chloro-6-(4-cyano-4-phenylpiperidin-l-yl)pyridin-3-yl)- 2,4-dimethoxy-benzene sulfonamide Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbon itrile was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-phenyl-piperidine-4-carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbon itrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.67 (d, J=2.4Hz, IH), 7.59 (m, 2H), 7.49 (m, 2H), 7.38 (m, IH), 7.08 (d, J=2.4Hz, IH), 5.24 (s, 2H), 3.48 (m, 4H), 3.07 (m, 4H); MS (ES): m/z 312.11.

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-phenylpiperidine-4-carbonitrile with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 73 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.84 (s, IH), 7.92 (d, J=2.1Hz, IH), 7.58 (d, J=7.5, 2.1Hz, 2H), 7.5 (d, J=2.1Hz, IH), 7.44 (t, J=7.5Hz, 2H), 7.39 (t, J=7.2Hz, IH), 7.30 (dd, J=8.4, 1.8Hz, IH), 7.2 (d, J=1.5Hz, IH), 7.09 (d, J=8.4Hz, IH), 3.72 (m, 2H), 3.10 (m, 2H), 2.3 (m, 2H), 2.1 (m, 2H); MS (ES): m/z 513.0 (M+l).

Example 11

N-(5-Cyano-6-(4-cyano-4-phenylpiperidin-l-yl)-2,4-dimethylpy ridin-3-yl)-3,4-dimethoxy benzenesulfonamide

Step 1 : 5-Amino-2-(4-cyano-4-phenylpiperidin-l-yl)-4,6-dimethylnicot inonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl-piperidine-4- carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-cyano-4- phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 3,4-dimethoxybenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.48 (s, IH), 7.58 (m, 2H), 7.49 (t, J=10.2Hz, 2H), 7.41 (m, IH), 7.26 (dd, J=8.4, 2.1Hz, IH), 7.13 (m, 2H), 4.33 (d, J=13.2Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.26 (m, 2H), 2.33 (d, J=14.1Hz, 2H), 2.13 (s, 3H), 2.10 (m, 2H), 2.01 (s, 3H); MS (ES): m/z 532.2 (M+l).

Example 12

N-(5-Chloro-6-(4-cyano-4-phenylpiperidin-l-yl)pyridin-3-yl)q uinoline-8-sulfonamide Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-phenyl-piperidine-4-carbo nitrile was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-phenyl-piperidine-4-carbonitrile by procedure as described in (C) and further reduction by procedure described in (D).

l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidine-4-carbon itrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.67 (d, J=2.4Hz, 1H), 7.59 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 7.08 (d, J=2.4Hz, 1H), 5.24 (s, 2H), 3.48 (m, 4H), 3.07 (m, 4H); MS (ES): m/z 312.11.

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-phenylpiperidine-4-carbonitrile with quinoline-8-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.82 (s, 1H), 9.1 (d, J=2.1Hz, 1H), 8.5 (d, J=6.9Hz, 1H), 8.35 (d, J=7.2Hz, 1H), 8.30 (d, J=8.1Hz, 1H), 7.9 (d, J=2.1Hz, 1H), 7.7 (t, J=5.4Hz, 2H), 7.5 (m, 3H), 7.4 (t, J=7.2Hz, 2H), 7.3 (t, 7.2Hz, 1H), 3.52 (m, 2H), 3.01 (m, 2H), 2.10 (m, 2H), 2.20 (m, 2H); MS (ES): m/z 504.0 (M+l).

Example 13

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyano-2, 4-dimethylpyridin-3-yl)-2-

(trifluoromethyl)benzenesulfonamide

Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethyl nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-

(4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethylnicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.54 (d, J= 8.4Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 5.10 (s, 1H), 4.78(s, 2H), 3.48 (m, 2H), 3.34 (m, 2H), 2.31 (s, 6H), 2.09 (m, 2H), 1.70 (m, 2H); MS

(ES): m z 356.85.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 2-(trifluoromethyl)benzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.09 (s, 1H), 8.00 (m, 2H), 7.78 (m, 2H), 7.48 (d, J=8.7Hz, 2H), 7.35 (d, J=8.7Hz, 2H), 6.17 (s, 1H), 4.35 (d, J=13.5Hz, 2H), 3.54 (t, J=12.0Hz, 2H), 2.22 (s, 3H), 2.19 (m, 2H), 2.11 (s, 3H), 1.88 (d, J=12.9 Hz, 2H); MS (ES): m/z 565.1 (M+l). Example 14

3,4-Dichloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidm^

pyridin-3-yl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethylnico tinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-(4- chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethylnicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 7.54 (d, J= 8.4Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 5.10 (s, 1H), 4.78(s, 2H), 3.48 (m, 2H), 3.34 (m, 2H), 2.31 (s, 6H), 2.09 (m, 2H), 1.70 (m, 2H); MS (ES): m/z 356.85.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 3 ,4-dichlorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.11 (s, 1H), 7.89 (m, 1H), 7.65 (m, 2H), 7.48 (d, J=8.7Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 6.06 (s, 1H), 4.38 (d, J=13.5Hz, 2H), 3.54 (t, J=12.6Hz, 2H), 2.29 (s, 3H), 2.23 (m, 2H), 2.19 (s, 3H), 1.88 (d, J=13.2 Hz, 2H); MS (ES): m/z 565.1 (M+l). Example 15

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)-2,4-dimethyl pyridin-3-yl)-2-(trifluoro methyl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl- piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 7.58 (m, 2H), 7.41(m, 2H), 7.31 (m, 1H), 4.15 (m, 4H), 3.8 (m, 4H), 2.41 (s, 3H), 2.36 (s, 3H); MS (ES): m/z 322.18.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 2-(trifluoromethyl)benzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 68 %; H NMR (300 MHz, DMSO-d ₆ ): δ 10.11 (s, 1H), 8.0 (t, J=5.7Hz, 2H), 7.80 (m, 2H), 7.54 (d, J=7.8Hz, 2H), 7.42 (d, J=7.2Hz, 2H), 7.33 (d, J=7.2Hz, 1H), 6.15 (s, 1H), 4.36 (d, J=13.2Hz, 2H), 3.58 (t, J=12.9Hz, 2H), 2.22 (s, 3H), 2.19 (m, 2H), 2.10 (s, 3H), 1.92 (d, J=12.6Hz, 2H); MS (ES): m/z 531.2 (M+l).

Example 16

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)-2,4-dimet hylpyridin-3-yl)-3-(trifluo methyl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl- piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 7.58 (m, 2H), 7.41(m, 2H), 7.31 (m, 1H), 4.15 (m, 4H), 3.8 (m, 4H), 2.41 (s, 3H), 2.36 (s, 3H); MS (ES): m/z 322.18.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin- l-yl)-4,6-dimethylnicotinonitrile with 3-(trifluoromethyl)benzene-l -sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.11 (s, 1H), 8.02 (m, 1H), 8.0 (d, J=8.1Hz, 1H), 7.93 (d, J=7.8Hz, 1H), 7.73 (t, J=7.8Hz, 1H), 7.55 (d, J=7.8Hz, 2H), 7.43 (t, J=7.2Hz, 2H), 7.33 (d, J=7.2Hz, 1H), 4.39 (d, J=13.2Hz, 2H), 3.60 (t, J=12.6Hz, 2H), 2.27 (m, 2H), 2.22 (s, 3H), 2.09 (s, 3H), 1.93 (d, J=12.9Hz, 2H); MS (ES): m/z 531.1 (M+l).

Example 17

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyano-2, 4-dimethylpyridin-3-yl)-3-

(trifluoromethyl)benzenesulfonamide

Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethyl nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-

(4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethylnicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 7.54 (d, J= 8.4Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 5.10 (s,

1H), 4.78(s, 2H), 3.48 (m, 2H), 3.34 (m, 2H), 2.31 (s, 6H), 2.09 (m, 2H), 1.70 (m, 2H); MS

(ES): m z 356.85. Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 3-(trifluoromethyl)benzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.12 (s, IH), 8.01 (m, 2H), 7.93 (d, J=7.8Hz, IH), 7.74 (t, J=7.8Hz, IH), 7.49 (m, 2H), 7.37 (m, 2H), 6.04 (s, IH), 4.38 (d, J=13.3Hz, 2H), 3.57 (t, J=12.3Hz, 2H), 2.23 (s, 3H), 2.19 (m, 2H), 2.09 (s, 3H), 1.89 (d, J=12.9Hz, 2H); MS (ES): m/z 565.1 (M+l).

Example 18

2-Chloro-N-(5-cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)- 2,4-dimethylpyridin-3-yl)-4- (trifluoromethyl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl- piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 7.58 (m, 2H), 7.41(m, 2H), 7.31 (m, IH), 4.15 (m, 4H), 3.8 (m, 4H), 2.41 (s, 3H), 2.36 (s, 3H); MS (ES): m/z 322.18.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin-l-yl)-4,6-dimethylnicotinonitrile with 2-chloro-4-(trifluoromethyl)benzene-

1 - sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.11 (s, IH), 8.10 (d, J=8.1Hz, IH), 7.88 (m, IH), 7.71 (d, J=8.4Hz, IH), 7.54 (d, J=7.5Hz, 2H), 7.42 (t, J=7.2Hz, 2H), 7.33 (d, J=7.2Hz IH), 6.50 (s, IH), 4.37 (d, J=13.2Hz, 2H), 3.58 (t, J=12.3Hz, 2H), 2.30 (s, 3H), 2.25 (m, 2H), 2.18 (s, 3H), 1.92 (d, J=12.6Hz, 2H); MS (ES): m/z 565.1 (M+l).

Example 19

2- Chloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-5-c yano-2,4-dimethylpyridin-3- yl)-4-(trifluoromethyl)benzenesulfonamide

Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethyl nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4- (4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethylnicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 7.54 (d, J= 8.4Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 5.10 (s, IH), 4.78(s, 2H), 3.48 (m, 2H), 3.34 (m, 2H), 2.31 (s, 6H), 2.09 (m, 2H), 1.70 (m, 2H); MS (ES): m/z 356.85.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin-l-yl)-4,6-dimethylnicotinonitrile with 2-chloro-4-

(trifluoromethyl)benzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.12 (s, IH), 8.10 (d, J=8.4Hz, IH), 7.89 (s, IH), 7.71 (d, J=8.4Hz, IH), 7.47 (d, J=8.4Hz, 2H), 7.37 (d, J=8.7Hz, 2H), 6.50 (s, IH), 4.36 (d, J=13.2Hz, 2H), 3.55 (t, J=12.0Hz, IH), 2.30 (s, 3H), 2.22 (m, 2H), 2.19 (s, 3H), 1.88 (d, J=13.2Hz, 2H); MS (ES): m/z 599.1 (M+l).

Example 20

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)pyridin-3-yl) -2,4-dilluorobenzene sulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-phenyl-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin-l-yl)nicotinonitrile with 2,4-difluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.59 (s, IH), 8.08 (d, J=2.7Hz, IH), 7.89 (m, IH), 7.67 (d, J=2.7Hz, IH), 7.62 (m, IH), 7.49 (m, 2H), 7.35 (m, 2H), 7.27 (m, 2H), 5.15 (s, IH), 4.10 (d, J=12.9Hz, 2H), 3.44 (d J=12.3Hz, 2H), 2.03 (dt, J=12.6, 4.2Hz, 2H), 1.71 (d, J=12.9Hz, 2H); MS (ES): m/z 471.12 (M+l).

Example 21

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyanopyr idin-3-yl)-2,4-difluoro benzenesulfonamide

Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)nicoti nonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D). Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin-l-yl)nicotinonitrile with 2,4-difluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.59 (s, 1H), 8.09 (d, J=2.7Hz, 1H), 7.89 (m, 1H), 7.68 (d, J=2.7Hz, 1H), 7.62 (m, 1H), 7.50 (m, 2H), 7.38 (m, 2H), 7.30 (m, 1H), 5.3 (s, 1H), 4.11 (m, 2H), 3.43 (m, 2H), 1.96 (m, 2H), 1.70 (m, 2H); MS (ES): m/z 505.1 (M+l).

Example 22

N-(5-Chloro-6-(4-hydroxy-4-phenylpiperidin-l-yl)pyridin-3-yl )-2,4-difluorobenzene sulfonamide

Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidin-4-ol was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-phenyl-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-phenylpiperidin-4-ol with 2,4-difluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.70 (s, 1H), .7.93 (d, J=2.4Hz, 1H), 7.90 (m, 1H), 7.62 (m, 1H), 7.49 (m, 3H), 7.35 (m, 3H), 7.25 (m, 1H), 5.02 (s, 1H), 3.52 (d, J=12.0Hz, 2H), 3.23 (t, J=12.3Hz, 2H), 2.05 (m, 2H), 1.69 (d, J=12.9Hz, 2H); MS (ES): m/z 479.9 (M+l).

Example 23

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)-2,4-dimethyl pyridin-3-yl)-2,4-difluoro benzenesulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl- piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 7.58 (m, 2H), 7.41(m, 2H), 7.31 (m, 1H), 4.15 (m, 4H), 3.8 (m, 4H), 2.41 (s, 3H), 2.36 (s, 3H); MS (ES): m/z 322.18.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 2,4-difluorobenzene- 1 -sulfonyl chloride by procedure as described in (E). Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.05 (s, 1H), 7.81 (m, 1H), 7.54 (d, J=7.8Hz, 2H), 7.42 (t, J=7.2Hz, 2H), 7.33 (m, 1H), 7.04 (m, 2H), 6.24 (s, 1H), 4.37 (d, J=12.9Hz, 2H), 3.58 (t, J=12.9Hz, 2H), 2.32 (s, 3H), 2.27 (m, 2H), 2.22 (m, 3H), 1.92 (d, J=13.2Hz, 2H); MS (ES): m/z 499.18 (M+l).

Example 24

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyano-2, 4-dimethylpyridin-3 difluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6- dimethylnicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-(4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethylnicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.54 (d, J= 8.4Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 5.10 (s, 1H), 4.78(s, 2H), 3.48 (m, 2H), 3.34 (m, 2H), 2.31 (s, 6H), 2.09 (m, 2H), 1.70 (m, 2H); MS

(ES): m/z 356.85.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 2,4-difluorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.17 (s, 1H), 7.83 (m, 1H), 7.48 (d, J=8.4Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 7.08-6.99 (m, 2H), 6.27 (s, 1H), 4.36 (d, J=13.5Hz, 2H), 3.55 (t, J=11.4Hz, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 2.19 (m, 2H), 1.88 (d, J=12.9Hz, 2H); MS (ES): m/z 533.1 (M+l). Example 25

4-Chloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-5 -cyanopyridin-3-yl)-2-fluoro benzenesulfonamide

Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)nicoti nonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin-l-yl)nicotinonitrile with 2-fluoro-4-chlorobenzene-l -sulfonyl chloride by procedure as described in (E). Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.65 (s, 1H), 8.09 (d, J=2.4Hz, 1H), 7.81 (m, 2H), 7.69 (d, J=2.4Hz, 1H), 7.51 (m, 3H), 7.38 (d, J=8.4Hz, 2H), 5.27 (s, 1H), 4.12 (d, J=12.3Hz, 2H), 3.43 (t, J=12.3Hz, 2H), 2.01 (m, 2H), 1.70 (d, J=12.6Hz, 2H); MS (ES): m/z 521.0 (M+l).

Example 26

3- Chloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-5-c yanopyridin-3-yl)-4- fluorobenzenesulfonamide

Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)nicoti nonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)-

4- hydroxypiperidin-l-yl)nicotinonitrile with 3-chloro-4-fluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.33 (s, 1H), 8.02 (d, J=3.0Hz, 1H), 7.94 (dd, J=6.6, 2.1Hz, 1H), 7.75 (m, 1H), 7.67 (m, 2H), 7.51 (d, J=8.4Hz, 2H), 7.38 (d, J=8.7Hz, 2H), 5.27 (s, 1H), 4.13 (d, J=12.9Hz, 2H), 3.44 (t, J=12.3Hz, 2H), 2.0 (m, 2H), 1.7 (d, J=12.9Hz, 2H); MS (ES): m/z 520.1 (M ⁺ ). Example 27

3- Chloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-5-c yano-2,4-dimethylpyridin-3- yl)-4-fluorobenzenesulfonamide

Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethyl nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5- nitronicotinonitrile with 4- (4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethylnicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 7.54 (d, J= 8.4Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 5.10 (s, 1H), 4.78(s, 2H), 3.48 (m, 2H), 3.34 (m, 2H), 2.31 (s, 6H), 2.09 (m, 2H), 1.70 (m, 2H); MS (ES): m z 356.85.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)-

4- hydroxypiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 3-chloro-4-fluorobenzene- 1 - sulfonyl chloride by procedure as described in (E). Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.08 (s, IH), 7.89 (dd, J=4.5Hz, IH), 7.66 (m, IH), 7.48 (d, J=8.7Hz, 2H), 7.37 (d, J=8.7Hz, 2H), 7.31 (m, IH), 6.02 (s, IH), 4.38 (d, J=13.2Hz, 2H), 3.37 (t, J=11.7Hz, 2H), 2.29 (s, 3H), 2.19 (m, 2H), 2.13 (s, 3H), 1.90 (d, J=13.2Hz, 2H); MS (ES): m/z 549.0 (M+l).

Example 28

2-Chloro-N-(5-cyano-6-(4-hydroxy-4^henylpiperidin-l-yl)-2,4- dimethylpyridin-3 fluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl- piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 7.58 (m, 2H), 7.41(m, 2H), 7.31 (m, IH), 4.15 (m, 4H), 3.8 (m, 4H), 2.41 (s, 3H), 2.36 (s, 3H); MS (ES): m/z 322.18.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 2-chloro-4-fluorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.11 (s, IH), 7.97 (dd, J=9.0, 6.0Hz, IH), 7.53 (d, J=7.3Hz, 2H), 7.42 (m, 2H), 7.37 (m, IH), 7.32 (d, J=7.2Hz, IH), 7.16 (m, IH), 6.44 (s, IH), 4.36 (d, J=13.2Hz, 2H), 3.57 (t, J=12.3Hz, 2H), 2.29 (s, 3H), 2.20 (s, 3H), 2.17 (m, 2H), 1.91 (d, J=12.9Hz, 2H); MS (ES): m/z 515.2 (M+l).

Example 29

2-Chloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl )-5-cyano-2,4-dimethylpyridin-3- yl)-4-fluorobenzenesulfonamide

Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethyl nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4- (4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethylnicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 7.54 (d, J= 8.4Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 5.10 (s, IH), 4.78(s, 2H), 3.48 (m, 2H), 3.34 (m, 2H), 2.31 (s, 6H), 2.09 (m, 2H), 1.70 (m, 2H); MS (ES): m/z 356.85.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin-l-yl)-4,6-dimethylnicotinonitrile with 2-chloro-4-fluorobenzene-l- sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.17 (s, IH), 7.98 (dd, J=9.0, 5.7 Hz, IH), 7.48 (d, J=8.7Hz, 2H), 7.39 (m, 3H), 7.16 (m, IH), 6.38 (s, IH), 4.35 (d, J=13.5Hz, 2H), 3.54 (t, J=12.6Hz, 2H), 2.30 (s, 3H), 2.21 (s, 3H), 2.19 (m, 2H), 1.88 (d, J=12.9Hz, 2H); MS (ES): m/z 549.12 (M+l).

Example 30

3-Chloro-N-(5-cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)-2,4 -dimethylpyridin-3-yl)-4- fluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl- piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 7.58 (m, 2H), 7.41(m, 2H), 7.31 (m, IH), 4.15 (m, 4H), 3.8

(m, 4H), 2.41 (s, 3H), 2.36 (s, 3H); MS (ES): m/z 322.18.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 3-chloro-4-fluorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.09 (s, IH), 7.90 (dd, J=6.6, 2.1Hz, IH),

7.69 (m, IH), 7.55 (m, 2H), 7.43 (t, J=7.2Hz, 2H), 7.33 (m, 2H), 6.04 (s, IH), 4.39 (m, 2H),

3.60 (m, 2H), 2.29 (s, 3H), 2.24 (m, 2H), 2.12 (s, 3H), 1.93 (d, J=13.2Hz, 2H); MS (ES): m/z

515.1 (M+l). Example 31

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyanopyr idin-3-yl)-3-fluoro-4- methoxybenzenesulfonamide Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)nicoti nonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin-l-yl)nicotinonitrile with 3-fluoro-4-methoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.17 (s, 1H), 8.01 (m, 1H), 7.63 (m, 1H), 7.57-7.48 (m, 4H), 7.38-7.35 (m, 3H), 5.26 (s, 1H), 4.09 (d, J=11.4Hz, 2H), 3.36 (m, 2H), 1.97 (m, 2H), 1.69 (d, J=12.9Hz, 2H); MS (ES): m/z 517.0 (M+l).

Example 32

2,4-Dichloro-N-(5-cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl) -2,4-dimethylpyridin-3- yl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl- piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 7.58 (m, 2H), 7.41(m, 2H), 7.31 (m, 1H), 4.15 (m, 4H), 3.8 (m, 4H), 2.41 (s, 3H), 2.36 (s, 3H); MS (ES): m/z 322.18.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin-l-yl)-4,6-dimethylnicotinonitrile with 2,4-dichloro-l-sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.08 (s, 1H), 7.88 (d, J=8.7Hz, 1H), 7.64 (d, J=1.8Hz, 1H), 7.54 (d, J=7.5Hz, 2H), 7.42 (m, 3H), 7.33 (m, 1H), 6.40 (s, 1H), 4.37 (d, J=13.2Hz, 2H), 3.57 (t, J=12.6Hz, 2H), 2.30 (s, 3H), 2.27 (m, 2H), 2.21 (s, 3H), 1.93 (d, J=12.9Hz, 2H); MS (ES): m/z 531.1 (M+l).

Example 33

2,4-Dichloro-N-(6-(4-(4-chlorophenyl)-4-hydroxypiperidin- l-yl)-5-cyano-2,4-dimethyl pyridin-3-yl)benzenesulfonamide

Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethyl nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4- (4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethylnicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 7.54 (d, J= 8.4Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 5.10 (s, 1H), 4.78(s, 2H), 3.48 (m, 2H), 3.34 (m, 2H), 2.31 (s, 6H), 2.09 (m, 2H), 1.70 (m, 2H); MS.(ES): m/z 356.85.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 2,4-dichlorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.09 (s, 1H), 7.88 (d, J=8.4Hz, 1H), 7.64 (d, J=2.1Hz, 1H), 7.48 (m, 2H), 7.42 (dd, J=8.7, 2.1Hz, 1H), 7.37 (m, 2H), 6.40 (s, 1H), 4.35 (d, J=13.2Hz, 2H), 3.54 (t, J=12.6Hz, 2H), 2.30 (s, 3H), 2.21 (s, 3H), 2.19 (m, 2H), 1.88 (d, J=13.2Hz, 2H); MS (ES): m/z 567.1. Example 34

3,4-Dichloro-N-(5-cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl) -2,4-dimethylpyridin-3- yl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl- piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 7.58 (m, 2H), 7.41(m, 2H), 7.31 (m, 1H), 4.15 (m, 4H), 3.8 (m, 4H), 2.41 (s, 3H), 2.36 (s, 3H); MS (ES): m/z 322.18.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin-l-yl)-4,6-dimethylnicotinonitrile with 3,4-dichloro-l-sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.11 (s, 1H), 7.89 (d, J=1.5Hz, 1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.43 (t, J=7.2Hz, 2H), 7.33 (d, J=7.2Hz, 1H), 6.05 (s, 1H), 4.40 (d, J=13.5Hz, 2H), 3.61 (t, J=12.9Hz, 2H), 2.29 (s, 3H), 2.24 (m, 2H), 2.13 (s, 3H), 1.93 (d, J=12.3Hz, 2H); MS (ES): m/z 531.1 (M+l). Example 35

N-(5-Chloro-6-(4-hydroxy-4-phenylpiperi

sulfonamide

Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidin-4-ol was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-phenyl-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-phenylpiperidin-4-ol with 2,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.94 (s, IH), 7.90 (d, J=2.4Hz, IH), 7.67 (d, J=9.0Hz, IH), 7.49 (m, 3H), 7.34 (t, J=7.8Hz, 2H), 7.23 (m, IH), 6.68 (d, J=2.4Hz, IH), 6.62 (dd, J=8.7, 2.1Hz, IH), 4.98 (s, IH), 3.87 (s, 3H), 3.81 (s, 3H), 3.46 (d, J=12.3Hz, 2H), 3.19 (t, J=13.2Hz, 2H), 2.04 (m, 2H), 1.68 (d, J=12.6Hz, 2H); MS (ES): m/z 504.0 (M+l). Example 36

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)pyridin-3-yl) -2,4-dimethoxybenzene sulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-phenyl-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin-l-yl)nicotinonitrile with 2,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.84 (s, IH), 8.06 (d, J=2.7Hz, IH), 7.64 (d, J=9.0Hz, IH), 7.60 (d, J=2.7Hz, IH), 7.48 (dd, J=8.4, 1.2Hz, IH), 7.34 (t, J=7.2Hz, 2H), 7.23 (m, IH), 6.70 (d, J=2.1Hz, IH), 6.60 (dd, J=8.7, 2.1Hz, IH), 5.12 (s, IH), 4.04 (m, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 2.04 (m, 2H), 1.70 (m, 2H); MS (ES): m/z 495.16 (M+l).

