HK1087103B

HK1087103B - Anilinopyrazole derivatives useful for the treatment of diabetes

Info

Publication number: HK1087103B
Application number: HK06107103.3A
Authority: HK
Inventors: Joachim Rudolph; Louis-David Cantin; Steven Magnuson; William Bullock; Ann-Marie Bullion; Libing Chen; Chih-Yuan Chuang; Sidney Liang; Dyuti Majumdar; Herbert Ogutu; Alan Olague; Ning Qi; Philip L. Wickens
Original assignee: Bayer Pharmaceuticals Corporation
Priority date: 2002-11-27
Filing date: 2003-11-25
Publication date: 2009-09-25

Description

Anilinopyrazole derivatives for the treatment of diabetes

The benefit of U.S. provisional application serial No. 60/429,917, filed on day 11, 27, 2002 and U.S. provisional application serial No. 60/498,214, filed on day 27, 8, 2003, the contents of which are hereby incorporated by reference in their entirety.

Technical Field

The present invention relates to anilinopyrazole compounds, pharmaceutical compositions, and methods for treating diabetes and related diseases.

Background

Diabetes mellitus is characterized by impaired glucose metabolism occurring in diabetic patients by elevated blood glucose levels. Diabetes is divided into two main types, depending on the deficiency. Type I diabetes or Insulin Dependent Diabetes Mellitus (IDDM) occurs when a patient lacks insulin-producing beta cells in their pancreatic ligand. Type II diabetes or non-insulin dependent diabetes mellitus (NIDDM) occurs when patients develop impaired beta-cell function and altered insulin action.

The current treatment for type I diabetics is by insulin injection, while most type II diabetics are treated with agents that stimulate beta-cell function or agents that enhance the patient's tissue sensitivity to insulin. Agents currently used to treat type II diabetes include: alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues and metformin.

Over time, almost half of type II diabetics lose their response to these agents. Insulin therapy has been established after failure of diet, exercise and oral medication to properly control blood glucose. The drawbacks of insulin therapy are the drug injections, the potential for hypoglycemia and weight gain.

Because of the problems with current therapies, there is a need for new therapies for type II diabetes. In particular, new therapeutic approaches require maintenance of normal (glucose-dependent) insulin secretion. Such new drugs must have the following characteristics: glucose dependence that promotes insulin secretion (i.e., a compound stimulates insulin secretion only when elevated glucose levels occur); low first and second failure rates; and preserving islet function.

INS-1 cells are a model of insulin secretion by islet beta cells. These cells retain many of the characteristics of islet beta-cells in situ when maintained in the presence of beta-mercaptoethanol. Cells may be according to EC₅₀Insulin is secreted at physiologically relevant glucose concentrations of 6mM glucose (Hohmeier, et al, Diabetes 49: 424, 2002).

These cells may also secrete insulin according to a variety of known secretagogues, including agents capable of elevating intracellular cyclic AMP, nutrients other than glucose, and potassium chloride. This characterization of INS-1 cells further suggests that these cells retain many of the signaling pathways involved in insulin secretory responses and are therefore suitable for identifying compounds that have utility for these pathways. Thus, INS-1 cells can be used as a tool for identifying compounds that are capable of stimulating insulin secretion in the presence of glucose and are therefore useful in the treatment of diabetes and related diseases.

Detailed Description

The present invention provides anilinopyrazole derivatives of formula (I) and pharmaceutically acceptable salts thereof,

wherein

R is H or (C)₁-C₆) An alkyl group;

R¹is a compound of formula (I) in the formula (H),

(C₁-C₆) Alkyl, the radical being optionally selected from (C)₁-C₄) Alkoxy, phenyl optionally substituted by halogen and [ tri (C)₁-C₄) Alkyl radical]One substituent of the silyl group is substituted,

(C₃-C₆) ChainAn alkenyl group, which is a radical of an alkenyl group,

(C₃-C₆) An alkynyl group,

(C₃-C₆) Cycloalkyl, the radical being optionally selected from (C)₁-C₃) Alkyl, CF₃And up to two substituents of halogen,

(C₁-C₃) Haloalkyl, or

Phenyl, the radical being optionally selected from

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

(C₁-C₆) Alkyl, the radical being optionally substituted by one (C)₁-C₄) The substitution of alkoxy groups is carried out,

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group;

R²is a compound of formula (I) in the formula (H),

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

(C₃-C₆) Cycloalkyl, the radical being optionally selected from (C)₁-C₃) Alkyl and halogen with up to two substituents,

(C₁-C₃) A halogenated alkyl group,

pyridyl optionally selected from(C₁-C₆) Alkoxy group, (C)₁-C₆) Alkylthio, halogen and optionally substituted by one (C)₁-C₄) Of alkoxy radicals (C)₁-C₆) Up to two substituents of the alkyl group,

a pyrimidine group,

phenyl, the radical being optionally selected from

(C₁-C₆) An alkoxy group,

a hydroxyl group(s),

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) An alkylthio group is a group of one or more,

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

CO₂R⁸，

(C₁-C₃) A halogenated alkoxy group,

(C₁-C₄) Acyl, and

up to four substituents of benzoyl substituted for the group,

or

Tetrahydronaphthyl, 2, 3-indanyl, benzodioxolyl or benzodioxanyl, each of which may optionally be chosen from (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkylthio, halogen and optionally substituted by one (C)₁-C₄) Alkoxy-substituted (C)₁-C₆) Up to two substituents of the alkyl group,

or

When R is¹And R²Is (C)₁-C₆) When alkyl, they may form a 5-or 6-membered carbocyclic ring together with the C atom to which they are attached,

or

R¹And R²May form together with the C atom to which it is attached a 6-membered N-containing atom and optionally be substituted on N by (C)₁-C₃) An alkyl-substituted heterocycle;

R³is (C)₁-C₆) An alkyl group, a carboxyl group,

(C₃-C₆) A cycloalkyl group,

benzyl, which radical is optionally selected from among the aryl radicals

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

(C₁-C₃) A halogenated alkyl group,

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) Alkylthio radicals, and

SO₂(C₁-C₃) Up to four substituents of the alkyl group,

(C₂-C₃) Haloalkyl, or

Phenyl, the radical being optionally selected from

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

(C₁-C₃) A halogenated alkyl group,

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) Alkylthio radicals, and

SO₂(C₁-C₃) Up to four substituents of alkyl;

R⁴is (C)₁-C₆) Alkyl, the radical being optionally substituted by one (C)₁-C₄) Alkoxy substitution (C)₁-C₆) An alkoxy group,

(C₁-C₆) An alkylthio group is a group of one or more,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

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

NR⁸R⁸，

pyrimidinyl radicals

A pyridyl group, a carboxyl group,

imidazolyl or

Phenyl, the radical being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) Up to four substituents of an alkylthio group;

n is 0, 1, 2 or 3;

x is CO₂R⁸、CONR⁵R⁶、SO₂NHR⁷Or optionally (C)₁-C₆) An alkyl substituted oxadiazolyl;

R⁵is a compound of formula (I) in the formula (H),

(C₁-C₆) An alkyl group, a carboxyl group,

(C₂-C₆) Alkyl radical, the radical being OR⁶The substitution is carried out by the following steps,

benzyl, which radical is optionally selected from among the aromatic rings thereof

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group,

phenyl, which radical is optionally substituted

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Alkylthio substituted by up to four substituents, pyridyl, which is optionally substituted by a substituent selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group,

SO₂-phenyl, said benzeneIs optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group;

R⁶is H or (C)₁-C₆) An alkyl group; or

R⁵And R⁶And the N atom to which it is attached, form a piperidine, morpholine, thiomorpholine or piperazine ring, said piperazine optionally being substituted on its N atom by (C)₁-C₃) Alkyl substitution;

R⁷is H or methyl;

R⁸is a compound of formula (I) in the formula (H),

(C₁-C₆) An alkyl group, a carboxyl group,

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

(C₁-C₃) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group,

or

Phenyl, the radical being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group;

with the following conditions: when R and R are²Is H and X is CO₂When H, R₁Is not H, methyl or ethyl, and further provided that: the compound of formula (I) is not

The terms identified above all have the following meanings:

the term "halogen" refers to F, Br, Cl and I.

Term "(C)₁-C₃) Alkyl group "," (C)₁-C₆) Alkyl "and" (C)₂-C₆) Alkyl "means about 1 to about 3C atoms, respectivelyA straight or branched chain saturated hydrocarbon group of up to about 6C atoms and about 2 to about 6C atoms. Such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

Term "(C)₃-C₆) Alkenyl "means a straight or branched chain unsaturated hydrocarbon group containing one double bond and about 3 to about 6C atoms. The double bond may be located between two possible carbon atoms in the chain. Such groups include allyl, isopropenyl, 2-butenyl, 2-ethyl-2-butenyl, 1-hexenyl, and the like.

Term "(C)₃-C₆) Alkynyl "refers to a straight or branched chain unsaturated hydrocarbon group containing one triple bond and about 3 to about 6C atoms. A triple bond may be located between two possible carbon atoms in the chain. Such groups include propargyl, 2-butynyl, 1-methyl-2-butynyl, 3-hexynyl, and the like.

Term "(C)₃-C₆) Cycloalkyl "includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Term "(C)₁-C₃) Alkoxy group "," (C)₁-C₄) Alkoxy "and" (C)₁-C₆) Alkoxy "refers to a straight or branched chain saturated hydrocarbon group containing from about 1 to about 3C atoms, from about 1 to about 4C atoms, and from about 1 to about 6C atoms, respectively, attached to one O atom. The O atom is the atom through which the alkoxy substituent is attached to the rest of the molecule. Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.

Term "(C)₁-C₃) Haloalkoxy "and" (C)₂-C₃) Haloalkoxy "means independently (C)₁-C₃) Alkoxy radical or (C)₂-C₃) An alkoxy group substituted on C with a halogen atom. Such groups include trifluoromethoxy, difluoromethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy, 2-chloroEthoxy, 3-chloropropoxy, 1-fluoro-2, 2-dichloroethoxy, and the like.

Term "(C)₁-C₃) Haloalkyl "and" (C)₂-C₃) Haloalkyl "means independently (C)₁-C₃) Alkyl radical or (C)₂-C₃) An alkyl group substituted on C with a halogen atom. Such groups include trifluoromethyl, difluoroethyl, 1-fluoro-2, 2-dichloroethyl, 3-chloropropyl, 4-bromohexyl, and the like.

The term "[ tris (C)₁-C₄) Alkyl silyl radical]"means with three (C)₁-C₄) The Si group of the alkyl substituent, each substituent being independently selected. The Si atom is the atom through which the group is attached to the rest of the molecule. Such groups include, but are not limited to, trimethylsilyl, t-butyl-dimethylsilyl, and the like.

Formula C (o) refers to a group in which the C atom carries one doubly bonded oxygen (oxygen containing substituent) and in which two other bonding positions remain, i.e. represents a group of the formula:

term "(C)₁-C₄) Acyl "means (C) substituted on C of the C (O) group₁-C₄) An alkyl group. The C atom of C (O) is the atom through which the substituent is attached to the rest of the molecule. Such groups include, but are not limited to, acetyl (CH)₃C (O), propionyl group (CH)₃CH₂C (O), isobutyryl [ (CH)₃)₂CHC(O)-]And the like.

The term "NR⁸R⁸"refers to two R groups attached to the N atom⁸The groups are each independently selected and may be the same as or different from each other.

Term "(C)₁-C₃) Alkylthio "and" (C)₁-C₆) Alkylthio "refers to a straight or branched chain saturated hydrocarbon radical containing from about 1 to about 3C atoms or from about 1 to about 6C atoms, respectively, attached to one S atom. The S atom is the atom through which the alkylthio substituent is attached to the rest of the molecule. Such groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio and the like.

The term "SO₂(C₁-C₃) Alkyl "refers to a straight or branched chain saturated hydrocarbon group containing from about 1 to about 3C atoms, said group being associated with SO₂The S atoms in the group are linked. SO (SO)₂The sulfur atom in the group being such that (C) is bonded through the atom₁-C₃) The atom to which the alkyl substituent is attached to the remainder of the molecule. Such groups include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl and the like.

The term "6-membered carbocyclic ring" refers to a partially unsaturated ring containing the C atoms fused to the pyrazole ring to form a tetrahydroindazole ring system. The ring may optionally be substituted in any possible position by (C)₁-C₆) Alkyl groups, up to a cumulative total of about 6C atoms.

The term "containing an N atom and being substituted on N by (C)₁-C₆) Alkyl-substituted 6-membered heterocycle "means a fused tetrahydropyrazolo [4, 3-c ] ring]Pyridine or tetrahydropyrazolo [3, 4-c]A heterocycle of a pyridine bicyclic ring system. As shown below, the N atom in the tetrahydropyridine heterocycle may be located at the 5-or 6-position of the bicyclic ring system. The N atom being optionally substituted by (C)₁-C₃) Alkyl substitution (denoted as R in the following description)^{opt sub})。

Tetrahydropyrazolo [4, 3-c ] pyridinetetrahydropyrazolo [3, 4-c ] pyridines

The terms "tetrahydronaphthyl", "2, 3-indanyl", "benzodioxanyl" or "benzodioxolyl" refer to bicyclic groups of the formula:

the group is attached to the rest of the molecule at any possible carbon of the phenyl ring. When a group is an optional substituent, the substituent may be attached at any possible carbon atom.

The term "optionally substituted" means that the modified moiety may bear from 0 up to at least the maximum number of substituents indicated. Each substituent may replace any H atom in the modified moiety as long as the substitution is chemically possible and chemically stable. When two or more substituents are present on any moiety, each substituent may be independently selected from any other substituent, and thus may be the same or different.

Additional forms of the novel compounds

The compounds of the present invention also include (a) stereoisomers thereof, (b) pharmaceutically acceptable salts thereof, (c) tautomers thereof, (d) protected and conjugated acids thereof, and (e) prodrugs thereof.

Stereoisomers of these compounds include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers may be prepared and isolated by conventional methods, such as by reaction of the enantiomeric starting materials or by separation of isomers of the compounds of the invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis-isomers or trans-isomers across a double bond. Other isomers of the compounds of the invention are also contemplated. The isomers can be used as the above-mentioned inhibitors in pure form or in the form of mixtures with other isomers.

Pharmaceutically acceptable salts of the compounds of the invention include those salts commonly used to form alkali metal salts or addition salts which form the free acid or free base. The nature of the salt is not limited, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from aliphatic acids, cycloaliphatic acids, aromatic acids, heterocyclic acids, carboxylic acids and organic acids sulfonic acids. Examples of organic and sulfo organic acids include, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, aminobenzoic, methanesulfonic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embellic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylsulfamic, stearic, alginic, N-hydroxybutyric, salicylic, galactaric, and galacturonic acids and combinations thereof.

Tautomers of the compounds of the invention are included within the scope of the invention. Thus, for example, carbonyl includes its hydroxyl tautomer.

Protected acids include, but are not limited to, esters, hydroxylamino derivatives, amides, and sulfonamides.

The present invention includes prodrugs and prodrug salts. The generation of prodrugs is well known in the art for the purpose of enhancing the properties of the parent compound; such properties include solubility, absorption biostability and release time (see, e.g., "Pharmaceutical Dosage Form and Drug delivery systems" (six Edition), edited by Ansel et al, publication. by Williams & Wilkins, pgs.27-29, (1995), which is incorporated herein by reference). Commonly used prodrugs are designed to take advantage of most prodrug biotransformation reactions and are also contemplated within the scope of the present invention. Most prodrug biotransformation reactions include N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis, glucosidation, sulfonation, and acetylation (see, e.g., Goodman and Gilman' S The pharmaceutical Basis of therapeutics (Ninth Edition), editormolinoff et al, publ. byMcGraw-Hill, pages 11-13, (1996), incorporated herein by reference).

A comprehensive listing of abbreviations used by organic chemists of ordinary skill in the art appears in the first paragraph of volumes of organic chemistry magazines; this listing typically occurs in tables with an abbreviation standard listing at the head. The abbreviations contained in said list and those used by organic chemists of ordinary skill in the art are hereby incorporated by reference.

For the purposes of the present invention, the chemical elements are identified in the periodic Table of the elements, CASversion, Handbook of Chemistry and Physics, 67th Ed., 1986-87.

General preparation method

In general, the compounds useful in the present invention can be prepared by standard methods well known in the art, using starting materials that are commercially available or are generated according to synthetic routes, according to conventional chemical methods, by well known analogous methods or by the methods described herein. The following preparative procedures were used to aid the reader in the synthesis of the compounds of the invention.

Reaction scheme A illustrates the preparation of formula (Ia) [ formula (I) wherein R is H ]]General methods for Compounds. Aminopyrazoles of formula (III) are coupled with 2-bromo or 2-iodobenzoic acids, benzoates, benzoic acid amides or benzenesulfonamides of formula (IV) using Ullmann-type conditions (copper (II) acetate in DMF, heating for 16 hours in a closed tube), or using Buchwald-type conditions (cesium carbonate, BINAP and Pd in anhydrous toluene)₂(dba)₃Heated to 110 ℃ under argon for 16 hours) with 2-bromobenzoate of formula (IV), benzoate, benzoic acid amide or benzenesulfonamide.

Reaction scheme A

Reaction scheme B illustrates the conversion of a compound of formula (Ib) to a compound containing at least one R⁴General methods for other compounds of formula (Ia) for substituents by Suzuki coupling conditions [ e.g., palladium catalyst, e.g., Pd (dppf) Cl₂Heboric acid (V)]The following reaction scheme is halogen (Ib).

Reaction scheme B

Reaction scheme C depicts a compound of formula (Id) [ wherein R²Is bromine or iodine of formula (I)]General procedure for the preparation of the compounds of formula (Ia). In this scheme, bromine or iodine is introduced into a compound of formula (Ic) [ wherein R²Formula (I) being H]The resulting compound of formula (Id) is allowed to react with boronic acid R²B(OH)₂Subjected to Suzuki reaction conditions.

Reaction scheme C

By combining reaction schemes A, B and C, various R groups can be prepared²And R⁴Compounds of formula (Ia) with substituents are shown in scheme D1. For example, coupling of dibromobenzoic acid, dibromobenzoate, or dibromobenzenesulfonamide of formula (Iva) with a pyrazole of formula (IIIa) affords intermediate formula (Ie). Suzuki reaction of (Ie) with a boronic acid derivative gives (If), followed by bromination or iodination gives (Id). Finally, (Id) can be converted to the compound of formula (Ia) by another Suzuki reaction.

Reaction scheme D1

Iodination with NIS, or with Selectfluor, respectively, from compounds of formula (If) as shown in reaction scheme D2Fluorination to produce compounds in which R²Other compounds of formula (I) which are iodine (formula (Ig)) or fluorine (formula (Ih)).

Reaction scheme D2

Wherein R is⁴Is an amino group NR⁵R⁶Or imidazoles, can be prepared by a specific sequence shown in scheme E.

Reaction scheme E

In this sequence, the 4-fluoro group in the benzene ring may be replaced by R in an aromatic nucleophilic substitution reaction⁴Group substitution, wherein R⁴＝NR⁵R⁶Or an imidazolyl group. The reaction being carried out in the presence of a base such as LiNME₂Or K₂CO₃Under the conditions of (1).

Wherein X is C (O) NR⁵R⁶Or oxadiazolyl, the compounds of formula (I) can be prepared by the route shown in reaction scheme F.

Reaction scheme F

The ester compound of formula (Im) is typically hydrolyzed In a slightly basic aqueous solution to an acid compound of formula (In). Then, by reaction with an amine R⁵R⁶NH and coupling agent or ArSO with optionally substituted benzenesulfonamides₂NH₂And a coupling agent to convert the compound of formula (In) to an amide of formula (Io) to provide the acyl sulfonamide of formula (Ip). The compound of formula (In) may also be converted to the compound of formula (Iq) by reaction with N-hydroxy-acetamidine promoted with a base such as triethylamine and a coupling agent such as HOAT and EDCI. When a compound of formula (VI) is subjected to cyclodehydration reaction conditions, such as (methoxycarbonylsulfamoyl) -triethylammonium hydroxide (Burgess reagent), an oxadiazole ring of formula (Iq) is formed.

Reaction scheme G depicts the preparation of wherein X ═ SO₂NHR⁷And R is⁷General process for the preparation of compounds of formula (I) which are H.

Reaction scheme G

The compound of formula (Ir) N, N-dibenzylsulfonamide was prepared according to the procedure described in reaction scheme a and debenzylation was carried out using sulfuric acid to give the compound of formula (Is).

Reaction scheme H

Compounds of formula (I) wherein R is (C) can be prepared by N-alkylating the corresponding compound wherein R is H using standard conditions as shown in reaction scheme H₁-C₆) Alkyl compounds of formula (I). Such conditions include the reaction of an alkylating agent (e.g., methyl iodide) with a base (e.g., sodium hydroxide)In an inert solvent such as DMF.

Intermediate synthesis

Intermediates are commercially available or can be prepared by standard procedures well known in the art and/or by one of the following analogous procedures.

5-aminopyrazoles

The 5-aminopyrazole starting material of formula (III) is commercially available or can be prepared by the methods shown in reaction scheme I, J or K below.

Reaction scheme I

In reaction scheme I, optionally substituted acetonitrile is condensed with an appropriately substituted ester of formula (VII) and a base to provide a cyanoketone of formula (VIII). If desired, wherein R¹Esters of formula (VII) which are optionally substituted phenyl groups may be prepared from the corresponding compounds of formula R¹Br Bromide compounds, by reaction with, for example, BuLi and CO₂Reaction to produce a compound of formula R¹-COOH acid, followed by esterification to formula (VII) to produce the ester of formula (VII). The compound of formula (VIII) is then reacted with a substituted hydrazine of formula (II) to provide the desired aminopyrazole of formula (III). If cyanoketone (VIII) is commercially available, the first step can be omitted.

Reaction scheme J

In scheme J, acetonitrile is condensed to enaminonitrile (IX), which is then reacted with hydrazine (II) to form (IIIa) [ wherein R²＝H]。

Reaction scheme K

R²⁰Is H, (C)₁-C₄) Alkyl radical

^*Suitable borate esters include

R²B(OR′)₂Wherein R 'is lower alkyl, or two R' groups form a ring, e.g.

And tribolyborates, e.g.