Example 37

N-(5-Chloro-6-(4-hydroxy-4-phenylpiperidin-l-yl)pyridin-3 -yl)-3,4-dimethoxybenzene sulfonamide Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-phenylpiperidin-4-ol was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-phenyl-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-phenylpiperidin-4-ol with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.14 (s, 1H), 7.88 (d, J=2.1Hz, 1H), 7.50 (m, 3H), 7.35 (m, 3H), 7.23 (m, 2H), 7.10 (d, J=8.7Hz, 1H), 5.01 (s, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.50 (m, 2H), 3.22 (m, 2H), 2.01 (m, 2H), 1.69 (m, 2H); MS (ES): m/z 504.0 (M+l).

Example 38

N-(5-Cyano-6-(4-hydroxy-4-phenylpiperidin-l-yl)pyridin-3-yl) -3,4-dimethoxybenzene sulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-phenyl-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin-l-yl)nicotinonitrile with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.05 (s, 1H), 8.01 (d, J=2.7Hz, 1H), 7.62 (d,

J=2.7Hz, 1H), 7.48 (m, 2H), 7.35 (m, 1H), 7.27 (m, 1H), 7.21 (m, 2H), 7.10 (d, J=8.4Hz, 1H),

5.14 (s, 1H), 4.08 (d, J=12.6Hz, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.43 (d, J=12.3Hz, 2H), 2.12

(m, 2H), 1.70 (m, 2H); MS (ES): m/z 495.16 (M+l). Example 39

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyanopyr idin-3-yl)-3,4-dimethoxy benzenesulfonamide

Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)nicoti nonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin-l-yl)nicotinonitrile with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E). Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.05 (s, 1H), 8.01 (m 1H), 7.62 (d, J=8.4Hz, 1H), 7.21 (s, 1H), 7.10 (d, J=8.7Hz, 1H), 5.26 (s, 1H), 4.08 (d, J=12.3Hz, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.41 (m, 2H), 1.99 (m, 2H), 1.69 (d, J=13.2Hz, 2H); MS (ES): m/z 529.0 (M+l).

Example 40

N-(5-Cyano-6-(4-hydroxy-4^henylpiperidm

benzenesulfonamide

Step 1 : 5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-phenyl- piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-hydroxy-4-phenylpiperidin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 7.58 (m, 2H), 7.41(m, 2H), 7.31 (m, 1H), 4.15 (m, 4H), 3.8 (m, 4H), 2.41 (s, 3H), 2.36 (s, 3H); MS (ES): m/z 322.18.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-hydroxy-4- phenylpiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 3,4-dimethoxybenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 68 % ; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.13 (s, 1H), 7.55 (d, J=7.8Hz, 2H), 7.43 (t, J=7.2Hz, 2H), 7.35 (m, 2H), 7.18 (s, 1H), 6.95 (d, J=8.4Hz, 1H), 5.83 (s, 1H), 4.35 (d, J=13.5Hz, 2H), 3.97 (s, 3H), 3.87 (s, 3H), 3.58 (t, J=12.0Hz, 2H), 2.28 (s, 3H), 2.24 (m, 2H), 2.11 (s, 3H), 1.93 (d, J=12.9Hz, 2H);. MS (ES): m/z 523.2 (M+l).

Example 41

N-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyano -2,4-dimethylpyridin-3-yl)-3,4- dimethoxybenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6- dimethylnicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-(4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-4,6-d imethylnicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 7.54 (d, J= 8.4Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 5.10 (s, 1H), 4.78(s, 2H), 3.48 (m, 2H), 3.34 (m, 2H), 2.31 (s, 6H), 2.09 (m, 2H), 1.70 (m, 2H); MS (ES): m z 356.85. Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin-l-yl)-4,6-dimethylnicotinonitrile with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.14 (s, 1H), 7.48 (m, 2H), 7.37 (m, 3H), 7.19 (d, J=2.1Hz, 1H), 6.95 (d, J=8.4Hz, 1H), 5.92 (s, 1H), 4.33 (d, J=13.2Hz, 2H), 3.97 (s, 3H), 3.87 (s, 3H), 3.54 (t, J=10.8Hz, 2H), 2.28 (s, 3H), 2.24 (m, 2H), 2.11 (s, 3H), 1.89 (d, J=13.2Hz, 2H); MS (ES): m/z 557.2 (M+l).

Example 42

N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypip eridin-l-yl)-5-cyanopyridin-3- yl)-2,4-difluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l- yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(4-chloro-3- trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chloro-3- (trifluoromethyl)phenyl)-4-hydroxypiperidin- 1 -yl)nicotinonitrile with 2,4-difluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 8.09 (d, J=2.7Hz, 1H), 7.94 (s, 1H), 7.89 (m, 1H), 7.78 (m, 1H), 7.68 (m, 2H), 7.62 (m, 1H), 7.30 (m, 1H), 5.51 (s, 1H), 4.15 (d, J=12.9Hz, 2H), 3.42 (m, 2H), 2.06 (m, 2H), 1.71(d, J=13.2Hz, 2H); MS (ES): m/z 573.1 (M+l).

Example 43

3-Chloro-N-(6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-h ydroxypiperidin-l-yl)-5- cyanopyridin-3-yl)-4-fluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l- yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(4-chloro-3- trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chloro-3- (trifluoromethyl)phenyl)-4-hydroxypiperidin- 1 -yl)nicotinonitrile with 3-chloro-4- fluorobenzene-l-sulfonyl chloride by procedure as described in (E). Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.34 (s, IH), 8.03 (d, J=2.4Hz, IH), 7.94 (m, 2H), 7.75 (m, IH), 7.72 (m, IH), 7.68 (m, 3H), 5.52 (s, IH), 4.16 (d, J=13.2Hz, 2H), 3.43 (m, 2H), 2.07 (m, 2H), 1.71 (d, J=12.6Hz, 2H); MS (ES): m/z 589.0 (M+l). Example 44

N-(5-Chloro-6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydr o

yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-(4-chloro-3-(trifluoromet hyl)phenyl) piperidin-4-ol was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-(4-chloro-3- trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-(4-chloro-3-(trifluoromethyl)phenyl)piperidin-4-ol with 3-(trifluoromethyl)benzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 64 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.46 (s, IH), 8.09 (d, J=7.8Hz, IH), 8.03 (d, J=8.1Hz, IH), 7.93 (s, 2H), 7.88-7.82 (m, 2H), 7.78 (d, J=8.4Hz, IH), 7.69 (d, J=8.4Hz, IH), 7.44 (d, J=2.1Hz, IH), 5.39 (s, IH), 3.56 (d, J=12.3Hz, 2H), 3.21 (t, J=12.0Hz, 2H), 2.05 (m, 2H), 1.70 (d, J=2.9 Hz, 2H); MS (ES): m/z 615.0. Example 45

N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperi din-l-yl)-5-cyanopyridin-3- yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l- yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(4-chloro-3- trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chloro-3-

(trifluoromethyl)phenyl)-4-hydroxypiperidin- 1 -yl)nicotinonitrile with 3 -

(trifluoromethyl)benzene-l -sulfonyl chloride by procedure as described in (E).

Yield: 65 %; H NMR (300 MHz, DMSO-d ₆ ): δ 10.38 (s, IH), 8.10 (m, IH), 7.02-7.93 (m,

4H), 7.87-7.82 (m, IH), 7.75 (m, IH), 7.69-7.62 (m, 2H), 5.52 (s, IH), 4.15 (d, J=12.0Hz,

2H), 3.43 (m, 2H), 2.05 (m, 2H), 1.71 (d, J=13.5Hz, 2H); MS (ES): m/z 605.1 (M+l). Example 46

N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperi din-l-yl)-5-cyan

dimethylpyridin-3-yl)-3-(trifluoromethyl)benzenesulfonami de

Step 1 : 5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l-yl)- 4,6-dimethylnicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5- nitronicotinonitrile with 4-(4-chloro-3-trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chloro-3- (trifluoromethyl)phenyl)-4-hydroxypiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 3- (trifluoromethyl)benzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ *H NMR (300 MHz, DMSO-d6): 9.86 (s, IH), 8.13 (d, J= 8.1Hz, IH), 8.03 (d, J=7.5Hz, IH), 7.94 (s, IH), 7.91 (t, J=7.8Hz, 2H), 7.79 (d, J=8.4Hz, IH), 7.70 (d, J=8.4Hz, IH), 5.52 (s, IH), 4.20 (d, J=12.6Hz, 2H), 3.43 (m, 2H), 2.05 (s, 8H ), 1.74 (d, J=12.9Hz, 2H); MS (ES): m z. 633.1 (M+l).

Example 47

N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperi din-l-yl)-5-cyanopyridin-3- yl)-3,4-dimethoxybenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l- yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(4-chloro-3- trifluoromethyl-phenyl)-piperi din-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chloro-3- (trifluoromethyl)phenyl)-4-hydroxypiperidin-l-yl)nicotinonit rile with 3,4- dimethoxy benzene- 1-sulfonyl chloride by procedure as described in (E).

Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.06 (s, IH), 8.02 (d, J=2.7 Hz, IH), 7.94 (m, IH), 7.77 (m, IH), 7.68 (m, IH), 7.62 (d, J=2.7Hz, IH), 7.29 (d, J=8.4Hz, IH), 7.22 (m, IH), 7.10 (d, J=8.7Hz, IH), 5.50 (s, IH), 4.11 (d, J=13.2Hz, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.33 (m, 2H), 2.06 (m, 2H), 1.71 (d, J=13.5Hz, 2H); MS (ES): m/z 597.1 (M+l).

Example 48

N-(5-Chloro-6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydr oxypiperidin-l-yl)pyridin-3- yl)-2,4-difluorobenzenesulfonamide Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-(4-chloro-3-(trifluoromet hyl) phenyl) piperidin-4-ol was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-(4-chloro-3- trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-(4-chloro-3-(trifluoromethyl)phenyl)piperidin-4-ol with 2,4-difluorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 65 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.65 (s, IH), 8.02 (m, IH), 8.00 (d, J=8.1Hz, IH), 7.93 (d, J=7.8Hz, IH), 7.73 (t, J=7.8Hz, IH), 7.55 (m, 2H), 7.43 (t, J=7.2Hz, IH), 7.33 (d, J=7.2Hz, IH), 6.01 (brs, IH), 4.39 (d, J=13.2Hz, 2H), 3.60 (t, J=12.6Hz, 2H ), 2.27 (m, 2H), 1.93 (d, J=12.9 Hz, 2H); MS (ES): m/z 582.1 (M+l).

Example 49

N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperi din-l-yl)-5-cyano-2,4- dimethylpyridin-3-yl)-2,4-difluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l-yl)- 4,6-dimethylnicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5- nitronicotinonitrile with 4-(4-chloro-3-trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chloro-3- (trifluoromethyl)phenyl)-4-hydroxypiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 2,4- difluorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.04 (s, IH), 7.96 (d, J=1.8Hz, IH), 7.79 (m, 2H), 7.69-7.63 (m, IH), 7.27 (m, 2H), 5.52 (brs, IH), 4.21 (d, J=12.0Hz, 2H), 3.42 (s, 2H), 2.16 (s, 3H ), 2.10 (m, 3H), 2.04 (m, 2H), 1.73 (d, J=12.9Hz, 2H); MS (ES): m/z 601.1 (M+l).

Example 50

3-Chloro-N-(5-chloro-6-(4-(4-chloro-3-(trifluoromethyl)pheny l)-4-hydroxypiperidin-l- yl)pyridin-3-yl)-4-fluorobenzenesulfonamide

Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-(4-chloro-3-(trifluoromet hyl)phenyl) piperidin-4-ol was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-(4-chloro-3- trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-(4-chloro-3-(trifluoromethyl)phenyl)piperidin-4-ol with 3-chloro-4-fluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 65 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.44 (s, 1H), 7.93 (m, 2H), 7.90 (m, 1H), 7.79-7.75 (m, 1H), 7.73-7.71 (m, 1H), 7.69-7.61 (m, 2H), 7.48 (d, J=2.1Hz, 1H), 5.40 (s, 1H), 3.57 (d, J=12.0Hz, 2H), 3.22 (t, J=12.0Hz, 2H ), 2.05 (m, 2H), 1.71 (d, J=12.6Hz, 2H); MS (ES): m/z 599.1.

Example 51

N-(5-Chloro-6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydr oxypiperidin-l-yl)pyridin-3- yl)-3,4-dimethoxybenzenesulfonamide

Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-(4-chloro-3-(trifluoromet hyl)phenyl) piperidin-4-ol was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-(4-chloro-3- trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-(4-chloro-3-(trifluoromethyl)phenyl)piperidin-4-ol with 3,4-dimethoxybenzene-l- sulfonyl chloride by procedure as described in (E).

Yield: 64 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.15 (s, 1H), 7.94 (s, 1H), 7.89 (d, J=2.4Hz, 1H), 7.75 (m, 1H), 7.69 (m, 1H), 7.47 (d, J=2.4Hz, 1H), 7.31 (dd, J=8.4, 2.1Hz, 1H), 7.21 (d, J=1.8Hz, 1H), 7.10 (d, J=8.4Hz, 1H), 5.39 (s, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.51(d, J=11.7Hz, 2H), 3.20 (t, J=12.0Hz, 2H), 2.04 (m, 2H), 1.70 (d, J=12.6Hz, 2H); MS (ES): m/z 606.1 (M+l).

Example 52

2,4-Dichloro-N-(5-chloro-6-(4-(4-chloro-3-(trifluoromethyl)p henyl)-4-hydroxypiperidin-l- yl)pyridin-3-yl)benzenesulfonamide

Step 1 : l-(5-Amino-3-chloropyridin-2-yl)-4-(4-chloro-3-(trifluoromet hyl)phenyl) piperidin-4-ol was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 4-(4-chloro-3- trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D). Step 2: The title compound was obtained by reacting l-(5-amino-3-chloropyridin-2- yl)-4-(4-chloro-3-(trifluoromethyl)phenyl)piperidin-4-ol with 2,4-dichlorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 64 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.79 (s, IH), 8.01 (d, J = 8.4Hz, IH), 7.94 (m, IH), 7.78 (m, IH), 7.69 (d, J=8.4Hz, 2H), 7.64 (dd, J=8.7, 2.1Hz, IH), 7.48 (d, J=2.4Hz, IH), 5.39 (s, IH), 3.53 (d, J=12.0Hz, 2H), 3.20 (t, J=l l.lHz, 2H ), 2.07 (m, 2H), 1.69 (d, J=12.6Hz, 2H); MS (ES): m/z 616.0.

Example 53

3-Chloro-N-(6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-h ydroxypiperidin-l-yl)-5-cyano- 2,4-dimethylpyridin-3-yl)-4-fluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l-yl)- 4,6-dimethylnicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5- nitronicotinonitrile with 4-(4-chloro-3-trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chloro-3- (trifluoromethyl)phenyl)-4-hydroxypiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 3-chloro- 4-fluorobenzene-l -sulfonyl chloride by procedure as described in (E).

Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 7.95 (s, IH), 7.88 (dd, J=6.6, 1.8Hz, IH), 7.80 (m, IH), 7.74-7.71 (m, IH), 7.70 (m, 2H), 5.52 (s, IH), 4.21 (d, J=12.3Hz, 2H), 3.44 (m, 2H), 2.12 (s, 3H), 2.10 (m, 2H), 2.03 (s, 3H), 1.74 (d, J=12.9Hz, 2H); MS (ES): m/z 617.1 (M+l).

Example 54

2,4-Dichloro-N-(6-(4-(4-chloro-3-(trifluoromethyl)phenyl) -4-hydroxypiperidin-l-yl)-5- cyanopyridin-3-yl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l- yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(4-chloro-3- trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chloro-3- (trifluoromethyl)phenyl)-4-hydroxypiperidin- 1 -yl)nicotinonitrile with 2,4-dichlorobenzene- 1 - sulfonyl chloride by procedure as described in (E). Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.67 (s, IH), 8.09 (d, J=2.4Hz, 2H), 7.98 (m, 2H), 7.77 (m, 2H), 7.67-7.60 (m, 2H), 5.51 (brs, IH), 4.14 (d, J=13.5Hz, 2H), 3.41 (m, 2H), 2.05 (m, 2H), 1.70 (d, J=12.6Hz, 2H); MS (ES): m/z 605.0 (M+l). Example 55

2,4-Dichloro-N-(6-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4- hydroxypiperidin-l-yl)-5- cyano-2,4-dimethylpyridin-3-yl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l-yl)-

4,6-dimethylnicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5- nitronicotinonitrile with 4-(4-chloro-3-trifluoromethyl -phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chloro-3-

(trifluoromethyl)phenyl)-4-hydroxypiperidin- 1 -yl)-4,6-dimethylnicotinonitrile with 2,4- dichlorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 64 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.99 (s, IH), 7.97 (m, 2H), 7.84 (d, J=8.4Hz,

IH), 7.79 (m, IH), 7.69 (d, J=8.4Hz, IH), 7.63 (dd, J=8.4, 1.8Hz, IH), 5.52 (s, IH), 4.21 (d,

J=12.9Hz, 2H), 3.42 (m, 2H), 2.14 (s, 3H), 2.08 (s, 3H), 2.04 (m, 2H), 1.73 (d, J=12.9Hz,

2H); MS (ES): m/z 635.1. Example 56

N-(6-(4-(4-Chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperi din-l-yl)-5-cyano-2,4- dimethylpyridin-3-yl)-3,4-dimethoxybenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxyp iperidin-l-yl)-

4,6-dimethylnicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5- nitronicotinonitrile with 4-(4-chloro-3-trifluoromethyl-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chloro-3-

(trifluoromethyl)phenyl)-4-hydroxypiperidin-l-yl)-4,6-dim ethylnicotinonitrile with 3,4- dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.41 (s, IH), 7.96 (d, J=1.8Hz, IH), 7.77 (m,

IH), 7.70 (m, IH), 7.27 (m, IH), 7.14 (m, 2H), 5.51 (s, IH), 4.13 (m, 2H), 3.84 (s, 3H), 3.74

(s, 3H), 3.37 (m, 2H), 2.10 (s, 3H), 2.03 (m, 2H), 1.74 (d, J=12.9Hz, 2H); MS (ES): m/z

625.1 (M+l). Example 57

3-Chloro-N-(5-cyano-6-(4-cyclohexylpiperazin-l-yl)pyridin-3- yl)-4-fluorobenzene sulfonamide

Step 1 : 5-Amino-2-(4-cyclohexylpiperazin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 1-cyclohexyl-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-cyclohexylpiperazin- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.89 (d, J= 3Hz, IH), 7.23 (d, J= 3Hz, IH ), 5.22 (s, 2H), 3.16 (m, 4H), 2.62 (m, 4H), 2.22 (m, IH), 1.76 (m, 4H), 1.27 (m, 4H), 1.17 (m, 2H).

Step 2: The title compound was obtained by reacting 5-amino-2-(4- cyclohexylpiperazin-l-yl)nicotinonitrile with 3-chloro-4-fluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.37 (s, IH), 8.13 (d, J=2.7Hz, IH), 7.96 (dd, J=2.1, 6.9Hz, IH), 7.79 (d, J=2.7Hz, IH), 7.75 (m, IH), 7.65 (t, J=6.3Hz, IH), 3.64 (m, 4H), 2.57 (m, IH), 2.49 (m, 4H), 1.58-1.21 (m, 10H); MS (ES): m/z 478.1 (M+l).

Example 58

N-(5-Chloro-6-(4-phenylpiperazin-l-yl)pyridin-3-yl)-2,4-difl uorobenzenesulfonamide

Step 1 : 5-Chloro-6-(4-phenylpiperazin-l-yl)pyridin-3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 1-phenyl-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-phenylpiperazin- l-yl)pyridin-3-amine with 2,4-difluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 2.97 g, (64 %); *H NMR (300 MHz, DMSO-d ₆ ): δ 10.79 (s, IH), 7.97 (d, J=2.1Hz, IH), 7.93 (m, J=8.4, 6.3 Hz, IH), 7.61 (m, IH), 7.55 (d, J=2.1Hz, IH), 7.31 (m, IH), 7.25 (t, J=8.1, 7.5 Hz, 2H), 6.98 (d, J=8.4Hz, 2H), 6.82 (t, J=7.5, 7.2Hz, IH ), 3.30 (m, 4H), 3.25 (m, 4H); MS (ES): m/z 464.9 (M+l), 462.8 (M-l). Example 59

3-Chloro-N-(5-chloro-6-(4-phenylpiperazin-l-yl)pyridin-3-yl) -4-fluorobenzene

sulfonamide Step 1 : 5-Chloro-6-(4-phenylpiperazin-l-yl)pyridin-3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 1-phenyl-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-phenylpiperazin- l-yl)pyridin-3-amine with 3-chloro-4-fluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.55 (s, IH), 7.92 (s, IH), 7.74 (m, IH), 7.67 (t, J=8.7, 8.7Hz, IH), 7.51 (d, J=1.5Hz, IH), 7.25 (t, J=7.5, 7.5Hz, 2H), 6.98 (d, J =8.1Hz, 2H), 6.82 (t, J=7.2, 7.2Hz, IH), 3.33 (m, 4H), 3.25 (m, 4H); MS (ES): m/z 480.9 (M+l), 478.8 (M-l).