Reaction scheme K illustrates how R, in addition to hydrogen, can be introduced by bromination and Suzuki or Stille coupling²Group, converting the aminopyrazole of formula (IIIa) to another aminopyrazole of formula (III). The Stille reaction product (IIIc) can also be reduced to the saturated compound of formula (IIId) by, for example, hydrogenation.

Examples of the preparation of aminopyrazoles are shown below in the description of intermediates B-M.

Hydrazine

The hydrazine starting material of formula (II) may be commercially available or may be obtained from phenylhydrazine (R)³Optionally substituted phenyl), it can be prepared by the method shown in reaction scheme L.

Reaction scheme L

R^{spt sub}(IIa), (II), R³Arbitrary substituted phenyl

Substituted anilines can be converted to diazonium salt intermediates, which are then reduced using tin (II) chloride as a reducing agent.

Examples of the preparation of arylhydrazines are shown below in the description of intermediate a.

2-bromobenzoic acid derivatives

The 2-bromobenzoic acid derivatives used in the coupling reaction with 5-aminopyrazole are either commercially available or prepared by direct methods well known in the art. An example of one such preparation is shown below in the description of intermediate N.

Specific embodiments of the invention

The following specific examples are intended to illustrate the invention described herein, but are in no way intended to limit the scope of the invention in any way.

Abbreviations and acronyms

When the following abbreviations are used in the disclosure of the present invention, they have the following meanings:

abs: absolute

Ac: acetyl group

AcOH: acetic acid

amu: atomic weight unit

aq: hydration of

BINAP: 2, 2 '-bis (diphenylphosphino) -1, 1' -dinaphthyl

Bn: benzyl radical

Boc: tert-butoxycarbonyl group

BTMAICl₂: benzyltrimethylammonium dichloroiodate

Bu: butyl radical

CDCl₃: chloroform (chloroform)

CDI: carbonyl diimidazoles

Celte: brands of diatomaceous earth filters, registered trademarks of the Celite company

CI-MS: chemical ionization mass spectrometry

And conc: concentrating

d: doublet peak

DCM: methylene dichloride

dd: doublet of doublet

ddd: doublet of doublet

DMAP: 4- (N, N-dimethyl) aminopyridine

DMF: n, N-dimethylformamide

DMSO, DMSO: dimethyl sulfoxide

DMSO-d₆: dimethyl sulfoxide-d₆

DOWEX66: dowex hydroxide, weakly basic anion, macroporous, 25-50 mesh

dppf: 1, 1' -bis (diphenylphosphino) ferrocene

EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EI: electron impact ionization

EI-MS: electron impact mass spectrometry

equiv: equivalent weight

ES-MS: electrospray mass spectrometry

Et: ethyl radical

Et₂O: diethyl ether

Et₃N: triethylamine

EtOAc: ethyl acetate

EtOH: ethanol

g: keke (Chinese character of 'Keke')

GC-MS: gas chromatography purification mass spectrometry

h: hour(s)

Hex: hexane (C)

¹H NMR: proton nuclear magnetic resonance

HOAT: 1-hydroxy-7-aza-benzotriazoles

HOBT: 1-hydroxybenzotriazoles

HPLC: high performance liquid chromatography

HPLC ES-MS: high performance liquid chromatography-electrospray mass spectrometry

KotBu: potassium tert-butoxide

L: lifting of wine

LC-MS: liquid chromatography/Mass Spectrometry

LDA: lithium diisopropylamide

m: multiple peaks

M: mole of

ml: milliliter (ml)

m/z: mass per unit charge

Me: methyl radical

MeCN: acetonitrile

MeOH: methanol

mg: milligrams of

MHz: megahertz

min: minute (min)

mmol: millimole

mol: mole of

mp: melting Point

MS: mass spectrometry

N: general of

NaOAc: sodium acetate

NBS: n-bromosuccinimide

NIS: n-iodosuccinimide

NMM: 4-methylmorpholine

NMR: nuclear magnetic resonance

Pd₂(dba)₃: tris (dibenzylideneacetone) dipalladium (0)

Pd(OAc)₂: palladium acetate

Pd(PPh₃)₄: tetrakis (triphenylphosphine) palladium (0)

Pd/C: palladium/carbon

Pd(dppf)Cl₂: [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)

Ph: phenyl radical

ppm: parts per million

Pr: propyl radical

psi: pounds per square inch

q: quartet peak

qt: quartet peak

R_f: TLC retention factor

rt: at room temperature

RT: retention time (HPLC)

s: single peak

TBAF: tetrabutyl ammonium chloride

TBDMS: tert-butyldimethylsilyl group

TBDMSCI: tert-butyldimethylsilyl chloride

TBS: tert-butyldimethylsilyl group

TFA: trifluoroacetic acid

THF: tetrahydrofuran (THF)

TLC: thin layer chromatography

TMS: tetramethylsilane

v/v: volume per unit volume

vol: volume of

weight per unit weight of w/w

General Experimental methods

Air and moisture sensitive liquids and solutions were transferred through syringes or catheters and introduced into the reaction vessel through a rubber septum. Commercial grade reagents and solvents were used without further purification. The term "concentration under reduced pressure" means that a Buchi rotary evaporator is used at about 15mm Hg. All temperatures are reported in uncorrected degrees Celsius (. degree. C.). Thin Layer Chromatography (TLC) was performed on EM Science pre-coated glass-backed silica gel 60A F-254250 μm plates. Column chromatography (flash chromatography) purification was performed in Biotage line using 32-63 μm 60A silica gel pre-loading kit. Purification by preparative reverse phase HPLC chromatography was accomplished using the Gilson 215 line, typically using a YMC Pro-C18 AS-342 (150X 20mm I.D.) column. Typically, aThe mobile phase used is H₂Mixtures of O (A) and MeCN (B). The water may be mixed or free of 0.1% TFA. A typical gradient is:

time [ min ]]	A：％	B：％	Flow rate [ mL/min]
time [ min ]]	A：％	B：％	Flow rate [ mL/min]	0.60	90.0	10.0	1.0
11.00	0.0	100.0	1.0	0.60	90.0	10.0	1.0
11.00	0.0	100.0	1.0	14.00	0.0	100.0	1.0
15.02	100.0	0.0	1.0	14.00	0.0	100.0	1.0

Electron impact mass spectrometry (EI-MS) was obtained by a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 gas chromatograph containing a J & W DB-5 column (0.25 μ M coating; 30M × 0.25 mm). The ion source was maintained at 25 ℃ and the spectra were scanned at 2 seconds/scan by 50-800 amu.

High pressure liquid chromatography/electrospray mass spectrometry (LC-MS) was obtained using the following:

(A) Hewlett-Packard 1100HPLC equipped with a four-stage pump, at 254nm equipped with a variable wavelength detector device, YMC pro C-18 column (2X 23mm, 120A), Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned at 120-. The eluent is A: acetonitrile/0.02% TFA in 2% water and B: water in 2% acetonitrile/0.018% TFA. Elution was performed with a 10% to 95% B gradient over 3.5 minutes at a flow rate of 1.0ml/min, starting at 0.5 minutes and ending at 95% B for 0.5 minutes. The total operating time was 6.5 minutes.

Or

(B) A Gilson HPLC system, equipped with two Gilson 306 pumps, a Gilson 215 autosampler, a Gilson diode array detector, a YMC pro C-18 column (2X 23mm, 120A), and a Micromass LCZ single quadruple mass spectrometer with z-spray electrospray ionization. The spectra were scanned over 1.5 seconds by 120-. ELSD (evaporative light scattering detector) data were obtained from a similar signal channel. The eluent is A: acetonitrile/0.02% TFA in 2% water and B: water in 2% acetonitrile/0.018% TFA. Elution was performed with a gradient from 10% to 90% B over 3.5 minutes at a flow rate of 1.5ml/min, starting at 0.5 minutes and ending at 90% B for 0.5 minutes. The total operating time was 4.8 minutes. Additional on-off valves were used for column switching and regeneration.

Conventional one-dimensional NMR spectra were measured on an 300/400MHz Varian Mercury-plus spectrometer. The sample was dissolved in a heavy hydrogen solvent obtained from Cambridge Isotrope Labs and transferred to 5mm ID Wilmad NMR tubes. Spectra were obtained at 293K. Chemical shifts are recorded on the ppm scale as a reference for appropriate solvent signals, e.g., for 1H spectra: 2.49ppm (DMSO-d)₆)、1.93ppm(CD₃CN)、3.30ppm(CD₃OD)、5.32ppm(CD₂Cl₂) And 7.26ppm (CDCl)₃) (ii) a For the 13C spectrum: 39.5ppm (DMSO-d)₆)、1.3ppm(CD₃CN)、49.0ppm(CD₃OD)、53.8ppm(CD₂Cl₂) And 77.0ppm (CDCl)₃)。

Synthesis of intermediates

Hydrazine

Intermediate A

Preparation of (2, 6-dimethylphenyl) hydrazine hydrochloride

To a cold (0 ℃) solution of 2, 6-dimethylaniline (5.0g, 41.3mmol) in 50% aqueous HCl (45ml) was slowly added a cold (0 ℃) solution of NaNO2(2.85g, 41.3mmol) in water (22.5ml) with stirring. The temperature was strictly controlled during the addition and was not allowed to exceed 5 ℃. After the addition was complete, the bright orange solution containing the diazonium salt intermediate was stirred at the same temperature for 20 minutes. SnCl was added to the reaction mixture at 0 ℃ over-5 minutes₂(11.0g, 57.8mmol) in concentrated HCl (30 ml). The reaction mixture was warmed to room temperature and stirred for 6 hours. The precipitate was collected by filtration and washed with a small amount of cold water. Drying in vacuo afforded the title compound as a white amorphous solid (7.00g, 98%). The product was used in the next step without further purification. ES-MS m/z 137.0 (MH)⁺)；HPLC RT(min)1.09。

5-aminopyrazoles

Intermediate B

Preparation of 3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazol-5-amine

Step 1: preparation of 3-cyclopentyl-3-oxopropanenitrile

To a suspension of NaH (2.75g, 68.7mmol) in THF (15ml) at 70 deg.C was added dropwise a solution of methyl cyclopentane (8.00g, 62.4mmol) and dry acetonitrile (3.91ml, 74.9mmol) in THF (5 ml). The mixture was stirred at 70-72 ℃ for 16 h, cooled to room temperature, and diluted with ethyl acetate and aqueous HCl. The organic layer was washed with water and brine, dried (MgSO)₄). The solvent was removed to give 3-cyclopentyl-3-oxopropanenitrile, which was used without further purification.

Step 2: preparation of 3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazol-5-amine

A solution of (2-methylphenyl) hydrazine hydrochloride (2.00g, 14.6mmol) and crude 3-cyclopentyl-3-oxopropanenitrile (2.32g, 14.6mmol) from the previous step in toluene (6ml) was heated for 16 hours. The solvent was removed under reduced pressure to give a residue which was purified by silica gel chromatography using hexane/EtOAc (3: 1, v/v) as eluent. Concentration under reduced pressure gave 3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazol-5-amine as a bright orange solid (2.19g, 62%).

ES-MSm/z241.9(MH⁺)；HPLC RT(min)1.69.¹H NMR(400MHz，CDCl₃)δ1.58-1.82(m，6H)，2.00-2.16(m，2H)，2.17-2.21(s，3H)，2.93-3.11(m，1H)，3.42-3.58(s，2H)，5.41-5.46(s，1H)，7.20-7.28(m，2H)7.29-7.37(m，2H).

Intermediate C

Preparation of 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-amine

4, 4-dimethyl-3-oxopropanenitrile (36.7g, 0.29mol), (2-methylphenyl) hydrazine hydrochloride (47.7g, 0.29mol) and glacial acetic acid (7.03g, 6.7ml, 0.12mol) were dissolved in anhydrous ethanol (585ml) and heated overnight for 18 h. After removal of the solvent under reduced pressure, EtOAc and water (500mL each) were added followed by careful addition of sodium bicarbonate (42g, 0.50 mol). After addition of hexane (500ml), the organic phase was separated, washed with brine (500ml) over Na₂SO₄And drying. The mixture was then filtered through a pad of silica gel (500g) on an embedded glass funnel. The pad was washed with hexane/EtOAc (1: 1, v/v) and the filtrate was concentrated under reduced pressure. The resulting solid was triturated with hexanes/EtOAc (9: 1, v/v), filtered, washed and dried in vacuo to give a colorless solid (61.5g, 93%).

¹H NMR(400MHz，CD₂Cl₂)δ1.29(s，9H)，2.12(s，3H)，3.56(br，2H)，5.48(s，1H)，7.28(m，2H)，7.31(m，2H).

Intermediate D

Preparation of 3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-amine

Step 1: system for makingPreparation of 3-amino-3- (4-fluorophenyl) acrylonitrile

To a solution of 4-fluorobenzonitrile (5.00g, 41.3mmol) and acetonitrile (4.35ml, 82.5mmol) in toluene (100ml) was added potassium tert-butoxide (13.9g, 124 mmol). The mixture was stirred for 24 hours, then the reaction was quenched by slowly adding aqueous sodium bicarbonate. The resulting suspension was extracted with dichloromethane (3X 50 ml). The organic solution was washed with water and dried (Na)₂SO₄) And concentrating under reduced pressure. Using EtOH/Et₂The residue was triturated to give 3-amino-3- (4-fluorophenyl) acrylonitrile (6.20g, 93%) as a white solid.

¹H NMR (300MHz, acetone-d₆)

δ4.23(s，1H)，6.20(s，2H)，7.22(ddd，2H)，7.71(m，2H).

Step 2: preparation of 3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-amine

To a solution of 3-amino-3- (4-fluorophenyl) acrylonitrile (600mg, 3.70mmol) in 1N HCl (6ml) was added (2-methylphenyl) hydrazine hydrochloride (558mg, 3.51 mmol). The reaction was refluxed for 16 hours and then cooled to room temperature. The resulting mixture was basified by slowly adding 1N aqueous sodium hydroxide solution to pH 12. The precipitate was collected by filtration and then eluted with EtOH/Et₂Recrystallization from O afforded intermediate (800mg, 81%) as a bright orange solid.

¹H NMR(400MHz，CD₂Cl₂)δ2.20(s，3H)，2.14

(br s，2H)，5.91(s，1H)，7.06(t，2H)，7.36(d，4H)，7.75(m，2H).

The product was used without further purification.

Intermediate E

Preparation of 3- (4-fluoro-2-methylphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-amine

Step 1: preparation of 4-fluoro-2-methylbenzoic acid

To a cold (-78 ℃ C.) solution of 2-bromo-5-fluorotoluene (10.0g, 52.9mmol) in diethyl ether (100ml) was added dropwise n-butyllithium (1.6M in hexane, 21.2ml, 52.9 mmol). The mixture was stirred for 5 minutes, slowly warmed to 0 ℃. Dry ice (100g, 2.27mol) was slowly added to the mixture with stirring, allowing to warm to room temperature over 16 hours. The mixture was adjusted to pH 2 and extracted with ethyl acetate (3 × 20 ml). The organic phase was concentrated and the resulting yellow residue was suspended in water (100 ml). The suspension was adjusted to pH 12 with 2N NaOH and washed with diethyl ether. The aqueous phase was then acidified to pH 2 with 2N HCl and extracted with diethyl ether (3 × 50 ml). The organic extract was washed with water and dried (MgSO)₄) Concentration under reduced pressure gave the product (5.0mg, 61%) as a white solid.

¹H NMR(400

MHz，DMSO-d₆)δ2.53(s，3H)，7.06-7.17(m，2H)，7.87(dd，1H)，12.85(s，1H).

Step 2: preparation 4-Fluoro-2-methylbenzoic acid methyl ester

To a solution of 4-fluoro-2-methylbenzoic acid (4.0g, 26.0mmol) in THF (30ml) was added cesium carbonate (8.45mg, 26.0mmol) and iodomethane (2.0M in t-butyl methyl ether, 13.0ml, 26.0mmol) in a pressure vessel. The vessel was sealed and the reaction stirred at 70 ℃ for 16 hours. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate (10ml) and water (50 ml). The aqueous layer was extracted with dichloromethane (3X 50ml) and then dried (Na)₂SO₄) The organic phase was concentrated under reduced pressure to give the crude product. The product was triturated with acetone and hexanes to give the pure product (3.8g, 87%) as a white solid.

¹H NMR (400MHz, acetone-d₆)δ2.60(s，3H)，3.86(s，3H)，7.05-7.12(m，2H)，7.96(s，1H)；ES-MS m/z188.2(MH⁺)；HPLC RT(min)3.20.

And step 3: preparation of 3- (4-fluoro-2-methylphenyl) -3-oxopropanenitrile

To a suspension of hexane-washed sodium hydride (60% oil dispersion, 995mg, 24.9mmol) was added dropwise a solution of methyl 4-fluoro-2-methylbenzoate (3.8g, 22.6mmol) and anhydrous acetonitrile (2.4ml, 45.2mmol) in THF (20 ml). The reaction was stirred at 70 ℃ for 16 hours and then cooled to room temperature. The resulting mixture was diluted with ethyl acetate (20ml) and 1N HCl (10ml) and the layers separated. The organic phase was washed with water (3X 20ml) and brine (20ml) and dried (Na)₂SO₄) Concentration under reduced pressure gave 4.0g of a yellow oil which was used in the next step without further purification.

ES-MS m/z178.2(MH⁺)；HPLC RT(min)2.22.

And 4, step 4: preparation of 3- (4-fluoro-2-methylphenyl) -1- (2-methylphenyl) -1H-pyrazole-5- Amines as pesticides

To a solution of 3- (4-fluoro-2-methylphenyl) -3-oxopropanenitrile (2.0g, 11.3mmol) in toluene (10ml) was added (2-methylphenyl) hydrazine hydrochloride (2.15g, 13.5 mmol). The reaction was stirred at 110 ℃ for 16 hours and then cooled to room temperature. Concentrated under reduced pressure and the residue purified by flash chromatography on silica gel (2: 1-1: 1 ═ hexane: ethyl acetate) to give the product as a yellow oil (500mg, 16%).

¹HNMR(400MHz，DMSO-d₆)δ2.12(s，3H)，2.44(s，3H)，5.74(s，1H)，7.02-7.14(m，2H)，7.34-7.43(m，4H)，7.52(dd，1H)；ES-MS m/z 282.4(MH⁺)；HPLC RT(min)3.36.

Intermediate F

Preparation of 3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-amine

3-Aminobutenenitrile (2.00g, 24.4mmol) was added to a stirred solution of (2-methylphenyl) hydrazine hydrochloride (3.67g, 23.1mmol) in 1M hydrochloric acid (20 ml). The reaction was heated (100 ℃ C.) for 18 hours and then cooled to room temperature. The pH of the solution was adjusted to > 12 using 1M aqueous sodium hydroxide. The mixture was extracted with dichloromethane (3 × 20ml) and the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 25-50% ethyl acetate/hexanes to give 3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-amine (3.97g, 87%) as an orange oil.

¹H NMR (300MHz, acetone-d₆)δ7.29(m，4H)，5.32(s，1H)，2.12(s，3H)，2.08(s，3H)；ES-MS m/z 188.2(MH⁺)，HPLC RT(min)0.79.

Intermediate G

Preparation of 2- (2-methylphenyl) -4, 5, 6, 7-tetrahydro-2H-imidazol-3-amine

To a solution of (2-methylphenyl) hydrazine hydrochloride (464mg, 2.92mmol) in ethanol (2ml) was added 2-oxocyclohexanecarbonitrile (300mg, 2.44mmol), the mixture was heated at 60 ℃ and stirred for 16 h. The flask was then cooled to room temperature and the solvent was evaporated to give a solid. The crude residue, 2- (2-methylphenyl) -4, 5, 6, 7-tetrahydro-2H-imidazol-3-amine hydrochloride (449mg, 70%), was used in the next step without further purification.

ES-MS m/z228.2(MH⁺)；HPLCRT(min)1.22.

Intermediate H

Preparation of 4- (4-fluorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-amine

Step 1: preparation of 4-bromo-3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-amine

To a solution of 3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-amine (intermediate F, 7.78g, 41.7mmol) in acetic acid (90ml) was added a solution of bromine (6.64g, 41.6mmol) in acetic acid (10 ml). The reaction mixture was stirred for 30 minutes. Water was added to the reaction mixture and the mixture was basified with cold KOH solution (1N). 4-bromo-3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-amine was collected as a white solid and used in the next step without further purification.

Step 2: preparation of 4- (4-fluorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazole-5- Amines as pesticides

4-bromo-3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-amine (2g, 7.52mmol), 4-fluorophenylboronic acid (2.10g, 11.3mmol) and Pd (PPh)₃)₄(434mg, 0.38mmol) was dissolved in DMF (20ml) and Na was added₂CO₃(saturated aqueous solution, 18 ml). The mixture was degassed for 10 minutes and then heated at 110 ℃ for 2 hours. The reaction mixture was diluted and the solid was filtered off. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 10 to 40% ethyl acetate in hexane to give 1.2g (90% pure, 51%) of the title compound.

¹H NMR

(300MHz，CD₂Cl₂)δ7.25-7.34(m，6H)，7.08(t，2H)，3.62(s，2H)，220(s，3H)，2.14(s，3H)，

Intermediate I

Preparation of tert-butyl (4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-yl) carbamate

Step 1: preparation of 4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-amine

To a solution of 3-tert-butyl-1-methyl-1H-pyrazol-5-amine (10g, 65.3mmol) in acetic acid (90ml) was added a solution of bromine (10.4g, 65.26mmol) in acetic acid (10 ml). The solution was stirred at room temperature for 30 minutes, then water (100ml) was added. The reaction mixture was basified to pH9 using KOH (1.0M ice cold solution). The resulting brown solid was collected by filtration and purified by flash chromatography on silica gel eluting with 10 to 30% ethyl acetate in hexanes to give 13.2g (87%) of the title compound as a white solid.

Step 2: preparation of (4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-yl) carbamic acid tert-butyl Butyl ester

The product of step 1 (2g, 8.62mmol), di-tert-butyl dicarbonate (2.82g, 12.92mmol) and DMAP (105mg, 0.86mmol) were dissolved in DCM (40ml) and stirred for 16 h. To the reaction mixture was added potassium carbonate (10% aqueous solution, 100ml), and stirring was continued for additional 4 hours. The organic layer was separated and concentrated under reduced pressure. Flash chromatography on silica gel eluting with 5 to 20% ethyl acetate in hexanes afforded 2.3g (80%) of the title compound.

¹H NMR(300MHz，CD₂Cl₂)δ3.55(s，3H)，1.37(s，9H)，1.31(s，9H).

Intermediate J

Preparation of 4-bromo-3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-amine

To a solution of 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-amine (1.00g, 4.36mmol) in acetic acid (10ml) was added dropwise bromine (662mg, 0.21ml, 4.14 mmol). The reaction mixture was stirred for 5 minutes, then diluted with water (50ml) and a solid precipitated. The solid was collected by filtration and dissolved in EtOAc (50 ml). With saturated NaHCO₃The EtOAc solution was washed with brine and dried (Na)₂SO₄) Concentration under reduced pressure gave the product (935mg, 70%) as a white solid.

¹H NMR(300MHz，DMSO-d₆)δ1.32(s，9H)，2.04(8，3H)5.02(s，2H)，7.20-7.38(m，4H).ES-MS m/z308.6(MH⁺)；HPLC RT(min)3.15.

Intermediate K

Preparation of 3-tert-butyl-4-methyl-1- (2-methylphenyl) -1H-pyrazol-5-amine

To a solution of 4-bromo-3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-amine (intermediate J, 800mg, 2.60mmol) in DMF (5ml) was added trimethylboroxine (0.73ml, 5.19mmol), [1, 1' -bis (diphenylphosphino) -butane]Palladium (II) dichloride (157mg, 0.26mmol) and potassium carbonate (1.08g, 7.79 mmol). The reaction mixture was stirred at 155 ℃ for 18 hours. After cooling, the reaction mixture was diluted with water (100ml) and extracted with EtOAc (3X 25 ml). The combined organic layers were washed with brine and dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. Flash silica gel chromatography of the residueElution with hexane/EtOAc (1: 9, v/v) afforded the product (243mg, 38%) as a white solid.

¹H NMR(300MHz，DMSO-d₆)δ1.24(s，9H)，1.97(s，3H)，2.03(s，3H)，4.48(s，2H)7.14-7.32(m，4H).ES-MS m/z244.2(MH⁺)；HPLC RT(min)1.17.

Intermediate L

Preparation of 3-tert-butyl-1-methyl-4-pyridin-3-yl-1H-pyrazol-5-amine

Tert-butyl (4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-yl) carbamate (intermediate I, 1.7g, 5.12mmol), pyridine-3-boronic acid (1.26g, 10.23mmol) and Pd (PPh)₃)₄(295mg, 0.26mmol) was dissolved in ethanol (25ml) and Na was added₂CO₃(2M aqueous solution, 25 ml). The mixture was degassed for 10 minutes. The reaction mixture was then heated to 80 ℃ for 16 hours. The mixture was diluted with ethyl acetate, the solid was filtered off and the filtrate was treated with TFA (5 ml). The mixture was stirred for 30 minutes, then concentrated under reduced pressure. The crude product is dissolved in methanol and passed through C₈-filtration through a silica gel plug. HPLC purification, eluting with a gradient of 5 to 60% acetonitrile in water, gave 300mg (25%) of the title compound.

¹H NMR(300

MHz，CD₃CD)δ8.73(d，1H)，8.64(s，1H)，8.14(d，1H)，7.81(dd，1H)，3.73(s，3H).1.20(s，9H).ES-MS m/z 231.2(MH⁺)；HPLC RT(min)0.23.

Intermediate M

Preparation of 4-ethyl-3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-amine

Step 1: preparation of 3- (4-fluorophenyl) -1- (2-methylphenyl) -4-vinyl-1H-pyrazole -5-amine

To a solution of 4-bromo-3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-amine (200mg, 0.58mmol) in toluene (10ml) were added tributylvinyltin (0.33ml, 366mg, 1.16mmol) and tetrakis (triphenylphosphine) palladium (O) (66mg, 0.06 mmol). The reaction mixture was heated at reflux and stirred for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100ml), washed with brine (50ml) and dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. Flash chromatography on silica gel eluting with 10% EtOAc in hexanes afforded 3- (4-fluorophenyl) -1- (2-methylphenyl) -4-vinyl-1H-pyrazol-5-amine (87mg, 51%).

¹H NMR(300MHz，DMSO-d₆)δ2.12(s，3H)，4.96(dd，1H)5.21(dd，1H)，5.26(s，2H)，6.55(dd，1H)，7.18-7.56(m，8H).ES-MS m/z 294.2(MH⁺)；HPLC RT(min)3.54.

Step 2: preparation of 4-ethyl-3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazole-5- Amines as pesticides

To wet palladium on carbon (10 wt%, 10mg) in EtOH (5ml) was added 3- (4-fluorophenyl) -1- (2-methylphenyl) -4-vinyl-1H-pyrazol-5-amine (8) in EtOH (5ml)7mg, 0.30 mmol). At H₂The reaction was mixed on a Parr mixer under an atmosphere (55psi) for 16 hours. The palladium catalyst was filtered through celite, rinsing with EtOH (3 × 20 ml). The solution was concentrated under reduced pressure to give the title compound (68mg, 77%) containing trace impurities. This product was used in the next reaction step without further purification.

ES-MS m/z 296.2(MH⁺)；HPLC RT(min)2.65.

2-bromobenzoic acid derivatives

Intermediate N

Preparation of methyl 2-bromo-5- (difluoromethoxy) benzoate

Step 1: preparation of methyl 2-bromo-5-hydroxybenzoate

To a cold (ice-water bath) solution of methyl 2-bromo-5-methoxybenzoate (2.00g, 8.16mmol) in dichloromethane (15ml) under an argon atmosphere was added AlCl₃(5.44g, 40.8mmol) and the reaction temperature was kept below 10 ℃ using an ice-water bath. The light brown suspension was stirred for 10 min, then EtSH (3.02ml, 40.8mmol) was added dropwise, the rate being such that the reaction temperature was kept below 5 ℃. After stirring at 10 ℃ for 2.5 hours, the reaction mixture was slowly poured into ice-chelated water with stirring. The organic layer was separated, the aqueous layer was extracted with DCM, the organic layer was washed with water over MgSO₄Dried, filtered and concentrated under reduced pressure to give a bright yellow oil which was used in the next step without further purification.

Step 2: preparation of methyl 2-bromo-5- (difluoromethoxy) benzoate

To a solution of methyl 2-bromo-5-hydroxybenzoate (5.63mmol, 1.30g) in DMF (8ml) were added cesium carbonate (11.3mmol, 3.67g) and methyl chlorodifluoroacetate (6.75mmol, 0.71ml), and the reaction mixture was stirred at 90 ℃ for 16 h. After cooling to room temperature, it was diluted with ethyl acetate, the mixture was filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexane/EtOAc (9: 1, v/v) to give the product as a bright yellow oil (560mg, 35%). GC-MS m/z: 280 (MH)⁺)。

Secondary and tertiary amides

In addition to the amine used in example 315, other amine precursors for all amide formation reactions are commercially available. The synthesis of which is described in the following section.

Intermediate O

Preparation of (2- { 4-methoxy-3- [ (4-methylpiperazin-1-yl) sulfonyl ] phenyl } ethyl) amine dihydrochloride

Step 1: preparation of 2, 2, 2-trifluoro-N- [2- (4-methoxyphenyl) ethyl]Acetamide

To 4-methoxyphenethylamine (2.5g, 16.5mmol) in CH at 0 deg.C₂Cl₂(45ml) solution was added with CH of trifluoroacetic anhydride₂Cl₂(5ml) solution. The reaction mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 1 hour. Addition of NH₄Aqueous solution of Cl, phase separation, using CH₂Cl₂The aqueous phase is extracted. Drying (Na)₂SO₄) The combined organic phases were filtered and concentrated under reduced pressure. From Et₂The resulting solid was recrystallized from O/hexane to give the product as a light brown solid (2.36g, 58%).

¹H NMR(400 MHz，CDCl₃)，δ2.82(t，2H)，3.62(q，2H)，3.81(s，3H)，6.19-6.30(broad，1H)，6.87(d，2H)，7.10(d，2H)；GC-MS m/z 247(M⁺)，1RT(min)12.22.

Step 2: preparation of 2, 2, 2-trifluoro-N- (2- { 4-methoxy-3- [ (4-methylpiperazine-1-) Yl) sulfonyl group]Phenyl } ethyl) acetamide

At 0, in N₂Then, 2, 2, 2-trifluoro-N- [2- (4-methoxyphenyl) ethyl]Chlorosulfonic acid (4ml) was added to a flask of acetamide (1.00g, 4.05 mmol). After 30 minutes, the temperature was raised to room temperature and stirring was continued for another 90 minutes. The reaction mixture was added dropwise to CH₂Cl₂And ice-water cooled in an ice bath [ vigorous reaction on contact with water]. Phase separation, using CH₂Cl₂The aqueous phase is extracted. Drying (Na)₂SO₄) The combined organic phases were filtered and concentrated under reduced pressure.

At 0 ℃ under N₂Next, the resulting sulfonyl chloride was dissolved in CH₂Cl₂(30ml), Et was added₃N (1.29ml, 8.10mmol) and 1-methylpiperazine (0.674ml, 6.08 mmol). The solution was warmed to room temperature and stirred for 14 hours. The reaction mixture was then concentrated and purified by flash chromatography on silica gel using EtOAc/MeOH (R) ((R))4: 1, v/v) to give the title compound as a yellow oil (1.26g, 75%).

¹H NMR(400MHz，CDCl₃).δ2.13(s，3H)，2.48(broad t，4H)，2.87(t，2H)，3.27(broad t，4H )，3.56(q，2H)，3.88(s，3H)，6.70-6.77(broad s，1H)，6.94(d，1H)，7.33(dd，1H)，7.69(dd，1H)；ES-MSm/z 410.3((MH)⁺)，432.1((M+Na)⁺)840.7((2M+Na)⁺)HPLC RT(min)1.19.

And step 3: preparation of (2- { 4-methoxy-3- [ (4-methylpiperazin-1-yl) sulfonyl group]Phenyl radical } Ethyl) amine dihydrochloride

To the 2, 2, 2-trifluoro-N- (2- { 4-methoxy-3- [ (4-methylpiperazin-1-yl) sulfonyl group]-phenyl } ethyl) acetamide (from step 2) (1.25g, 3.05mmol) in MeOH (30ml) and H₂To a solution of O (8ml) was added K₂CO₃(2.11g, 15.3mmol), the solution was stirred at 60 ℃ for 2 h. After cooling to room temperature, MeOH was evaporated under reduced pressure. By means of CH₂Cl₂(6X 50ml) the remaining aqueous mixture was extracted and dried (Na)₂SO₄) The combined organic phases were filtered and concentrated under reduced pressure. The residue was dissolved in MeOH and 4 equivalents of 1N HCl in MeOH were added to cause a white precipitate to form. The solvent was evaporated under reduced pressure from MeOH/Et₂The resulting solid was recrystallized from O to give the title compound [ presumably the di-HCl salt [ ]]As a white solid (457mg, 48%).

¹HNMR(400MHz，CD₃OD)δ2.29(s，3H)，2.48(broad t，4H)，2.78(dd，2H)，2.87-2.92(m，2H)，3.23(broad t，4H)，3.91(s，3H)7.16(d，1H)，7.47(dd，1H)，7.68(d，1H)；ES-MS m/z(MH⁺)314.2，HPLC RT(min)0.70.

Example 1

Preparation of 2- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino ] -5-methoxybenzoic acid

A mixture of 2-bromo-5-methoxybenzoic acid (2.26g, 9.79mmol), potassium carbonate (1.49g, 10.8mmol), 5-amino-3-tert-butyl-1-methylpyrazole (1.50g, 9.79mmol) and copper (II) acetate (35mg, 0.20mmol) in DMF (20ml) was heated in a closed tube for 16 h (150 ℃). After cooling, the reaction mixture was diluted with water (10ml) and acidified to pH4 with acetic acid. The mixture was extracted with dichloromethane (3X 20ml) and the combined organic extracts were washed with water (2X 30ml) over Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by HPLC (YMC propack C18 column, 150 × 20mm ID, 30% -80% acetonitrile/water gradient elution) to give the title compound (973mg, 31%) as a pale yellow solid.

¹H NMR(300MHz，DMSO-d₆)δ13.22(brs，1H)，9.24(br s，1H)，7.38(d，1H)，7.10(dd，1H)，6.80(d，1H)，5.95(s，1H)，3.70(s，3H)，3.55(s，3H)，1.21(s，9H)：ES-MS m/z 304.2(MH⁺)，HPLC RT(min)2.58.

Example 2

Preparation of 2- { [3- (4-chlorophenyl) -1-methyl-1H-pyrazol-5-yl ] amino } -4, 5-dimethoxybenzoic acid trifluoroacetate

In a closed tube, 2-bromo-5-methoxybenzoic acid (105mg, 0.40mmol), potassium carbonate (61mg, 0.44mmol), 5-amino-3- (4-chlorobenzene) in DMF (2ml) was heated (150 ℃ C.)1-methylpyrazole (84mg, 0.40mmol) and copper (II) acetate (2mg, 0.01mmol) for 16 h. After cooling, the reaction mixture was diluted with water (2ml) and acidified to pH4 with acetic acid. The mixture was extracted with dichloromethane (3X 5ml) and the combined organic extracts were washed with water (2X 5ml) over Na₂SO₄Dried, filtered and concentrated under reduced pressure. HPLC-MS purification of the residue (HPLC: YMC propack C18 column, 100X 20mm ID, 10% -95% acetonitrile/TFA (0.1%) in a water/TFA (0.1%) gradient elution; MS: 120-1000amu in Micromass LCZ single quartet, electrospray ionization) gave the title compound (28mg, 14%) as a white solid.

¹H NMR(300MHz，DMSO-d₆)δ9.78(s，1H)，7.82(ddd，2H)，7.42(ddd，2H)，7.36(s，1H)，6.74(s，1H)，6.56(s，1H)，3.74(s，3H)，3.71(s，6H)；ES-MS m/z 388.2(MH⁺)，HPLC RT(min)2.58.

Example 3

Preparation of 2- { [3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid

To a solution of 3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-amine (intermediate D, 100mg, 0.37mmol) in DMF (3ml) were added 2-iodobenzoic acid (93mg, 0.37mmol), potassium carbonate (62mg, 0.45mmol) and copper (II) acetate (3mg, 0.01 mmol). The mixture was stirred at 150 ℃ for 18 hours and then cooled to room temperature. The solution was adjusted to pH4 using glacial acetic acid. The mixture was extracted with dichloromethane (3X 5ml), the combined organic extracts were washed with brine and dried (MgSO 5)₄) Filtered and concentrated under reduced pressure. The residue was purified by HPLC (45-90% acetonitrile in water) to give the title compound (17mg, 12%) as a bright yellow solid.

¹H NMR(400MHz，DMSO-d₆)δ2.08(s，3H)，6.85(ddd，1H)，6.93(s，1H)，7.24(ddd，2H)，7.42(m，6H)，7.84(dd，1H)，7.92(ddd，2H)，10.02(s，1H)，13.23(s，1H)；ES-MS m/z 388.2(MH⁺)；HPLC RT(min)3.47.

Example 4

Preparation of 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid

To a solution of 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-amine (intermediate C, 1.00g, 4.36mmol) in DMF (20ml) were added 2-bromo-5-methoxybenzoic acid (1.01g, 4.36mmol), potassium carbonate (723mg, 5.23mmol) and copper (II) acetate (32mg, 0.17 mmol). The mixture was stirred at 150 ℃ for 18 hours and then cooled to room temperature. The solution was adjusted to pH4 using glacial acetic acid. The mixture was extracted with dichloromethane (3X 5ml), the combined organic extracts were washed with brine and dried (MgSO 5)₄) Filtered and concentrated under reduced pressure. The residue was purified by HPLC (45-90% acetonitrile in water) to give the title compound (500mg, 33%) as a bright yellow solid.

¹H NMR(400MHz，DMSO-d₆)δ1.29(s，9H)，1.98(s，3H)，3.69(s，3H)，6.19(s，1H)，7.14(dd，1H)，7.26-7.37(m，6H)，9.49(s，1H)，13.25(s，1H)；ES-MSm/z 380.3(MH⁺)；HPLC RT(min)3.18.

The following analogs were synthesized using a similar procedure as described in examples 1-4. The products obtained in examples 7 and 28 were salts as described in example 2.

In Table 1a, R⁴The radical positions are as follows.

TABLE 1a

Remarks are as follows: sources of aminopyrazoles used in the coupling reaction: c is commercially available; h, I, J, K ═ is prepared using the methods described in reaction schemes H, I, J, or K above.

TABLE 1b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	5	2- [ (1-Ethyl-1H-pyrazol-5-yl) amino]Benzoic acid
6	2- [ (1-phenyl-1H-pyrazol-5-yl) amino-5- (methylthio)]Benzoic acid	5	2- [ (1-Ethyl-1H-pyrazol-5-yl) amino]Benzoic acid
6		7	2- [ (1, 3-dimethyl-1H-pyrazol-5-yl) amino]-4-Fluorobenzoic acid trifluoroacetic acid salt
8	2- [ (1, 3-dimethyl-1H-pyrazol-5-yl) amino]-3- (trifluoromethyl) benzoic acid	7
8		9	2- [ (1-benzyl-3-methyl-1H-pyrazol-5-yl) amino]-4-fluorobenzoic acid
10	5-methoxy-2- [ (3-methyl-1-phenyl-1H-pyrazol-5-yl) amino]Benzoic acid	9
10		11	2- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino]Benzoic acid
12	2- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino]-5- (methylthio) benzoic acid	11
12		13	2- [ (3-tert-butyl-1-ethyl-1H-pyrazol-5-yl) amino]-4, 5-dimethoxybenzoic acid
14	2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	13
14		15	2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -4, 5-dimethoxybenzoic acid
16	2- ([ 3-tert-butyl-1- (2, 4-dimethylphenyl) -1H-pyrazol-5-yl)]Amino } -5-methoxybenzoic acid	15
16		17	2- { [ 3-tert-butyl-1- (2-ethylphenyl) -1H-pyrazol-5-yl]Amino } -4, 5-dimethoxybenzoic acid
18	2- { [ 3-tert-butyl-1- (2-ethylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	17
18		19	2- { [ 3-tert-butyl-1- (2-ethylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	20	2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -6-fluorobenzoic acid
21	2- { [ 3-tert-butyl-1- (2, 5-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -4-fluorobenzoic acid	20
21		22	2- { [ 3-tert-butyl-1- (2, 5-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -5-fluorobenzoic acid
23	2- { [ 3-tert-butyl-1- (2, 5-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -6-fluorobenzoic acid	22
23		24	2- { [ 3-tert-butyl-1- (2, 5-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -4-methylbenzoic acid
25	2- { [ 3-tert-butyl-1- (2, 5-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid	24
25		26	2- { [ 3-tert-butyl-1- (4-chlorophenyl) -1H-pyrazol-5-yl]Amino } -4, 5-dimethoxybenzoic acid
27	2- { [ 3-tert-butyl-1- (2-methoxyphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	26
27		28	4, 5-dimethoxy-2- [ (1-methyl-3-phenyl-1H-pyrazol-5-yl) amino]Benzoic acid trifluoroacetic acid salt
29	2- [ (1, 3-diphenyl-1H-pyrazol-5-yl) amino]-5-methoxybenzoic acid	28
29		30	2- { [1- (2-methylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino benzoic acid
31	4, 5-dimethoxy-2- { [1- (2-methylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino benzoic acid	30
31		32	5-methoxy-2- { [1- (2-methylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino benzoic acid
33	2- { [1- (2, 5-dimethylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino } -4-fluorobenzoic acid	32

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	34	2- { [1- (2, 5-dimethylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino } -6-fluorobenzoic acid
35	2- { [1- (2, 5-dimethylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino } -4-methylbenzoic acid	34
35		36	2- { [1- (2, 5-dimethylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid
37	2- { [1- (2, 5-dimethylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino benzoic acid	36
37		38	2- { [1- (2, 5-dimethylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
39	2- { [1- (2, 5-dimethylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino } -4, 5-dimethoxybenzoic acid	38
39		40	4-fluoro-2- { [1- (2-methylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino benzoic acid
41	2-fluoro-6- { [1- (2-methylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino benzoic acid	40
41		42	4-chloro-2- { [1- (2-methylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino benzoic acid
43	5-methyl-2- { [1- (2-methylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino benzoic acid	42
43		44	2- { [1- (2-ethylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
45	2- { [1- (2-ethylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino } -4, 5-dimethoxybenzoic acid	44
45		46	2- { [3- (4-fluorophenyl) -1-phenyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
47	2- { [3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	46

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	48	2- { [3- (4-methoxyphenyl) -1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
49	2- { [1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	48
49		50	5-methoxy-2- { [1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
51	4, 5-dimethoxy-2- { [1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	50
51		52	2- { [3- (4-methoxyphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino) benzoic acid
53	5-methoxy-2- { [3- (4-methoxyphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	52
53		54	2- { [3- (4-chlorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -4, 5-dimethoxybenzoic acid
55	2- { [1, 3-bis (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	54
55		56	4-fluoro-2- { [3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
57	2-fluoro-6- { [3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	56
57		58	2- { [3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -4-methylbenzoic acid
59	2- { [3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid	58
59		60	2- { [1, 3-bis (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
61	4-fluoro-2- { [1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	60

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	62	2-fluoro-6- { [1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
63	4-chloro-2- { [1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	62
63		64	4-methyl-2- { [1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
65	5-methyl-2- { [1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	64
65		66	2- { [1- (2, 5-dimethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino } -4-fluorobenzoic acid
67	2- { [1- (2, 5-dimethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino } -4-fluorobenzoic acid	66
67		68	2- { [1- (2, 5-dimethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino } -6-fluorobenzoic acid
69	2- { [1- (2, 5-dimethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino } -4-methylbenzoic acid	68
69		70	2- { [1- (2, 5-dimethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid
71	2- { [1- (2, 5-dimethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	70
71		72	2- { [1- (2, 5-dimethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino } -4, 5-dimethoxybenzoic acid
73	2- { [1- (2-methylphenyl) -3- (3-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	72
73		74	5-methoxy-2- { [1- (2-methylphenyl) -3- (3-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
75	2-fluoro-6- { [4- (4-fluorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	74