Example 60

N-(5-Chloro-6-(4-phenylpiperazin- 1 -yl)pyridin-3-yl)-3 ,4-dimethoxybenzenesulfonamide

Step 1 : 5-Chloro-6-(4-phenylpiperazin-l-yl)pyridin-3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 1-phenyl-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-phenylpiperazin- l-yl)pyridin-3-amine with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.24 (s, IH), 7.92 (s, IH), 7.50 (s, IH), 7.32 (d, J=8.1Hz, IH), 7.22 (s, 3H), 7.10 (d, J=8.1Hz, IH), 6.97 (d, J=7.5Hz, 2H), 6.81 (t, J=6.6Hz, IH), 3.80 (s, 3H), 3.76 (s, 3H), 3.29 (m, 8H); MS (ES): m/z 489.0 (M+l), 486.9 (M-l). Example 61

N-(5-Cyano-6-(4-(3-(trifluoromethyl)phenyl)piperazin-l-yl)py ridin-3-yl)-4-(trifluoromethyl) benzenesulfonamide

Step 1 : 5-Amino-2-(4-(3-(trifluoromethyl)phenyl)piperazin-l-yl)nicot inonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(3-trifluoromethyl-phenyl)- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(3- (trifluoromethyl)phenyl)piperazin- 1 -yl)nicotinonitrile with 4-(trifluoromethyl)benzene- 1 - sulfonyl chloride by procedure as described in (E). Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.54 (s, IH), 8.05 (d, J=2.4Hz, IH), 7.97 (d, J=8.7Hz, 2H), 7.93 (d, J=8.7Hz, 2H), 7.69 (d, J=2.4Hz, IH), 7.43 (t, J=8.7Hz, IH), 7.23 (d, J=8.4Hz, IH), 7.17 (s, IH), 7.07 (d, J=7.8Hz, IH), 3.68 (m, 4H), 3.34 (m, 4H); MS (ES): m/z 555.1(M ⁺ ).

Example 62

N-(5-Cyano-6-(4-(3-(trifluoromethyl)phenyl)piperazin-l-yl)py ridin-3-yl)-2,4-diflu^ benzenesulfonamide

Step 1 : 5-Amino-2-(4-(3-(trifluoromethyl)phenyl)piperazin-l-yl)nicot inonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(3-trifluoromethyl-phenyl)- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(3- (trifluoromethyl)phenyl)piperazin- 1 -yl)nicotinonitrile with 2,4-difluorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.69 (s, IH), 8.14 (d, J= 2.7Hz, IH), 7.90 (m, IH), 7.74 (d, J=2.7Hz, IH), 7.62 (m, IH), 7.46 (t, J=8.1, 8.1 Hz, IH), 7.56 (m, IH), 7.23 (m, IH), 7.12 (dd, J=8.1, 1.8Hz IH), 6.56 (dd, J=8.1, 1.8Hz, IH), 3.31 (m, 4H), 3.25 (m, 4H); MS (ES): m/z 524.1 (M+l), 522.1 (M-l).

Example 63

2,4-Dichloro-N-(5-cyano-6-(4-(3-(trifluoromethyl)phenyl)pipe razin-l-yl)pyridin-3- yl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(3-(trifluoromethyl)phenyl)piperazin-l-yl)nicot inonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(3-trifluoromethyl-phenyl)- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(3- (trifluoromethyl)phenyl)piperazin- 1 -yl)nicotinonitrile with 2,4-dichlorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.74 (s, IH), 8.11 (d, J=2.7Hz, IH), 7.96 (d, J=8.4Hz, IH), 7.89 (d, J=2.1Hz, IH), 7.69 (d, J=2.7Hz, IH), 7.60 (dd, J=2.1, 8.4Hz, IH), 7.40 (t, J=8.1Hz, IH), 7.23 (d, J=8.1Hz, IH), 7.17 (m, IH), 7.07 (d, J=7.5Hz, IH), 3.67 (m, 4H), 3.35 (m, 4H); MS (ES): m/z 556.3 (M+l). Example 64

N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-cyano-2,4-di^

methyl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(3-chlorophenyl)piperazin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(3-chloro- phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(3-chlorophenyl)piperazin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.25 (t, J= 8.1Hz, IH), 6.99 (s, IH ), 6.95 (m, IH), 6.81 (d, J= 7.8Hz, IH), 4.87 (s, 2H), 3.35 (m, 8H), 2.50 (s, 6H); MS (ES): m/z 341.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(3- chlorophenyl)piperazin-l-yl)-4,6-dimethylnicotinonitrile with 3-(trifluoromethyl)benzene-l- sulfonyl chloride by procedure as described in (E).

Yield: 72 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.91 (s, IH), 8.13.(d, J=7.8Hz, IH), 8.02 (d, J=8.1Hz, IH), 7.91-7.85 (m, 2H), 7.26 (t, J=8.4, 8.1Hz, IH), 6.99-6.92 (m, 2H), 6.82 (dd, IH), 3.72 (m, 4H), 2.05 (s, 3H), 2.01 (s, 3H); MS (ES): m/z 550.1 (M+l).

Example 65

N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-cyano-2,4-dimethyl pyridin-3-yl)-2,4-difluoro benzenesulfonamide

Step 1 : 5-Amino-2-(4-(3-chlorophenyl)piperazin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(3-chloro-phenyl)- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5- Amino-2-(4-(3-chlorophenyl)piperazin- 1 -yl)-4,6-dimethylnicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.25 (t, J= 8.1Hz, IH), 6.99 (s, IH ), 6.95 (m, IH), 6.81 (d, J= 7.8Hz, IH), 4.87 (s, 2H), 3.35 (m, 8H), 2.50 (s, 6H); MS (ES): m z 341.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(3- chlorophenyl)piperazin-l-yl)-4,6-dimethylnicotinonitrile with 2,4-difluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.09 (s, IH), 7.79-7.71 (m, IH), 7.61-7.60 (m, IH), 7.29-7.20 (m, 2H), 6.98-6.92 (m, 2H), 6.82 (dd, IH), 3.72 (m, 4H), 3.33 (m, 4H), 2.17 (s, 3H), 2.13 (s, 3H); MS (ES): m/z 518.1 (M+l). Example 66

3-Chloro-N-(6-(4-(3-chlorophenyl)pipera

fluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-(3-chlorophenyl)piperazin-l-yl)-4,6-dimethylnic otinonitri^ was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(3-chloro-phenyl)- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(3-chlorophenyl)piperazin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.25 (t, J= 8.1Hz, IH), 6.99 (s, IH ), 6.95 (m, IH), 6.81 (d, J= 7.8Hz, IH), 4.87 (s, 2H), 3.35 (m, 8H), 2.50 (s, 6H); MS (ES): m/z 341.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(3- chlorophenyl)piperazin- l-yl)-4,6-dimethylnicotinonitrile with 3-chloro-4-fluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 69; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.46 (s, IH), 7.25-7.21 (m, IH), 7.14 (m, IH), 7.11-7.08 (m, IH), 6.99-6.91 (m, 2H), 6.82-6.79 (m, IH), 3.84 (m, 4H), 3.72 (m, 4H), 2.11 (s, 3H), 2.01 (s, 3H); MS (ES): m/z 534.1(M+1).

Example 67

2,4-Dichloro-N-(6-(4-(3-chlorophenyl)piperazin-l-yl)-5-cyano -2,4-dimethylpyridin-3- yl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(3-chlorophenyl)piperazin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(3-chloro-phenyl)- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5- Amino-2-(4-(3-chlorophenyl)piperazin- 1 -yl)-4,6-dimethylnicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.25 (t, J= 8.1Hz, IH), 6.99 (s, IH ), 6.95 (m, IH), 6.81 (d, J= 7.8Hz, IH), 4.87 (s, 2H), 3.35 (m, 8H), 2.50 (s, 6H); MS (ES): m z 341.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(3- chlorophenyl)piperazin- 1 -yl)-4,6-dimethylnicotinonitrile with 2,4-dichlorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 73 %; H NMR (300 MHz, DMSO-d ₆ ): δ 10.04 (s, IH), 7.98 (d, J=1.8Hz,lH), 7.83 (d, J= 8.7Hz, IH), 7.62-7.59 (d, J=2.1Hz, IH), 7.25-7.20 (t, J=8.1 Ηζ,ΙΗ), 6.98-6.92 (m, 2H), 6.82 (dd, IH), 3.72 (m, 4H), 3.33 (m, 4H), 2.15 (s, 3H), 2.10 (s, 3H); MS (ES): m/z 552.0. Example 68

N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-methylpyridin-3-yl )-2,5-dimetho

sulfonamide

Step 1 : 6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-methylpyridin-3-amine was obtained by reacting 2-chloro-3-methyl-5-nitropyridine with l-(3-chloro-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 6-(4-(3-chlorophenyl)piperazin-l- yl)-5-methylpyridin-3-amine with 2,5-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 65 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.99 (s, IH), 8.13 (d, J=7.8Hz, IH), 8.02 (d, J=7.8Hz, IH), 7.94 (d, J=2.4Hz, 1H),7.88 (m, IH), 6.85 (d, J= 9.3Hz, 2H), 6.59 (d, J=9.0Hz, 2H), 6.54 (d, J=2.4Hz, IH), 3.71 (s, 3H), 3.69 (m, 4H), 3.13 (m, 4H), 2.04 (s, 3H), 2.01 (s, 3H); MS (ES): m/z 504.01. Example 69

N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-cyano-2,4-dimethyl pyridin-3-yl)-2,5- dimethoxybenzenesulfonamide.

Step 1 : 5-Amino-2-(4-(3-chlorophenyl)piperazin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(3-chloro-phenyl)- piperazine. by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(3-chlorophenyl)piperazin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.25 (t, J= 8.1Hz, IH), 6.99 (s, IH ), 6.95 (m, IH), 6.81 (d, J= 7.8Hz, IH), 4.87 (s, 2H), 3.35 (m, 8H), 2.50 (s, 6H); MS (ES): m/z 341.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(3- chlorophenyl)piperazin- l-yl)-4,6-dimethylnicotinonitrile with 2,5-dimethoxybenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 73 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.43 (s, IH), 7.25-7.21 (m, 3H), 7.09 (m, IH), 6.98-6.91 (m, 2H), 6.81 (d, IH), 3.82 (s, 3H), 3.71 (m, 7H), 3.33 (m, 4H), 2.18 (s, 3H), 2.12 (s, 3H); MS (ES): m/z 542.1 (M+l). Example 70

N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-methylpyridin-3-yl )-3,4-dimetho

sulfonamide

Step 1 : 6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-methylpyridin-3-amine was obtained by reacting 2-chloro-3-methyl-5-nitropyridine with l-(3-chloro-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 6-(4-(3-chlorophenyl)piperazin-l- yl)-5-methylpyridin-3-amine with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 65 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.20 (s, IH), 7.80 (d, IH), 7.41 (bs, IH), 7.32-7.21 (m, 3H), 7.09 (d, J=9.0Hz, IH), 7.02 (bs, IH), 6.98 (d, J=8.1Hz, IH), 6.84 (d, J=7.8Hz, IH), 3.80 (s, 3H), 3.76 (s, 3H), 3.30-3.19 (m, 8H), 2.23 (s, 3H); MS (ES): m/z 503.1 (M+l). Example 71

N-(6-(4-(3-Chlorophenyl)piperazin-l-yl)-5-cyano-2,4-dimethyl pyridin-3-yl)-3,4- dimethoxybenzenesulfonamide

Step 1 : 5-Amino-2-(4-(3-chlorophenyl)piperazin-l-yl)-4,6-dimethylnic otinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(3-chloro-phenyl)- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(3-chlorophenyl)piperazin-l-yl)-4,6-dimethylnic otinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.25 (t, J= 8.1Hz, IH), 6.99 (s, IH ), 6.95 (m, IH), 6.81 (d, J= 7.8Hz, IH), 4.87 (s, 2H), 3.35 (m, 8H), 2.50 (s, 6H); MS (ES): m z 341.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(3- chlorophenyl)piperazin- 1 -yl)-4,6-dimethylnicotinonitrile with 3 ,4-dimethoxybenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.46 (s, IH), 7.23 (m, 2H), 7.14-7.08 (m, 2H), 6.98-6.92 (m, 2H), 6.82-6.80 (m, IH), 3.84 (s, 3H), 3.71 (s, 6H), 2.71 (s, 3H), 2.01 (s, 3H); MS (ES): m/z 543.1. Example 72

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-3-fluoro-4-meth^ sulfonamide

Step 1 : 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(3-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.62 (d, J= 2.4Hz, 1H), 7.12 (m, 1H), 7.06 (d, J=2.4Hz, 1H), 6.55 (m, 1H), 6.46 (m, 1H), 6.36 (d, J= 7.8, 1.8Hz, 1H), 5.17 (s, 2H), 3.69 (s, 3H), 3.31 (m, 4H) 3.1 (m, 4H); MS (ES): m/z 318.12.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(3- methoxyphenyl)piperazin- 1 -yl)pyridin-3-amine with 3-fluoro-4-methylbenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 67.3 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.56 (s, 1H), 7.95 (d, J=2.4Hz, 1H), 7.55 (d, J=6, 3.6Hz, 2H), 7.49 (s, 1H), 7.47 (d, J=1.5Hz, 1H), 7.23 (t, J=8.1Hz, 1H), 6.77 (m, 2H), 6.55 (d, 1H), 3.74 (s, 3H), 3.38 (m, 8H), 2.28 (s, 3H); MS (ES): m/z 491.1 (M+l), 489.1 (M- 1)·

Example 73

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin- 1 -yl)pyridin-3-yl)-4-(trifluoromethyl)benzene sulfonamide

Step 1 : 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(3-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.62 (d, J= 2.4Hz, 1H), 7.12 (m, 1H), 7.06 (d, J=2.4Hz, 1H), 6.55 (m, 1H), 6.46 (m, 1H), 6.36 (d, J= 7.8, 1.8Hz, 1H), 5.17 (s, 2H), 3.69 (s, 3H), 3.31 (m, 4H) 3.1 (m, 4H); MS (ES): m/z 318.12.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(3- methoxyphenyl)piperazin-l-yl)pyridin-3-amine with 4-(trifluoromethyl)benzene-l -sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.65 (s, 1H), 8.01 (m, 4H), 7.93 (d, J=2.4Hz, 1H), 7.51 (d, J=2.4Hz, 1H), 7.14 (t, J=8.1Hz, 1H), 6.57 (dd, J=9.6, 1.5Hz, 1H), 6.48 (t, 1H), 6.40 (dd, J =8.1, 2.1Hz, 1H), 3.72 (s, 3H), 3.31 (m, 4H), 3.29 (m, 4H); MS (ES): m/z 526.9 (M+l).

Example 73A

N-(5-chloro-6-(4-(3-methoxyphenyl)piperazin- 1 -yl)pyridin-3-yl)-4-(trifluoromethyl) benzenesulfonamide hydrochloride

Compound obtained in Example 73 (100 mg, 0.190 mmol) was dissolved in DCM. To this solution n-butanol (15.47 mg, 0.209 mmol) and trimethylchlorosilane (0.027 mL, 0.209 mmol) were added under stirring. The suspension was stirred for 1 h and the precipitate was filtered off. The solid was washed with DCM and dried to obtain the title compound.

*H NMR (300 MHz, DMSO-d ₆ ): δ 10.84 (s, 1H), 7.98 (m, 5H), 7.56 (d, J=3Hz, 1H), 7.29 (t, J=9Hz, 1H), 6.92 (s, 2H), 6.68 (d, J=9Hz, 1H), 3.75 (s, 3H), 3.48 (d, J=9Hz, 8H).

Example 73B

N-(5-chloro-6-(4-(3-methoxyphenyl)piperazin- 1 -yl)pyridin-3-yl)-4-(trifluoromethyl) benzene sulfonamide hydrobromide

Compound obtained in Example 73 (0.1 g, 0.190 mmol) was dissolved in DCM. To it HBr (0.077 g, 0.949 mmol) was added drop wise. The suspension was stirred for 1 h and the precipitate was filtered off. The solid was washed with DCM and dried to obtain the title compound.

*H NMR (300 MHz, DMSO-d ₆ ): δ 10.69 (s, 1H), 7.98 (d, J=3Hz, 3H), 7.94 (d, J=3Hz, 2H), 7.53 (d, J=3Hz, 1H), 7.22 (t, J=9Hz, 1H), 6.73 (brs, 2H), 6.51 (s, 1H), 4.79 (brs, 8H), 3.82 (s, 3H). Example 74

2-Chloro-N-(5-chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)py ridin-3-yl)-4-(trifluoro methyl)benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(3-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.62 (d, J= 2.4Hz, 1H), 7.12 (m, 1H), 7.06 (d, J=2.4Hz, 1H), 6.55 (m, 1H), 6.46 (m, 1H), 6.36 (d, J= 7.8, 1.8Hz, 1H), 5.17 (s, 2H), 3.69 (s, 3H), 3.31 (m, 4H) 3.1 (m, 4H); MS (ES): m/z 318.12. Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(3- methoxyphenyl)piperazin- 1 -yl)pyridin-3-amine with 2-chloro-4-(trilluoromethyl)benzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 69.5 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 11.03 (s, IH), 8.24 (d, J=8.1Hz, IH), 8.17 (s, IH), 7.98 (d, J=2.1Hz, IH), 7.94 (dd, J=8.4Hz, IH), 7.55 (d, J=2.4Hz, IH), 7.14 (t, J=8.1, 8.1Hz, IH), 6.56 (dd, IH), 6.48 (t, IH), 6.39 (dd, J=8.1, 21Hz, IH), 3.71 (s, 3H), 3.30 (m, 4H), 3.24 (m, 4H); MS (ES): m/z 561 (M+l).

Example 75

4-(N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyrid in-3-yl)sulfamoyl)benzoic acid Step 1 : 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(3-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e

H NMR (300 MHz, DMSO-d ₆ ): δ 7.62 (d, J= 2.4Hz, IH), 7.12 (m, IH), 7.06 (d, J=2.4Hz, IH), 6.55 (m, IH), 6.46 (m, IH), 6.36 (d, J= 7.8, 1.8Hz, IH), 5.17 (s, 2H), 3.69 (s, 3H), 3.31 (m, 4H) 3.1 (m, 4H); MS (ES): m/z 318.12.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(3- methoxyphenyl)piperazin-l-yl)pyridin-3-amine with 4-(chlorosulfonyl)benzoic acid by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 8.15 (d, J=8.1Hz, 2H), 7.86-7.81 (m, 3H), 7.55 (d, J=2.4Hz, IH), 7.18 (t, J=8.1, 8.1Hz, 2H), 6.66 (m, IH), 6.56 (t, IH), 6.47 (m, IH), 4.64 (m, 4H), 3.78 (s, 3H), 3.48 (m, 4H); MS (ES): m/z 503.1 (M+l). Example 76

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-2,4-difluorobenzene sulfonamide

Step 1 : 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(3-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e *H NMR (300 MHz, DMSO-d ₆ ): δ 7.62 (d, J= 2.4Hz, IH), 7.12 (m, IH), 7.06 (d, J=2.4Hz, IH), 6.55 (m, IH), 6.46 (m, IH), 6.36 (d, J= 7.8, 1.8Hz, IH), 5.17 (s, 2H), 3.69 (s, 3H), 3.31 (m, 4H) 3.1 (m, 4H); MS (ES): m/z 318.12.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(3- methoxyphenyl)piperazin-l-yl)pyridin-3-amine with 2,4-fluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.66 (s, IH), 7.98-7.92 (m, 5H), 7.51 (d, J=2.4Hz, IH), 7.75 (t, J=8.4Hz, IH), 6.56 (m, IH), 6.40 (m, IH), 3.72 (s, 3H), 3.24 (m, 4H), 3.22 (m, 4H).

Example 77

3-Chloro-N-(5-chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)py ridin-3-yl)-4-lluorobenzene sulfonamide

Step 1 : 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(3-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.62 (d, J= 2.4Hz, IH), 7.12 (m, IH), 7.06 (d, J=2.4Hz, IH), 6.55 (m, IH), 6.46 (m, IH), 6.36 (d, J= 7.8, 1.8Hz, IH), 5.17 (s, 2H), 3.69 (s, 3H), 3.31 (m, 4H) 3.1 (m, 4H); MS (ES): m/z 318.12.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(3- methoxyphenyl)piperazin- 1 -yl)pyridin-3-amine with 3-chloro-4-fluorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): 610.54 (s, IH), 7.95 (d, IH), 7.94 (m, IH), 7.75 (m, IH), 7.67 (m, IH), 7.52 (d, IH), 7.09 (m, IH), 6.57 (m, IH), 6.48 (s, IH), 6.39(m, IH), 3.74 (s, 3H), 3.25 (m, 4H), 3.23 (m, 4H); MS (ES): m/z 509.1 (M-l), 511.1 (M+l).

Example 78

2,4-Dichloro-N-(5-chloro-6-(4-(3-methoxyphenyl)piperazin-l-y l)pyridin-3-yl)benzene sulfonamide

Step 1 : 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(3-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D). 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e *H NMR (300 MHz, DMSO-d ₆ ): δ 7.62 (d, J= 2.4Hz, IH), 7.12 (m, IH), 7.06 (d, J=2.4Hz, IH), 6.55 (m, IH), 6.46 (m, IH), 6.36 (d, J= 7.8, 1.8Hz, IH), 5.17 (s, 2H), 3.69 (s, 3H), 3.31 (m, 4H) 3.1 (m, 4H); MS (ES): m/z 318.12.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(3- methoxyphenyl)piperazin-l-yl)pyridin-3-amine with 2,4-dichlorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.86 (s, IH), 8.03 (d, J=8.7Hz, IH), 7.97 (d, J=2.4Hz, IH), 7.92 (d, J=1.8Hz, IH), 7.65 (dd, J=8.4, 2.1Hz, IH), 7.61 (m, IH), 7.52 (d, J = 2.4Hz, IH), 6.56 (dd, J = 8.1,1.8 Hz, IH), 6.48 (t, J =1.8 Hz, IH), 6.39 (dd, J = 8.1, 1.8Hz, IH), 3.72 (s, 3H), 3.29 (m, 4H), 3.24 (m, 4H); MS (ES): m/z 527 (M+l).

Example 79

3,4-Dichloro-N-(5-chloro-6-(4-(3-methoxyphenyl)piperazin-l-y l)pyridin-3- yl)benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(3-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(3-methoxyphenyl)piperazin- 1 -yl)pyridin-3-amine

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.62 (d, J= 2.4Hz, IH), 7.12 (m, IH), 7.06 (d, J=2.4Hz,

IH), 6.55 (m, IH), 6.46 (m, IH), 6.36 (d, J= 7.8, 1.8Hz, IH), 5.17 (s, 2H), 3.69 (s, 3H), 3.31

(m, 4H) 3.1 (m, 4H); MS (ES): m/z 318.12.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(3- methoxyphenyl)piperazin-l-yl)pyridin-3-amine with 3,4-dichlorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 75 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.57 (s, IH), 7.93-7.86 (m, 2H), 7.68 (d,

J=7.5Hz, IH), 7.52 (d, J=0.9Hz, IH), 7.14-7.09 (t, J=8.1 Hz, IH), 6.57-6.37 (m, 4H), 3.71 (s,

3H), 3.35 (m, 8H); MS (ES): m/z 529.0. Example 80

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-2,5-dimethoxybenzene sulfonamide Step 1 : 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(3-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.62 (d, J= 2.4Hz, IH), 7.12 (m, IH), 7.06 (d, J=2.4Hz, IH), 6.55 (m, IH), 6.46 (m, IH), 6.36 (d, J= 7.8, 1.8Hz, IH), 5.17 (s, 2H), 3.69 (s, 3H), 3.31 (m, 4H) 3.1 (m, 4H); MS (ES): m/z 318.12.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(3- methoxyphenyl)piperazin- 1 -yl)pyridin-3-amine with 2,5-dimethoxybenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.16 (s, IH), 7.96 (d, J=2.4Hz, IH), 7.52 (d, J=2.1Hz, IH), 7.23 (t, J=5.4, 2.7Hz, IH), 7.18 (m, J=2.7Hz, 2H), 7.14 (t, J=8.1Hz, IH), 6.56 (dd, J=8.1, 1.8 Hz, IH), 6.48 (t, J=1.8 Hz, IH), 6.39 (dd, J= 8.1, 1.8Hz, IH), 3.81 (s, 3H), 3.72 (s, 3H), 3.71 (s, 3H), 3.26 (m, 8H); MS (ES): m/z 519 (M+l), 517 (M-l).

Example 81

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-3,4-dimethoxybenzene sulfonamide

Step 1 : 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(3-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.62 (d, J= 2.4Hz, IH), 7.12 (m, IH), 7.06 (d, J=2.4Hz, IH), 6.55 (m, IH), 6.46 (m, IH), 6.36 (d, J= 7.8, 1.8Hz, IH), 5.17 (s, 2H), 3.69 (s, 3H), 3.31 (m, 4H) 3.1 (m, 4H); MS (ES): m/z 318.12.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(3- methoxyphenyl)piperazin- 1 -yl)pyridin-3-amine with 3,4-dimethoxybenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.22 (s, IH), 7.92 (d, J=2.4Hz, IH), 7.50 (d, J=2.4Hz, IH), 7.32 (dd, J=8.4, 2.1 Hz, IH), 7.22 (d, J=1.8Hz, IH), 7.14 (m, IH), 6.57 (m, 4H), 3.82 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 3.27 (m, 4H), 3.25 (m, 4H); MS (ES): m/z 519.1 (M+l), 517.1 (M-l). Example 82

N-(5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-y l)-[l,l'-biphenyl^

sulfonamide

Step 1 : 5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(3-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(3-methoxyphenyl)piperazin-l-yl)pyridin-3-amin e

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.62 (d, J= 2.4Hz, IH), 7.12 (m, IH), 7.06 (d, J=2.4Hz, IH), 6.55 (m, IH), 6.46 (m, IH), 6.36 (d, J= 7.8, 1.8Hz, IH), 5.17 (s, 2H), 3.69 (s, 3H), 3.31 (m, 4H) 3.1 (m, 4H); MS (ES): m/z 318.12.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(3- methoxyphenyl)piperazin-l-yl)pyridin-3-amine with biphenyl-4-sulfonyl chloride by procedure as described in (E).

Yield: 64.8 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.49 (s, 1H),7.96 (d, J=2.4 Hz, IH), 7.91 (m, 2H), 7.83 (m, 2H), 7.71 (m, 2H), 7.53 (d, J=2.4Hz, IH), 7.50 (m, 3H), 7.14 (t, J=8.1, 8.1 Hz, IH), 6.56 (dd, J=8.1, 1.8 Hz, IH), 6.48 (t, J=1.8 Hz, IH), 6.39 (dd, J=8.1, 1.8 Hz, IH), 3.71 (s, 3H), 3.29 (m, 4H), 3.28 (m, 4H); MS (ES): m/z 535.1 (M+l), 533 (M-l).

Example 83

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dime thylpyridin-3-yl)-3-(trifluoro methyl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-methoxy- phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 6.95 (d, J=7.8Hz, 2H), 6.84 (d, J=7.8Hz, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.28 (m, 4H), 3.15 (m, 4H), 2.31 (s, 3H), 2.26 (s, 3H); MS (ES): m/z 337.19.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- methoxyphenyl)piperazin- 1 -yl)-4,6-dimethylnicotinonitrile with 3-(trifluoromethyl) benzene - 1-sulfonyl chloride, by procedure as described in (E). Yield 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.67 (s, 1H), 8.13 (d, J=7.8Hz, 1H), 8.02 (d, J=7.8Hz, 1H), 7.88-7.85 (m, 2H), 6.97 (d, J=9.0Hz, 2H), 6.85 (d, J=9.0Hz, 2H), 3.71 (m, 4H), 3.69 (s, 3H), 3.13 (m, 4H), 2.04 (s, 3H), 2.01 (s, 3H); MS (ES): m/z 546.0 (M+l). Example 84

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dimethy lpyridin-3-yl)-4-(trifluoro methyl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-methoxy- phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 6.95 (d, J=7.8Hz, 2H), 6.84 (d, J=7.8Hz, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.28 (m, 4H), 3.15 (m, 4H), 2.31 (s, 3H), 2.26 (s, 3H); MS (ES): m/z 337.19.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- methoxyphenyl)piperazin- 1 -yl)-4,6-dimethylnicotinonitrile with 4-(trifluoromethyl) benzene - 1 -sulphonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.95 (s, 1H), 8.03 (d, J=6Hz, 2H), 7.93 (d, J=8.4Hz, 2H), 6.96 (d, J=9.3Hz, 2H), 6.85 (d, J=9Hz, 2H), 3.72 (m, 4H), 3.69 (s, 3H), 3.13 (m, 4H), 2.07(s, 3H), 2.02 (s, 3H); MS (ES): m/z 546.2 (M+l).

Example 85

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)pyridin-3-yl )-4-fluoro-2-methylbenzene sulfonamide

Step 1 : 5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-methoxyphenyl)piperazin- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.92 (d, J=2.7Hz, 1H), 7.27 (d, J=2.7Hz, 1H ), 6.96 (d, J=9Hz, 2H), 6.84 (d, J=9Hz, 2H), 5.30 (s, 2H), 3.69 (s, 3H), 3.34 (m, 4H), 3.26 (m, 4H); MS (ES): m/z 309.16. Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- methoxyphenyl)piperazin- 1 -yl)nicotinonitrile with 4-lluoro-2-methylbenzene- 1 -sulf onyl chloride by procedure as described in (E).

Yield: 72 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.43 (s, IH), 8.09 (d, J=2.7Hz, IH), 7.86- 7.81 (m, IH), 7.66 (d, J=2.7Hz, IH), 7.36 -7.32 (dd, J=9.2, 2.4Hz, IH), 7.22-7.17 (m, J=2.7, 2.4Hz, IH), 6.94 (m, 2H), 6.84 (m, 2H), 3.68 (s, 3H), 3.66 (t, 4H), 3.12 (t, 4H), 2.60 (s, 3H); MS (ES): m/z 482.2 (M+l).

Example 86

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)pyridin-3 -yl)-2,4-difluorobenzene sulfonamide

Step 1 : 5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-methoxyphenyl)piperazin- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.92 (d, J=2.7Hz, IH), 7.27 (d, J=2.7Hz, IH ), 6.96 (d, J=9Hz, 2H), 6.84 (d, J=9Hz, 2H), 5.30 (s, 2H), 3.69 (s, 3H), 3.34 (m, 4H), 3.26 (m, 4H); MS (ES): m/z 309.16.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- methoxyphenyl)piperazin-l-yl)nicotinonitrile with 2,4-difluoro-benzene-l -sulf onyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.67 (s, IH), 8.13 (d, J=2.4Hz, IH), 7.90- 7.82 (m, IH), 7.30 (d, J=2.7Hz, IH), 7.61-7.55 (m, IH), 7.29-7.24 (m, IH), 6.94 (d, J=9.0Hz, 2H), 6.84 (d, J=9.0Hz, 2H), 3.68 (m, 7H), 3.16 (m, 4H); MS (ES): m/z 486.1 (M+l).

Example 87

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dimethy lpyridin-3-yl)-2,4-difluoro benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-methoxy- phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 6.95 (d, J=7.8Hz, 2H), 6.84 (d, J=7.8Hz, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.28 (m, 4H), 3.15 (m, 4H), 2.31 (s, 3H), 2.26 (s, 3H); MS (ES): m/z 337.19.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- methoxyphenyl)piperazin-l-yl)-4,6-dimethylnicotinonitrile with 2,4-difluoro-benzene-l- sulfonyl chloride by procedure as described in (E).

Yield: 73 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.09 (s, IH), 7.79-7.71 (m, IH), 7.66-7.60 (m, IH), 7.29-7.24 (m, IH), 6.95 (m, 2H), 6.85 (m, 2H), 3.72 (m, 7H), 3.13 (m, 4H); MS (ES): m/z 514.5 (M+l).

Example 88

2,4-Dichloro-N-(5-cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl )pyridin-3-yl)benzene sulfonamide

Step 1 : 5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-methoxyphenyl)piperazin- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.92 (d, J=2.7Hz, IH), 7.27 (d, J=2.7Hz, IH ), 6.96 (d, J=9Hz, 2H), 6.84 (d, J=9Hz, 2H), 5.30 (s, 2H), 3.69 (s, 3H), 3.34 (m, 4H), 3.26 (m, 4H); MS (ES): m/z 309.16.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- methoxyphenyl)piperazin-l-yl)nicotinonitrile with 2,4-dichlorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.75 (s, IH), 8.13 (d, J=2.7Hz, IH), 7.98 (d, J=8.4Hz, IH), 7.92 (d, J=2.1Hz, IH), 7.72 (d, J=2.1Hz, IH), 7.63-7.59 (dd, J=8.4, 2.1Hz, IH), 6.94 (m, 2H), 6.84 (m, 2H), 3.68 (s, 3H), 3.66 (m, 4H), 3.12 (m, 4H); MS (ES): m/z 518.1 (M+l).

Example 89

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)pyridin-3 -yl)-3,4-dimethoxybenzene sulfonamide Step 1 : 5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-methoxyphenyl)piperazin- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.92 (d, J=2.7Hz, 1H), 7.27 (d, J=2.7Hz, 1H ), 6.96 (d, J=9Hz, 2H), 6.84 (d, J=9Hz, 2H), 5.30 (s, 2H), 3.69 (s, 3H), 3.34 (m, 4H), 3.26 (m, 4H); MS (ES): m/z 309.16.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- methoxyphenyl)piperazin-l-yl)nicotinonitrile with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.13 (s, 1H), 8.05 (d, J=2.7Hz, 1H), 7.67 (d, J=2.7Hz, 1H), 7.32 (dd, 1H), 7.21 (d, J=2.1Hz, 1H), 7.09 (d, J=6.6Hz, 1H), 6.94 (d, J=9.3Hz, 2H), 6.84 (d, J=9.0Hz, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.68 (s, 3H), 3.65 (m, 4H), 3.11 (m, 4H); MS (ES): m/z 510.2 (M+l).

Example 90

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dimethy lpyridin-3-yl)-3,4- dimethoxybenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-methoxy-phenyl)- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 6.95 (d, J=7.8Hz, 2H), 6.84 (d, J=7.8Hz, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.28 (m, 4H), 3.15 (m, 4H), 2.31 (s, 3H), 2.26 (s, 3H); MS (ES): m/z 337.19.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- methoxyphenyl)piperazin- 1 -yl)-4,6-dimethylnicotinonitrile with 3 ,4-dimethoxybenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 73 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.45 (s, 1H), 7.25-7.22 (dd, J=6.3, 2.1Hz, 1H), 7.14-7.11 (d, 1H), 7.08 (d, J=2.1Hz, 1H), 6.96 (m, 2H), 6.85 (m, 2H), 3.84 (s, 3H), 3.72 (m, 4H), 3.69 (s, 3H), 3.34 (m, 4H), 2.11 (s, 3H), 2.01 (s, 3H); MS (ES): m/z 538.2 (M+l). Example 91

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)pyridin-3-yl )-4-(trifluoromethoxy) benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4-methoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-methoxyphenyl)piperazin- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.92 (d, J=2.7Hz, 1H), 7.27 (d, J=2.7Hz, 1H ), 6.96 (d, J=9Hz, 2H), 6.84 (d, J=9Hz, 2H), 5.30 (s, 2H), 3.69 (s, 3H), 3.34 (m, 4H), 3.26 (m, 4H); MS (ES): m/z 309.16.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- methoxyphenyl)piperazin- 1 -yl)nicotinonitrile with 4-(trifluoromethoxy)benzene- 1 -sulf onyl chloride by procedure as described in (E).

Yield: 68 %; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.42 (s, 1H), 8.06 (d, J=2.7Hz, 1H), 7.87 (m, 2H), 7.67 (d, J=2.7Hz, 1H), 7.60 (d, J=8.1Hz, 2H), 6.94 (d, J=9Hz, 2H), 6.84 (d, J=9Hz, 2H), 3.68 (d, 7H), 3.16 (t, 4H); MS (ES): m/z 534.1 (M+l).

Example 92

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dimethy lpyridin-3-yl)-4-(trifluoro methoxy)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-methoxy- phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-methoxyphenyl)piperazin- 1 -yl)-4,6-dimethylnicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 6.95 (d, J=7.8Hz, 2H), 6.84 (d, J=7.8Hz, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.28 (m, 4H), 3.15 (m, 4H), 2.31 (s, 3H), 2.26 (s, 3H); MS (ES): m/z 337.19.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- methoxyphenyl)piperazin-l-yl)-4,6-dimethylnicotinonitrile with 4-

(trifluoromethoxy)benzene- 1 -sulf onyl chloride by procedure as described in (E). Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.18 (s, 1H), 7.84 (d, J=9Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 6.96 (d, J=9.3Hz, 2H), 6.85 (d, J=9Hz, 2H), 3.71 (s, 3H), 3.1 (m, 4H), 2.07 (s, 3H), 2.03 (s, 3H); MS (ES): m/z 562.2 (M+l). Example 93

N-(5-Cyano-6-(4-(4-methoxyphenyl)piperazin-l-yl)-2,4-dimethy lpyridin-3-yl)-[l,l'- biphenyl] -4-sulf onamide

Step 1 : 5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-methoxy- phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-methoxyphenyl)piperazin-l-yl)-4,6-dimethylni cotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 6.95 (d, J=7.8Hz, 2H), 6.84 (d, J=7.8Hz, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.28 (m, 4H), 3.15 (m, 4H), 2.31 (s, 3H), 2.26 (s, 3H); MS (ES): m/z 337.19.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- methoxyphenyl)piperazin-l-yl)-4,6-dimethylnicotinonitrile with biphenyl-4-sulfonyl chloride by procedure as described in (E).

Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.70 (s, 1H), 7.93 (d, J=9.0Hz, 2H), 7.77 (d, J=9.0Hz, 4H), 7.55-7.45 (m, 3H), 6.96 (m, 2H), 6.85 (m, 2H), 3.72 (m, 4H), 3.69 (s, 3H), 3.14 (m, 4H), 2.12 (s, 3H), 2.07 (s, 3H); MS (ES): m/z 554.2 (M+l).

Example 94

N-(5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin -3-yl)-3-(trifluoromethyl) benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(2,4-dimethoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin-3- amine

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.64 (s, 1H), 7.06 (s, 1H), 6.88 (d, J=8.4Hz, 1H), 6.53 (s, 1H), 6.45 (d, J=8.4Hz, 1H), 5.1 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.1 (m, 8H); MS (ES): m/z 348.14. Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(2,4- dimethoxyphenyl)piperazin- 1 -yl)pyridin-3-amine with 3-(trifluoromethyl)benzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.52 (s, 1H), 8.19 (m, 2H), 7.96 (s, 1H), 7.88 (m, 2H), 7.45 (d, J=2.1Hz, 1H), 6.87 (d, J=8.7Hz, 1H), 6.54 (d, J=2.7Hz, 1H), 6.46 (dd, J=8.4, 2.4Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.31 (m, 4H), 2.99 (m, 4H); MS (ES): m/z 557.1 (M+l).

Example 95

N-(5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyri din-3-yl)-2,4-difluorobenzene sulfonamide

Step 1 : 5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(2,4-dimethoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin- 1 -yl)pyridin-3 -amine

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.64 (s, 1H), 7.06 (s, 1H), 6.88 (d, J=8.4Hz, 1H), 6.53 (s, 1H), 6.45 (d, J=8.4Hz, 1H), 5.1 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.1 (m, 8H); MS (ES): m/z 348.14.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(2,4- dimethoxyphenyl)piperazin-l-yl)pyridin-3-amine with 2,4-difluorobenzene-l -sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.76 (s, 1H), 7.95 (d, J=3.3Hz, 1H), 7.93 (m, 1H), 7.62 (m, 1H), 7.51 (d, J=4.2Hz, 1H), 7.31 (m, 1H), 6.87 (d, J=9.3Hz, 1H), 6.54 (d, J=3.3Hz, 1H), 6.46 (m, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.25 (m, 4H), 2.98 (m, 4H); MS (ES): m/z 525.1 (M+l).

Example 96

2,4-Dichloro-N-(5-chloro-6-(4-(2,4-dimethoxyphenyl)piperazin -l-yl)pyridin-3-yl) benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(2,4-dimethoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin-3- amine *H NMR (300 MHz, DMSO-d ₆ ): δ 7.64 (s, IH), 7.06 (s, IH), 6.88 (d, J=8.4Hz, IH), 6.53 (s, IH), 6.45 (d, J=8.4Hz, IH), 5.1 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.1 (m, 8H); MS (ES): m/z 348.14.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(2,4- dimethoxyphenyl)piperazin-l-yl)pyridin-3-amine with 2,4-dichlorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.84 (s, IH), 8.03 (d, J=8.7Hz, IH), 7.96 (d, J=2.4Hz, IH), 7.93 (d, J=1.8Hz, IH), 7.66 (dd, J=8.7Hz, IH), 7.50 (d, J=8.4Hz,lH), 6.86 (d, J=8.4Hz, IH), 6.54 (d, J=2.4Hz, IH), 6.45 (dd, IH), 3.76 (s, 3H), 3.71 (s, 3H), 3.28 (m, 4H), 2.98 (m, 4H); MS (ES): m/z 559.1.

Example 97

N-(5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin -3-yl)-2,5-dimethoxy benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(2,4-dimethoxy-phenyl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(2,4-dimethoxyphenyl)piperazin-l-yl)pyridin-3- amine

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.64 (s, IH), 7.06 (s, IH), 6.88 (d, J=8.4Hz, IH), 6.53 (s, IH), 6.45 (d, J=8.4Hz, IH), 5.1 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.1 (m, 8H); MS.(ES): m/z 348.14.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(2,4- dimethoxyphenyl)piperazin- 1 -yl)pyridin-3-amine with 2,5-dimethoxybenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.20 (s, IH), 7.91 (d, J=2.4Hz, IH), 7.48 (d, J=2.4Hz, IH), 7.30 (dd, J=8.7, 2.1Hz, IH), 7.22 (d, J=2.1Hz, IH), 7.11 (d, J=8.4Hz, IH), 6.87 (d, J=8.7Hz, IH), 6.54 (d, J=2.4Hz, IH), 6.46 (dd, J=8.7, 2.7Hz, IH), 3.81 (s, 3H), 3.77 (s, 6H), 3.71 (s, 3H), 3.28 (m, 8H); MS (ES): m/z 549 (M+l). Example 98

N-(5-Chloro-6-(4-(pyridin-2-yl)piperazin- 1 -yl)pyridin-3-yl)-4-cyanobenzene sulfonamide

Step 1 : 5-Chloro-6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-pyridin-2-yl-piperazine by procedure as described in (C) and further reduction by procedure described in (D). Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(pyridin-2- yl)piperazin-l-yl)pyridin-3-amine with 4-cyanobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.66 (s, IH), 8.11 (dd, J=1.5Hz, IH), 8.07 (s, IH), 8.04 (s, IH), 7.89-7.86 (m, 3H), 7.55-7.49 (m, IH), 7.49 (d, J=2.4Hz, IH), 6.84 (d, J=8.7Hz, IH), 6.66-6.62 (q, J=6.9, 5.1Hz, IH), 3.58-3.54 (m, 4H), 3.26-3.23 (m, 4H); MS (ES): m/z 455.1 (M+l).

Example 99

2,4-Difluoro-N-(6-(4-(pyridin-2-yl)piperazin-l-yl)-5-(tri fluoromethyl)pyridin-3-yl) benzenesulfonamide

Step 1 : 6-(4-(Pyridin-2-yl)piperazin-l-yl)-5-(trifluoromethyl)pyridi n-3-amine was obtained by reacting 2-chloro-3-trifluoromentyl-5-nitropyridine with l-pyridin-2-yl- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 6-(4-(pyridin-2-yl)piperazin-l- yl)-5-(trifluoromethyl)pyridin-3-amine with 2,4-difluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.95 (s, IH), 8.24 (d, J= 2.4Hz, IH), 8.13 (m, IH), 7.91-7.86 (m, IH), 7.70 (d, J=2.4Hz,lH), 7.58-7.52 (m, 2H), 7.30-7.25 (m, IH), 6.86 (d, J=9Hz, IH), 6.68-6.64 (m, IH), 3.58 (m, 4H), 3.18 (m, 4H); MS (ES): m/z 498.1 (M- 1)·

Example 100

2,4-Dichloro-N-(5-chloro-6-(4-(pyridin-2-yl)piperazin-l-y l)pyridin-3-yl)benzene

sulfonamide

Step 1 : 5-Chloro-6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-pyridin-2-yl-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(pyridin-2- yl)piperazin-l-yl)pyridin-3-amine with 2,4-dichlorobenzene-l-sulfonyl chloride by procedure as described in (E). Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.87 (s, IH), 8.12 (d, J=3.6Hz, IH), 8.03 (d, J=8.7Hz, IH), 7.97 (d, J=1.8Hz, IH), 7.91 (d, J=1.5Hz, IH), 7.64-7.61 (dd, J=8.4, 1.5Hz, IH), 7.57 (d, J=1.5Hz, IH), 7.54-7.512 (m, IH), 6.86 (d, J=8.7Hz, IH), 6.67-6.64 (dd, J=6.6, 5.6Hz, IH), 3.57 (s, 4H), 3.23 (s, 4H); MS (ES): m/z 498.1 (M+l).

Example 101

2,4-Dichloro-N-(6-(4-(pyridin-2-yl)piperazin- 1 -yl)-5-(trifluoromethyl)pyridin3-yl) benzene sulfonamide

Step 1 : 6-(4-(Pyridin-2-yl)piperazin-l-yl)-5-(trifluoromethyl)pyridi n-3-amine was obtained by reacting 2-chloro-3-trifluoromentyl-5-nitropyridine with l-pyridin-2-yl- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 6-(4-(pyridin-2-yl)piperazin-l- yl)-5-(trifluoromethyl)pyridin-3-amine with 2,4-dichlorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 11.10 (s, IH), 8.06 (m, IH), 7.93 (m, 2H), 7.87 (d, J=9.0Hz, IH), 7.73 (d, J= 3.0Hz, IH), 7.67 (dd, J=9.0 Hz, IH), 7.38 (dd, J=9.0 Hz, IH), 7.30 (m, IH), 6.93 (t, J=6.0Hz, IH), 3.72 (m, 4H), 3.27 (m, 4H); MS (ES): m/z 532.0 (M+l).

Example 102

N-(5-Chloro-6-(4-(pyridin-2-yl)piperazin- 1 -yl)pyridin-3-yl)-4-methoxybenzene sulfonamide Step 1 : 5-Chloro-6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-pyridin-2-yl-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(pyridin-2- yl)piperazin-l-yl)pyridin-3-amine with 4-methoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.28 (s, IH), 8.12 (d, J=3.6Hz, IH), 7.92 (d, J=2.1Hz, IH), 7.69 (d, J=8.7Hz, 2H), 7.62 (m, 1H),7.49 (d, J=2.1Hz, IH), 7.11 (d, J=9Hz, 2H), 6.94 (d, J=8.4Hz, IH), 3.81 (s, 3H), 3.60 (m, 4H), 3.27 (m, 4H); MS (ES): m/z 460.2 (M+l). Example 103

N-(5-Chloro-6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-yl)- 3,4-dimethoxyb

sulfonamide

Step 1 : 5-Chloro-6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-pyridin-2-yl-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(pyridin-2- yl)piperazin-l-yl)pyridin-3-amine with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.22 (s, IH), 8.13-8.11 (dd, J=4.5, 1.2Hz, IH), 7.92 (d, J=2.4Hz, IH), 7.56 (m, IH), 7.50 (d, J=2.1Hz, IH), 7.34-7.28 (dd, J=6, 2.1Hz, IH), 7.22 (d, J=2.1Hz, IH), 7.10 (d, J=8.4Hz, IH), 6.88 (d, J=8.4Hz, IH), 6.69-6.65 (dd, J=6.9, 3Hz, IH), 3.81 (s, 3H), 3.76 (s, 3H), 3.60 (m, 4H), 3.27 (m, 4H); MS (ES): m/z 488.1 (M-l).