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	76	2- { [ 3-tert-butyl-1- (5-fluoro-2-methylphenyl) -1H-pyrazol-5-yl]Amino } -6-fluorobenzoic acid
77	2- { [ 3-tert-butyl-1- (5-fluoro-2-methylphenyl) -1H-pyrazol-5-yl]Amino } -4-fluorobenzoic acid	76
77		78	2- { [ 3-tert-butyl-1- (2-methoxyphenyl) -1H-pyrazol-5-yl]Amino } -4-fluorobenzoic acid
79	2- { [ 3-tert-butyl-1- (2-methoxyphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid	78
79		80	2- ({ 3-tert-butyl-1- [2- (methylthio) phenyl)]-1H-pyrazol-5-yl } amino) -5-methoxybenzoic acid
81	2- { [ 3-tert-butyl-1- (2-ethoxyphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	80
81		82	2- { [ 3-tert-butyl-1- (2-ethoxyphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
83	2- { [ 3-tert-butyl-1- (2-ethoxyphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid	82
83		84	2- { [ 3-tert-butyl-1- (2-chlorophenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
85	2- { [ 3-tert-butyl-1- (2-chlorophenyl) -1H-pyrazol-5-yl]Amino } -4-fluorobenzoic acid	84
85		86	2- { [3- (4-fluoro-2-methylphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
87	2- { [3- (4-fluoro-2-methylphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	86
87		88	2- { [1- (5-fluoro-2-methylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino benzoic acid
89	2- { [1- (2-ethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino benzoic acid	88

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	90	4-fluoro-2- { [3- (4-fluorophenyl) -1- (2-methoxyphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
91	2- { [1- (2-ethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	90
91		92	2- { [3- (4-fluorophenyl) -1- (2-methoxyphenyl) -1H-pyrazol-5-yl]Amino } -4, 5-dimethoxybenzoic acid
93	2- { [1- (5-fluoro-2-methylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	92
93		94	2- { [3- (4-fluorophenyl) -1- (2-methoxyphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid
95	2- { [1- (5-fluoro-2-methylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid	94
95		96	2- { [3- (4-fluorophenyl) -1- (2-methoxyphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
97	4-fluoro-2- { [3- (3-methoxyphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	96
97		98	4, 5-dimethoxy-2- { [3- (3-methoxyphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
99	2- { [3- (3-methoxybenzene)1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	98
99		100	5-methoxy-2- { [3- (3-methoxyphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
101	2- { [3- (3-methoxyphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid	100
101		102	5-chloro-2- { [ 3-methyl-1- (2-methylphenyl) -4-pyridin-3-yl-1H-pyrazol-5-yl]Trifluoroacetic acid amino } benzoate
103	2- { [ 3-tert-butyl-4-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	102

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	104	2- { [ 3-tert-butyl-4-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
105	2- { [3- (4-fluoro)Phenyl) -4-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino) -5-methoxybenzoic acid	104
105		106	2- { [ 3-tert-butyl-1- (2-methoxyphenyl) -4-methyl-1H-pyrazol-5-yl]Amino benzoic acid
107	2- { [ 3-tert-butyl-1- (2-methoxyphenyl) -4-methyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	106

Example 108

Preparation of methyl 2- { [ 3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoate

Under an argon atmosphere, 3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazol-5-amine (intermediate B, 400mg, 1.66mmol), methyl 2-bromobenzoate (297mg, 1.38mmol), cesium carbonate (630mg, 1.93mmol), BINAP (87mg, 0.14mmol) and Pd₂(dba)₃A mixture of (72mg, 0.07mmol) of dry toluene (4ml) was heated to 110 ℃ for 16 h to cool the reaction mixture to room temperature, diluted with ethyl acetate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with EtOAc/hexanes (1: 8, v/v) to give the product as a bright yellow oil (303mg, 58%). ES-MSm/z 376.3 (MH)⁺)；HPLCRT(min)3.94。

Example 109

Preparation of 2- { [ 3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid

To a solution of methyl 2- { [ 3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoate (0.59mmol, 220mg) in MeOH (1.8ml) were added THF (5.4ml) and 1N aqueous NaOH (1.8 ml). The mixture was stirred at room temperature for 21 hours. The organic solvent was removed under reduced pressure, the residue diluted with water and the aqueous solution extracted with diethyl ether (2X 5 ml). The aqueous layer was acidified with 1N HCl solution to pH 1 to 2. The mixture was extracted with ethyl acetate (3X 5 ml). After removal of the solvent under reduced pressure, the product was obtained as a white solid (169mg, 79%).

¹H NMR(400MHz，DMSO-d₆)δ1.58-1.62(m，2H)，1.65-1.78(m，4H)，1.90-2.01(m，2H)，2.06(s，3H)，2.99-3.10(m，1H)，6.23(s，1H)，6.80(t，1H)，7.20-7.30(m，3H)，7.30-7.40(m，2H)，7.42-7.51(m，1H)，7.81(d，1H)，9.84(s，1H)，13.14(s，1H).ES-MS m/z 362.3(MH⁺)，HPLC RT(min)3.39.

The following analogs were prepared using the procedure described above for example 109.

In Table 2a, R⁴The positions of the groups are shown below.

TABLE 2a

Remarks are as follows: sources of aminopyrazoles used in the coupling reaction: c is commercially available; prepared using the method described in reaction scheme I above.

TABLE 2b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	110	2- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino]-5-methylbenzoic acid
111	2- [ (3-tert-butyl-1-phenyl-1H-pyrazol-5-yl) amino]-5-methoxybenzoic acid	110
111		112	2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-fluorobenzoic acid

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	113	2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid
114	2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -4-methylbenzoic acid	113
114		115	2- ({ 3-tert-butyl-1- [2- (trifluoromethyl) phenyl]-1H-pyrazol-5-yl } amino) -5-methoxybenzoic acid
116	2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5- (difluoromethoxy) benzoic acid	115
116		117	2- { [ 3-tert-butyl-1- (2, 5-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
118	2- { [ 3-tert-butyl-1- (2, 5-dimethylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	117
118		119	2- { [ 3-tert-butyl-1- (5-fluoro-2-methylphenyl) -1H-pyrazole-5-yl]Amino } -5-methoxybenzoic acid
120	2- { [ 3-tert-butyl-1- (5-fluoro-2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	119
120		121	2- { [ 3-tert-butyl-1- (2, 3-dimethylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
122	2- { [ 3-tert-butyl-1- (2, 6-dimethylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	121
122		123	2- { [ 3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
124	2- { [ 3-cyclopentyl-1- (2, 5-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	123
124		125	5-methoxy-2- [ (2-phenyl-4, 5, 6, 7-tetrahydro-2H-imidazol-3-yl) amino]Benzoic acid
126	5-methoxy-2- [ (3-methyl-1, 4-diphenyl-1H-pyrazol-5-yl) amino]Benzoic acid	125

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	127	2- { [1- (2, 5-dimethylphenyl) -3- (1-methylcyclopropyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
128	2- ([1- (2, 5-dimethylphenyl) -3- (1-methylcyclopropyl) -1H-pyrazol-5-yl)]Amino benzoic acid	127
128		129	2- { [1- (2, 6-dimethylphenyl) -3-isopropyl-1H-pyrazol-5-yl]Amino benzoic acid
130	2- { [ 3-isobutyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	129
130		131	2- { [ 3-cyclohexyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
132	2- { [ 3-cyclohexyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	131
132		133	5-methoxy-2- { [ 1-methyl-4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl]Amino benzoic acid
134	5-methoxy-2- { [1- (2-methyl)Phenyl) -4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl]Amino benzoic acid	133
134		135	2- { [1- (2, 5-dimethylphenyl) -4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
136	2- { [ 3-tert-butyl-1- (2-methoxy-5-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	135
136		137	2- { [ 3-tert-butyl-1- (2, 3-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
138	2- { [ 3-tert-butyl-1- (5-chloro-2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	137
138		139	2- { [ 3-tert-butyl-1- (2-methoxy-6-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
140	2- { [ 3-tert-butyl-1- (5-methoxy-2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	139

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	141	2- { [ 3-tert-butyl-1- (2-methoxy-6-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
142	2- { [ 3-tert-butyl-1- (5-chloro-2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	141
142		143	2- { [ 3-tert-butyl-1- (2, 6-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
144	2- { [1- (4-chloro-2-methylphenyl) -3-methyl-4-phenyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	143
144		145	5-methoxy-2- ({ 3-methyl-4-phenyl-1- [2- (trifluoromethyl) phenyl]-1H-pyrazol-5-yl } amino } benzoic acid
146	2- { [1- (2-methoxyphenyl) -3-methyl-4-phenyl-1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid	145
146		147	2- { [1- (2, 5-dimethylphenyl) -3-methyl-4-phenyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
148	2- { [1- (5-fluoro-2-methylphenyl) -3-methyl-4-phenyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	147
148		149	2- { [1- (2-chlorophenyl) -3-methyl-4-phenyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
150	2- { [1- (2, 6-dimethylphenyl) -3-isobutyl-1H-pyrazol-5-yl]Amino benzoic acid	149
150		151	2- { [1- (2, 6-dimethylphenyl) -3- (1-methylcyclopropyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
152	2- { [1- (2, 6-dimethylphenyl) -3-isobutyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	151
152		153	2- { [1- (2, 6-dimethylphenyl) -3- (1-methylcyclopropyl) -1H-pyrazol-5-yl]Amino benzoic acid
154	2- { [1- (2, 6-dimethylphenyl) -3- (3, 3, 3-trifluoropropyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	153

Example 155

Preparation of methyl 2- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino ] -5-methoxybenzoate

To a 100ml oven-dried flask was added 5-amino-3-tert-butyl-1-methylpyrazole (2.00g, 13.1mmol), methyl 2-bromo-5-methoxybenzoate (2.67g, 10.9mmol), cesium carbonate (4.96g, 15.2mmol), Pd₂(dba)₃(337mg, 0.33mmol), BINAP (338mg, 0.54mmol) and toluene (35 ml). Degassing the reaction mixture and placing in N₂Under an atmosphere, then stirred at 110 ℃ for 16 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30ml) was added. The mixture was filtered, the filter cake was washed with EtOAc (10mL), and the filtrate was concentrated under reduced pressure. Flash silica chromatography of the residue (eluent: 10 to 30% EtOAc in hexane) afforded the title compound as a bright yellow oil (1.34g, 38%).

¹H NMR(400MHz，CDCl₃)δ1.28(s，9H)，3.63(s，3H)，3.78(s，3H)，3.94(s，3H)，5.97(s，1H)，6.82(d，1H)，7.10(dd，1H)，7.47(d，1H).

Example 156

Preparation of methyl 2- [ (4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino ] -5-methoxybenzoate

To a solution of 2- (5-tert-butyl-2-methyl-2H-pyrazol-3-ylamino) -5-methoxy-benzoic acid methyl ester (example 155, 1.34g, 4.22mmol) in acetic acid (27ml) was added dropwise Br₂(6.74g, 4.22mmol) in acetic acid (5 ml). The reaction was stirred for 5 minutes, then water (100ml) was added. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with water and then with NaHCO₃Washed 10 times (10% aqueous solution). Drying the organic layer (Na)₂SO₄) Filtered and concentrated under reduced pressure. Flash silica chromatography of the residue (eluent: 5 to 10% EtOAc in hexane) afforded the title compound as a bright yellow solid (1.49g, 89%).

¹H NMR(400MHz，CDCl₃)δ1.40(s，9H)，3.66(s，3H)，3.78(s，3H)，4.05(s，3H)，6.32(d，1H)，7.06(dd，1H)，7,48(d，1H).

Example 157

Preparation of 2- { [ 3-tert-butyl-4- (4-methoxyphenyl) -1-methyl-1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid

To methyl 2- (4-bromo-5-tert-butyl-2-methyl-2H-pyrazol-3-ylamino) -5-methoxybenzoate (example 96, 100mg, 0.25mmol), 4-methoxyphenylboronic acid (153.4mg, 1.01mmol), PdCl₂(dppf)·CH₂Cl₂To a solution of (18.46mg, 0.03mmol) in toluene (6.1ml) and dioxane (1.22ml) was added 2M aqueous sodium carbonate solution (1.22ml, 2.44 mmol). Ar was introduced into the reaction mixture for 15 minutes, and then the reaction was stirred at 75 ℃ for 18 hours. The reaction mixture was then cooled to room temperature and filtered through a plug of silica gel. The filtrate was concentrated under reduced pressure and the residue was dissolved in a mixture of THF (4ml), MeOH (2ml) and water (4 ml). Lithium hydroxide (60mg, 2.52mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (27.9mg, 27%) as a white solid.

¹H NMR(400MHz，CDCl₃)δ1.21(s，9H)，3.61(s，3H)，3.74(s，6H)，6.41(d，1H)，6.70(d，2H)，7.04(dd，1H)，7.09(d，2H)，7.39(d，1H).ES-MS m/z 410.2(MH⁺)；HPLC RT(min)3.66.

The analogs listed in Table 3a were synthesized using the methods described above. The products obtained in examples 162, 163, 173, 182, 183, 186 and 187 are trifluoroacetates.

In Table 3a, R⁴The radical positions are as follows.

TABLE 3a

Remarks are as follows: sources of aminopyrazoles used in the coupling reaction: c is commercially available; i and J are prepared using the methods described in reaction schemes I and J above.

TABLE 3b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	158	2- [ (1, 4-Diphenyl-1H-pyrazol-5-yl) amino]-5-methoxybenzoic acid
159	5-methoxy-2- { [4- (4-methoxyphenyl) -1-phenyl-1H-pyrazol-5-yl]Amino benzoic acid	158
159		160	2- { [4- (2, 4-difluorophenyl) -1-phenyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
161	2- { [4- (4-acetylphenyl) -1-phenyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	160
161		162	5-methoxy-2- [ (1-phenyl-4-pyridin-4-yl-1H-pyrazol-5-yl) amino]Benzoic acid trifluoroacetic acid salt
163	5-methoxy-2- [ (1-phenyl-4-pyridin-3-yl-1H-pyrazol-5-yl) amino]Benzoic acid trifluoroacetic acid salt	162
163		164	5-methoxy-2- { [ 3-methyl-1- (2-methylphenyl) -4-phenyl-1H-pyrazol-5-yl]Amino benzoic acid
165	2- { [4- (4-fluorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	164
165		166	5-methoxy-2- { [ 3-methyl-1- (2-methylphenyl) -4- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
167	5-methoxy-2- { [4- (4-methoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	166
167		168	2- { [4- (4-chlorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	169	2- { [4- (2, 4-difluorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
170	2- { [4- (3-fluoro-4-methoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	169
170		171	2- { [4- (4-acetylphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
172	5-methoxy-2- ({ 3-methyl-1- (2-methylphenyl) -4- [4- (trifluoromethoxy) phenyl]-1H-pyrazol-5-yl } amino) benzoic acid	171
172		173	5-methoxy-2- { [ 3-methyl-1- (2-methylphenyl) -4-pyridin-4-yl-1H-pyrazol-5-yl]Trifluoroacetic acid amino } benzoate
174	5-methoxy-2- { [ 3-methyl-1- (2-methylphenyl) -4-pyridin-3-yl-1H-pyrazol-5-yl]Trifluoroacetic acid amino } benzoate	173
174		175	5-methoxy-2- { [4- (6-methoxypyridin-3-yl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
176	5-fluoro-2- { [ 3-methyl-1- (2-methylphenyl) -4-pyridin-3-yl-1H-pyrazol-5-yl]Amino benzoic acid	175
176		177	2- { [4- (3-chlorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
178	2- { [4- (2-chlorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	177
178		179	2- { [4- (4-fluoro-2-methylphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
180	2- { [4- (4-fluoro-3-methylphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	179

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	181	2- { [4- (4-ethoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
182	2- { [ 3-tert-butyl-4- (4-chlorophenyl) -1-methyl-1H-pyrazol-5-yl]Amino } -5-methoxyBenzoic acid trifluoroacetic acid salt	181
182		183	2- [ (3-tert-butyl-1-methyl-4-phenyl-1H-pyrazol-5-yl) amino]-5-methoxybenzoic acid trifluoroacetate
184	2- { [ 3-tert-butyl-1-methyl-4- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	183
184		185	2- { [ 3-tert-butyl-4- (6-methoxypyridin-3-yl) -1-methyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
186	2- [ (3-tert-butyl-1-methyl-4-pyridin-4-yl-1H-pyrazol-5-yl) amino]-5-Methoxybenzoic acid trifluoroacetic acid salt	185
186		187	2- [ (3-tert-butyl-1-methyl-4-pyridin-3-yl-1H-pyrazol-5-yl) amino]-5-Methoxybenzoic acid trifluoroacetic acid salt
188	2- { [ 3-tert-butyl-4- (3-methoxyphenyl) -1-methyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	187
188		189	2- { [ 3-tert-butyl-4- (2-fluorophenyl) -1-methyl-1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid
190	2- [ (3-tert-butyl-1-methyl-4-phenyl-1H-pyrazol-5-yl) amino]-5-methylbenzoic acid	189
190		191	2- { [ 3-tert-butyl-1-methyl-4- (4-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
192	2- { [ 3-tert-butyl-4- (4-fluorophenyl) -1-methyl-1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid	191
192		193	2- { [ 3-tert-butyl-4- (4-fluorophenyl) -1-methyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
194	2- [ (3-tert-butyl-1-methyl-4-pyridin-4-yl-1H-pyrazol-5-yl) amino]-5-methylbenzoic acid	193

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	195	2- { [4- (4-fluorophenyl) -1- (2-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
196	2- { [1- (2, 5-dimethylphenyl) -3-ethyl-4- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	195
196		197	5-methoxy-2- { [1- (2-methylphenyl) -4-pyridin-4-yl-3- (trifluoromethyl) -1H-pyrazol-5-yl]Amino benzoic acid
198	5-methoxy-2- { [4- (4-methoxyphenyl) -1- (2-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Amino benzoic acid	197
198		199	2- { [ 3-Ethyl-4- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
200	2- { [ 3-Ethyl-1- (2-methylphenyl) -4-phenyl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	199
200		201	2- { [1- (2, 5-dimethylphenyl) -3-ethyl-4-phenyl-IH-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
202	2- { [ 3-Ethyl-4- (6-methoxypyridin-3-yl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	201
202		203	2- { [ 3-Ethyl-1- (2-methylphenyl) -4-pyridin-4-yl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
204	2- { [ 3-Ethyl-4- (4-methoxyphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	203
204		205	2- { [1- (2, 5-dimethylphenyl) -3-ethyl-4-pyridin-4-yl-1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
206	2- { [1- (2, 5-dimethylphenyl) -3-ethyl-4- (4-methoxyphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	205
206		207	2- { [4- (4-benzoylphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	208	2- { [4- (4-fluorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid
209	2- { [4- (2-Isopropoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid	208
209		210	5-methyl-2- { [ 3-methyl-1- (2-methylphenyl) -4- (4-methylphenyl) -1H-pyrazol-5-yl]Amino groupBenzoic acid
211	5-methyl-2- { [ 3-methyl-1- (2-methylphenyl) -4- (2-propoxyphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	210
211		212	2- { [4- (2-butoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid
213	2- { [4- (3-fluoro-4-methoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid	212
213		214	5-methoxy-2- { [ 3-methyl-1- (2-methylphenyl) -4- (3-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
215	2- { [4- (2-methoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid	214
215		216	2- { [4- (3-fluorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
217	2- { [4- (2-Isopropoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	216
217		218	2- { [4- (4-methoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid
219	2- { [4- (2-fluorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	218
219		220	2- { [4- (2-ethoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methylbenzoic acid
221	5-methoxy-2- { [4- (2-methoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	220

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	222	5-methoxy-2- { [4- (3-methoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
223	5-methyl-2- { [ 3-methyl-1- (2-methylphenyl) -4-pyridin-3-yl-1H-pyrazol-5-yl]Amino benzoic acid	222
223		224	2- { [4- (2-ethoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazole-5-yl]Amino } -5-methoxybenzoic acid
225	2- { [4- (2, 4-dichlorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	224
225		226	2- { [4- (2-ethylphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
227	2- { [4- (5-chloro-2-methoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	226
227		228	5-methoxy-2- { [ 3-methyl-1- (2-methylphenyl) -4- (2-propoxyphenyl) -1H-pyrazol-5-yl]Amino benzoic acid
229	5-methoxy-2- { [1- (2-methoxyphenyl) -3-methyl-4-phenyl-1H-pyrazol-5-yl]Amino benzoic acid	228
229		230	2- { [4- (2, 2-difluoro-1, 3-benzodioxol-4-yl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
231	2- { [4- (5-fluoro-2-methoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid	230
231		232	2- { [4- (2, 4-Dimethoxyphenyl) -3-methyl-1- (2-methyl)Phenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid
233	5-methoxy-2- ({ 3-methyl-1- (2-methylphenyl) -4- [2- (methylthio) phenyl]-1H-pyrazol-5-yl } amino) benzoic acid	232

Example 234

Preparation of methyl 5-bromo-2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoate

Into a dry 25ml flask was introduced 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-amine (intermediate C, 220mg, 0.96mmol), methyl 2, 5-dibromobenzoate (235mg, 0.80mmol), Pd₂(dba)₃(36.6mg, 0.04mmol), BINAP (49.8mg, 0.08mmol) and Cs₂CO₃(365mg, 1.12 mmol). The flask was degassed by the addition of toluene (1ml) and the mixture was then heated to 110 ℃ for 20 h. The mixture was cooled to room temperature and diluted with ethyl acetate. The solid was filtered off and the solvent was removed under reduced pressure. The residue was dissolved in methanol/THF (4: 1, v/v) via C₂-filtration through a silica gel plug. HPLC purification, eluting with a 10% to 90% acetonitrile/water gradient, gave 110mg (31%) of the title compound.

¹H NMR(300 MHz，CD₂Cl₂)δ9.21(s，1H)，7.41(d，1H)，7.20-7.30(m，5H)，7.10(d，1H)，6.09(s，1H)，3.72(s，3H)，2.04(s，3H)，1.30(s，9H)，ES-MS m/z 444.1(MH⁺)；NPLC RT(min)4.30.

Example 235

Preparation of methyl 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-ethylbenzoate

To 5-bromo-2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } benzoic acid methyl ester (example 234, 1.15g, 4.13mmol), ethylboronic acid (1.16g, 15.7mmol) and Pd (dppf) Cl₂·CH₂Cl₂To a mixture of (114mg, 0.16mmol) was added toluene (20ml) and dioxane (5 ml). The resulting solution was degassed under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium bicarbonate (2M aqueous solution, 15 ml). The mixture was heated to 85 ℃ for 16 hours. The reaction mixture was allowed to cool to room temperature. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 0 to 10% ethyl acetate/hexanes to give 606mg (61%) of the title compound.

¹H NMR(300MHz，CD₂Cl₂)δ9.17(s，1H)，7.68(s，1H)，7.22-7.33(m，6H)，6.08(s，1H)，3.70(s，3H)，2.51(q，2H)，2.05(s，3H)，1.30(s，9H)，1.14(t，3H).ES-MS m/z 392.2(MH⁺)；HPLC RT(min)4.62.

Example 236

Preparation of 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-ethylbenzoic acid

To a solution of methyl 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-ethylbenzoate (example 235, 115mg, 0.29mmol) in a mixture of methanol (1ml) and THF (1ml) was added a solution of lithium hydroxide monohydrate (123mg, 2.94mmol) in water (2ml), and the mixture was heated to 40 ℃ for 1 hour. The reaction mixture was cooled to room temperature and the solution pH was adjusted to 5 using 0.5n hcl solution. The solvent was removed under reduced pressure and the residue was purified by HPLC, eluting with a gradient of 10% to 90% acetonitrile/water to give 109.6mg (99%) of the title compound.

¹H NMR(300MH_z，CD₂Cl₂)δ9.28(s，1H)，7.76(s，1H)，7.26-7.37(m，6H)，6.15(s，1H)，2.60(q，2H)，2.08(s，3H)，1.37(s，9H)，1.23(t，3H).ES-MS m/z 378.3(MH⁺)；HPLC RT(min)3.64.

The following analogs were synthesized using the procedure described in example 236 above.

TABLE 4a

Remarks are as follows: sources of aminopyrazoles used in the coupling reaction: c is commercially available; j ═ was prepared using the procedure described in reaction scheme J above.

TABLE 4b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	237	5-Ethyl-2- { [1- (2-methylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino benzoic acid
238	5-Ethyl-2- { [3- (4-fluorophenyl) -1- (2-rh-ethylphenyl) -1H-pyrazol-5-yl]Amino benzoic acid	237
238		239	5-Ethyl-2- ([1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl)]Amino benzoic acid
240	2- { [1- (2, 5-dimethylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino } -5-ethyl-benzoic acid	239
240		241	2- ([1- (2, 5-dimethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl)]Amino } -5-ethyl-benzoic acid

Example 242

Preparation of methyl 2- ([ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -4-chlorobenzoate

This compound was prepared according to the procedure described for the preparation of example 234, using intermediate C and methyl 2-bromo-4-chlorobenzoate as starting materials.

¹HNMR(300MHz，CD₂Cl₂)δ9.33(s，1H)，7.84(d，1H)，7.20-7.30(m，4H)，7.15(s，1H)，6.68(d，1H)，6.13(s，1H)，3.72(s，3H)，2.06(s，3H)，1.31(s，9H).ES-MS m/z398.3(MH)⁺；HPLC RT(min)4.27.

Example 243

Preparation of methyl 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -4-ethylbenzoate

To 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -4-chlorobenzoic acid methyl ester (example 242, 50mg, 0.13mmol), ethylboric acid (18.56mg, 0.26mmol), Pd₂(dba)₃To a mixture of (5.8mg, 0.006mmol), tri (tert-butyl) phosphine (2.54mg, 0.013mmol) and potassium chloride (14.6mg, 0.25mmol) was added dioxane (1 ml). The resulting solution was degassed under argon for 30 minutes and then heated to 110 ℃ for 16 hours. The reaction mixture was cooled to room temperature. Diluted with ethyl acetate and filtered through a plug of silica gel. The solvent was removed under reduced pressure and the crude product purified by HPLC eluting with a 30 to 100% acetonitrile/water gradient to give 39.8mg (81%) of the title compound.

¹H NMR(300MHz，CD₂Cl₂)δ9.23(s，1H)，7.74(d，1H)，7.23-7.29(m，4H)，7.03(s，1H)，6.57(d，1H)，6.09(s，1H)，3.69(s，3H)，2.55(q，2H)，2.06(s，3H)，1.30(s，9H)，1.15(t，3H).ES-MS m/z 392.2(MH⁺)；HPLC RT(min)4.65.

Example 244

Preparation of 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -4-ethylbenzoic acid

This compound was prepared using the hydrolysis method described in example 243.

¹H NMR(300MH_z，CD₂Cl₂)δ9.45(s，1H)，7.81(d，1H)，7.20-7.35(m，4H)，7.09(s，1H)，6.68(d，1H)，6.13(s，1H)，2.61(q，2H)，2.03(s，3H)，1.33(s，9H)，1.19(t，3H)，ES-MS m/z 378.2(MH⁺)；HPLC RT(min)4.12.

Example 245

Preparation of 2- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino ] -4-pyrimidine-5-carboxylic acid

The title compound was prepared analogously using the methods described for example 244. ES-MS m/z352.2 (MH)⁺)；HPLC RT(min)2.94。

Example 246

Preparation of methyl 2- [ (3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl) amino ] -4-fluorobenzoate

Into a dry 25ml flask was introduced 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-amine (intermediate C, 110mg, 0.48mmol), methyl 2-bromo-4-fluorobenzoate (93.1mg, 0.40mmol), Pd₂(dba)₃(18.3mg, 0.02mmol), BINAP (24.9mg, 0.04mmol) and Cs₂CO₃(182mg, 0.56 mmol). The flask was degassed by the addition of toluene (1ml) and the mixture was heated to 110 ℃ for 20 h. The mixture was then cooled to room temperature and diluted with ethyl acetate. The solid was filtered off and the solvent was removed under reduced pressure. The residue was dissolved in methanol/THF (4: 1, v/v) and filtered through a plug of C1-silica gel. HPLC purification using a 30% to 90% acetonitrile/water gradient to give136.2mg (89%) of the title compound.

¹HNMR(300MHz，CD₂Cl₂)δ9.42(s，1H)，7.85(dd，1H)，7.21-7.30(m，4H)，6.86(dd，1H)，6.44(dt，1H)，6.11(s，1H)，3.70(s，3H)，2.04(s，3H)，1.30(s，9H).ES-MS m/z 381.9(MH⁺)；HPLCRT(min)4.50.

Example 247

Preparation of 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -4- (1H-imidazol-1-yl) benzoic acid

To a mixture of methyl 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -4-fluorobenzoate (example 246, 50mg, 0.13mmol), imidazole (17.8mg, 0.26mmol) and potassium carbonate (90.6mg, 0.66mmol) was added DMF (1 ml). The mixture was then heated at 110 ℃ for 16 hours. The reaction mixture was allowed to cool to room temperature. The solvent was removed under reduced pressure and the residue was purified by HPLC using a gradient of 10 to 80% acetonitrile/water to give 13.8mg (25%) of the title compound

¹H NMR(300MHz，CD₃OD)δ9.48(t，1H)，8.15(d，1H)，8.07(t，1H)，7.76(t，1H)，7.52(d，1H)，7.28-7.42(m，4H)，7.10(dd，1H)，6.48(s，1H)，2.06(s，3H)，1.35(s，9H).ES-MS m/z 416.2(MH⁺)；HPLC RT(min)2.21.

Example 248

Preparation of 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -4-fluorobenzoic acid

This compound was prepared using the hydrolysis method described in example 246.

¹H NMR(300MHz，CD₂Cl₂)δ9.49(s，1H)，7.89(dd，1H)，7.19-7.32(m，4H)，6.91(dd，1H)，6.47(dt，1H)，6.13(s，1H)，2.01(s，3H)，1.31(s，9H).ES-MSm/z 368.1(MH⁺)；HPLC RT(min)4.01.

Example 249

Preparation of 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -4- (dimethylamino) benzoic acid

To 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl at-40 ℃ under a nitrogen atmosphere]To a solution of amino } -4-fluorobenzoic acid (example 248, 35mg, 0.09mmol) in THF (1ml) was added LiNME₂(0.19ml, 1M in hexanes). The mixture was then stirred at room temperature for 30 minutes, gradually warming to room temperature over 4 hours. The solution was adjusted to pH5 and extracted with ethyl acetate. The organic layer was washed with brine over Na₂SO₄Drying, and concentrating under reduced pressure. The crude product was purified by HPLC eluting with a gradient of 10 to 80% acetonitrile/water to give 5.7mg (15%) of the title compound.

¹HNMR(300 MHz，CD₂Cl₂)δ9.55(s，1H)，7.73(d，1H)，7.22-7.35(m，4H)，6.44(d，1H)，6.18(dd，1H)，6.15(s，1H)，3.00(s，6H)，2.04(s，3H)，1.32(s，9H).ES-MS m/z 393.2(MH⁺)；HPLCRT(min)2.84.

In the Suzuki reaction, bromination reaction (R)²) A second Suzuki reaction and a post-hydrolysis followed by a Buchwald type coupling reaction, the example compounds shown in table 5a were prepared. All reaction steps are described in the previous examples.

TABLE 5a

TABLE 5b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	250	2- { [ 3-tert-butyl-4- (3-methoxyphenyl) -1-methyl-1H-pyrazol-5-yl]Amino } -5-ethyl-benzoic acid
251	2- { [ 3-tert-butyl-4- (4-methoxyphenyl) -1-methyl-1H-pyrazol-5-yl]Amino } -5-ethyl-benzoic acid	250
251		252	2- [ (3-tert-butyl-1-methyl-4-phenyl-1H-pyrazol-5-yl) amino]-5-ethylbenzoic acid
253	2- [ (3-tert-butyl-1-methyl-4-pyrimidin-5-yl-1H-pyrazol-5-yl) amino]-5-ethylbenzoic acid	252
253		254	2- { [ 3-tert-butyl-1-methyl-4- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-ethyl-benzoic acid
255	2- [ (3-tert-butyl-1-methyl-4-pyridin-4-yl-1H-pyrazol-5-yl) amino]-5-Ethylbenzoic acid trifluoroacetic acid salt	254

The following examples represent carboxylic acid esters which can be prepared by using an Ullmann-type coupling reaction followed by an esterification reaction step.

Example 256

Preparation of isopropyl 5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino ] benzoate

Step 1: preparation of 5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzoic acid

A mixture of 2-bromo-5-methoxybenzoic acid (1.31g, 5.7mmol), potassium carbonate (859mg, 6.2mmol), 5-amino-1-phenyl-pyrazole (900mg, 5.7mmol) and copper (II) acetate (21mg, 0.11mmol) in DMF (12ml) was heated (150 ℃ C.) in a closed tube for 16 h. After cooling, the reaction mixture was diluted with water (5ml) and acidified to pH4 with acetic acid. The mixture was extracted with dichloromethane (3X 10ml) and the combined organic extracts were washed with water (2X 10ml) over Na₂SO₄Dried, filtered and concentrated under reduced pressure. HPLC purification of the residue (YMC propack C18 column, 150X 20mm ID, 30% -80% acetonitrile/water eluent) to give 5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzoic acid (450mg, 26%) as a pale yellow solid.

¹HNMR(300MHz，DMSO-d₆)δ13.33(brs，1H)，9.62(brs，1H)，7.64(d，1H)，7.34-7.58(m，6H)，7.00-7.11(m，2H)，6.30(d，1H)，3.69(s，3H)；ES-MS m/z 310.1(MH⁺)；HPLC RT(min)2.74.

Step 2: preparation of 5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzoic acid Isopropyl ester

Cesium carbonate (105mg, 0.19mmol) and 2-iodopropane (18mg, 0.11mmol) were added to the intermediate 5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzoic acid (30mg, 0.10mmol) in DMF (4 ml). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (5ml) and then extracted with dichloromethane (3 × 5 ml). The combined organic layers were washed with water (5ml) over Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by HPLC (YMC propack C18 column, 150X 20mmID, 30% -80% acetonitrile/water eluent) to give the desired product as a white solid (20mg, 59%).

¹H NMR(300MHz，DMSO-d₆)δ9.07(s，1H)，7.65(d，1H)，6.96-7.56(m，9H)，6.29(dd，1H)，5.06(q，1H)，3.69(s，3H)，1.24(d，6H)；ES-MS m/z 352.1(MH⁺)；HPLC RT(min)3.53.

The following analogs were prepared using the methods described above. The aminopyrazoles used for the coupling reaction are commercially available.

TABLE 6a

Example number	R	LC-MSRT(min)	LC-MS[M+H]
Example number	R	LC-MSRT(min)	LC-MS[M+H]	257	Bn	3.68	400.1
258	Me	3.15	324.1	257	Bn	3.68	400.1
258	Me	3.15	324.1	259	Et	3.31	338.3
260	i-Bu	3.75	366.2	259	Et	3.31	338.3
260	i-Bu	3.75	366.2	261	4-MeOBn	3.68	430.1

TABLE 6b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	257	5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzyl benzoate
258	5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzoic acid methyl ester	257
258		259	5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzoic acid ethyl ester
260	5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzoic acid isobutyl ester	259
260		261	4-methoxybenzyl-5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzoic acid esters

The following compounds were synthesized using the procedure described for example 108.

In Table 7a, R⁴The radical positions are as follows.

TABLE 7a

TABLE 7b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	262	5-methoxy-2- { [1- (4-methoxyphenyl) -1H-pyrazol-5-yl]Amino } benzoic acid methyl ester
263	2-{[1- (4-methoxyphenyl) -1H-pyrazol-5-yl]Amino } benzoic acid methyl ester	262
263		264	5-methoxy-2- [ (3-methyl-1-phenyl-1H-pyrazol-5-yl) amino]Benzoic acid methyl ester
265	2- { [ 3-tert-butyl-1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid methyl ester	264
265		266	2- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino]-5-Methylbenzoic acid methyl ester
267	2- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino]-3-Methylbenzoic acid methyl ester	266
267		268	2- [ (3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl) amino]-5-Methoxybenzoic acid methyl ester
269	2- [ (3, 4-dimethyl-1-phenyl-1H-pyrazol-5-yl) amino]-5-Methoxybenzoic acid methyl ester	268
269		270	5-methoxy-2- [ (5-methyl-2-phenyl-4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-c)]Pyridin-3-yl) amino]Benzoic acid methyl ester
271	2- [ (5-methyl-2-phenyl-4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-c)]Pyridin-3-yl) amino]Benzoic acid methyl ester	270
271		272	2- { [ 3-cyclohexyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid methyl ester
273	2- { [ 3-isobutyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid methyl ester	272
273		274	2- { [ 3-tert-butyl-1- (5-methoxy-2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid methyl ester
275	2- { [ 3-tert-butyl-1- (2, 6-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid methyl ester	274

The following analogs were synthesized from the C1 precursor in a similar manner as in example 242, using a similar procedure as described in example 243. The boric acid used is a commercially available product.

TABLE 8a

TABLE 8b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	276	3- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino]-3' -Fluorobiphenyl-4-carboxylic acid methyl ester
277	3- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino]-4' -Fluorobiphenyl-4-carboxylic acid methyl ester	276
277		278	2- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino]-4-pyrimidine-5-benzoic acid methyl ester

The following examples represent carboxylic acid amides, which can be prepared using Ullmann-type coupling reactions.

Example 279

Preparation of 2- { [ 3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzamide

A mixture of 3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-amine (intermediate F, 1.00g, 5.3mmol), 2-bromobenzamide (1.07g, 5.3mmol), potassium carbonate (0.89g, 6.4mmol) and copper (II) acetate (39mg, 0.2mmol) in DMF (20ml) was heated (150 ℃ C.) in a closed tube for 18H. After cooling the solution, the pH of the solution was adjusted to 4 using glacial acetic acid. The reaction mixture was extracted with dichloromethane (3 × 20ml) and the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash silica gel chromatography of the residue eluting with 33-50% ethyl acetate/hexanes afforded a yellow solid, which was washed with diethyl ether to afford 2- { [ 3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzamide (350mg, 21%) as a white solid.

¹H NMR(300MHz，DMSO-d₆)δ10.48(s，1H)，8.01(s，1H)，7.67(dd，1H)，7.32(m，7H)，8.77(ddd，1H)，6.08(s，1H)，2.19(s，3H)，2.00(s，3H)；ES-MS m/z 307.1(MH⁺)；HPLC RT(min)2.41.

The following analogs were prepared using the procedure described for example 279.

In Table 9a, R⁴The positions of the groups are shown below.

TABLE 9a

TABLE 9b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	280	2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzamide
281	5-methoxy-2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzamide	280
281		282	2- { [1- (4-chlorophenyl) -3-methyl-1H-pyrazol-5-yl]Amino benzamide
283	2- { [1- (4-methoxyphenyl) -3-methyl-1H-pyrazol-5-yl]Amino benzamide	282

The following examples show carboxylic acid 1⁰Amides, which are obtained from their corresponding carboxylic acids derived from Ullmann-type coupling reactions.

Example 284

Preparation of 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzamide

To a solution of 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid (example 4) (130mg, 0.34mmol) in DMF (5ml) were added ammonium chloride (22mg, 0.41mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (79mg, 0.41mmol), HOBT hydrate (56mg, 0.41mmol) and triethylamine (0.17ml, 1.20 mmol). The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure. The residue was purified by HPLC (45-90% acetonitrile/water) to give the product (63mg, 49%) as a white solid.

¹H NMR(400MHz，DMSO-d_s)δ1.26(s，9H)，1.97(s，3H)，3.71(s，3H)，6.03(s，1H)，7.04(dd，1H)，7.24-7.37(m，6H)，7.44(s，1H)，8.05(s，1H)，10.01(s，1H)；ES-MS m/z379.3(MH⁺)；HPLC RT(min)2.83.

The analogs shown in tables 10a, 10b, 11a and 11b were synthesized by the method described in example 284 above.

In Table 10a, R⁴The positions of the groups are shown below.

TABLE 10a

TABLE 10b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	285	5-methoxy-2- ({ 3-methyl-1- [4- (methylsulfonyl) phenyl)]-1H-pyrazol-5-yl } amino) benzamide
286	5-methoxy-2- { [ 3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzamide	285
286		287	2- [ (3-tert-butyl-1-isopropyl-1H-pyrazol-5-yl) amino]-4, 5-dimethoxybenzamide
288	2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -4, 5-dimethoxybenzamide	287

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	289	2- { [ 3-tert-butyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzamide
290	2- { [ 3-tert-butyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzamide	289
290		291	2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino benzamide
292	2- { [ 3-tert-butyl-1- (2, 4-dimethylphenyl) -1H-pyrazol-5-yl]Amino benzamide	291
292		293	2- { [ 3-tert-butyl-1- (3-methylphenyl) -1H-pyrazol-5-yl]Amino benzamide
294	2- { [ 3-tert-butyl-1- (2-ethylphenyl) -1H-pyrazol-5-yl]Amino } -4, 5-dimethoxybenzamide	293
294		295	2- { [ 3-tert-butyl-1- (2, 4-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzamide
296	2- { [ 3-tert-butyl-1- (2, 4-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -4, 5-dimethoxybenzamide	295
296		297	2- [ (1, 3-diphenyl-1H-pyrazol-5-yl) amino]-5-methoxybenzamide
298	2- { [1- (2-methylphenyl) -3-phenyl-1H-pyrazol-5-yl]Amino benzamide	297
298		299	2- { [1- (2, 4-dimethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl]Amino benzamide
300	2- { [ 3-tert-butyl-1- (2, 6-dimethylphenyl) -1H-pyrazol-5-yl]Amino benzamide	299

The following examples represent primary amides derived from a series of processes consisting of Buchwald-type coupling reactions, hydrolysis and amide formation reactions.

In Table 10a, R⁴The positions of the groups are shown below.

TABLE 11a

TABLE 11b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	301	5-methoxy-2- { [1- (4-methoxyphenyl) -1H-pyrazol-5-yl]Amino benzamide
302	2- [ (1-benzyl-3-tert-butyl-1H-pyrazol-5-yl) amino]Benzamide derivatives	301
302		303	2- { [ 3-tert-butyl-1- (2, 5-dimethylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzamide
304	2- [ (3-tert-butyl-1-phenyl-1H-pyrazol-5-yl) amino]Benzamide derivatives	303

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	305	2- [ (3-tert-butyl-phenyl-1H-pyrazol-5-yl) amino]-5-methoxybenzamide
306	2- { [ 3-tert-butyl-1- (4-chloro-2-methylphenyl) -1H-pyrazole-5-yl]Amino benzamide	305
306		307	2- { [1- (2-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Amino benzamide

The following examples represent secondary and tertiary amides, which were prepared by a process consisting of an Ullmann-type coupling reaction followed by an amide formation reaction.

Example 308

Preparation of N-benzyl-5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino ] benzamide

Reacting 5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino]A mixture of benzoic acid (prepared by the Ullmann reaction described in example 1, 42.0mg, 0.14mmol), benzylamine hydrochloride (23.4mg, 0.16mmol), EDCI (31.2mg, 0.16mmol), HOBT (22.0mg, 0.16mmol) and triethylamine (0.066ml, 0.48mmol) in DMF (3ml) was stirred at room temperature for 16 h. The reaction was quenched with water (20ml) and extracted with ethyl acetate (10 ml). The organic layer was washed with brine over Na₂SO₄Dried, filtered and concentrated under reduced pressure. Flash silica gel chromatography of the residue, eluting with 20% ethyl acetate/hexanes, afforded the title compound (16.1mg, 30%) as a white solid.

¹H NMR(300MHz，DMSO-d_s)δ9.72(s，1H)，9.14(t，1H)，7.57(d，1H)，7.38-7.51(m，4H)，7.16-7.36(m，7H)，6.967.06(m，2H)，6.15(s，1H)，4.37(d，2H)，3.70(s，3H)；ES-MS m/z399.1(MH⁺)，HPLC RT(min)3.72.

The analogs shown in tables 12a, 12b, 13a and 13b were synthesized using the method described in example 308 above.

In Table 12a, R⁴The positions of the groups are shown below.

TABLE 12a

Example number	R	R	R	R	R	LC-MSRT(min)	LC-MS[M+H]	Remarks for note
Example number	R	R	R	R	R	LC-MSRT(min)	LC-MS[M+H]	Remarks for note	309	H	Ph	5-OMe	Et	Et	3.24	365.1	c
310	H	Ph	5-SMe	Me	H	2.82	339.1	c	309	H	Ph	5-OMe	Et	Et	3.24	365.1	c
310	H	Ph	5-SMe	Me	H	2.82	339.1	c	311	H	Ph	5-SMe	Et	H	3.02	353.1	c
312	H	Ph	5-SMe	i-Pr	H	3.19	367.1	c	311	H	Ph	5-SMe	Et	H	3.02	353.1	c
312	H	Ph	5-SMe	i-Pr	H	3.19	367.1	c	313	H	Ph	5-SMe	Et	Et	3.00	381.1	c

Remarks are as follows: sources of aminopyrazoles used in the coupling reaction: c is commercially available.