Example 104

3,5-Dimethoxy-N-(6-(4-(pyridin-2-yl)piperazin-l-yl)-5-(trifl uoromethyl)pyridin-3-yl) benzenesulfonamide

Step 1 : 6-(4-(Pyridin-2-yl)piperazin-l-yl)-5-(trifluoromethyl)pyridi n-3-amine was obtained by reacting 2-chloro-3-trifluoromentyl-5-nitropyridine with l-pyridin-2-yl- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 6-(4-(pyridin-2-yl)piperazin-l- yl)-5-(trifluoromethyl)pyridin-3-amine with 3,5-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 72 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.46 (s, IH), 8.28 (d, J=2.4Hz, IH), 8.06 (m, IH), 7.77 (d, J=3.3Hz, IH), 7.44 (d, J= 9.6Hz, IH), 7.27-7.22 (m, 2H), 7.14 (m, IH), 7.01 (t, J=6.6Hz, IH), 6.81 (m, IH), 3.85 (m, 4H), 3.80 (s, 3H), 3.73 (s, 3H), 3.24 (m, 4H); MS (ES): m/z 524.2 (M+l).

Example 105

3,4-Dimethoxy-N-(6-(4-(pyridin-2-yl)piperazin-l-yl)-5-(trifl uoromethyl)pyridin-3-yl) benzene sulfonamide Step 1 : 6-(4-(Pyridin-2-yl)piperazin-l-yl)-5-(trifluoromethyl)pyridi n-3-amine was obtained by reacting 2-chloro-3-trifluoromentyl-5-nitropyridine with l-pyridin-2-yl- piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 6-(4-(pyridin-2-yl)piperazin-l- yl)-5-(trifluoromethyl)pyridin-3-amine with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.57 (s, 1H), 8.27 (d, J=2.4Hz, 1H), 8.06 (dd, 1H), 7.99-7.94 (m, 1H), 7.74 (d, J=2.4Hz, 1H), 7.34-7.31 (m, 2H), 7.27 (d, J=2.4Hz, 1H), 7.13-7.08 (d, J=2.4Hz, 1H), 3.80 (m, 7H), 3.57 (m, 3H), 3.25 (m, 4H); MS (ES): m/z 524.1 (M+l).

Example 106

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyridin-2-y l)piperazin-l-yl)pyridin-3-yl)- 2,4-difluorobenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyridin-2-yl)p iperazin- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trifluoromethyl-pyridin-2-yl)-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4-

(trifluoromethyl)pyridin-2-yl)piperazin- 1 -yl)nicotinonitrile with 2,4-difluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.56 (s, 1H), 8.49 (s, 1H), 7.79 (m, 1H), 7.14-7.01 (m, 2H), 6.95-6.78 (m, 2H), 3.92 (m, 4H), 3.84 (m, 4H), 2.34 (s, 3H), 2.24 (s, 3H); MS (ES): m/z 553.0 (M+l).

Example 107

N-(5-Cyano-2,4-dimethyl-6-(4-(6-mo holino-4-(trifluoromethyl)pyridin-2-yl)piperazin-l- yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(6-mo holino-4-(trifluoromethyl)pyridin-2-yl) piperazin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5- nitronicotinonitrile with 4-(6-piperazin-l-yl-4-trifluoromethyl-pyridin-2-yl)-mo holine by procedure as described in (C) and further reduction by procedure described in (D). 5-Amino-4,6-dimethyl-2-(4-(6-mo holino-4-(triίluoromethyl)pyridin-2-yl) piperazin- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 6.36 (s, IH), 6.30 (s, IH), 4.87 (s, 2H), 3.67 (m, 8H), 3.48 (m,8H), 2.51 (s, 3H), 2.28 (s, 3H); MS (ES): m/z 461.22.

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(6- mo holino-4-(trifluoromethyl)pyridin-2-yl) piperazin- l-yl)nicotinonitrile with 2,4- dilluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.09 (s, IH), 7.75-7.73 (m, IH), 7.63 (m, IH), 7.27-7.26 (m, IH), 6.63 (d, 2H), 3.67 (m, 12H), 3.48 (m, 4H), 2.17 (s, 3H), 2.12 (s, 3H); MS (ES): m/z 638.3 (M+l).

Example 108

N-(5-Cyano-2,4-dimethyl-6-(4-(6-mo holino-4-(triίluoromethyl)pyridin-2-yl)piperazin-l- yl)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(6-mo holino-4-(triίluoromethyl)pyridin-2-yl) piperazin- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5- nitronicotinonitrile with 4-(6-piperazin-l-yl-4-triίluoromethyl-pyridin-2-yl)-moφhol ine by procedure as described in (C) and further reduction by procedure described in (D).

5- Amino-4,6-dimethyl-2-(4-(6-morpholino-4-(trifluoromethyl)pyr idin-2-yl) piperazin- 1 - yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 6.36 (s, IH), 6.30 (s, IH), 4.87 (s, 2H), 3.67 (m, 8H), 3.48 (m,8H), 2.51 (s, 3H), 2.28 (s, 3H); MS (ES): m z 461.22.

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(6- moφholino-4-(trifluoromethyl)pyridin-2-yl) piperazin- l-yl)nicotinonitrile with 3,4- dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield 68%; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.46 (s, IH), 7.24-7.21 (dd, J= 6.6, 2.1Hz, IH), 7.13-7.09 (m, 2H), 6.34 (d, 2H),3.84 (s, 3H), 3.72 (s, 3H), 3.66 (m, 12H), 3.47 (m, 4H), 2.11 (s, 3H), 2.01 (s, 3H); MS (ES): m/z 662.3 (M+l). Example 109

N-(5-Chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-yl )-4-cyanobenzene sulfonamide Step 1 : 5-Chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 2-piperazin-l-yl-pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(pyrimidin-2- yl)piperazin-l-yl)pyridin-3-amine with 4-cyanobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.70 (s, IH), 8.39 (d, J=4.8Hz, 2H), 8.09 (d, J=8.4Hz, 2H), 7.91-7.89 (m, 3H), 7.52 (d, J=2.4Hz, IH), 6.67-6.64 (t, J=9.6Hz, IH), 3.85- 3.82 (t, 4H), 3.30-3.22 (t, 4H); MS (ES): m/z 456.1 (M+l).

Example 110

N-(5-Chloro-6-(4-(pyrimidin-2-yl)piperazin- 1 -yl)pyridin-3-yl)-4-fluorobenzene sulfonamide Step 1 : 5-Chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 2-piperazin-l-yl-pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(pyrimidin-2- yl)piperazin-l-yl)pyridin-3-amine with 4-fluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.28 (s, IH), 8.38 (d, J=4.5Hz, 2H), 7.91 (d, J=2.4Hz, IH), 7.69 (d, J=8.7Hz, 2H), 7.48 (d, J=2.4Hz, IH), 7.10 (d, J=8.7Hz, 2H), 6.66 (t, J=9.6, 4.8Hz, IH), 3.83 (s, 4H), 3.22 (t, 4H); MS (ES): m/z 449.1 (M+l).

Example 111

N-(5-Cyano-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-yl) -2,4-difluorobenzene sulfonamide

Step 1 : 5-Amino-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 2-piperazin-l-yl-pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(pyrimidin-2- yl)piperazin-l-yl)nicotinonitrile with 2,4-difluorobenzene-l-sulfonyl chloride by procedure as described in (E). Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.23 (s, IH), 8.40 (d, J=3.0Hz, IH), 8.18 (d, J=2.7Hz, 2H), 7.75-7.73 (m, J=8.1 , 2.7 Hz, 4H), 6.68-6.65 (t, J=9.6, 3Hz, IH), 3.87-3.84 (m, 4H), 3.60-3.57 (m, 4H); MS (ES): m/z 458.1 (M+l). Example 112

N-(5-Cyano-2-methyl-6-(4-(pyrimidin-2-yl)pip^

benzenesulfonamide

Step 1 : 5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotin onitrile was obtained by reacting 2-chloro-6-methyl-5-nitronicotinonitrile with 2-piperazin-l-yl- pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotin onitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.39 (d, J= 4.8Hz, 2H), 7.22 (s, IH), 6.67 (t, J=4.8Hz, IH), 5.05 (s, IH), 3.87 (m, 4H), 3.28 (m, 4H), 2.27 (s, 3H); MS (ES): m/z 295.15.

Step 2: The title compound was obtained by reacting 5-amino-6-methyl-2-(4-

(pyrimidin-2-yl)piperazin-l-yl)nicotinonitrile with 2,4-difluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.25 (s, IH), 8.40 (d, J=6.0Hz, 2H), 7.76 (m, IH), 7.61 (m, 2H), 7.26 (m, IH), 6.69 (t, J=6.0Hz, IH), 3.85 (m, 4H), 3.72 (m, 4H), 2.21 (s, 3H); MS (ES): m/z 472.1 (M+l).

Example 113

2,4-Dichloro-N-(5-chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl )pyridin-3-yl)benzene sulfonamide

Step 1 : 5-Chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 2-piperazin-l-yl-pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(pyrimidin-2- yl)piperazin-l-yl)pyridin-3-amine with 2,4-dichlorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.87 (s, IH), 8.38 (d, J=4.5Hz, IH), 8.02 (d, J=6.0Hz, IH), 7.96 (d, J=2.1Hz, 2H), 7.91 (d, J=1.5Hz, IH), 7.64 (dd, J=1.5Hz, IH), 7.52 (d, J=2.1Hz, IH), 6.66 (t, J=9.0, 4.8Hz, IH), 3.86 (s, 4H), 3.21 (s, 4H); MS (ES): m/z 501.1. Example 114

2,4-Dichloro-N-(5-cyano-2-methyl-6-(4-(pyri

sulfonamide

Step 1 : 5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotin onitrile was obtained by reacting 2-chloro-6-methyl-5-nitronicotinonitrile with 2-piperazin-l-yl- pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotin onitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.39 (d, J= 4.8Hz, 2H), 7.22 (s, IH), 6.67 (t, J=4.8Hz, IH), 5.05 (s, IH), 3.87 (m, 4H), 3.28 (m, 4H), 2.27 (s, 3H); MS (ES): m/z 295.15.

Step 2: The title compound was obtained by reacting 5-amino-6-methyl-2-(4- (pyrimidin-2-yl)piperazin-l-yl)nicotinonitrile with 2,4-dichlorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.24 (s, IH), 8.40 (d, J=4.5Hz, 2H), 7.96 (d, J=1.5Hz, IH), 7.84 (d, J=8.4Hz, IH), 7.60-7.57 (m, 2H), 6.69-6.66 (t, J=4.8, 4.5Hz, IH), 3.84 (m, 4H), 3.70 (m, 4H), 2.19 (s, 3H); MS (ES): m/z 504.1 (M+l).

Example 115

3,4-Dichloro-N-(5-cyano-2-methyl-6-(4-(pyrimidin-2-yl)pipera zin-l-yl)pyridin-3-yl) benzenesulfonamide

Step 1 : 5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotin onitrile was obtained by reacting 2-chloro-6-methyl-5-nitronicotinonitrile with 2-piperazin-l-yl- pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.39 (d, J= 4.8Hz, 2H), 7.22 (s, IH), 6.67 (t, J=4.8Hz, IH), 5.05 (s, IH), 3.87 (m, 4H), 3.28 (m, 4H), 2.27 (s, 3H); MS (ES): m z 295.15.

Step 2: The title compound was obtained by reacting 5-amino-6-methyl-2-(4- (pyrimidin-2-yl)piperazin-l-yl)nicotinonitrile with 3,4-dichlorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.03 (s, IH), 8.40 (d, J=4.8Hz, 2H), 7.90- 7.86 (m, 2H), 7.63 (dd, J=2.1Hz, IH), 7.54 (s, IH), 6.69-6.66 (t, J=4.8Hz, IH), 3.87-3.84 (m, 4H), 3.73-3.70 (m, 4H), 2.11 (s, 3H); MS (ES): m/z 504.1 (M+l). Example 116

N-(5-Cyano-2-methyl-6-(4-(pyrimidm

benzenesulfonamide

Step 1 : 5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotin onitrile was obtained by reacting 2-chloro-6-methyl-5-nitronicotinonitrile with 2-piperazin-l-yl- pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotin onitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.39 (d, J= 4.8Hz, 2H), 7.22 (s, IH), 6.67 (t, J=4.8Hz, IH), 5.05 (s, IH), 3.87 (m, 4H), 3.28 (m, 4H), 2.27 (s, 3H); MS (ES): m/z 295.15.

Step 2: The title compound was obtained by reacting 5-amino-6-methyl-2-(4- (pyrimidin-2-yl)piperazin-l-yl)nicotinonitrile with 2,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.45 (s, IH), 8.40 (d, J=3Hz, 2H), 7.54-7.51 (m, J=8.7, 3.0Hz, 2H), 6.72 (d, J=2.1Hz, IH), 6.68-6.65 (t, J= 9.3, 4.5Hz, IH), 6.59 (dd, J=2.1Hz, IH), 3.84-3.83 (d, 9H), 3.67 (m, 4H), 2.22 (s, 3H); MS (ES): m/z 496.2 (M+l).

Example 117

N-(5-Chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-yl )-3,4-dimethoxybenzene sulfonamide

Step 1 : 5-Chloro-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with 2-piperazin-l-yl-pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(pyrimidin-2- yl)piperazin-l-yl)pyridin-3-amine with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 69 %· Ή. NMR (300 MHz, DMSO-d ₆ ): δ 10.25 (s, IH), 8.39 (d, J=4.9 Hz, 2H), 7.92 (d, J=2.4 Hz, IH), 7.51 (d, J=2.4 Hz, IH), 7.32-7.29 (dd, J=2.1 , 2.1 Hz, IH), 7.23 (d, J=2.1 Hz, IH), 7.11 (d, J=8.4 Hz, IH), 6.68-6.65 (t, J=9.3, 4.8 Hz, IH), 3.85 (m, 4H), 3.82 (s, 3H), 3.76 (s, 3H), 3.23-3.20 (m, 4H); MS (ES): m/z 491.1 (M+l). Example 118

N-(5-Cyano-6-(4-(pyrimidin-2-yl)piperazin-l-yl)pyridin-3-yl) -3,4-dimethox

sulfonamide

Step 1 : 5-Amino-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 2-piperazin-l-yl-pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(pyrimidin-2- yl)piperazin-l-yl)nicotinonitrile with 3,4-dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.13 (s, IH), 8.39 (d, J=4.8Hz, 2H), 8.68 (d, J=2.7Hz, IH), 7.68 (d, J=2.7Hz, IH), 7.29-7.26 (J=9.6, 3Hz, IH), 7.22 (d, J=1.8Hz, IH), 7.10 (d, J=6.0Hz, IH), 7.2 (J= 9.6, 3Hz, IH), 3.87-3.84 (m, 4H), 3.60-3.57 (m, 4H); MS (ES): m/z 482.3 (M+l). Example 119

N-(5-Cyano-2-methyl-6-(4-(pyrimidin-2-yl)piperazin- 1 -yl)pyridin-3-yl)-[ 1 , 1 '-biphenyl]-4- sulfonamide

Step 1 : 5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotin onitrile was obtained by reacting 2-chloro-6-methyl-5-nitronicotinonitrile with 2-piperazin-l-yl- pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotin onitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.39 (d, J=4.8Hz, 2H), 7.22 (s, IH), 6.67 (t, J=4.5Hz, IH), 5.75 (s, 2H), 3.87 (m, 4H), 3.28 (s, 4H), 2.27 (s, 3H); MS (ES): m/z 295.15.

Step 2: The title compound was obtained by reacting 5-amino-6-methyl-2-(4-

(pyrimidin-2-yl)piperazin-l-yl)nicotinonitrile with biphenyl-4-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; ^l U NMR (300 MHz, DMSO-d ₆ ): δ 9.86 (s, IH), 8.40 (d, J=6Hz, 2H), 7.92 (d, J=9.0Hz, 2H), 7.75-7.73 (m, 4H), 7.51-7.49 (m, 4H), 6.67 (t, IH), 3.85 (m, 4H), 3.69 (m, 4H), 2.07 (s, 3H); MS (ES): m/z 512.2 (M+l). Example 120

3-Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(5-(trifluorom

yl)pyridin-3-yl)-4-methylbenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(5- trifluoromethyl-pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-4,6-dimethyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile

H NMR (300 MHz, CDC1 ₃ ): δ 8.34 (s, IH), 7.58 (d, J=8.4Hz,lH), 6.55 (d, J=9Hz,lH), 3.99 (m, 2H), 3.83 (m, 2H), 3.67 (m,4H), 3.27 (m, 2H), 2.10 (s, 6H); MS (ES): m/z 390.18.

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(5- (trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3-chloro-4-methylbenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.80 (s, IH), 8.39 (s, IH), 7.72 (d, J=1.5Hz, IH), 7.64 (dd, J=2.4, 6.6Hz, IH), 7.53 (dd, J=1.5, 9.0Hz, IH), 7.39 (d, J=8.1Hz, IH), 6.59 (d, J=9.0Hz, IH), 4.1 (m, 4H), 3.9 (m, 2H), 3.7 (m, 2H), 2.5 (s, 3H), 2.2 (s, 6H), 2.1 (m, 2H); MS (ES): m/z 579.0 (M+l). Example 121

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazep an-l-yl)pyridin-3-yl)-3- (trifluoromethyl)benzenesulfonamide

Step 1 : 5- Amino-2-(4-(5 -(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(5- trifluoromethyl-pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan- l-yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d6): δ 8.34(s, IH), 7.82(d, d=2.7Hz, IH), 7.72(dd, d=9Hz, 2.4Hz, IH), 7.12(d, J=2.4Hz, IH), 6.82(d, J= 9Hz, IH), 4.95(s, 2H), 3.95(m, 2H), 3.75(m, 4H), 3.57(m, 2H), 1.96(m, IH). MS (ES): m/z 362.15

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(5- (trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3-

(trifluoromethyl)benzene-l -sulfonyl chloride by procedure as described in (E) . Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.21 (s, IH), 8.35 (s, IH), 8.0 (d, IH), 7.93- 7.88 (m, 3H), 7.83 (t, IH), 7.73 (d, J=4.8Hz, IH), 7.45 (s, IH), 6.85 (d, J=5.4Hz, IH), 3.92 (s, 4H), 3.76 (m, 2H), 3.67 (m, 2H), 1.93 (t, 2H); MS (ES): m/z 571.2 (M+l). Example 122

N-(5-Cyano-2,4-dimethyl-6-(4-(5-(trifluo

3-(trifluoromethyl)benzenesulfonamide.

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)- l,4-diazepan-l- yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(5-trilluoromethyl-pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-4,6-dimethyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 8.34 (s, IH), 7.58 (d, J=8.4Hz, IH), 6.55 (d, J=9Hz, IH), 3.99 (m, 2H), 3.83 (m, 2H), 3.67 (m, 4H), 3.27 (m, 2H), 2.10 (s, 6H); MS (ES): m/z 390.18.

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(5- (trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3-(trifluoromethyl)benz ene-l-sulfonyl chloride by procedure as described in (E).

Yield: 69 %; H NMR (300 MHz, DMSO-d6): 9.79 (s, IH), 8.39 (s, IH), 7.99 (d, J=6.3Hz, IH), 7.94 (d, J=6.9Hz, IH), 7.92 (m, 2H), 7.56 (t, J=7.8Hz, IH), 7.60 (dd, J=2.4, 13.1Hz, IH), 4.1 (t, 4H), 3.9 (m, 2H), 3.6 (m, 2H), 2.2 (s, 3H), 2.1 (m, 2H), 2.6 (s, 3H); MS (ES): m/z 598.4 (M ⁺ ).

Example 123

N-(5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-di azepan-l-yl)pyridin-3-yl)-4- (trifluoromethyl)benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(5-trifluoromethyl- pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan -l-yl)pyridin-3-amine *H NMR (300 MHz, DMSO-d ₆ ): δ 8.36 (s, IH), 7.66 (d, d=2.7Hz, IH), 7.59 (dd, d=9Hz, 2.4Hz, IH), 7.04 (d, J=2.7Hz, IH), 6.55 (d, J=9Hz, IH), 3.99 (m, 2H), 3.82 (m, 2H), 3.54 (m, 2H), 3.36 (m, 2H), 2.1 (m, 2H); MS (ES): m/z 371.11. Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(5- (trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 4-

(trifluoromethyl)benzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.79 (s, IH), 8.45 (s, IH), 8.05 (d, J=3.00Hz, IH), 7.93 (d, J=9.00Hz, 2H), 7.82 (d, J=9.00Hz, IH), 7.72 (d, J=9.00Hz, 2H), 7.48 (d, J=3.00Hz, IH), 6.89 (d, J=9.00Hz, IH), 4.10 (m, 2H), 3.87 (m, 2H), 3.77 (m, 2H), 3.57 (m, 2H), 2.17 (m, 2H); MS (ES): m/z 580.1 (M+l).

Example 124

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-dia zepan-l-yl)pyridin-3-yl)-4- (trifluoromethyl)benzenesulfonamide

Step 1 : 5- Amino-2-(4-(5 -(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(5- trifluoromethyl-pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan- l-yl)nicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 8.34 (s, IH), 7.82 (d, d=2.7Hz, IH), 7.72 (dd, d=9Hz, 2.4Hz, IH), 7.12 (d, J=2.4Hz, IH), 6.82 (d, J=9Hz, IH), 4.95 (s, 2H), 3.95 (m, 2H), 3.75 (m, 4H), 3.57 (m, 2H), 1.96 (m, IH); MS (ES): m/z 362.15.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(5-

(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 4-

(trifluoromethyl)benzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.33 (s, IH), 8.35 (s, IH), 7.95 (d, 3H), 7.87 (d, 2H), 7.73 (d, J=5.4Hz, IH), 7.50 (s, IH), 6.86 (d, J=6.0Hz, IH), 3.92 (s, 4H), 3.75 (m, 2H), 3.68 (m, 2H), 1.93 (m, 2H); MS (ES): m/z 571.2 (M+l).

Example 125

N-(5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diaze pan-l-yl)pyridin-3-yl)-2- fluorobenzenesulfonamide

Step 1 : 5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan -l-yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(5-trifluoromethyl- pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D). 5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-^^

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.36 (s, IH), 7.66 (d, d=2.7Hz, IH), 7.59 (dd, d=9Hz, 2.4Hz, IH), 7.04 (d, J=2.7Hz, IH), 6.55 (d, J=9Hz, IH), 3.99 (m, 2H), 3.82 (m, 2H), 3.54 (m, 2H), 3.36 (m, 2H), 2.1 (m, 2H); MS (ES): m/z 371.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(5-

(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 2-fluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.80 (s, IH), 8.41 (s, IH), 7.8 (m, 2H), 7.6 (d, J=2.7Hz, 2H), 7.5 (d, J=2.4Hz, IH), 7.2 (m, 2H), 6.5 (d, J=9.0Hz, IH), 3.9 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 3.7 (m, 2H), 3.6 (m, 2H); MS (ES): m/z 529.9 (M+l).

Example 126

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazep an-l-yl)pyridin-3-yl)-2,4- difluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan- l- yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(5- trifluoromethyl-pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan- l-yl)nicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 8.34 (s, IH), 7.82 (d, d=2.7Hz, IH), 7.72 (dd, d=9Hz,

2.4Hz, IH), 7.12 (d, J=2.4Hz, IH), 6.82 (d, J=9Hz, IH), 4.95 (s, 2H), 3.95 (m, 2H), 3.75 (m,

4H), 3.57 (m, 2H), 1.96 (m, IH); MS (ES): m/z 362.15.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(5-

(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 2,4-difluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.44 (s, IH), 8.30 (s, IH), 7.81 (m, IH),

7.67 (s, IH), 7.73 (d, J=5.5Hz, IH), 7.54 (m, 2H), 7.25-7.21 (t, J=5.1Hz, IH), 6.85 (d, J= 6.0

Hz, IH), 3.92 (m, 4H), 3.75 (m, 2H), 3.68 (m, 2H), 1.98 (m, 2H); MS (ES): m/z 539.2 (M+l). Example 127

N-(5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diaze pan-l-yl)pyridin-3-yl)-2,4- difluorobenzenesulfonamide. Step 1 : 5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(5-trifluoromethyl- pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan -l-yl)pyridin-3-amine *H NMR (300 MHz, DMSO-d ₆ ): δ 8.36 (s, IH), 7.66 (d, d=2.7Hz, IH), 7.59 (dd, d=9Hz, 2.4Hz, IH), 7.04 (d, J=2.7Hz, IH), 6.55 (d, J=9Hz, IH), 3.99 (m, 2H), 3.82 (m, 2H), 3.54 (m, 2H), 3.36 (m, 2H), 2.1 (m, 2H); MS (ES): m/z 371.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(5- (trifluoromethyl)pyridin-2-yl)-l ,4-diazepan-l-yl)pyridin-3-amine with 2,4-difluorobenzene- 1-sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 8.39 (s, IH), 7.99 (dd, J=6.9, 2.7Hz, IH), 7.78 (d, J=2.4Hz, IH), 7.60 (dd, J=2.4, 7.5Hz, IH), 7.30 (dd, J=2.4, 7.5Hz, IH), 7.09 (dd, J=2.7, 7.2Hz, IH), 6.85 (m, IH), 6.5 (d, J=9.0Hz, IH), 3.9 (m, 2H), 3.7 (m, 2H), 3.6 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H); MS (ES): m/z 547.9 (M+l).

Example 128

N-(5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diaze pan-l-yl)pyridin-3-yl)-2,6- difluorobenzenesulfonamide.

Step 1 : 5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan -l-yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(5-trifluoromethyl- pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan -l-yl)pyridin-3-amine *H NMR (300 MHz, DMSO-d ₆ ): δ 8.36 (s, IH), 7.66 (d, d=2.7Hz, IH), 7.59 (dd, d=9Hz,

2.4Hz, IH), 7.04 (d, J=2.7Hz, IH), 6.55 (d, J=9Hz, IH), 3.99 (m, 2H), 3.82 (m, 2H), 3.54 (m,

2H), 3.36 (m, 2H), 2.1 (m, 2H); MS (ES): m/z 371.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(5-

(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 2,6-difluorobenzene- 1-sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 8.37 (s, IH), 7.86 (d, J=2.4Hz,

IH), 7.62 (d, J=6.9Hz, IH), 7.58 (d, J=2.4Hz, IH), 7.51 (d, J=6.9Hz, IH), 7.05 (d, J=7.5Hz, IH), 6.87 (m, IH), 6.54 (d, J=7.5Hz, IH), 3.9 (m, 2H), 3.8 (m, 2H), 3.6 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H); MS (ES): m/z 547.9 (M+l).

Example 129

2-Chloro-N-(5-chloro-6-(4-(5-(trifluoromethyl)pyridin-2-y l)-l,4-diazepan-l-yl)pyridm 4-fluorobenzenesulfonamide

Step 1 : 5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(5-trifluoromethyl- pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan -l-yl)pyridin-3-amine *H NMR (300 MHz, DMSO-d ₆ ): δ 8.36 (s, IH), 7.66 (d, d=2.7Hz, IH), 7.59 (dd, d=9Hz, 2.4Hz, IH), 7.04 (d, J=2.7Hz, IH), 6.55 (d, J=9Hz, IH), 3.99 (m, 2H), 3.82 (m, 2H), 3.54 (m, 2H), 3.36 (m, 2H), 2.1 (m, 2H); MS (ES): m/z 371.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(5-

(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 2-chloro-4- fluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 8.39 (s, IH), 7.99 (dd, J=5.7, 3.0Hz, IH), 7.78 (d, J=2.4Hz, IH), 7.60 (dd, J=2.4, 7.5Hz, IH), 7.30 (dd, J=2.4, 7.5Hz, IH), 7.09 (dd, J=2.7, 7.2Hz, IH), 6.85 (m, IH), 6.5 (d, J=9.0Hz, IH), 3.9 (m, 2H), 3.7 (m, 2H), 3.6 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H); MS (ES): m/z 564.3 (M ⁺ ).

Example 130

3-Chloro-N-(5-cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l ,4-diazepan-l-yl)pyridin-3-yl)- 4-fluorobenzenesulfonamide

Step 1 : 5- Amino-2-(4-(5 -(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(5- trifluoromethyl-pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan- l-yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.34 (s, IH), 7.82 (d, d=2.7Hz, IH), 7.72 (dd, d=9Hz,

2.4Hz, IH), 7.12 (d, J=2.4Hz, IH), 6.82 (d, J=9Hz, IH), 4.95 (s, 2H), 3.95 (m, 2H), 3.75 (m,

4H), 3.57 (m, 2H), 1.96 (m, IH); MS (ES): m/z 362.15. Step 2: The title compound was obtained by reacting 5-amino-2-(4-(5- (trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3-chloro-4- fluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.18 (s, IH), 8.36 (s, IH), 7.92 (s, IH), 7.84 (d, J=4.2Hz, IH), 7.74 (s, J=5.4Hz, IH), 7.64-7.58 (m, 2H), 7.52 (d, IH), 6.86 (d, J=5.4Hz, IH), 3.93 (s, 4H), 3.76 (m, 2H), 3.68 (m, 2H), 1.94 (t, 2H); MS (ES): m/z 555.1 (M+l).

Example 131

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazep an-l-yl)pyridin-3-yl)-3-fluoro- 4-methoxybenzenesulfonamide

Step 1 : 5- Amino-2-(4-(5 -(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5- nitronicotinonitrile with l-(5- trifluoromethyl-pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan- l-yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.34 (s, IH), 7.82 (d, d=2.7Hz, IH), 7.72 (dd, d=9Hz,

2.4Hz, IH), 7.12 (d, J=2.4Hz, IH), 6.82 (d, J=9Hz, IH), 4.95 (s, 2H), 3.95 (m, 2H), 3.75 (m,

4H), 3.57 (m, 2H), 1.96 (m, IH); MS (ES): m/z 362.15.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(5- (trifluoromethyl)pyridin-2-yl)-l ,4-diazepan-l-yl)nicotinonitrile with 3-fluoro-4- methoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.02 (s, IH), 8.35 (s, IH), 7.92 (s, IH), 7.73 (d, J=5.7Hz, IH), 7.49-7.44 (m, 3H), 7.32-7.29 (t, J=5.1, 4.8Hz, IH), 6.86 (d, J=5.4Hz, IH), 3.92 (s, 4H), 3.90 (s, 3H), 3.75 (m, 2H), 3.68 (m, 2H), 1.98 (m, 2H); MS (ES): m/z 551.2 (M+l).

Example 132

3-Chloro-N-(5-cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l ,4-diazepan-l-yl)pyridin-3- yl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan- l- yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(5- trifluoromethyl-pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D). 5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2^

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.34 (s, IH), 7.82 (d, d=2.7Hz, IH), 7.72 (dd, d=9Hz, 2.4Hz, IH), 7.12 (d, J=2.4Hz, IH), 6.82 (d, J=9Hz, IH), 4.95 (s, 2H), 3.95 (m, 2H), 3.75 (m, 4H), 3.57 (m, 2H), 1.96 (m, IH); MS (ES): m/z 362.15.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(5-

(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3-chlorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.17 (s, IH), 8.35 (s, IH), 7.91 (s, IH), 7.73 (m, IH), 7.66 (s, IH), 7.60 (m, 2H), 7.48 (s, IH), 6.85 (d, J=5.4Hz, IH), 3.92 (s, 4H), 3.76 (t, 3H), 3.68 (m, 2H), 1.98 (m, 2H); MS (ES): m/z 537.1 (M+l).

Example 133

3- Chloro-N-(5-chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l, 4-diazepan-l-yl)pyridin-3- yl)benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(5-trifluoromethyl- pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan -l-yl)pyridin-3-amine

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.36 (s, IH), 7.66 (d, d=2.7Hz, IH), 7.59 (dd, d=9Hz, 2.4Hz, IH), 7.04 (d, J=2.7Hz, IH), 6.55 (d, J=9Hz, IH), 3.99 (m, 2H), 3.82 (m, 2H), 3.54 (m, 2H), 3.36 (m, 2H), 2.1 (m, 2H); MS (ES): m/z 371.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(5- (trifluoromethyl)pyridin-2-yl)-l ,4-diazepan-l-yl)pyridin-3-amine with 3-chlorobenzene-l- sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.79 (s, IH), 8.43 (s, IH), 7.79 (d, J=2.4Hz, IH), 7.93 (m, 2H), 7.82 (d, J=7.8Hz, IH), 7.72 (d, J=6.8Hz, 2H), 7.47 (d, J=2.4Hz, IH), 6.87 (d, J=7.8Hz, IH), 4.10 (m, 2H), 3.87 (m, 2H), 3.75 (m, 2H), 3.57 (m, 2H), 2.14 (m, 2H); MS (ES): m/z 546.0 (M+l).

Example 134

4- Chloro-N-(5-chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l, 4-diazepan-l-yl)pyridin-3- yl)benzenesulfonamide Step 1 : 5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(5-trifluoromethyl- pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan -l-yl)pyridin-3-amine *H NMR (300 MHz, DMSO-d ₆ ): δ 8.36 (s, IH), 7.66 (d, d=2.7Hz, IH), 7.59 (dd, d=9Hz, 2.4Hz, IH), 7.04 (d, J=2.7Hz, IH), 6.55 (d, J=9Hz, IH), 3.99 (m, 2H), 3.82 (m, 2H), 3.54 (m, 2H), 3.36 (m, 2H), 2.1 (m, 2H); MS (ES): m/z 371.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(5- (trifluoromethyl)pyridin-2-yl)-l ,4-diazepan-l-yl)pyridin-3-amine with 4-chlorobenzene-l- sulfonyl chloride by procedure as described in (E).

Yield: 70 %; H NMR (300 MHz, DMSO-d ₆ ): 9.80 (s, IH), 8.3 (s, IH), 8.1 (d, J=8.4Hz, 2H), 7.9 (d, J=6.3Hz, 2H), 7.7 (d, J=2.1Hz, IH), 7.4 (dd, J=6.3, 2.4HZ, IH), 7.2 (d, J=2.4Hz, IH), 6.5 (d, J=9.0Hz, IH), 3.9 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 3.7 (m, 2H), 3.6 (m, 2H); MS (ES): m z 546.3 (M+l).

Example 135

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazep an-l-yl)pyridin-3-yl)-2,5- dimethoxybenzenesulfonamide

Step 1: 5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan- l- yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(5- trifluoromethyl-pyridin-2-yl)- [ 1 ,4] diazepane by

procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan- l-yl)nicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 8.34 (s, IH), 7.82 (d, d=2.7Hz, IH), 7.72 (dd, d=9Hz,

2.4Hz, IH), 7.12 (d, J=2.4Hz, IH), 6.82 (d, J=9Hz, IH), 4.95 (s, 2H), 3.95 (m, 2H), 3.75 (m,

4H), 3.57 (m, 2H), 1.96 (m, IH); MS (ES): m/z 362.15.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(5-

(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 2,5-dimethoxybenzene- 1-sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.84 (s, IH), 8.35 (s, IH), 7.99 (s, IH), 7.73

(d, J=5.4Hz, IH), 7.50 (s, IH), 7.18 (m, 3H), 6.85 (d, J=5.4Hz, IH), 3.89 (m, 3H), 3.73 (m,

5H), 3.70 (s, 3H), 3.66 (s, 3H), 1.92 (m, 2H); MS (ES): m/z 563.2 (M+l). Example 136

N-(5-Cyano-2,4-dimethyl-6-(4-(5-(trifluoromethyl)pyridin-2-y l)piperazin-l-yl)pyrW

2,5-dimethoxybenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(5- trifluoromethyl-pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-4,6-dimethyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile

H NMR (300 MHz, CDC1 ₃ ): δ 8.34 (s, IH), 7.58 (d, J=8.4Hz,lH), 6.55 (d, J=9Hz,lH), 3.99 (m, 2H), 3.83 (m, 2H), 3.67 (m,4H), 3.27 (m, 2H), 2.10 (s, 6H); MS (ES): m/z 390.18.

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(5- (trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 2,5-dimethoxybenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.82 (s, IH), 8.37 (s, IH), 7.63 (dd, J=6.9, 2.1Hz, IH), 7.09 (d, J=12.0Hz, IH), 7.13 (dd, J=3.0, 6.0Hz, IH), 6.58 (d, J=9Hz, IH), 6.46 (s, IH), 4.1 (m, 4H), 4.0 (s, 6H), 3.9 (m, 2H), 3.7 (m, 2H), 2.5 (s, 6H), 2.2 (m, 2H); MS (ES): m/z 590.6 (M+l). Example 137

N-(5-Cyano-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazep an-l-yl)pyridin-3-yl)-3,4- dimethoxybenzenesulfonamide

Step 1 : 5- Amino-2-(4-(5 -(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(5- trifluoromethyl-pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan- l-yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.34 (s, IH), 7.82 (d, d=2.7Hz, IH), 7.72 (dd, d=9Hz, 2.4Hz, IH), 7.12 (d, J=2.4Hz, IH), 6.82 (d, J=9Hz, IH), 4.95 (s, 2H), 3.95 (m, 2H), 3.75 (m, 4H), 3.57 (m, 2H), 1.96 (m, IH); MS (ES): m/z 362.15.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(5- (trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3 ,4-dimethoxybenzene- 1 -sulfonyl chloride by procedure as described in (E). Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.88 (s, IH), 8.36 (s, IH), 7.92 (s, IH), 7.74 (d, J=5.4Hz, IH), 7.4 (s, IH), 7.20 (m, 2H), 7.05 (d, J=4.8Hz, IH), 6.86 (d, J=5.4Hz, IH), 3.94 (s, 4H), 3.80 (s, 3H), 3.74 (m, 5H), 3.67 (m, 2H), 1.93 (t, 2H); MS (ES): m/z 563.2 (M+l).

Example 138

N-(5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diaze pan-l-yl)pyridin-3-yl)-3,4- dimethoxybenzenesulfonamide

Step 1 : 5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3- amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(5-trifluoromethyl- pyridin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(5-(trifluoromethyl)pyridin-2-yl)-l,4-diazepan -l-yl)pyridin-3-amine

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.36 (s, IH), 7.66 (d, d=2.7Hz, IH), 7.59 (dd, d=9Hz, 2.4Hz, IH), 7.04 (d, J=2.7Hz, IH), 6.55 (d, J=9Hz, IH), 3.99 (m, 2H), 3.82 (m, 2H), 3.54 (m,

2H), 3.36 (m, 2H), 2.1 (m, 2H); MS (ES): m/z 371.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(5-

(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 3,4- dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 8.35 (s, IH), 7.84 (d, J=2.4Hz,

IH), 7.62 (d, J=6.9Hz, IH), 7.58 (d, J=2.4Hz, IH), 7.51 (d, J=6.9Hz, IH), 7.05 (d, J=7.8Hz,

IH), 6.87 (m, IH), 6.53 (d, J=7.8Hz, IH), 3.9 (m, 2H), 3.8 (m, 2H), 3.6 (m, 2H), 3.5 (m, 2H),

2.0 (m, 2H); MS (ES): m/z 572.0 (M+l). Example 139

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3-yl)-4-isopropylbenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )- 1 ,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D). Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 4-isopropylbenzene- 1-sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 7.3 (d, J=7.4Hz, 2H), 7.6 (d, J=11.4Hz, 2H), 8.3 (d, J=4.5Hz, IH), 6.7 (d, J=5.1Hz, IH), 4.1 (m, 4H), 3.8 (m, 4H), 3.0 (m, IH), 2.2 (s, 6H), 2.1 (m, 2H), 1.9 (m, 6H); MS (ES): m/z 573.6 (M+l).

Example 140

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3-yl)-4-fluoro-2-methylbenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )- 1 ,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4-

(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 4-fluoro-2- methylbenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.80 (s, IH), 7.84 (d, J=5.7Hz, IH), 7.71 (dd, J=2.4, 5.4Hz, IH), 7.08 (d, J=2.4Hz, IH), 7.01 (d, J=10.2Hz, IH), 6.58 (d, J=9.3Hz, IH), 4.1 (m, 4H), 3.9 (m, 2H), 3.6 (m, 2H), 2.6 (s, 3H), 2.2 (s, 6H), 2.1 (m, 2H); MS (ES): m/z 563.5 (M+l).

Example 141

N-(5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-dia zepan-l-yl)pyridin-3-yl)-4- fluoro-2-methylbenzenesulfonamide

Step 1 : 5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-

3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(4-trifluoromethyl- pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine

*H NMR (300 MHz, CDC1 ₃ ): δ 8.48 (d, J=4.5Hz,lH), 7.66 (d, d=2.7Hz, IH), 7.04 (d, d=2.7Hz, IH), 6.72 (d, J=3.0Hz, IH), 4.09 (m, 2H), 3.93 (m, 2H), 3.69 (m, 2H), 3.38 (m,

2H), 2.10 (m, 2H); MS (ES): m/z 372.11. Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 4-fluoro-2- methylbenzene-l-sulfonyl chloride by procedure as described in (E).

Yield 69%; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 8.53 (d, J=7.2Hz, IH), 7.72 (m, 2H), 7.53 (m, IH), 7.49 (d, J=2.4Hz, IH), 7.3 (d, J=2.4Hz, IH), 6.7 (d, J=7.2Hz, IH), 4.0 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 3.3 (m, 2H), 2.65 (s, 3H), 2.0 (m, 2H); MS (ES): m/z 544.9 (M+l).

Example 142

3-Chloro-N-(5-chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl )-l,4-diazepan-l-yl)pyridin-3- yl)-4-methylbenzenesulfonamide

Step 1 : 5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin- 3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(4-trifluoromethyl- pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine *H NMR (300 MHz, CDC1 ₃ ): δ 8.48 (d, J=4.5Hz,lH), 7.66 (d, d=2.7Hz, IH), 7.04 (d, d=2.7Hz, IH), 6.72 (d, J=3.0Hz, IH), 4.09 (m, 2H), 3.93 (m, 2H), 3.69 (m, 2H), 3.38 (m, 2H), 2.10 (m, 2H); MS (ES): m/z 372.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 3-chloro-4- methylbenzene-l-sulfonyl chloride by procedure as described in (E).

Yield 70%; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 8.5 (d, J=2.4Hz, IH), 7.7 (d, J=1.8Hz, 2H), 7.5 (d, J=1.8Hz, IH), 7.49 (d, J=2.4Hz, IH), 7.3 (d, J=8.1Hz, IH), 6.7 (d, J=4.8Hz, IH), 4.0 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 3.3 (m, 2H), 2.0 (m, 2H).

Example 143

3-Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)py rimidin-2-yl)-l,4-diazepan-l- yl)pyridin-3-yl)benzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )-l,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D). Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3-chloro-4- methylbenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.77 (s, IH), 8.51 (d, J=4.8Hz, IH), 7.97 (d ,J=7.8Hz, IH), 7.92 (d, J=7.8Hz, IH), 7.72 (t, J=8.1Hz, IH), 6.79 (d, J=4.8Hz, IH), 4.1 (m, 4H), 3.9 (t, 2H), 3.6 (t, 2H), 2.6 (s, 3H), 2.4 (s, 6H), 2.2 (m, 2H); MS (ES): m/z 580.0 (M+l).

Example 144

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3-yl)-2-(trifluoromethyl)benzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )- 1 ,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trilluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4-

(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 2-

(trifluoromethyl)benzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 8.5 (d, J=4.8Hz, IH), 8.1 (d, J=7.8Hz, IH), 7.8 (m, 2H), 7.6 (t, J=7.5Hz, IH), 6.8 (d, J=4.8Hz, IH), 4.1 (m, 4H), 3.8 (m, 4H), 2.3 (s, 6H), 2.1.(m, 2H); MS (ES): m/z 599.5 (M+l).

Example 145

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )-l,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trilluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)-l,4-diazepan-l-yl)nicotinon itrile with 3-(trifluoromethyl) benzene- 1-sulfonyl chloride by procedure as described in (E). Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.80 (s, IH), 8.5 (d, J=6.9Hz, IH), 7.7 (m, IH), 7.05 (m, 2H), 6.7 (m, IH), 6.5 (d, J=6.9Hz, IH), 4.1 (m, 2H), 3.7 (m, 2H), 3.6 (m, 2H), 3.3 (m, 2H), 2.0 (m, 2H); MS (ES): m/z 599.5 (M+l). Example 146

N-(5-Cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-diaz epan-l-yl)pyridin

(trifluoromethyl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4- trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.61 (d, J=4.5Hz, IH), 8.48 (d, J=4.2Hz,lH), 7.76 (d,

J=4.5Hz, IH), 6.94 (d, J=4.2Hz, IH), 4.94 (s, 2H), 3.97 (m, 4H), 3.75 (m, 4H), 3.61 (m, 2H); MS (ES): m/z 363.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-

(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3-

(trifluoromethyl)benzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.20 (s, IH), 8.59 (d, J=4.5Hz, IH), 8.05 (d, J=7.8Hz, IH), 7.90-7.77 (m, 4H), 7.44 (m, IH), 6.91 (s, IH), 3.94 (m, 4H), 3.78 (m, 4H),

1.96 (bs, 2H); MS (ES): m z 572.2 (M+l).

Example 147

N-(5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-dia zepan-l-yl)pyridin-3-yl)-3- (trifluoromethyl)benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-

3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(4-trifluoromethyl- pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine

*H NMR (300 MHz, CDC1 ₃ ): δ 8.48 (d, J=4.5Hz, IH), 7.66 (d, d=2.7Hz, IH), 7.04 (d, d=2.7Hz, IH), 6.72 (d, J=3.0Hz, IH), 4.09 (m, 2H), 3.93 (m, 2H), 3.69 (m, 2H), 3.38 (m,

2H), 2.10 (m, 2H); MS (ES): m/z 372.11. Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 3-

(trifluoromethyl)benzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.79 (s, IH), 8.48 (d, J=6.0Hz, IH), 7.92 (d, J=8.7Hz, IH ), 7.86 (d, J=8.7Hz, IH), 7.67 (t, J=8.4Hz, IH), 7.61 (m, IH), 7.41 (d, J=2.7Hz, IH), 6.75 (d, J=6.0Hz, IH), 6.47 (m, IH), 4.08 (t, J=6.0Hz, 2H), 3.84 (t, J=6.0Hz, 2H), 3.76 (t, J=6.0Hz, 2H), 3.63 (m, 2H), 2.09-2.01(m, 2H); MS (ES): m/z 581.0 (M+l).