TABLE 12b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	309	N, N-diethyl-5-methoxy-2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzamide derivatives
310	N-methyl-5- (methylthio) -2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzamide derivatives	309
310		311	N-ethyl-5- (methylthio) -2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzamide derivatives
312	N-isopropyl-5- (methylthio) -2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzamide derivatives	311
312		313	N, N-diethyl-5- (methylthio) -2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzamide derivatives
314	N- [4- (methylthio) -2- (piperidin-1-ylcarbonyl) phenyl]-1-phenyl-1H-pyrazol-5-amines	313
314		315	N- (2- { 3-methoxy-4- [ (4-methylpiperazin-1-yl) sulfonyl group]Phenyl } ethyl } -5- (methylthio) -2- [ (1-phenyl-1H-pyrazol-5-yl) amino]Benzamide derivatives
316	N-isopropyl-2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzamide	315

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	317	2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino } -N-phenylbenzamides
318	5-methoxy-N-methyl-2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzamide	317
318		319	N-ethyl-5-methoxy-2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzamide
320	N-isopropyl-5-methoxy-2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzamide	319
320		321	5-methoxy-2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino } -N-phenylbenzamides
322	2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino } -N- (2-methylphenyl) benzamide	321
322		323	N- (2-fluorophenyl) -2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino benzamide
324	2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino } -N-pyridin-4-ylbenzamides	323
324		325	2- { [ 3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]Amino } -N-pyridin-3-ylbenzamides

The following examples represent secondary and tertiary amides, which were prepared by a process consisting of hydrolysis by a Buchwald-type coupling reaction followed by amide formation.

TABLE 13a

Example number	R	R	R	R	LC-MSRT(min)	LC-MS[M+H]
Example number	R	R	R	R	LC-MSRT(min)	LC-MS[M+H]	326	Me	Ph	Pr	H	2.80	365.1
327	Ph	Ph	(CH)OH	H	3.56	429.2	326	Me	Ph	Pr	H	2.80	365.1

TABLE 13b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	326	N-isopropyl-5-methoxy-2- [ (3-methyl-1-phenyl-1H-pyrazol-5-yl) amino]Benzamide derivatives
327	2- [ (1, 3-diphenyl-1H-pyrazol-5-yl) amino]-N- (2-hydroxyethyl) -5-methoxybenzamide	326

The following examples represent N-acyl sulfonamides derived from coupling of carboxylic acid precursors using sulfonamides.

Example 328

Preparation of 2- [ (1, 3-diphenyl-1H-pyrazol-5-yl) amino ] -5-methoxy-N- [ (2-methylphenyl) sulfonyl ] benzamide

To 2- [ (1, 3-diphenyl-1H-pyrazol-5-yl) amino group]To a solution of-5-methoxybenzoic acid (example 29) (100mg, 0.26mmol) in dichloromethane (3ml) were added o-toluenesulfonamide (53.3mg, 0.31mmol), EDCI (99.47mg, 0.52mmol), DMAP (63.40mg, 0.52mmol) and triethylamine (0.127ml, 0.91 mmol). The reaction mixture was stirred for 2 hours and then diluted with dichloromethane (10ml) and water (20 ml). The organic phase was separated, washed with brine and dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 90% EtOAc in hexanes to give the product (13.9mg, 10.0%) as a white solid.

¹H NMR(300MHz，DMSO-d₆)δ2.56(s，3H)，3.74(s，3H)6.67(s，1H)，7.03(dd，2H)，7.26-7.60(m，14H)，7.84(dd，2H)，7.94(d，1H)，ES-MS m/z 539.1(MH⁺)；HPLC RT(min)3.71.

The following compounds were synthesized by the same method as in example 328.

TABLE 14a

TABLE 14b

Example number	IUPAC nomenclature
Example number	IUPAC nomenclature	329	2- [ (1, 3-diphenyl-1H-pyrazol-5-yl) amino]-N- [ (3-fluorophenyl) sulfonyl]-5-methoxybenzamide
330	2- [ (1, 3-diphenyl-1H-pyrazol-5-yl) amino]-N- [ (2-fluorophenyl) sulfonyl]-5-methoxybenzamide	329

The following examples represent oxadiazole compounds derived from the conversion of a carboxylic acid group to an oxadiazole moiety.

Example 331

Preparation of N- [ 4-methoxy-2- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl ] -3-methyl-1-phenyl-1H-pyrazol-5-amine

Step 1: preparation of N-hydroxy-acetamidines

To a solution of hydroxylamine (2.21g, 67mmol) in water (5ml) was added acetonitrile (3.5ml, 2.75g, 67 mmol). Ethanol was added dropwise until a clear solution was obtained. The mixture was cooled to 0 ℃ and sodium ethoxide (21.7g of 21% ethanol solution, 67mmol) was added. After the addition was complete, the reaction mixture was warmed to 35 ℃ and stirred at this temperature for 3 days. The reaction mixture was cooled to room temperature and the solid residue (NaCl) was isolated by filtration and washed with acetonitrile. The filtrate and washings were combined, part of the solvent was evaporated in vacuo and concentrated HCl was added until the pH was approximately 1.0. The solvent was evaporated until a yellow residue appeared. The residue was dissolved in hot EtOH and reprecipitated by addition of diethyl ether. The needle-like crystals appearing in the solution were filtered off. The filtrate was stored and placed in the cold room for several days to give a second product. The product was obtained as colorless crystals (1.12g, 15%).

¹HNMR(400MHz，DMSO-d₆) Δ 2.09(s, 3H), 8.45(br, s, 1H), 10.64-10 (br, 1H), 12.2-12.5(br, 1H).

Step 2: preparation of N- [ (1Z) -N-hydroxyethylimino]-5-methoxy-2- [ (3-methyl- 1-phenyl-1H-pyrazol-5-yl) amino]Benzamide derivatives

At-20 deg.C, to 2- [ (II) ((III))3-methyl-1-phenyl-1H-pyrazol-5-yl) amino]Triethylamine (0.45ml, 3.25mmol) was added to a mixture of benzoic acid (400mg, 1.04mmol) (prepared by Buchwald-type coupling and hydrolysis in analogy to examples 108 and 109), HOAT (186mg, 1.39mmol) and EDCI (263mg, 1.39mmol) in DMF (7 ml). After stirring at this temperature for 15 minutes, N-hydroxy-acetamidine (305mg, 2.78mmol) was added and the temperature was slowly raised to room temperature. Stirring was continued for 16 h, the solvent was evaporated in vacuo and the residue partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. Using 5% citric acid, saturated Na₂CO₃The combined organic layers were washed sequentially with aqueous and brine, dried (MgSO)₄) Filtered and concentrated to give 147mg of a crude solid. The solid was used in the next step without further purification. ES-MS m/z 380.1 (MH)⁺)；HPLC RT(min)2.53。

And step 3: preparation of N- [ 4-methoxy-2- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl ] -3-methyl-1-phenyl-1H-pyrazol-5-amine

To a solution of crude N- [ (1Z) -N-hydroxyethylimino ] -2- [ (3-methyl-1-phenyl-1H-pyrazol-5-yl) amino ] benzamide (257mg, 0.41mmol) in THF (3ml) was added (methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess reagent) (145mg, 0.61 mmol). The flask was flushed with argon and refluxed for 3 hours under argon. The reaction mixture was cooled to room temperature, filtered through a small plug of silica gel, and the plug of silica gel was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC on silica gel eluting with EtOAc/hexanes (1: 2, v/v) to give the title product as a solid (5.5mg, 4% overall yield).

¹H NMR(400MHz，CD₃CH).δ2.30(s，3H)，2.32(s，3H)，3.82(s，3H)，6.16(s，1H)，7.09(dd，1H)，721(d，1H)，7.38-7.42(m，1H)，7.42-7.50(m，3H)，7.50-7.58(m，2H)，9.46(br，s，1H).ES-MS m/z 362.2(MH⁺)；HPLC RT(min)3.28.

Example 332

Preparation of N- [ 4-methoxy-2- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenyl ] -1-phenyl-1H-pyrazol-5-amine

The title compound was prepared analogously using the methods described for example 331. ES-MS m/z348.3 (MH)⁺)；HPLC RT(min)3.25。

The following examples represent sulfonamides, which were prepared by the following method: coupling the appropriate dibenzylsulfonamide precursor with 5-aminopyrazole, followed by deprotection of the two benzyl groups.

Example 333

Preparation of 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino) benzenesulfonamide

Step 1: preparation of N, N-dibenzyl-2-bromobenzenesulfonamide

2-bromobenzenesulfonyl chloride (1.0g, 3.91mmol) and triethylamine (455mg, 0.63ml, 4.5mmol) were dissolved in THF (15ml), the mixture was cooled to 10 ℃ and dibenzylamine 849mg, 0.83ml, 4.3mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature for 10 hours and then at 60 ℃ for 6 hours.After cooling to room temperature, the solvent was removed under reduced pressure and ethyl acetate was added. Using 1N HCl, water, half-saturated Na₂CO₃The organic layer was washed sequentially with aqueous solution, water and brine. In the presence of Na₂SO₄After drying and filtration, the solvent was removed under reduced pressure to give the title compound as off-white crystals (1.44g, 88%).

¹H NMR(400MHz，CDCl₃)δ4.42(s，4H)，7.08(m，4H)，7.27(m，6H)，7.41(m，2H)，7.78(d，1H)，8.19(d，1H).

Step 2: preparation of N, N-dibenzyl-2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pir-inyl Azol-5-yl]Amino-benzenesulfonamides

N, N-dibenzyl-2-bromobenzenesulfonamide (obtained from step 1, 333mg, 0.80mmol), 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-amine (intermediate C), cesium carbonate (365mg, 1.12mmol), Pd were added under a nitrogen atmosphere₂(dba)₃(41.4mg, 0.04mmol) and BINAP (49.8mg, 0.08mmol) were dissolved in toluene (7ml), and the flask was heated at 110 ℃ for 20 hours. The reaction mixture was cooled to room temperature and filtered to remove solid residue. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica eluting with EtOAc/hexanes (1: 12, v/v) to give the title compound as a viscous oil (348mg, 77%).

¹H NMR(400MHz，CDCl₃)δ1.40(s，9H)，2.03(s，3H)，3.99(s，4H)，6.10(s，1H)，6.88(m，4H)，7.07(m，1H)，7.10-7.27(m，10H)，7.38(d，1H)，7.47(t，1H)，7.71(s，1H)，7.77(d，1H).ES-MS m/z 565.4(MH)⁺；HPLCRT(min)4.37.

Step 3 preparation of 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino group } Benzenesulfonamides

Reacting N, N-dibenzyl-2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } benzenesulfonamide (obtained from step 2, 240mg, 0.42mmol) was added to concentrated H₂SO₄(3ml), the mixture was stirred vigorously for 20 minutes. The mixture was poured into ice and concentrated NaOH solution was added until the pH was about 7.5. Extract the aqueous layer with 2 × EtOAc and use Na₂SO₄The combined organic layers were dried, filtered and concentrated under reduced pressure. Flash chromatography on silica eluting with EtOAc/hexanes (1: 3, v/v) afforded the title compound as a white solid (104mg, 64%).

¹H NMR(400MHz，CD₂Cl₂)δ1.39(s，9H)，2.09(s，3H)，4.50(br，2H)，6.20(s，1H)，7.94(t，1H)，7.23(m，4H)，7.34(m，2H)，7.45(t，1H)，7.73(d，1H)，ES-MS m/z 385.2(MH⁺)HPLC RT(min)3.11.

Example 334

Preparation of 2- { [1- (2-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] amino } benzenesulfonamide

The title compound was prepared analogously using the methods described for example 333. ES-MS m/z397.1 (MH)⁺)；HPLC RT(min)3.18。

Example 335

Preparation of 2- { [ 4-iodo-1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-methylbenzoic acid

To a solution of 5-methyl-2- { [1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid (example 65) (49.5mg, 0.13mmol) in AcOH/DCM (1: 1, v/v) (2ml) was added a solution of NIS (28mg, 0.13mmol) in DCM (1 ml). The reaction was stirred at room temperature for 3 hours. Water (1ml) was added to the reaction mixture. The aqueous layer was extracted with DCM (2ml), the combined organic layers were washed with sodium sulfite and brine and concentrated under reduced pressure. The crude product was purified by HPLC eluting with a 30% to 95% acetonitrile/water gradient to give 9.1mg (14%) of the title compound.

¹H NMR(300MHz，CD₂Cl₂)δ8.88(s，1H)，7.85(d，2H)，7.74(s，1H)，7.18-7.32(m，7H)，6.58(d，1H)，2.41(s，3H)，2 25(s，3H)，221(s，3H).ES-MS m/z 524.1(MH⁺)；HPLC RT(min)4.35.

Example 336

Preparation of 2- { [ 3-tert-butyl-4-fluoro-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid

To 2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl]Amino } -5-methoxybenzoic acid (example 4) (49mg, 0.13mmol) in CH₃To a CN (1ml) solution was added [ (1- (chloromethyl) -4-fluoro-1, 4-diazoniabicyclo [2.2.2 ]]Octane bis (tetrafluoroborate)) (SELECTFLUOR)) (46mg, 0.13mmol), and the mixture was stirred at room temperature for 16 hours. The solid was filtered off and the filtrate was purified by HPLC eluting with a gradient of 10% to 90% acetonitrile/waterThis gave 4mg (8%) of the title compound.

¹H NMR(300MHz，CD₂Cl₂)δ8.62(s，1H)，7.40(d，1H)，7.16-7.35(m，4H)，7.05(dd，1H)，7.76(dd，1H)，3.75(s，3H)，2.12(s，3H)，1.40(s，9H).ES-MS m/z 398.2(MH⁺)；HPLC RT(min)4.06.

Example 337

Preparation of methyl 5-methoxy-2- { methyl [ 3-methyl-1- (2-methylphenyl) -4-phenyl-1H-pyrazol-5-yl ] amino } benzoate

Step 1: preparation of 5-methoxy-2- { methyl [ 3-methyl (2-methylphenyl) -4-phenyl- 1H-pyrazol-5-yl]Amino } benzoic acid methyl ester

To a suspension of NaH (60%, dispersed in mineral oil; 0.28g, 7mmol) in DMF (10ml) was added dropwise 5-methoxy-2- { [ 3-methyl-1- (2-methylphenyl) -4-phenyl-1H-pyrazol-5-yl at room temperature]Amino } benzoic acid methyl ester (1.495g, 3.5mmol) in DMF (15 ml). The mixture was stirred for 0.5 h, then iodomethane (0.88ml, 14mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Water (100ml) was carefully added and the mixture was extracted with ethyl acetate (25 ml. times.3). The combined organic phases were washed with saturated aqueous sodium bicarbonate (50ml) and dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. Flash chromatography on silica gel (EtOAc/hexanes 1: 12) purified the residue to give the title compound (1.18g, 68%) as a pale yellow solid.

¹H NMR (400MHz, CKetone-d₆)δ2.1(s，3H)，2.3(s，3H)，2.9(s，3H)，3.65(s，3H)，3.7(s，3H)，6.87-6.92(m，2H)，6.94-6.98(m，1H)，7.03-7.09(m，1H)，7.15-7.27(m，4H)，7.30-7.36(m，2H)，7.39-7.43(m，2H).ES-MS m/z 442.3(MH⁺)；HPLC RT(min)3.96.

Step 2: preparation of 5-methoxy-2- { methyl [ 3-methyl-1- (2-methylphenyl) -4-phenyl -1H-pyrazol-5-yl]Amino benzoic acid

To a solution of the compound of step 1 (60mg, 0.129mmol) in a mixture of THF (4ml), water (4ml) and MeOH (2ml) was added LiOH (32mg, 1.32 mmol). The reaction mixture was stirred vigorously for 24 hours, after which it was concentrated under reduced pressure and diluted with water (10 ml). Acidifying the solution to pH about 1 with 1N HCl and using CH₂Cl₂(3X 20ml) extraction. Drying (Na)₂SO₄) The combined organic phases were filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (32mg, 58%) as a white solid.

¹H NMR (400MHz, acetone-d₆)δ2.12(s，3H)，2.23(s，3H)，2.9(s，3H)，3.74(s，3H)，6.87-6.90(m，2H)，6.92-6.98(m，1H)，7.03-7.11(m，1H)，7.16-7.27(m，4H)，7.30-7.36(m，2H)，7.40-7.45(m，2H)；ES-MS m/z428.3(MH⁺)；HPLC RT(min)3.54.

Example 338

Preparation of 2- { [ 3-tert-butyl-1- (2, 6-dimethylphenyl) -1H-pyrazol-5-yl ] (methyl) amino } -5-methoxybenzoic acid

This compound was prepared using the procedure described for the preparation of example 337.

¹H NMR(400MHz，CD₃OD)δ1.40(s，9H)，1.95(s，6H)，3.26(s，3H)，3.74(s，3H)，6.81(dd，1H)，6.93(m，4H)，7.13(m，1H)，7.26(d，1H).ES-MS m/z 408.3(MH⁺)；HPLC RT(min)2.65.

The following compounds were prepared using the procedures described for examples 108 and 109. The aminopyrazole used in the coupling reaction can be prepared from commercially available methyl or ethyl carboxylates by the method described for intermediate B.

Watch 15

The compounds of the invention are useful for the treatment of diabetes, including type I and type II diabetes (non-insulin dependent diabetes). This treatment may also delay the onset and complications of diabetes. The compounds are useful for preventing subjects with impaired glucose tolerance from developing type II diabetes. Other diseases or conditions which can be treated or prevented using the compounds of the invention in the methods of the invention include: maturity onset Diabetes of the young (MODY) (Herman, et al, Diabetes 43: 40, 1994); potentially autoimmune Diabetes mellitus (LADA) in adults (Zimmet, et., Diabetes Med.11: 299, 1994) Impairs Glucose Tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitis, Diabetes Care 22 (Supp.1): S5, 1999); impaired Fasting Glucose (IFG) (Charles, et al., Diabetes 40: 796, 1991); gestational Diabetes mellitus (Metzger, Diabetes, 40: 197, 1991); and metabolic syndrome X.

The compounds of the present invention also have utility in the treatment of diseases such as obesity, atherosclerotic diseases, hyperlipidemia, hypercholesterolemia, low HDL levels, hypertension, cardiovascular diseases (including atherosclerosis, coronary heart disease, coronary artery disease and hypertension), cerebrovascular diseases and peripheral vascular diseases.

The compounds of the invention are also useful in the treatment of physiological disorders associated with, for example, cell differentiation to produce lipid accumulating cells, regulation of insulin sensitivity and blood glucose levels, which may include, for example: abnormal pancreatic beta-cell function; insulin-secreting tumors and/or autoimmune hypoglycemia due to insulin autoantibodies, insulin receptor autoantibodies, or autoantibodies that stimulate beta cells; macrophage differentiation capable of forming atherosclerotic plaques; an inflammatory response; carcinogenesis; hyperplastic diseases; adipocyte gene expression; differentiation of fat cells; a decrease in pancreatic β -cell mass; insulin secretion; sensitivity of tissues to insulin; growing liposarcoma cells; polycystic ovarian disease; chronic anovulation; male hormone excess; progesterone generation; steroid production; cell redox capacity and oxidative stress; nitric Oxide Synthase (NOS) production; gamma-glutamyl transpeptidase, catalytic enzymes, increased plasma triglyceride, HDL and LDL cholesterol levels, and the like.

The compounds of the invention are also useful in the treatment of Diabetes of secondary cause (Expert Committee on Classification of Diabetes Mellitis, Diabetes Care 22 (Supp.1): S5, 1999). Such secondary causes include glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes. Drugs may include, but are not limited to, pyriminil, nicotinic acid, glucocorticoids, phenytoin, thyroid hormone, beta-adrenergic agents, alpha-interferon, and drugs for HIV infection.

The compounds of the present invention may be used alone or in combination with additional compounds known to those of ordinary skill in the art of treating and/or managing diabetes and related disorders. In addition, some or all of the methods and compounds described herein may be used in conjunction with therapy.

The compounds of the present invention may also be used in combination with other well-known therapeutic agents for the treatment of diabetes, including: PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α -glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin and anti-obesity drugs. Such agents may be administered prior to, concurrently with, or subsequent to the administration of the compounds of the present invention. Insulin includes both long-acting or short-acting forms and insulin preparations. PPAR agonists include any PPAR subclass agonist or combinations thereof. For example, PPAR agonists may include PPAR- α, PPAR- γ, PPAR- δ, or combinations of two or three of the subclasses of PPAR. PPAR agonists include, for example, rosiglitazone and pioglitazone. Sulphonylureas include, for example, glibenclamide, glimepiride, chlorpropamide, and glipizide. Alpha-glucosidase inhibitors useful for the treatment of diabetes, when taken with the compounds of the invention, include acarbose, miglitol and voglibose. Insulin sensitizers which may be used in the treatment of diabetes include thiazolidinediones and non-thiazolidinediones. When taken with the compounds of the present invention, hepatic glucose output lowering compounds useful for the treatment of diabetes include metformin, such as glyburide and glyburide XR. Insulin secretagogues for the treatment of diabetes mellitus include the sulfonylureas and non-sulfonylureas, when administered in combination with the compounds of the present invention: GLP-1, GIP, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide and glipizide. GLP-1 includes GLP-1 derivatives having a longer half-life than GLP-1 itself, such as GLP-1 fatty acid derivatives and exendin. In one embodiment of the invention, the compounds of the invention may be used in conjunction with an insulin secretagogue to enhance the sensitivity of pancreatic β -cells to the insulin secretagogue.

The compounds of the present invention may also be used in the methods of the present invention in combination with anti-obesity agents. Anti-obesity agents include beta-3 agonists, CB-1 antagonists, anorectic agents such as sibutramine (Meridia), and lipase inhibitors such as orlistat (xenoica).