Example 148

N-(5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4- diazepan-l-yl)pyridin-3-yl)-4- (trifluoromethyl)benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin- 3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(4-trifluoromethyl- pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine *H NMR (300 MHz, CDC1 ₃ ): δ 8.48 (d, J=4.5Hz, IH), 7.66 (d, d=2.7Hz, IH), 7.04 (d, d=2.7Hz, IH), 6.72 (d, J=3.0Hz, IH), 4.09 (m, 2H), 3.93 (m, 2H), 3.69 (m, 2H), 3.38 (m, 2H), 2.10 (m, 2H); MS (ES): m/z 372.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(4-

(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 4-

(trifluoromethyl)benzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.79 (s, IH), 8.48 (d, J=6.8Hz, IH), 7.88 (d, J=8.4Hz, 2H), 7.77 (d, J=8.4Hz, 2H), 7.67 (d, J=2.1Hz, IH ), 7.44 (d, J=2.1Hz, IH), 6.75 (d, J=6.8Hz, IH), 4.08 (t, J=5.7Hz, 2H), 3.86 (t, J=5.7Hz, 2H), 3.77 (t, J=5.7Hz, 2H), 3.63 (t, J=5.7Hz, 2H), 2.10-2.02 (m, 2H); MS (ES): m/z 580.0 (M+).

Example 149

N-(5-Cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-diaz epan-l-yl)pyridin-3-yl)-4- (trifluoromethyl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4- trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 8.61 (d, J=4.5Hz, IH), 8.48 (d, J=4.2Hz,lH), 7.76 (d, J=4.5Hz, IH), 6.94 (d, J=4.2Hz, IH), 4.94 (s, 2H), 3.97 (m, 4H), 3.75 (m, 4H), 3.61 (m, 2H); MS (ES): m/z 363.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 4-

(trifluoromethyl)benzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.35 (s, IH), 8.57 (d, IH), 7.95-7.84 (m, 5H), 7.47 (d, J= 8.4Hz, IH), 6.90 (s, IH), 3.95 (s, 4H), 3.77 (m, 4H), 1.96 (bs, 2H); MS (ES): m/z 572.2 (M+l).

Example 150

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidi n-2-yl)-l,4-diazepan-l- yl)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )- 1 ,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 4-(trifluoromethyl) benzene- 1-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.80 (s, IH), 7.9 (d, J=8.1Hz, 2H), 7.8 (d, J=8.4Hz, 2H), 8.5 (d, J=4.8Hz, IH), 6.7 (d, J=4.8Hz, IH), 4.1 (m, 4H), 3.8 (m, 4H), 2.3 (s, 6H), 2.1.(m, 2H); MS (ES): m/z 599.5 (M+l).

Example 151

N-(5-Cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-diaz epan-l-yl)pyridin-3-yl)-2,4- difluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4- trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 8.61 (d, J=4.5Hz, IH), 8.48 (d, J=4.2Hz,lH), 7.76 (d, J=4.5Hz, IH), 6.94 (d, J=4.2Hz, IH), 4.94 (s, 2H), 3.97 (m, 4H), 3.75 (m, 4H), 3.61 (m, 2H); MS (ES): m/z 363.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 2,4-difluorobenzene- 1-sulfonyl chloride by procedure as described in (E).

Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.41 (s, IH), 8.59 (d, J=3.9Hz, IH), 7.94 (s, IH), 7.77 (m, IH), 7.56-7.48 (m, 2H), 7.25-7.20 (dt, J=8.4, 6.8, 2.1Hz, IH), 6.92 (s, IH), 4.09-3.95 (m, 4H), 3.78 (m, 4H), 1.88 (bs, 2H); MS (ES): m/z 540.1 (M+l).

Example 152

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidi n-2-yl)-l,4-diazepan-l- yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )- 1 ,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 2,4-difluorobenzene- 1-sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.80 (s, IH), 8.6 (d, J=4.8Hz, IH), 7.8 (dd, J=10.7, 3.0Hz, IH), 7.4 (dd, J=2.4, 10.5Hz, IH), 7.2 (dd, J=5.7, 2. 4Hz, IH), 6.5 (d, J=4.8Hz, IH), 4.1 (m, 4H), 3.8 (m, 4H), 2.4 (s, 6H), 2.2 (m, 2H); MS (ES): m/z 567.5 (M+l).

Example 153

N-(5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-dia zepan-l-yl)pyridin-3-yl)-2,3,4- trifluorobenzenesulfonamide

Step 1 : 5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin- 3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(4-trifluoromethyl- pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine *H NMR (300 MHz, CDC1 ₃ ): δ 8.48 (d, J=4.5Hz, IH), 7.66 (d, d=2.7Hz, IH), 7.04 (d, d=2.7Hz, IH), 6.72 (d, J=3.0Hz, IH), 4.09 (m, 2H), 3.93 (m, 2H), 3.69 (m, 2H), 3.38 (m, 2H), 2.10 (m, 2H); MS (ES): m/z 372.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 2,3,4- trifluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield 65%; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.78 (s, IH), 8.5 (d, J=7.8Hz, IH), 7.8 (d, J=2.4Hz, IH), 7.6 (d, J=2.4Hz, IH), 7.49 (d, J=6.9Hz, IH), 7.10 (d, J=6.9Hz, IH), 6.78 (d, J=7.8Hz, IH), 3.9 (m, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 3.1 (m, 2H) 1.98 (m, 2H); MS (ES): m/z 566.9 (M+l). Example 154

2-Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)py rimidin-2-yl)-l,4-diazepan-l- yl)pyridin-3-yl)-4-fluorobenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )- 1 ,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4-

(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 2-chloro-4- fluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 68 % ; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 8.5 (d, J=4.8Hz, IH), 7.9 (dd,

J=10.7, 3.0Hz, IH), 7.3 (dd, J=2.4, 10.5Hz, IH), 7.1 (dd, J=5.7, 2. 4Hz, IH), 6.7 (d, J=4.8Hz,

IH), 4.1 (m, 4H), 3.8 (m, 4H), 2.3 (s, 6H), 2.2 (m, 2H); MS (ES): m z 583.9 (M+l).

Example 155

3-Chloro-N-(5-cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2- yl)-l,4-diazepan-l-yl)pyridin-3- yl)-4-fluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4- trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 8.61 (d, J=4.5Hz, IH), 8.48 (d, J=4.2Hz,lH), 7.76 (d, J=4.5Hz, IH), 6.94 (d, J=4.2Hz, IH), 4.94 (s, 2H), 3.97 (m, 4H), 3.75 (m, 4H), 3.61 (m, 2H); MS (ES): m/z 363.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3-chloro-4- fluorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.16 (s, IH), 8.60 (d, J=4.2Hz, IH), 7.88- 7.81 (m, 2H), 7.61-7.56 (m, 2H), 7.47 (m, IH), 6.92 (s, IH), 3.95 (s, 4H), 3.79-3.77 (m, 4H), 1.89 (brs, 2H); MS (ES): m/z 556.1 (M+l).

Example 156

N-(5-Cyano-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-d iazepan-l-yl)pyridin-3-yl)-3- fluoro-4-methoxybenzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4- trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 8.61 (d, J=4.5Hz, IH), 8.48 (d, J=4.2Hz,lH), 7.76 (d, J=4.5Hz, IH), 6.94 (d, J=4.2Hz, IH), 4.94 (s, 2H), 3.97 (m, 4H), 3.75 (m, 4H), 3.61 (m, 2H); MS (ES): m/z 363.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-

(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3-fluoro-4- methoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.99 (s, IH), 8.59 (d, J=3.6Hz, IH), 7.87 (s, IH), 7.43 (m, 3H), 7.32-7.26 (m, IH), 6.91 (s, IH), 3.95 (m, 4H), 3.88 (s, 3H), 3.79-3.75 (m, 4H), 1.96 (brs, 2H); MS (ES): m z 552.2 (M+l). Example 157

3-Chloro-N-(5-cyano-6-(4-(4-(trifluoro

yl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4- trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 8.61 (d, J=4.5Hz, IH), 8.48 (d, J=4.2Hz,lH), 7.76 (d, J=4.5Hz, IH), 6.94 (d, J=4.2Hz, IH), 4.94 (s, 2H), 3.97 (m, 4H), 3.75 (m, 4H), 3.61 (m, 2H); MS (ES): m/z 363.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3-chlorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.17 (s, IH), 8.60 (s, IH), 7.88 (m, IH), 7.74 (d, IH), 7.67 (s, IH), 7.59 (m, 2H), 7.48 (d, IH), 6.93 (m, IH), 4.01 (m, 4H), 3.80 (m, 4H), 1.91 (brs, 2H); MS (ES): m/z 538.1 (M+l).

Example 158

3-Chloro-N-(5-chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l-yl)pyridin-3- yl)benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-

3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(4-trifluoromethyl- pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine

*H NMR (300 MHz, CDC1 ₃ ): δ 8.48 (d, J=4.5Hz, IH), 7.66 (d, d=2.7Hz, IH), 7.04 (d, d=2.7Hz, IH), 6.72 (d, J=3.0Hz, IH), 4.09 (m, 2H), 3.93 (m, 2H), 3.69 (m, 2H), 3.38 (m,

2H), 2.10 (m, 2H); MS (ES): m/z 372.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(4-

(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 3-chlorobenzene- 1 - sulfonyl chloride by procedure as described in (E). Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.80 (s, 1H), 8.5 (d, J=4.5Hz, 2H), 7.7 (m, 2H), 7.05 (m, 2H), 6.7 (m, 2H ), 3.9 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 3.7 (m, 2H), 3.6 (m, 2H); MS (ES): m/z 547.3 (M+l). Example 159

3-Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)py rimidin-2-yl)-l,4-diazepan-l- yl)pyridin-3-yl)benzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )- 1 ,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4-

(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3-chlorobenzene- 1 -sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.82 (s, 1H), 7.74 (dd, J=1.8, 3.6Hz, 1H), 7.62 (dd,

J=1.5Hz, 1H), 7.63 (d, J=3.3Hz, 1H), 7.61 (d, J=3.6Hz, 1H), 7.49 (t, J =7.8Hz, 1H), 6.59 (d,

J=9.0Hz, 1H), 4.1 (m, 4H), 3.9 (m, 2H), 3.6 (m, 2H), 2.2 (s, 6H), 2.1 (m, 2H); MS (ES): m z 566.0

(M+l). Example 160

4-Chloro-N-(5-chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl )-l,4-diazepan-l-yl)pyridin-3- yl)benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin- 3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(4-trifluoromethyl- pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine *H NMR (300 MHz, CDC1 ₃ ): δ 8.48 (d, J=4.5Hz, 1H), 7.66 (d, d=2.7Hz, 1H), 7.04 (d, d=2.7Hz, 1H), 6.72 (d, J=3.0Hz, 1H), 4.09 (m, 2H), 3.93 (m, 2H), 3.69 (m, 2H), 3.38 (m, 2H), 2.10 (m, 2H); MS (ES): m/z 372.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 4-chlorobenzene- 1 - sulfonyl chloride by procedure as described in (E). Yield 70%; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 8.4 (d, J=7.8Hz, 2H), 8.1 (d, J=2.4Hz, IH), 7.9 (d, J=6.9Hz, 2H), 7.7 (d, J=2.4Hz, IH), 7.4 (d, J=6.9Hz, 2H), 3.9 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 3.7 (m, 2H), 3.6 (m, 2H); MS (ES): m/z 547.3 (M+l). Example 161

2,4-Dichloro-N-(5-cyano-6-(4-(4-(trifluorom

3-yl)benzenesulfonamide

Step 1 : 5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 - yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with l-(4- trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile *H NMR (300 MHz, DMSO-d ₆ ): δ 8.61 (d, J=4.5Hz, IH), 8.48 (d, J=4.2Hz,lH), 7.76 (d, J=4.5Hz, IH), 6.94 (d, J=4.2Hz, IH), 4.94 (s, 2H), 3.97 (m, 4H), 3.75 (m, 4H), 3.61 (m, 2H); MS (ES): m/z 363.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 2,4-dichlorobenzene- 1-sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.47 (s, IH), 8.56 (d, IH), 7.94-7.86 (m, 3H), 7.59-7.55 (dd, J=8.4, 1.8Hz, IH), 7.51 (d, J=9Hz, IH), 6.91 (s, IH), 3.94.(s, 4H), 3.77.(m, 4H), 1.87.(s, 2H); MS (ES): m/z 572.1 (M+l).

Example 162

2,4-Dichloro-N-(5-chloro-6-(4-(4-(trifluoromethyl)pyrimidin- 2-yl)-l,4-diazepan-l- yl)pyridin-3-yl)benzenesulfonamide

Step 1 : 5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-

3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(4-trifluoromethyl- pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine

*H NMR (300 MHz, CDC1 ₃ ): δ 8.48 (d, J=4.5Hz, IH), 7.66 (d, d=2.7Hz, IH), 7.04 (d, d=2.7Hz, IH), 6.72 (d, J=3.0Hz, IH), 4.09 (m, 2H), 3.93 (m, 2H), 3.69 (m, 2H), 3.38 (m,

2H), 2.10 (m, 2H); MS (ES): m/z 372.11. Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine with 2,4- dichlorobenzene-l-sulfonyl chloride by procedure as described in (E).

Yield 70%; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 8.53 (d, J=2.4Hz, IH), 7.72 (m, 2H), 7.53 (m, IH), 7.49 (d, J=2.4Hz, IH), 7.3 (d, J=7.2Hz, IH), 6.7 (d, J=7.2Hz, IH), 4.0 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 3.3 (m, 2H), 2.0 (m, 2H); MS (ES): m/z 581.8 (M+l).

Example 163

2,4-Dichloro-N-(5-cyano-2,4-dimethyl-6-(4-(4-(trifluoromethy l)pyrimidin-2-yl)-l,4- diazepan-l-yl)pyridin-3-yl)benzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )- 1 ,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trilluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4-

(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 2,4-dichlorobenzene-

1-sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.77 (s, IH), 8.5 (d, J=4.8Hz, IH), 7.8 (d, J=8.7Hz, IH), 7.6 (d, J=2.1Hz, IH), 7.4 (dd, J=6.3, 2.1Hz, IH), 6.8 (d, J=5.1Hz, IH), 3.8 (m, 4H), 2.3 (s, 6H), 2.1 (m, 2H); MS (ES): m/z 600.4 (M+l).

Example 164

3,4-Dichloro-N-(5-cyano-2,4-dimethyl-6-(4-(4-(trifluoromethy l)pyrimidin-2-yl)-l,4- diazepan- 1 -yl)pyridin-3-yl)benzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )-l,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)nicotinonitrile with 3,4-dichlorobenzene- 1-sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.79 (s, IH), 8.51 (d, J=4.8Hz, IH), 7.8 (d, J=1.8Hz, IH), 7.63 (dd, J=8.1, 2.1Hz, IH), 7.58 (d, J=6.3Hz, IH), 6.79 (d, J=4.8Hz, IH), 4.1 (m, 4H), 3.9 (m, 2H), 3.6 (m, 2H), 2.3 (s, 6H), 2.1 (m, 2H); MS (ES): m/z 600.4 (M+l). Example 165

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-di

yl)pyridin-3-yl)-3-methoxybenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )-l,4-diazepan l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)-l,4-diazepan-l-yl)nicotinon itrile with 3-methoxybenzene-l- sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.80 (s, IH), 8.7 (d, J=6.9Hz, IH), 7.64 (dd, J=1.8, 7.2Hz, IH) 7.44 (t, J=7.2Hz, IH), ,7.17 (dd, J=1.8, 7.2Hz, IH), 7.32 (m, IH), 6.59 (d, J=6.9Hz, IH), 4.1 (m, 2H), 3.8 (s, 3H), 3.6-3.4 (m, 6H), 2.1 (m, 2H); MS (ES): m/z 561.2 (M ⁺ ).

Example 166

N-(5-Cyano-2,4-dimethyl-6-(4-(4-(trifluoromethyl)pyrimidin-2 -yl)-l,4-diazepan-l- yl)pyridin-3-yl)-2,5-dimethoxybenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(4-(trifluoromethyl)pyrimidin-2-yl )-l,4-diazepan- l-yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with l-(4-trifluoromethyl-pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(4- (trifluoromethyl)pyrimidin-2-yl)-l,4-diazepan-l-yl)nicotinon itrile with 2,5- dimethoxybenzene-l-sulfonyl chloride by procedure as described in (E).

Yield: 71 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.80 (s, IH), 8.50 (d, J=4.8Hz, IH), 7.28 (d, J=3Hz, IH), 7.13 (dd, J=3Hz, IH), 7.10 (d, J=3Hz, IH), 6.77 (d, J=6Hz, IH), 4.1 (m, 4H), 3.9 (t, 2H), 3.6 (t, 2H), 2.2 (s, 6H), 2.1 (m, 2H); MS (ES): m z 591.6 (M+l).

Example 167

N-(5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-l,4-dia zepan-l-yl)pyridin-3- yl)quinoline-8-sulfonamide Step 1 : 5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin- 3-amine was obtained by reacting 2,3-dichloro-5-nitro-pyridine with l-(4-trifluoromethyl- pyrimidin-2-yl)-[l,4]diazepane by procedure as described in (C) and further reduction by procedure described in (D).

5-Chloro-6-(4-(4-(trifluoromethyl)pyrimidin-2-yl)- 1 ,4-diazepan- 1 -yl)pyridin-3-amine

*H NMR (300 MHz, CDC1 ₃ ): δ 8.48 (d, J=4.5Hz, 1H), 7.66 (d, d=2.7Hz, 1H), 7.04 (d, d=2.7Hz, 1H), 6.72 (d, J=3.0Hz, 1H), 4.09 (m, 2H), 3.93 (m, 2H), 3.69 (m, 2H), 3.38 (m, 2H), 2.10 (m, 2H); MS (ES): m/z 372.11.

Step 2: The title compound was obtained by reacting 5-chloro-6-(4-(4- (trifluoromethyl)pyrimidin-2-yl)-l,4-diazepan-l-yl)pyridin-3 -amine with quinoline-8- sulfonyl chloride by procedure as described in (E).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, 1H), 9.2 (dd, J=2.7, 7.5Hz, 1H), 8.3 (m, 2H), 8.1 (m, 1H), 7.7 (dd, J=2.7, 7.5Hz, 2H), 7.5 (m, 2H), 6.7 (m, 2H), 3.9 (m, 2H), 3.7 (m, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 2.0 (m, 2H); MS (ES): m/z 563.9 (M+l).

Example 168

N-(5-Cyano-2,4-dimethyl-6-(3-methyl-3,8-diazabicyclo[3.2.1]o ctan-8-yl)pyridin-3-yl)-4- isopropylbenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.1] octan- 8-yl)nicot inonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 3- methyl-3,8-diaza-bicyclo[3.2.1]octane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-4,6-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octa n-8-yl)nicotinonitrile *H NMR (300 MHz, CDC1 ₃ ): δ 4.51 (s, 2H), 3.29 (m, 2H), 2.75 (m, 2H), 2.54 (m, 2H), 2.33 (s,3H), 2.31 (s, 3H), 2.18 (s, 3H), 1.91 (m, 4H); MS (ES): m/z 271.18.

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(3- methyl- 3 , 8 -diazabicyclo [3.2.1] octan- 8 -yl)nicotinonitrile with 4-isopropylbenzene- 1 -sulf onyl chloride by procedure as described in (E).

Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.79 (s, 1H), 7.7-7.8 (d, J=8.1Hz, 2H), 7.9- 8.0 (d, J=8.1Hz, 2H), 4.8 (m, 2H), 3.5 (m, 1H), 3.2 (m, 4H), 2.39 (s, 6H,), 2.31 (s, 3H), 1.9 (d, 6H), 2.1 (m, 4H); MS (ES): m/z 453.6 (M+l). Example 169

N-(5-Cyano-2,4-dimethyl-6-(3-methyl-3,8-diazabicyclo[3.2.1]o ctan-8-yl)pyridin-3-yl) (trifluoromethyl)benzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2. l]octan-8- yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 3-methyl-3,8-diaza-bicyclo[3.2.1]octane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-4,6-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octa n-8-yl)nicotinonitrile *H NMR (300 MHz, CDC1 ₃ ): δ 4.51 (s, 2H), 3.29 (m, 2H), 2.75 (m, 2H), 2.54 (m, 2H), 2.33 (s,3H), 2.31 (s, 3H), 2.18 (s, 3H), 1.91 (m, 4H); MS (ES): m/z 271.18.

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(3- methyl- 3 , 8 -diazabicyclo [3.2.1] octan- 8 -yl)nicotinonitrile with 4-(trifluoromethyl)benzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.81 (s, IH), 7.7-7.9 (d, J=8.4Hz, 2H), 7.3- 7.5 (d, J=8.4Hz, 2H), 4.8 (m, 2H), 3.2 (m, 4H) 2.7 (s, 3H), 2.3 (m, 4H), 2.1 (s, 6H); MS (ES): m/z 479.5 (M+l).

Example 170

N-(5-Cyano-2,4-dimethyl-6-(3-methyl-3,8-diazabicyclo[3.2.1]o ctan-8-yl)pyridin-3-yl)-4- fluorobenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2. l]octan-8- yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with

3-methyl-3,8-diaza-bicyclo[3.2.1]octane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-4,6-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octa n-8-yl)nicotinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 4.51 (s, 2H), 3.29 (m, 2H), 2.75 (m, 2H), 2.54 (m, 2H), 2.33

(s,3H), 2.31 (s, 3H), 2.18 (s, 3H), 1.91 (m, 4H); MS (ES): m/z 271.18.

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(3- methyl- 3 , 8 -diazabicyclo [3.2.1] octan- 8 -yl)nicotinonitrile with 3 -chloro-4-fluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 67 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.80 (s, IH), 7.6 (d, J=2.1Hz, IH), 7.4 (dd,

J=8.1, 2.1Hz, IH), 7.1 (d, J=7.8Hz, IH), 4.8 (m, 2H), 3.2 (m, 4H), 2.2 (s, 6H), 2.1 (m, 4H),

1.98 (s, 3H); MS (ES): m/z 463.95 (M+l). Example 171

N-(5-Cyano-2,4-dimethyl-6-(3-methyl-3,8-diazabicyclo[3.2.1]o ctan-8-yl)pyridin-3-yl) dimethoxybenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2. l]octan-8- yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 3-methyl-3,8-diaza-bicyclo[3.2.1]octane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-4,6-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octa n-8-yl)nicotinonitrile *H NMR (300 MHz, CDC1 ₃ ): δ 4.51 (s, 2H), 3.29 (m, 2H), 2.75 (m, 2H), 2.54 (m, 2H), 2.33 (s,3H), 2.31 (s, 3H), 2.18 (s, 3H), 1.91 (m, 4H); MS (ES): m/z 271.18.

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(3- methyl- 3 , 8 -diazabicyclo [3.2.1] octan- 8 -yl)nicotinonitrile with 3 ,4-dimethoxybenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 66 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.80 (s, IH), 6.9 (d, J=7.2Hz, IH), 7.4 (dd, J=1.8, 7.2Hz, IH), 6.7 (d, J=1.8Hz, IH), 4.8 (m, 2H), 3.7 (s, 6H), 3.2 (m, 4H,), 2.7 (s, 3H), 2.1 (m, 4H), 2.0 (s, 6H); MS (ES): m/z 472.1 (M+l).