The compounds of the present invention may also be used in the methods of the present invention in combination with drugs commonly used in lipid disorders in diabetic patients. Such agents include, but are not limited to, HMG-CoA reductase inhibitors, nicotinic acid, bile acid sequestrants, and fibric acid derivatives. The compounds of the present invention may also be used in combination with antihypertensive agents (e.g., beta-3 blockers and ACE inhibitors) in the methods of the present invention.

Such adjunctive therapeutic agents may be administered in any combination of two or more drugs, e.g., a compound of the invention is administered in combination with an insulin stabilizing agent and an anti-obesity agent. Such adjunctive therapeutic agents may be administered in the form of pharmaceutical compositions, as described above.

Various terms used in this class are defined as follows.

When introducing elements of the present invention or the preferred embodiments thereof, the definite article, indefinite article or "the" means that there are one or more of the elements. The terms "comprising," "including," and "containing" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

The term "subject" includes mammals (e.g., humans and animals).

The term "treatment" includes any process, act, application, treatment, etc., in which a subject, including a human, receives medical assistance, either directly or indirectly, to ameliorate a lesion in the subject, or to slow the progression of a lesion or disease in the subject.

The term "combination therapy" or "adjuvant therapy" refers to the administration of two or more therapeutic agents for the treatment of a diabetic condition and/or disease. Such administration includes adjunctive administration of two or more therapeutic agents in a substantially simultaneous manner, e.g., with a fixed ratio of active ingredient in a single capsule, or with inhibitors in multiple, separate capsules. In addition, such administration includes the use of various types of therapeutic agents in a continuous manner.

The phrase "therapeutically effective" refers to the amount of each agent administered for the purpose of improving the severity of a diabetic condition or disease while avoiding or minimizing the side effects associated with the given treatment regimen.

The term "pharmaceutically acceptable" means that the host component for the pharmaceutical preparation is suitable.

Effective dosages of the compounds of the present invention for addressing various indicative behaviors can be readily determined based on well-known methods for determining the efficacy of treatment of the disease identified in the aforementioned mammals and by comparing these results with those of known drugs used to treat such diseases. The amount of active ingredient (e.g., compound) administered to treat one of these conditions can vary widely according to the following considerations: the particular compound and dosage unit employed, the mode of administration, the treatment period, the age and sex of the patient being treated, and the nature and extent of the disease being treated.

The total amount of active ingredient administered will generally range from about 0.0001mg/kg to about 200mg/kg body weight, preferably from about 0.01mg/kg to about 200 mg/kg. The unit dose may contain from about 0.05mg to about 1500mg of the active ingredient, which may be administered one or more times per day. Daily dosages for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, as well as using infusion techniques, may range from about 0.01 to about 200 mg/kg. The daily dosage for rectal administration may be from about 0.01 to 200mg/kg of total body weight. The daily maintenance dose for transdermal administration may be about 0.01 to 200 mg/kg.

The particular initial and consecutive doses for each patient will, of course, vary depending upon the nature and severity of the condition as determined by the clinician, the activity of the particular compound employed, the age of the patient, the diet of the patient, the time of administration, the route of administration, the rate of excretion of the drug, the drug combination, and the like. The desired mode of treatment and dosage regimen of the compounds of the invention can be determined by one skilled in the art using routine therapeutic testing.

The compounds of the present invention can be used to achieve a desired pharmacological effect by administering to a patient in need of treatment a suitable pharmaceutical composition formulation. For the purposes of the present invention, a patient may be a mammal, including a human, in need of treatment for a particular lesion or disease. Thus, the invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound. A pharmaceutically acceptable carrier can be any carrier that is relatively non-toxic and non-injurious to the patient at concentrations consistent with the effective activity of the active ingredient, so that any side effect of the carrier does not impair the effective activity of the active ingredient. A therapeutically effective amount of a compound is an amount that produces a result or effect on the particular lesion to be treated. The compounds described herein may be administered with a pharmaceutically acceptable carrier using any effective conventional dosage unit form, including immediate release and slow release formulations, by oral, parenteral, topical, etc.

For oral administration, the compounds may be presented as solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, troches, powders, solutions, suspensions, or emulsions prepared according to methods well known in the art of producing pharmaceutical compositions. The solid unit dosage form may be a conventional hard or soft gelatin type capsule containing surfactants, lubricants and inert fillers such as lactose, sucrose, calcium phosphate and corn starch.

In another embodiment, the compounds of the present invention may be formulated in the form of tablets containing conventional tablet bases such as lactose, sucrose and corn starch in combination with the following adjuvants: binding agents, such as acacia, corn starch or gelatin; disintegrants such as potato starch, alginic acid, corn starch and guar gum, which help to break up and dissolve the tablet after administration; lubricants, such as talc, stearic acid or magnesium stearate, calcium or zinc, to improve the flow of the tablet particles and prevent the tablet material from sticking to the tablet die and punches; a dye; a colorant; and flavoring agents to enhance the aesthetic quality of the tablet and make it more acceptable to the patient.

Suitable excipients for oral liquid dosage forms include diluents, such as water and alcohols (e.g., ethanol, benzyl alcohol, and polyethylene glycol), with or without the addition of pharmaceutically acceptable surfactants, suspending agents, or emulsifying agents. Various other materials may be present in the form of coatings or other modifications that modify the physical properties of the dosage unit. For tablets, pills or capsules of the invention, shellac, sugar or both may be coated.

Dispersible powders and granules are suitable for preparing aqueous suspensions. They may provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are described above. Additional excipients, such as sweetening, flavoring and coloring agents described above, may also be present.

The pharmaceutical compositions of the present invention may also be oil-in-water emulsions. The oil phase may be a vegetable oil, such as a liquid olefin or a vegetable oil mixture. Suitable emulsifying agents may be (1) natural gums, such as gum acacia and tragacanth, (2) natural phosphatides, such as soya bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, and (4) condensation products of the said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavors.

Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, castor oil or cocoa butter; or by suspending the active ingredient in a mineral oil, such as a liquid olefin. The oily suspensions may contain a thickening agent, for example beeswax, hard olefin or cetyl alcohol. The suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more sweetening agents, such as sucrose or saccharin.

Syrups or elixirs may also be formulated to contain sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring agent and a coloring agent

The compounds of the present invention may also be administered parenterally, such as subcutaneously, intravenously, intramuscularly or intraperitoneally, in an injectable dosage form of the compound comprising a physiologically acceptable diluent in admixture with a pharmaceutically acceptable carrier. The diluent may be a sterile liquid or liquid mixture, such as water, saline, hydrated dextrose and related sugar solutions; alcohols, such as ethanol, isopropanol or hexadecanol; glycols, such as propylene glycol or polyethylene glycol; glycerol ketals, such as 2, 2-dimethyl-1, 1-dioxolane-4-methanol; ethers, such as poly (ethylene glycol) 400; oils; a fatty acid; fatty acid esters or glycerides; or acetylated fatty acid glycerides with or without the addition of pharmaceutically acceptable surfactants (such as after-soaps or detergents), suspending agents (such as gums, carbomers, methylcellulose hydroxypropyl methylcellulose or carboxymethylcellulose), or emulsifying agents or other pharmaceutically acceptable adjuvants.

Illustrative examples of oils which may be used in the parenteral formulations of the invention are petroleum, animal, vegetable or synthetic oils, such as peanut oil, soybean oil, castor oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include the alkali metal, ammonium and triethanolamine salts of the fatty acids. Suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridine halide salts, and alkylamine acetates; anionic detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers; and amphoteric detergents such as alkyl-beta-aminopropionates and 2-alkylimidazolidine quaternary ammonium salts, and mixtures thereof.

The parenteral compositions of the invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution thereof. Preservatives and buffers may also be advantageously employed. To minimize or eliminate pain at the site of injection, such compositions may comprise a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of from about 12 to about 17. The amount of surfactant in such formulations is from about 5% to about 15% by weight. The surfactant may be a single component having the above-mentioned HLB, or may be a mixture of two or more components having the above-mentioned HLB.

Illustrative examples of surfactants for parenteral formulations are polyethylene sorbitan fatty acid esters such as sorbitan monooleate and the addition product of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol.

The pharmaceutical compositions may be presented as a sterile injectable aqueous suspension. Such suspensions may be prepared by known methods using suitable dispersing or wetting agents and suspending agents. Such suspending agents as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone xanthil gum and acacia gum; the dispersing or wetting agent may be a naturally occurring phosphatide, for example lecithin, condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, condensation products of an alkylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. Diluents and solvents which can be used are, for example, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, stable oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by the following method: the drug (e.g., compound) is mixed with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature so that it will melt in the rectum to release the drug. Such materials may be, for example, cocoa butter and polyethylene glycols.

Another formulation for use in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or non-continuous infusion of the compounds of the present invention in controlled amounts. The manufacture and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see U.S. Pat. No. 5,023,252, which is incorporated herein by reference). Such patches may be formulated as a continuous, pulsatile or on demand delivery of pharmaceutical agents.

It is desirable or necessary to introduce a pharmaceutical composition into a patient via a mechanical delivery device. The manufacture and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for direct drug delivery to the brain generally involve placing a drug delivery catheter into the ventricular system of a patient, thereby bypassing the blood-brain barrier. One type of implantable delivery system for delivering an agent to a particular anatomical region of the body is described in U.S. patent No. 5,011,472, which is incorporated herein by reference.

The compositions of the present invention may also contain other conventional ingredients for pharmaceutically acceptable compounds, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of the present invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional methods of preparing the compositions in suitable dosage forms may be used.

Common pharmaceutical ingredients that can be used to form a suitable dosage form for the desired route of administration include: acidulants such as, but not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid; alkalizing agents, for example. But are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine.

Other pharmaceutical ingredients include, but are not limited to, for example, inhalantsAdjuncts such as powdered cellulose and activated carbon; aerosol propellants, e.g. carbon dioxide, CCl₂F₂、F₂ClC-CClF₂And CClF₃(ii) a Air displacement agents such as nitrogen and argon; antifungal preservatives, such as benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate; antibacterial preservatives such as benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenyl silver nitrate and thimerosal; antioxidants, such as ascorbic acid, ascorbyl palmitate butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite; adhesive materials such as block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, and styrene-butadiene copolymers; buffering agents such as potassium metaphosphate, potassium monobasic phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate monohydrate; carrier agents such as acacia syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, corn oil, mineral oil, peanut oil, castor oil, antibacterial sodium chloride injection and antibacterial water injection; chelating agents, such as disodium ethylenediaminetetraacetate and ethylenediaminetetraacetic acid; colorants, e.g. FD&C3 red, FD&C20 Red, FD&C6 yellow, FD&C2 blue and D&C5 green, D&C5 orange and D&Red No. C8, caramel, and red iron oxide; clarifying agents, such as bentonite; emulsifying agents, such as, but not limited to, acacia, cetyl macrogel, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate; forming capsules, such as gelatin and cellulose acetate phthalate; flavoring agents, such as anise oil, cinnamon oil, cocoa powder, menthol, orange oil, peppermint oil, and vanillin; humectants such as glycerol, propylene glycol and sorbitol; abrasives, such as mineral oil and glycerin; oils, e.g. groundnut oil, mineral oil, olive oil, peanut oil, castor oil, hydrophilic ointments and vegetable oilsVegetable oil; ointment bases, such as lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment and rose water ointment; penetration enhancers (transdermal delivery) such as monohydric or polyhydric alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones, and ureas; plasticizers, such as diethyl phthalate and glycerol; solvents such as alcohols, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, pure water, water for injection, sterile water for injection and water for rinsing; hardening agents, such as cetyl alcohol, cetyl esters wax, microcrystalline wax, olefins, stearic alcohol, white wax and yellow wax; suppository bases such as cocoa butter and polyethylene glycols (mixtures); surfactants such as benzalkonium chloride, nonoxynol 10, oxoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate; suspending agents such as agar, bentonite carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, kaolin, methylcellulose, xanthan gum and veegum; sweetening agents, such as aspartame, glucose, glycerol, mannitol, propylene glycol, sodium saccharin, sorbitol and sucrose; antiadherents for tablets, such as magnesium stearate and talc; tablet binding agents, such as acacia, alginic acid, sodium carboxymethylcellulose compressed sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pyrrolidone, pregelatinized starch; tablet and capsule diluents such as dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium phosphate, sorbitol, and starch; tablet coating agents such as liquid glucose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, cellulose acetate phthalate and shellac; direct compression agents for tablets, such as dibasic calcium phosphate; disintegrating agents for tablets, such as alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, sodium alginate, sodium starch glycolate and starch; tablet release agents, e.g. colloidal silica, cornStarch and talc; tablet lubricants, such as calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate; tablet/capsule opacifiers such as titanium dioxide; tablet polishing agents such as carnuba wax and white wax; thickening agents, such as beeswax, cetyl alcohol and olefins; enhancers, such as glucose and sodium chloride; viscosity increasing agents such as alginic acid, bentonite carbomer, sodium carboxymethylcellulose, methylcellulose, pyrrolidone, sodium alginate, and xanthan gum; and moisturizers such as heptadecaethyleneoxycetanol, lecithin, polyethylene sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate.

The compounds described herein may be administered alone or in combination with one or more other agents that do not cause unacceptable side effects. For example, the compounds of the present invention may be administered in combination with known anti-obesity agents, or with known anti-diabetic or other agents, their combinations, or combinations thereof.

The compounds described herein may also be used as free bases or in compositions, or may be used as analytical reference standards, etc., in research and diagnostics. Accordingly, the present invention includes compositions comprising an inert carrier and an effective amount of a compound, or a salt or ester thereof, as determined by the methods described herein. The inert carrier can be any material that does not interact with the contained compound, which provides a carrier, a means of delivery, bulk and trace materials, etc. for the contained compound. An effective amount of a compound is an amount that will produce a result or effect on the particular process being treated.

Formulations suitable for subcutaneous, intravenous, intramuscular, and the like, suitable pharmaceutical carriers, and methods of forming and administering the drugs are available by methods well known in the art (see, e.g., Remington's pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20^th edition，2000)。

The following examples are intended to illustrate the invention, but are not intended to limit the scope of the invention in any way.

Capsule preparation

The capsule formulation can be prepared by:

compounds of the invention	10mg
compounds of the invention	10mg	Starch	109mg
Magnesium stearate	1mg	Starch	109mg

Mixing the above materials, sieving with proper mesh, and encapsulating with hard gelatin capsule. Tablet formulation

Tablets may be prepared by:

compounds of the invention	25mg
compounds of the invention	25mg	Microcrystalline cellulose	200mg
Colloidal silica	10mg	Microcrystalline cellulose	200mg
Colloidal silica	10mg	Stearic acid	5.0mg

Mixing the above materials, and tabletting. To enhance flatness, improve elegance and stability or delay absorption, suitable hydrated or non-hydrated coatings may be applied.

Sterile IV solution

A mg/ml solution of the compound of the invention is prepared using sterile water for injection, and the pH is adjusted, if necessary. At the time of administration, the solution was diluted with sterile 5% glucose and administered as an IV infusion.

Intramuscular suspensions

Intramuscular suspensions can be prepared by:

compounds of the invention	50μg/ml
compounds of the invention	50μg/ml	Sodium carboxymethylcellulose	5mg/ml
TWEEN 80	4mg/ml	Sodium carboxymethylcellulose	5mg/ml
TWEEN 80	4mg/ml	Sodium chloride	9mg/ml
Benzyl alcohol	9mg/ml	Sodium chloride	9mg/ml

The suspension is administered intramuscularly.

Hard shell capsule

A standard two-piece hard meat roll capsule was filled with powdered active ingredient, 150mg lactose, 50mg cellulose and 6mg magnesium stearate, respectively, to prepare a large number of unit dose capsules.

Soft gelatin capsule

A mixture of the active ingredients in digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected into molten gelatin by positive pressure piston pump to form soft gelatin capsule containing the above active ingredients. The capsules were rinsed and dried. The active ingredient may be dissolved in a mixture of polyethylene glycol and sorbitol to produce a water-miscible pharmaceutical composition.

Immediate release tablet/capsule

These formulations are prepared in solid oral dosage forms by conventional and novel methods. These unit doses can be administered orally in the absence of water for immediate dissolution and delivery of the drug. The active ingredients are mixed in a liquid containing sugar, gelatin, gum and sweetener. These liquids can be solidified into solid tablets or caplets by freeze-drying and solid extraction techniques. The pharmaceutical compound can be compressed in the absence of water with viscoelastic and thermoplastic sugars and polymers or with effervescent ingredients capable of producing an immediate release porous medium.

It will be apparent to one of ordinary skill in the art that changes and modifications can be made to the invention without departing from the spirit of the invention or the scope of the invention described herein.

Biological evaluation

For a better understanding of the present invention, the following examples are set forth herein. These examples are provided only to disclose the present invention, and are not intended to limit the scope of the present invention in any way. All publications mentioned above are incorporated by reference in their entirety.

Demonstration of the activity of the compounds of the invention may be accomplished by in vitro, in vitro and in vivo assays well known in the art. For example, to demonstrate the efficacy of pharmaceutical formulations for the treatment of diabetes and related diseases, such as syndrome X, impaired glucose resistance, impaired fasting glucose and hyperinsulinemia, the following assays may be used.

In vitro assay

Secretion of insulin by INS-1 cells

INS-1 cells were isolated from X-ray induced rat insulinomas (Asfari, et al, Endocrinology 130: 167, 1992). INS-1 cells were seeded at 30,000 cells per well in Biocoat CollagenlCellware 96-well plates and incubated for 4-5 days. Cells were treated with whole medium (RPMI 1640, 10% fetal bovine serum, 100. mu.g/ml penicillin/streptomycin, 0.5mM sodium pyruvate, 10mM HEPES, and 50. mu.M. beta. -mercaptoethanol) adjusted to 3mM glucose for 2 days. After two days of treatment, cells were washed with Krebs-Ringer bicarbonate-HEPES (KRBH) containing 3mM glucose. Then incubated in the same buffer for 30 minutes. Incubate for an additional 2 hours in the presence of the desired concentrations of glucose and compound. The supernatant was collected.

To determine the amount of insulin secreted, the supernatant was mixed with anti-insulin antibody and a trace amount of phosphate buffered saline containing 0.5% bovine serum albumin¹²⁵I-mixing insulin. Protein a beads coated with SPA (scintillation proximity assay) were added. The plates were incubated for 5-20 hours and counted in a scintillation counter to measure insulin levels. The activity of the compound at a given concentration is expressed as the fold of stimulated insulin secretion relative to the control group.

As a result, the compounds of the present invention (measured at 10. mu.M) were found to be active in the INS-1 assay.

Secretion of insulin from dispersed rat islet cells

Insulin secretion from a number of dispersed rat islet cells mediated by a compound of the invention was determined according to the following method. Langerhans islets were isolated from male Sprague-Dawley rats (200-250g) and classified by collagenase. Dispersed islet cells were treated with insulin and plated in 96V-bottom well plates to make pellets. Cells were cultured overnight in saturated and medium not containing the compounds of the invention. The medium was aerated and the cells were pre-incubated for 30 min at 37 ℃ with Krebs-Ringer-HEPES buffer containing 3mM glucose. The pre-administration buffer is removed and incubated at 37 ℃ for an appropriate period of time with Krebs-Ringer-HEPES buffer containing an appropriate glucose concentration (e.g., 8mM) with or without the compound of the invention. In some studies, GLP-1 or forskolin is also included. A portion of the supernatant was removed and its insulin content was determined by SPA. The results are expressed as "fold control" (FOC).

In vivo assays

Effect of Compounds on intraperitoneal glucose resistance in rats

The compounds of the invention were tested for in vivo activity by oral administration in rats. Overnight fasted rats were given oral doses of controls and compounds. After 3 hours the basal blood glucose level was determined and 2g/kg glucose was administered to the rats via the peritoneum. 15. Blood glucose levels were measured after 30 and 60 minutes. Representative invention significantly reduced blood glucose levels relative to vehicle after IPGTT (intraperitoneal glucose tolerance test).

Identifying targets

The compounds of formula (I) used to identify biological targets for compounds of formula (I) of the present invention may also be used to identify compounds related to biological targets (e.g., nucleic acids, peptides, polypeptides, proteins, carbohydrates, lipids or other molecules) that affect the functional response of insulin secretion. Such targets or protein molecules modulated by the compounds of the invention can be identified in several ways.

For example, one such method of targeted identification can be accomplished by optical affinity labeling techniques well known in the art. In this method, a compound of formula (I) containing an optically active group (e.g., a benzoylphenyl group) is prepared and labeled with a radioisotope (e.g., tritium). By way of example, a suitable compound of formula (I) for use in this experiment is a radiolabeled derivative of the benzophenone analog described in example 207. The process for preparing such compounds is illustrated in reaction scheme M below, wherein a compound of formula (X) is used as starting material. Chlorine-containing starting materials can be prepared in a similar manner to that described in example 142. In a stepwise manner, the starting material is functionalized with a benzoyl group and allowed to undergo a tritium-halogen conversion reaction, thereby providing the probe compound of formula (XIII). The replacement of chlorine atoms by tritium is a technique well known in the art and can be accomplished without affecting the integrity of the ketone group of the benzophenone moiety (e.g., Mesange, et al, bioconj. chem. 13: 766-772, 2002; Held, et al, Labelled, Comp. radiopharm. 39: 501-508, 1997; Kaspersen, et al, Rec. Trav. Chim. Pays-Bas 112: 191-199, 1993; Hergert, et al, Pharmazie 38: 28-29, 1983).

The probe molecule containing the suspected target is then allowed to contact a homogeneous mixture of pancreatic β -cell lysate (or any biological specimen, such as a biological organism (e.g., a human) or a constituent of a biological organism (e.g., a cell, biological tissue, or bodily fluid), a cell line, or a tissue culture specimen, or a specimen that may be derived from a patient including, but not limited to, a tissue or cell thereof), incubated for a time sufficient for the probe molecule to interact with the target protein, and the mixture is then irradiated with light at the wavelength of the photoactive group of the probe molecule. The covalently bound protein and probe molecule formed as a result of irradiation are then purified using standard methods, facilitating the radioactivity of the probe molecule/target complex as a means of separating it from the remaining lysate mixture. The purified protein (probe molecule/target complex) is then identified using methods well known in the art (see, e.g., Dorman, et al, Tibtech.18: 64-77, 2000).