Example 172

l-(6-(4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl)-5-cyano pyridin-3-yl)-3-(3- (trifluoromethyl)phenyl)urea

Step 1: 5-Amino-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)nicoti nonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(4-chloro-phenyl)-piperidin-4-ol by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(4-chlorophenyl)- 4-hydroxypiperidin-l-yl)nicotinonitrile with 3-trifluoromethyl-l-isocyanatobenzene by procedure as described in (F).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.25 (s, IH), 8.87 (s, IH), 8.45 (d, J=3Hz, IH), 8.20 (d, J=3Hz, IH), 8.00 (s, IH), 7.60 (bs, IH), 7.45 (s, IH), 7.54 (d, J=9Hz, 2H), 7.40 (d, J=9Hz, 2H), 7.34 (bs, IH), 5.26 (s, IH), 4.00 (d, J=12Hz, 2H), 3.40 (d, J=12Hz, 2H), 2.04 (d, J=12 Hz, 2H), 1.73 (d, J=12 Hz, 2H); MS (ES): m/z 516.2 (M+l).

Example 173

l-(5-Cyano-6-(4-phenylpiperazin-l-yl)pyridin-3-yl)-3-(2,4 -difluorophenyl) -urea Step 1 : 5-Amino-2-(4-phenylpiperazin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 1-phenyl-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-phenylpiperazin- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.93 (s, IH), 7.24 (m, 3H), 7.0 (d, 2H), 6.81 (s, IH), 5.31 (s, IH), 3.35 (m, 4H), 3.29 (m, 4H); MS (ES): m/z 279.15.

Step 2: The title compound was obtained by reaction of 5-amino-2-(4- phenylpiperazin-l-yl)nicotinonitrile with 2,4-difluoro-l-isocyanatobenzene by procedure as described in (F).

Yield: 72 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.15 (brs, IH), 8.64 (brs, IH), 8.23 (d, J=3Hz, IH), 8.12 (d, J=3Hz, IH), 8.06 (m, IH), 7.36 (m, IH), 7.24 (m, 2H), 7.05 (m, IH), 7.01 (m, 2H), 6.83 (t, J=6Hz & 6Hz IH); MS (ES): m/z 435.2 (M+l).

Example 174

l-(5-Cyano-2-methyl-6-(4-(pyrimidin-2-yl)piperazin-l-yl)p yridin-3-yl)-3-(2,4- difluorophenyl)urea

Step 1 : 5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin-l-yl)nicotin onitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 2-piperazin-l-yl-pyrimidine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-6-methyl-2-(4-(pyrimidin-2-yl)piperazin- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 8.39 (d, J=4.8Hz, 2H), 7.22 (s, IH), 6.67 (t, J=4.8Hz, IH), 5.05 (s, IH), 3.87 (m, 4H), 3.28 (m, 4H), 2.27 (s, 3H); MS (ES): m z 295.15.

Step 2: The title compound was obtained by reaction of 5-amino-6-methyl-2-(4- (pyrimidin-2-yl)piperazin-l-yl)nicotinonitrile with 2,4-difluoro-l-isocyanatobenzene by procedure as described in (F).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 8.90 (brs, IH), 8.48 (brs, IH), 8.41-8.39 (m, 2H), 8.32 (s, IH), 8.10 (m, IH), 7.35 (m, IH), 7.05 (m, IH), 6.67 (m, IH), 3.88 (brs, 4H), 3.59 (brs, 4H), 2.43 (s, 3H); MS (ES): m/z 451.1 (M+l).

Example 175

1 -(2-Chlorophenyl)-3 -(5-cyano-6-(4-cyclohexylpiperazin- 1 -yl)pyridin- Step 1 : 5-amino-2-(4-cyclohexylpiperazin-l-yl)nicotinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 1-cyclohexyl-piperazine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-cyclohexylpiperazin- 1 -yl)nicotinonitrile

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.89 (d, J= 3Hz, IH), 7.23 (d, J= 3Hz, IH ), 5.22 (s, 2H), 3.16 (m, 4H), 2.62 (m, 4H), 2.22 (m, IH), 1.76 (m, 4H), 1.27 (m, 4H), 1.17 (m, 2H).

Step 2: The title compound was obtained by reaction of 5-amino-2-(4- cyclohexylpiperazin-l-yl)nicotinonitrile with l-chloro-2-isocyanatobenzene by procedure as described in (F).

Yield: 75 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (bs, IH), 8.43 (s, IH), 8.40 (d, J=3Hz, IH), 8.23 (d, J=3Hz, IH), 8.13 (d, J=6Hz, IH), 7.48 (d, J=6Hz, IH), 7.33 (t, J=9Hz & 6Hz, IH), 7.07 (t, J=6Hz & 9Hz IH), 3.62 (t, J=6Hz & 6Hz IH), 3.45 (s, 4H), 2.62 (s, 4H), 1.78- 1.74 (m, 4H), 1.24-1.18 (m, 4H), 1.14 (m, IH); MS (ES): m/z 439.2 (M+l). Example 176

Ethyl 4-(3-cyano-5-(3-(2,4-dimethoxyphenyl)ureido)pyridin-2-yl)pip erazine-l-carboxylate

Step 1 : Ethyl 4-(5-amino-3-cyanopyridin-2-yl)piperazine-l-carboxylatewas obtained by reacting 2-chloro-5-nitronicotinonitrile piperazine-l-carboxylic acid ethyl ester by procedure as described in (C) and further reduction by procedure described in (D).

Ethyl 4-(5-amino-3-cyanopyridin-2-yl)piperazine-l-carboxylate

*H NMR (300 MHz, DMSO-d ₆ ): δ 7.91 (s, IH), 7.27 (s, IH), 5.32 (s, 2H), 4.10 (q, J=6.9Hz, 2H), 3.50 (m, 4H), 3.15 (m, 4H), 1.22 (t, J=6.9Hz, 3H); MS (ES): m/z 275.14.

Step 2: The title compound was obtained by reaction of ethyl 4-(5-amino-3- cyanopyridin-2-yl)piperazine-l-carboxylate with l-isocyanato-2,4-dimethoxybenzene by procedure as described in (F).

Yield 67%; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.31 (s, IH), 8.40 (d, J=3Hz, IH), 8.26 (d, J=3Hz, IH), 8.10 (s, IH), 7.89 (d, J=9Hz, IH), 6.63 (d, J=3Hz, IH), 6.50 (dd, J=9Hz & 9Hz, IH), 4.11 (q, J= 6Hz, 6Hz & 6Hz, 2H), 3.85 (s, 3H), 3.73 (s, 3H), 3.53 (m, 4H), 3.41 (m, 4H), 1.23 (t, 6Hz & 6Hz, 3H); MS (ES): m/z 455.2 (M+l).

Example 177

l-(5-Cyano-2,4-dimethyl-6-(3-methyl-3,8-diazabicyclo[3.2. 1]octan-8-yl)pyridin-3-yl)-3-(2,4- dimethoxyphenyl)urea Step 1 : 5-Amino-4,6-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2. l]octan-8- yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 3-methyl-3,8-diaza-bicyclo[3.2.1]octane by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-4,6-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octa n-8-yl)nicotinonitrile *H NMR (300 MHz, CDC1 ₃ ): δ 4.51 (s, 2H), 3.29 (m, 2H), 2.75 (m, 2H), 2.54 (m, 2H), 2.33 (s,3H), 2.31 (s, 3H), 2.18 (s, 3H), 1.91 (m, 4H); MS (ES): m/z 271.18.

Step 2: The title compound was obtained by reaction of 5-amino-4,6-dimethyl-2-(3- methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)nicotinonitrile (2 mmol) with l-isocyanato-2,4- dimethoxybenzene by procedure as described in (F).

Yield: 68 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 7.98 (d, J=7.2 Hz, IH), 6.65 (dd, J=1.8, 7.2 Hz, IH), 6.53 (d, J=1.8Hz, IH), 5.98 (s, 2H), 4.8 (m, 2H), 3.89 (s, 6H), 3.2 (m, 4H), 2.56 (s, 6H), 2.47 (s, 3H), 2.1 (m, 4H); MS (ES): m/z 450.5 (M ⁺ ). Example 178

tert-Butyl-(3-(4-(3-cyano-5-(2,4-difluorophenylsulfonamid o)pyridin-2-yl)piperazin-l-yl)-3- oxopropyl)carbamate

Step 1 : tert-Butyl-(3-(4-(5-amino-3-chloropyridin-2-yl)piperazin-l-y l)-3-oxopropyl) carbamate was obtained by reacting 2,3-dichloro-5-nitro-pyridine with tert-butyl (3-oxo-3- (piperazin-l-yl)propyl)carbamate by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting tert-butyl-(3-(4-(5-amino-3- chloropyridin-2-yl)piperazin- l-yl)-3-oxopropyl)carbamate with 2,4-difluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.79 (s, IH), 8.11 (brs, IH), 7.95 (d, J=2.1Hz, IH), 7.90 (m, IH), 7.58 (m, IH), 7.52 (d, J=2.1Hz, IH), 7.28 (m, IH), 3.84 (m, 4H), 3.61 (m, 4H), 3.41 (m, 2H), 2.48 (m, 2H), 1.36 (s, 9H); MS (ES): m/z 560 (M+l).

Example 179

3-Chloro-N-(5-cyano-6-(4-(cyclohexanecarbonyl)piperazin-l -yl)pyridin-3-yl)-4- fluorobenzene sulfonamide

Step 1 : 5-Amino-2-(4-(cyclohexanecarbonyl)piperazin-l-yl)nicotinonit rile was obtained by reacting 2-chloro-5-nitronicotinonitrile with cyclohexyl(piperazin-l- yl)methanone by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4- (cyclohexanecarbonyl)piperazin- 1 -yl)nicotinonitrile with 3-chloro-4-fluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.33 (s, 1H), 8.07 (m, 1H), 7.90 (d, J=3.0Hz, 1H), 7.72-7.66 (m, 2H), 7.21 (m, 1H), 3.74 (m, 4H), 3.57 (m, 4H), 2.39 (m, 1H), 1.81-1.43 (m, 10H); MS (ES): m/z 506.0 (M+l). Example 180

N-(5-Cyano-2,4-dimethyl-6-(4-(2-(trifluoromethyl)benzoyl)pip erazin-l-yl)pyridin-3-yl)-3-

(trifluoromethyl)benzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(2-(trifluoromethyl)benzoyl)pipera zin-l- yl)nicotinonitrile was obtained by 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with piperazine-l-yl-(2-trifluoromethyl-phenyl)-methanone by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(2-

(trifluoromethyl)benzoyl)piperazin- 1 -yl)nicotinonitrile with 3-trifluoromethylbenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.92 (s, 1H), 8.13 (d, J=8.4Hz, 1H), 8.02 (d,

J=8.1Hz, 1H), 7.82 (m, 4H), 7.67 (d, J=8.1Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 3.74 (m, 2H), 3.45

(m, 4H), 3.20 (m, 2H), 2.05 (s, 3H), 1.97 (s, 3H); MS (ES): m/z 612.0 (M+l).

Example 181

N-(5-Cyano-2,4-dimethyl-6-(4-(2-(trifluoromethyl)benzoyl) piperazin-l-yl)pyridin-3-yl)-2,4- difluorobenzenesulfonamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(2-(trifluoromethyl)benzoyl)pipera zin-l- yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with piperazine-l-yl-(2-trifluoromethyl-phenyl)-methanone by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(2- (trifluoromethyl)benzoyl)piperazin- 1 -yl)nicotinonitrile with 2,4-difluorobenzene- 1 -sulfonyl chloride by procedure as described in (E). Yield: 69 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.10 (s, IH), 7.84 (m, IH), 7.78-7.69 (m, 2H), 7.66 (m, 2H), 7.53 (m, IH), 7.27 (m, IH), 3.79-3.41 (m, 3H), 3.32-3.18 (m, 5H), 2.16 (s, 3H), 2.11 (s, 3H); MS (ES): m/z 580.1 (M+l). Example 182

3-Chloro-N-(5-chloro-6-(4-(2-(trifluoromethyl)benzoyl)pipera zin-l-yl)pyridin-3-yl)-4- fluorobenzenesulfonamide

Step 1 : (4-(5-Amino-3-chloropyridin-2-yl)piperazin- 1 -yl)(2-(trifluoromethyl)phenyl) methanone was obtained by reacting 2,3-dichloro-5-nitro-pyridine with piperazine-l-yl-(2- trifluoromethyl-phenyl)-methanone by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting (4-(5-amino-3-chloropyridin-2- yl)piperazin-l-yl)(2-(trifluoromethyl)phenyl) methanone with 3-chloro-4-fluorobenzene-l- sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.12 (s, IH), 8.02 (d, J=2.7Hz, IH), 7.87

(dd, J=2.1, 6.6Hz, IH), 7.76 (d, J=8.1HZ, IH), 7.65 (m, 2H), 7.61 (m, 2H), 7.38 (d, J=7.2Hz,

IH), 4.11 (m, 2H), 3.90 (m, 2H), 3.35 (m, 2H); MS (ES): m/z 577.0 (M+l).

Example 183

3-Chloro-N-(5-cyano-6-(4-(2-(trifluoromethyl)benzoyl)pipe razin-l-yl)pyridin-3-yl)-4- fluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-(2-(trifluoromethyl)benzoyl)piperazin-l-yl)nico tinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrilewith piperazine-l-yl-(2-trifluoromethyl- phenyl)-methanone by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(2- (trifluoromethyl)benzoyl)piperazin- 1 -yl)nicotinonitrile with 3-chloro-4-fluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.56 (s, IH), 8.02 (d, J=2.7Hz, IH), 7.89 (dd, J=2.1, 6.6Hz, IH), 7.78 (d, J=8.1HZ, IH), 7.67 (m, 2H), 7.63 (m, 2H), 7.39 (d, J=7.2Hz, IH), 3.74 (m, 2H), 3.45 (m, 2H), 3.20 (m, 2H); MS (ES): m/z 568.0 (M+l). Example 184

3-Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(2-(trifluoromethyl)be nzoyl) piperazin-l-yl)pyridin- 3 -yl) -4-fluorobenzenesulf onamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(2-(trifluoromethyl)benzoyl)pipera zin-l- yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with piperazine-l-yl-(2-trifluoromethyl-phenyl)-methanone by procedure as described in (C) and further reduction by procedure described in (D).

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(2- (trifluoromethyl)benzoyl)piperazin- 1 -yl)nicotinonitrile with 3-chloro-4-fluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 9.87 (s, 1H), 7.85 (m, 2H), 7.77 (m, 1H), 766 (m, 3H), 7.56 (m, 1H), 3.75 (m, 2H), 3.44 (m, 4H), 3.21 (m, 2H), 2.12 (s, 3H), 1.99 (s, 3H); MS (ES): m/z 596.1 (M+l). Example 185

3-Chloro-N-(5-cyano-2,4-dimethyl-6-(4-(2-(trifluoromethyl)ph enoxy) piperidin- 1 -yl)pyridin-

3 -yl) -4-fluorobenzenesulf onamide

Step 1 : 5-Amino-4,6-dimethyl-2-(4-(2-(trifluoromethyl)phenoxy)piperi din-l- yl)nicotinonitrile was obtained by reacting 2-chloro-4,6-dimethyl-5-nitronicotinonitrile with 4-(2-trifluoromethyl-phenoxy)-piperidine by procedure as described in (C) and further reduction by procedure described in (D).

5- Amino-4,6-dimethyl-2-(4-(2-(trifluoromethyl)phenoxy)piperidi n- 1 - yl)nicotinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 7.60 (d, J=7.5Hz, 1H), 7.51 (m, 1H), 7.05 (m, 2H), 4.69 (m,

1H), 3.64 (m, 2H), 3.45 (m, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 2.1 (m, 4H); MS (ES): m/z 390.17

Step 2: The title compound was obtained by reacting 5-amino-4,6-dimethyl-2-(4-(2- (trifluoromethyl)phenoxy)piperidin- 1 -yl)nicotinonitrile with 3-chloro-4-fluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.59 (s, 1H), 7.89 (dd, J=2.4. 6.9Hz, 1H), 7.70-7.65 (m, 1H), 7.62 (d, J=7.8Hz, 1H), 7.50 (t, J=75Hz, 1H), 7.31 (d, J=6.9Hz, 1H), 7.04- 7.00 (m, 2H), 4.82 (m, 1H), 3.97 (m, 2H), 3.81 (m, 2H), 2.28 (s, 3H), 2.09 (s, 3H), 2.05 (m, 4H); MS (ES): m/z 583.1 (M+l). Example 186

3-Chloro-N-(5-cyano-6-(4-(2-(trifluoromethyl)phenoxy)piperid in-l-yl)pyridin-3-yl)-4- fluorobenzenesulfonamide

Step 1 : 5-Amino-2-(4-(2-(trifluoromethyl)phenoxy)piperidin-l-yl)nico tinonitrile was obtained by reacting 2-chloro-5-nitronicotinonitrile with 4-(2-trifluoromethyl-phenoxy)- piperidine by procedure as described in (C) and further reduction by procedure described in (D).

5-Amino-2-(4-(2-(trifluoromethyl)phenoxy)piperidin-l-yl)nico tinonitrile

*H NMR (300 MHz, CDC1 ₃ ): δ 8.02 (s, IH), 7.60 (d, J=7.8Hz, IH), 7.51 (m, IH), 7.04 (m, 3H), 4.7 (m, IH), 3.63 (bs, 2H), 3.61 (m, 4H), 2.1 (m, 4H); MS (ES): m/z 362.14.

Step 2: The title compound was obtained by reacting 5-amino-2-(4-(2- (trifluoromethyl)phenoxy)piperidin- 1 -yl)nicotinonitrile with 3-chloro-4-fluorobenzene- 1 - sulfonyl chloride by procedure as described in (E).

Yield: 70 %; *H NMR (300 MHz, DMSO-d ₆ ): δ 10.68 (s, IH), 7.96 (d, J=2.1Hz, IH), 7.88 (dd, J=2.1, 6.6Hz, IH), 7.62 (m, 3H), 7.50 (t, J=7.5Hz, IH), 7.03 (m, 2H), 6.43 (m, IH), 4.81 (m, IH), 3.99 (m, 2H), 3.82 (m, 2H), 2.09 (m, 4H); MS (ES): m/z 555.9 (M+l).

Pharmacological assays

The pharmacological activity of the compounds can be confirmed by a number of pharmocological assays known in the art. The exemplified pharmacological assay, given below, has been carried out with the representative compounds of the present invention synthesized in the above Examples.

Example 187

Insulin resistance (IR) assay

The assay was carried out in accordance with the method substantially as described in British Journal of Pharmacology, 130, 351-58, 2000, the disclosure of which is incorporated herein by reference for the teachings of the assay and related protocol.

The solution of the test compound (representative compound of above examples; 10 μΜ) was prepared by dissolving the compound in DMSO. Rosiglitazone (0.1 μΜ in DMSO) was used as standard.

Differentiation into adipocytes was induced by the known methods as described in the reference, J. Biol. Chem., 260, 2646-2652, 1985, the disclosure of which is incorporated herein by reference for the teachings of adipocyte differentiation and related protocol. Culture medium containing 0.5 nM l-methyl-3-isobutylxanthine (IBMX), 0.25 μΜ dexamethasone, 5 μg/mL insulin (bovine/human), 10 mM N-(2-hydroxyethyl)-piperazine-N'- 2-ethanesulfonic acid buffer (HEPES buffer) and fetal bovine serum (FBS) 10 % by volume in Dulbecco's modified Eagle's medium (DMEM) was used for differentiation.

3T3 LI fibroblasts were seeded in 24- or 6- well plates at a density of 0.5-2xl0 ⁴ cells/well and were allowed to reach maximal confluency.

The confluent fibroblasts were exposed to culture medium for 2 days. After this period, fresh culture medium (DMEM) containing only insulin was used, 10 % FBS was added and cultured for 4 days with change of medium every 2 days. After 7 days the cultures received DMEM containing 10 % FBS with no exposure to insulin. By the end of 8-10 days, more than 95 % of the cells have become differentiated into adipocytes. The mature adipocytes were exposed to dexamethasone, 100 nM added in ethanol, in culture medium and incubated for 2 days. On the third day, solution of the test compound was added along with 100 nM dexamethasone containing medium for 4 days with a change in medium after every 2 days. Vehicle control contained 1 % v/v of DMSO. Rosiglitazone was used as a standard and was added at a final concentration of 0.1 μΜ along with 100 nM dexamethasone containing medium for 4 days with a change in medium after every 2 days. Test compound was tested at a final concentration of 10 μΜ. After a total period of 6 days, the cells were processed for glucose uptake as follows.

The insulin resistant adipocytes were exposed to serum-free DMEM containing 0.1 % bovine serum albumin for 3-4 h at 37 °C in CO ₂ atmosphere. The test compound was also present during this period. After 3-4 h, the medium was aspirated and replaced with Kreb's Ringer phosphate (KRP) buffer at pH 7.4 and with human/porcine insulin, 200 nM. The cells were incubated for 30 min at 37 °C. At the end of 30 min, 0.05 or 0.1 μθ of ¹⁴ C-2- deoxyglucose was added to each well of either 24- or 6- well plates respectively and was incubated for exactly 5 min. After exactly 5 min, the plates were transferred to ice trays and medium was rapidly aspirated. The cell layer was washed twice with ice-cold phosphate buffered saline (PBS), pH 7.4. Finally the cell layer was lysed with 150 μΕ of 0.1 % sodium dodecyl sulfate (SDS) and the radioactivity of the cell lysate was determined in liquid scintillation counter. Non-specific glucose uptake was assayed in wells exposed to cytochalasin B, inhibitor of glucose transport. Test compounds that showed statistically significant increase in the glucose transport/uptake expressed as CPM/well above the level in cells exposed to insulin vehicle are considered actives in this assay. The cut off limit for activity in this IR assay was defined as the increase 1.50 fold of vehicle, assay value of 1.0 for vehicle. Activity was also expressed as % of rosiglitazone, which is used as a standard for comparison. Statistical analysis was performed using unpaired t-test. Results are summarized in Table 1.

Table 1 : Activity of compounds in insulin resistance model

comparison with Rosiglitazone

Conclusion:

Representative compounds of the present invention showed insulin sensitizing activity in increasing glucose uptake in the insulin resistance model.

Example 188

Human Peroxisome Proliferator- Activated Receptor gamma (PPARy) transactivation assay

The assay was carried out in accordance with the method substantially as described in

Biochem. Biophys. Res. Comm., 175, 865-871, 1991, the disclosure of which is incorporated by reference for the teaching of the assay.

Human PPARy activity was evaluated by transactivation using a luciferase reporter gene. The pBL-TK-luciferase reporter plasmid AOX-3X PPRE-TK-LUC contains three copies of the rat acyl CoA oxidase PPRE cloned upstream of the minimal herpes simplex virus thymidine kinase (TK) promoter. Human full length PPARy cDNA was cloned into pSG5 expression vector (Stratagene, Lo Jolla, CA).

HEK293 cells were seeded in 24- well plates and grown in DMEM supplemented with 10 % (v/v) FCS. After 24 h, they were transfected with 100 ng of hPPARy receptor and 300 ng of AOX-3X PPRE-LUC reporter construct per well using Fugen 6 transfection reagent (Roche, Indianapolis, IN). Test compounds (representative compounds of above examples) or rosiglitazone (standard) (dissolved in DMSO were added 24 h after transfection. The control was 0.1 % DMSO. After 48 h, transactivation activity was determined by lucif erase assay using Steady Glow reagent (Promega, Madison, WI). The results are summarized in Table 2.

Table 2: Activity of compounds in human PPARy transactivation assay

Conclusion: Representative compounds of the present invention did not exhibit any PPARy activation in human transactivation PPARy assay.

It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" includes a mixture of two or more compounds. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise. All publications and patent applications in this specification are indicative of the level of ordinary skill in the art to which this invention pertains.

The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.