Reaction scheme M

Another method by which the compounds of formula (I) can be used to identify biologically affected insulin secretion function responses to targeting is the so-called drug "folding" assay (see, e.g., Graves, et al, Rec. prog. Horm. Res.58: 1-24, 2003). Compounds of formula (I) containing functional groups suitable for chemical coupling reactions (e.g. carboxyl, amino, alcohol groups) can be coupled with commercially available polymers (resins) containing suitable reactive linking groups. For example, polymer beads containing amino linking groups can be reacted with compounds of the formula (I) in which X ═ COOH to give amides which bind to the polymer beads and can thus be immobilized. The polymer beads containing immobilized compound (I) can be used as temptation for appropriate pancreatic-cell tissue lysates by: the polymer beads are contacted with the lysate and incubated sufficient to allow the targeted protein to form a complex containing the polymer, unbound protein material is removed from the polymer, and the bound protein is cleaved from the polymer. Thus, the purified protein targets of interest can be identified by mass spectrometry using techniques well known in the art (see, e.g., Kim, et., biochem. mol. biol. 36: 299-304, 2003).

All publications and patent documents mentioned in the above specification are herein incorporated by reference. Various modifications and alterations of the compositions and methods of the present invention described above will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention will be described in conjunction with specific embodiments, it will be understood that the invention as claimed should not be unduly limited to such specific embodiments.

Indeed, the above-described modes for carrying out the invention which are obvious to those skilled in molecular biology or related fields are intended to be within the scope of the following claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. Compounds of formula (I) and pharmaceutically acceptable salts thereof,

wherein

R is H or (C)₁-C₆) An alkyl group;

R¹is a compound of formula (I) in the formula (H),

(C₃-C₆) An alkenyl group which is a radical of an alkylene group,

(C₃-C₆) An alkynyl group,

(C₁-C₃) Haloalkyl, or

Phenyl, the radical being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group;

R²is a compound of formula (I) in the formula (H),

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

(C₁-C₃) A halogenated alkyl group,

pyridyl optionally selected from (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkylthio, halogen and optionally substituted by one (C)₁-C₄) Alkoxy-substituted (C)₁-C₆) Up to two substituents of the alkyl group,

a pyrimidine group,

phenyl, the radical being optionally selected from

(C₁-C₆) An alkoxy group,

a hydroxyl group(s),

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) An alkylthio group is a group of one or more,

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

CO₂R⁸，

(C₁-C₃) A halogenated alkoxy group,

(C₁-C₄) Acyl, and

up to four substituents of benzoyl substituted for the group,

or

R³is (C)₁-C₆) An alkyl group, a carboxyl group,

(C₃-C₆) A cycloalkyl group,

benzyl, which radical is optionally selected from among the aryl radicals

(C₁-C₆) Alkyl, the radical being optionally substituted by one(C₁-C₄) Alkoxy substitution, halogen,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) Alkylthio radicals, and

SO₂(C₁-C₃) Up to four substituents of the alkyl group,

(C₂-C₃) Haloalkyl, or

Phenyl, the radical being optionally selected from

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

(C₁-C₃) A halogenated alkyl group,

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) Alkylthio radicals, and

SO₂(C₁-C₃) Up to four substituents of alkyl;

R⁴is (C)₁-C₆) Alkyl, the radical being optionally substituted by one (C)₁-C₄) The substitution of alkoxy groups is carried out,

(C₁-C₆) An alkoxy group,

(C₁-C₆) An alkylthio group is a group of one or more,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

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

NR⁸R⁸，

pyrimidinyl radicals

A pyridyl group, a carboxyl group,

imidazolyl or

Phenyl, the radical being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radical

(C₁-C₆) Up to four substituents of an alkylthio group;

n is 0, 1, 2 or 3;

R⁵is a compound of formula (I) in the formula (H),

(C₁-C₆) An alkyl group, a carboxyl group,

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group,

phenyl, which radical is optionally substituted

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group,

pyridyl, which radical is optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group,

SO₂-phenyl, said phenyl being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group;

R⁶is H or (C)₁-C₆) An alkyl group; or

R⁵And R⁶And the N atom to which they are attached form a piperidine, morpholine, thiomorpholine or piperazine ring,

said piperazine being optionally substituted on its N atom by (C)₁-C₃) Alkyl substitution;

R⁷is H or methyl;

R⁸is a compound of formula (I) in the formula (H),

or

(C₁-C₆) An alkyl group, a carboxyl group,

And further conditions are:

the compound of formula (I) is not N- (1, 3-dimethylpyrazol-5-yl) anthranilate methyl ester; methyl N- (3-methyl-1-propylpyrazol-5-yl) anthranilate, methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate; 5-chloro-N- (3-ethyl-1-methylpyrazol-5-yl) anthranilic acid methyl ester; 5-fluoro-N- (1, 3-dimethylpyrazol-5-yl) anthranilic acid methyl ester; methyl N- (1, 3-dimethylpyrazol-5-yl) -5-methoxyanthranilate; methyl N- (1, 3-dimethylpyrazol-5-yl) -5- (methylthio) anthranilate; 4-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilic acid methyl ester; or methyl N- (1, 3-dimethylpyrazol-5-yl) -4-methoxyanthranilate.

2. A compound according to claim 1, wherein

R¹Is phenyl, the radical being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group;

and

R、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸x and n are as defined in claim 1.

3. A compound according to claim 1, wherein

R²Is a pyridyl group, optionally selected from (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkylthio, halogen and optionally substituted by one (C)₁-C₄) Alkoxy-substituted (C)₁-C₆) Up to two substituents of the alkyl group,

or

Phenyl, the radical being optionally selected from

(C₁-C₆) An alkoxy group,

a hydroxyl group(s),

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) An alkylthio group is a group of one or more,

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

CO₂R⁸，

(C₁-C₃) A halogenated alkoxy group,

(C₁-C₄) Acyl, and

up to four substituents of benzoyl substituted for the group,

and

R、R¹、R³、R⁴、R⁵、R⁶、R⁷、R⁸x and n are as defined in claim 1.

4. A compound according to claim 1, wherein

X＝CO₂R⁸；

And

R、R¹、R²、R³、R⁴、R⁸and n is as defined in claim 1.

5. A compound according to claim 1, wherein

R¹Is phenyl, the radical being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group;

R²is a compound of formula (I) in the formula (H),

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

(C₃-C₆) Cycloalkyl, the radical being optionally selected from (C)₁-C₃) Alkyl and halogen, or

(C₁-C₃) A halogenated alkyl group,

and

R、R³、R⁴、R⁵、R⁶、R⁷、R⁸x and n are as defined in claim 1.

6. A compound according to claim 1, wherein

R¹Is a compound of formula (I) in the formula (H),

(C₃-C₆) An alkenyl group which is a radical of an alkylene group,

(C₃-C₆) An alkynyl group,

(C₃-C₆) Cycloalkyl, the radical being optionally selected from (C)₁-C₃) Alkyl, CF₃And up to two substituents of halogen, or

(C₁-C₃) A haloalkyl group;

R²is a compound of formula (I) in the formula (H),

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

(C₁-C₃) A halogenated alkyl group,

and

R、R³、R⁴、R⁵、R⁶、R⁷、R⁸x and n are as defined in claim 1.

7. A compound according to claim 1, wherein

R¹Is a compound of formula (I) in the formula (H),

(C₃-C₆) An alkenyl group which is a radical of an alkylene group,

(C₃-C₆) An alkynyl group,

(C₁-C₃) A haloalkyl group;

R²is a pyridyl group, optionally selected from (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkylthio, halogen and optionally substituted by one (C)₁-C₄) Alkoxy-substituted (C)₁-C₆) Up to two substituents of the alkyl radical, or

Phenyl, the radical being optionally selected from

(C₁-C₆) An alkoxy group,

a hydroxyl group(s),

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) An alkylthio group is a group of one or more,

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

CO₂R⁸，

(C₁-C₃) A halogenated alkoxy group,

(C₁-C₄) Acyl, and

up to four substituents of benzoyl substituted for the group,

and

R、R³、R⁴、R⁵、R⁶、R⁷、R⁸x and n are as defined in claim 1.

8. A compound according to claim 1, wherein

R¹Is phenyl, the radical being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group;

R²is a compound of formula (I) in the formula (H),

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

(C₁-C₃) A haloalkyl group;

x is CO₂R⁸；

And

R、R³、R⁴、R⁸and n is as defined in claim 1.

9. A compound according to claim 1, wherein

R¹Is a compound of formula (I) in the formula (H),

(C₃-C₆) An alkenyl group which is a radical of an alkylene group,

(C₃-C₆) An alkynyl group,

(C₁-C₃) A haloalkyl group;

R²is a compound of formula (I) in the formula (H),

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

(C₁-C₃) A haloalkyl group;

x is CO₂R⁸；

And

R、R³、R⁴、R⁸and n is as defined in claim 1.

10. A compound according to claim 1, wherein

R¹Is a compound of formula (I) in the formula (H),

(C₃-C₆) An alkenyl group which is a radical of an alkylene group,

(C₃-C₆) An alkynyl group,

(C₁-C₃) A haloalkyl group;

R²is a pyridyl group, optionally selected from (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkylthio, halogen and optionally substituted by one (C)₁-C₄) Alkoxy-substituted(C₁-C₆) Up to two substituents of the alkyl radical, or

Phenyl, the radical being optionally selected from

(C₁-C₆) An alkoxy group,

a hydroxyl group(s),

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) An alkylthio group is a group of one or more,

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

CO₂R⁸，

(C₁-C₃) A halogenated alkoxy group,

(C₁-C₄) Acyl, and

up to four substituents of benzoyl substituted for the group;

x is CO₂R⁸；

And

R、R³、R⁴、R⁸and n is as defined in claim 1.

11. A compound according to claim 1, wherein

R is H;

R¹is a compound of formula (I) in the formula (H),

(C₁-C₆) Alkyl, the radical being optionally selected from (C)₁-C₄) Alkoxy, phenyl optionally substituted by halogen and [ tri (C)₁-C₄) Alkyl radical]One substituent of silyl group, (C)₃-C₆) Cycloalkyl, the radical being optionally selected from (C)₁-C₃) Alkyl, CF₃And up to two substituents of halogen,

(C₁-C₃) Haloalkyl, or

Phenyl, the radical being optionally selected from

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

(C₁-C₆) Alkyl radical, the radical beingChoose one of the places (C)₁-C₄) The substitution of alkoxy groups is carried out,

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group;

R²is a compound of formula (I) in the formula (H),

pyridyl optionally selected from (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkylthio, halogen and optionally substituted by one (C)₁-C₄) Alkoxy-substituted (C)₁-C₆) Up to two substituents of the alkyl radical, or

Phenyl, the radical being optionally selected from

(C₁-C₆) An alkoxy group,

a hydroxyl group(s),

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) An alkylthio group is a group of one or more,

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

CO₂R⁸，

(C₁-C₃) A halogenated alkoxy group,

(C₁-C₄) Acyl, and

up to four substituents of benzoyl substituted for the group,

R³is (C)₁-C₆) An alkyl group, a carboxyl group,

(C₃-C₆) Cycloalkyl radicals, or

Phenyl, the radical being optionally selected from

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

(C₁-C₃) A halogenated alkyl group,

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) Alkylthio radicals, and

SO₂(C₁-C₃) Up to four substituents of alkyl;

(C₁-C₆) An alkoxy group,

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

phenyl, the radical being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radical

(C₁-C₆) Up to four substituents of an alkylthio group;

n is 0, 1, 2 or 3;

x is CO₂R⁸；

And

R⁸is a compound of formula (I) in the formula (H),

(C₁-C₆) An alkyl group, a carboxyl group,

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

(C₁-C₃) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

cyano radicals, and

(C₁-C₆) Up to four substituents of alkylthio, or

Phenyl, the radical being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

cyano radicals, and

(C₁-C₆) Alkylthio groups are substituted with up to four substituents.

12. A compound according to claim 1, wherein

R is H;

R¹is a compound of formula (I) in the formula (H),

(C₁-C₆) Alkyl, the radical being optionally selected from (C)₁-C₄) Alkoxy, optionally substituted by halogen

Phenyl and [ tri (C)₁-C₄) Alkyl radical]A substituent of the silyl group, or phenyl, which group is optionally substituted by a substituent selected from the group consisting of

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group;

R²is a compound of formula (I) in the formula (H),

halogen, or

(C₁-C₆) Alkyl, the radical being optionally substituted by one (C)₁-C₄) Alkoxy substitution; r³Is (C)₁-C₆) Alkyl, or

Phenyl, the radical being optionally selected from

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

(C₁-C₃) A halogenated alkyl group,

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

the cyano group(s),

(C₁-C₆) Alkylthio radicals, and

SO₂(C₁-C₃) Up to four substituents of alkyl;

(C₁-C₆) An alkoxy group,

(C₁-C₆) An alkylthio group is a group of one or more,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

halogen;

n is 0, 1, 2 or 3;

x is CONR⁵R⁶；

R⁵Is a compound of formula (I) in the formula (H),

(C₁-C₆) An alkyl group, a carboxyl group,

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group,

phenyl, which radical is optionally substituted

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group,

pyridyl, which radical is optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group,

or

SO₂-phenyl, said phenyl being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

NR⁸R⁸，

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group;

R⁶is H or (C)₁-C₆) An alkyl group; or

R⁸is a compound of formula (I) in the formula (H),

(C₁-C₆) An alkyl group, a carboxyl group,

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

(C₁-C₃) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

cyano radicals, and

(C₁-C₆) Up to four substituents of an alkylthio group,

or

Phenyl, the radical being optionally selected from

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

(C₁-C₆) An alkoxy group,

(C₁-C₃) A halogenated alkyl group,

(C₁-C₃) A halogenated alkoxy group,

cyano radicals, and

(C₁-C₆) Alkylthio groups are substituted with up to four substituents.

13. A compound according to claim 1, selected from:

2- [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino ] -5-methoxybenzoic acid;

2- { [ 3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzamide;

2- { [3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

2- { [ 3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid;

2- { [ 3-tert-butyl-1- (2-methoxyphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid;

2- [ (1, 3-diphenyl-1H-pyrazol-5-yl) amino ] -5-methoxybenzoic acid;

2-fluoro-6- { [3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

2-fluoro-6- { [1- (2-methylphenyl) -3- (4-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

2- { [ 3-tert-butyl-1- (5-fluoro-2-methylphenyl) -1H-pyrazol-5-yl ] amino } -6-fluorobenzoic acid;

2- ({ 3-tert-butyl-1- [2- (methylthio) phenyl ] -1H-pyrazol-5-yl } amino) -5-methoxybenzoic acid;

2- { [ 3-tert-butyl-1- (2-ethoxyphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

2- { [ 3-tert-butyl-1- (2-ethoxyphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid;

2- { [3- (3-methoxyphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

5-methoxy-2- { [3- (3-methoxyphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

2- { [3- (3-methoxyphenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-methylbenzoic acid;

2- { [ 3-tert-butyl-1- (2-methoxyphenyl) -4-methyl-1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid;

2- [ (3-tert-butyl-1-phenyl-1H-pyrazol-5-yl) amino ] -5-methoxybenzoic acid;

2- { [ 3-tert-butyl-1- (5-fluoro-2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

2- { [ 3-tert-butyl-1- (2, 6-dimethylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

2- { [ 3-tert-butyl-1- (2-methoxy-5-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

2- { [ 3-tert-butyl-1- (2, 3-dimethylphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid;

2- { [ 3-tert-butyl-1- (2-methoxy-6-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid;

2- { [ 3-tert-butyl-1- (2, 6-dimethylphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid;

2- { [1- (2, 6-dimethylphenyl) -3- (1-methylcyclopropyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

2- { [1- (2, 6-dimethylphenyl) -3- (3, 3, 3-trifluoropropyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid;

5-methoxy-2- { [ 3-methyl-1- (2-methylphenyl) -4-phenyl-1H-pyrazol-5-yl ] amino } benzoic acid;

5-methoxy-2- { [4- (6-methoxypyridin-3-yl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

5-methoxy-2- { [1- (2-methylphenyl) -4-pyridin-4-yl-3- (trifluoromethyl) -1H-pyrazol-5-yl ] amino } benzoic acid;

5-methoxy-2- { [4- (4-methoxyphenyl) -1- (2-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] amino) benzoic acid;

2- { [ 3-ethyl-4- (6-methoxypyridin-3-yl) -1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid;

2- { [4- (2-fluorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid;

5-methoxy-2- { [1- (2-methoxyphenyl) -3-methyl-4-phenyl-1H-pyrazol-5-yl ] amino } benzoic acid; and

2- { [4- (2, 4-dimethoxyphenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl ] amino } -5-methoxybenzoic acid.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt of claim 1 in combination with a pharmaceutically acceptable carrier.

15. The use of a compound according to claim 1 and the following compounds for the preparation of a medicament for the treatment and/or prophylaxis of diabetes and diabetes-related diseases: methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (3-methyl-1-propylpyrazol-5-yl) anthranilate, methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (3-ethyl-1-methylpyrazol-5-yl) anthranilate monohydrochloride; methyl 5-fluoro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (1, 3-dimethylpyrazol-5-yl) -5-methoxyanthranilate; methyl N- (1, 3-dimethylpyrazol-5-yl) -5- (methylthio) anthranilate monohydrochloride; 4-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilic acid methyl ester; or methyl N- (1, 3-dimethylpyrazol-5-yl) -4-methoxyanthranilate.

16. The use according to claim 15, wherein the diabetes is selected from the group consisting of type I diabetes, type II diabetes, maturity onset diabetes in young adults, latent autoimmune diabetes in adults and gestational diabetes.

17. The use of a compound of claim 1, and the following compounds, for the preparation of a medicament for the treatment of syndrome X: methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (3-methyl-1-propylpyrazol-5-yl) anthranilate, methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (3-ethyl-1-methylpyrazol-5-yl) anthranilate monohydrochloride; methyl 5-fluoro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (1, 3-dimethylpyrazol-5-yl) -5-methoxyanthranilate; methyl N- (1, 3-dimethylpyrazol-5-yl) -5- (methylthio) anthranilate monohydrochloride; 4-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilic acid methyl ester; or methyl N- (1, 3-dimethylpyrazol-5-yl) -4-methoxyanthranilate.

18. The use according to claim 15, wherein the diabetes-related disease is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose resistance, impaired fasting glucose, disorders of lipid metabolism, hypertriglyceridemia and insulin resistance.

19. The use of a compound of claim 1, and the following compounds for the preparation of a medicament for the treatment of obesity: methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (3-methyl-1-propylpyrazol-5-yl) anthranilate, methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (3-ethyl-1-methylpyrazol-5-yl) anthranilate monohydrochloride; methyl 5-fluoro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (1, 3-dimethylpyrazol-5-yl) -5-methoxyanthranilate; methyl N- (1, 3-dimethylpyrazol-5-yl) -5- (methylthio) anthranilate monohydrochloride; 4-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilic acid methyl ester; or methyl N- (1, 3-dimethylpyrazol-5-yl) -4-methoxyanthranilate.

20. The use of a compound of claim 1 and the following compounds for the preparation of a medicament for the treatment of cardiovascular diseases: methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (3-methyl-1-propylpyrazol-5-yl) anthranilate, methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (3-ethyl-1-methylpyrazol-5-yl) anthranilate monohydrochloride; methyl 5-fluoro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (1, 3-dimethylpyrazol-5-yl) -5-methoxyanthranilate; methyl N- (1, 3-dimethylpyrazol-5-yl) -5- (methylthio) anthranilate monohydrochloride; 4-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilic acid methyl ester; or methyl N- (1, 3-dimethylpyrazol-5-yl) -4-methoxyanthranilate.

21. The use of a compound according to claim 1 and of the following compounds for the preparation of a medicament for the treatment and/or prophylaxis of diabetes of a second cause: methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (3-methyl-1-propylpyrazol-5-yl) anthranilate, methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (3-ethyl-1-methylpyrazol-5-yl) anthranilate monohydrochloride; methyl 5-fluoro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (1, 3-dimethylpyrazol-5-yl) -5-methoxyanthranilate; methyl N- (1, 3-dimethylpyrazol-5-yl) -5- (methylthio) anthranilate monohydrochloride; 4-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilic acid methyl ester; or methyl N- (1, 3-dimethylpyrazol-5-yl) -4-methoxyanthranilate.

22. The use according to claim 21, wherein said second cause is selected from the group consisting of glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug induced diabetes.

23. The use of a compound of claim 1 and the following compounds for the preparation of a medicament: methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (3-methyl-1-propylpyrazol-5-yl) anthranilate, methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (3-ethyl-1-methylpyrazol-5-yl) anthranilate monohydrochloride; methyl 5-fluoro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (1, 3-dimethylpyrazol-5-yl) -5-methoxyanthranilate; methyl N- (1, 3-dimethylpyrazol-5-yl) -5- (methylthio) anthranilate monohydrochloride; 4-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilic acid methyl ester; or methyl N- (1, 3-dimethylpyrazol-5-yl) -4-methoxyanthranilate, which stimulates insulin secretion in a subject in need thereof by administering to said subject a compound according to claim 1 in combination with the following compounds.

24. A medicament comprising at least one compound of claim 1 in association with at least one pharmaceutically acceptable, pharmaceutically safe carrier or excipient.

25. The medicament according to claim 24 for the treatment and/or prophylaxis of diabetes, wherein the compound is present in an effective amount.

26. A method of identifying a biological target, the method comprising the steps of:

contacting a biological sample with a compound of claim 1 and: methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (3-methyl-1-propylpyrazol-5-yl) anthranilate, methyl N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate; methyl 5-chloro-N- (3-ethyl-1-methylpyrazol-5-yl) anthranilate monohydrochloride; methyl 5-fluoro-N- (1, 3-dimethylpyrazol-5-yl) anthranilate monohydrochloride; methyl N- (1, 3-dimethylpyrazol-5-yl) -5-methoxyanthranilate; methyl N- (1, 3-dimethylpyrazol-5-yl) -5- (methylthio) anthranilate monohydrochloride; 4-chloro-N- (1, 3-dimethylpyrazol-5-yl) anthranilic acid methyl ester; or methyl N- (1, 3-dimethylpyrazol-5-yl) -4-methoxyanthranilate;

forming a complex with the compound and the biological target;

isolating the compound-target complex; and

identifying the target.

27. The method of claim 26, wherein the biological specimen is pancreatic β -cells.

28. The method according to claim 26, wherein said compound is labeled with a photosensitive group and/or a radioisotope.

29. The method of claim 26, wherein the compound is coupled to a polymer.