TW201819361A - Novel indazole compounds - Google Patents

Abstract

The present invention relates to substituted indazole compounds, their pharmaceutically acceptable salts, and their isomers, steroisomers, atropisomers, conformers, tautomers, polymorphs, hydrates or solvates. The present invention also encompasses pharmaceutically acceptable compositions of said compounds and process for preparing novel compounds. The invention further relates to the use of the above mentioned compounds for the preparation of medicament for use as pharmaceuticals.

Description

Novel indazole compounds

The present invention relates to substituted indazole compounds, pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers, conformers, and tautomers , Polytypes, hydrates and solvates. The invention also includes a pharmaceutically acceptable composition of the compound and a method for preparing the novel compound. The invention further relates to the use of the above compounds in the preparation of pharmaceuticals for use as pharmaceuticals.

Prostaglandin D2 (PGD2) is an acid lipid medium derived from arachidic acid under the continuous action of cyclooxygenase (COX) and PGD2 synthase. In addition to some other white blood cells (such as dendritic cells and helper T cells 2 (Th2) cells), PGD2 is released in large amounts by activated giant cells and plays a key role in the inflammatory response to allergic symptoms. PGD2 exerts its effects by interacting with G protein-coupled receptors, which include the prostaglandin receptor DP1 and PD2 or CRTH2 (chemically attractive receptor homologous molecules expressed on Th2 cells) receptors. The DP1 receptor greatly mediates the vascular effects of PGD2, such as the stimulation of vasodilation and the inhibition of platelet aggregation, while the CRTH2 receptor mainly regulates the inflammatory effects of PGD2. CRTH2 receptors are typically expressed in a large number of eosinophils, basophils and Th2 helper cells. It is known that they are involved in the tendency and activation of these cells to form a key event that triggers an inflammatory response in allergic diseases ( Clin Pharmacol Drug Dev . 2016 Jul ; 5 (4): 306-13 ).

In vivo, injecting PGD2 can cause allergic reactions in the lungs and skin of mice. The use of DK-PGD2, a naturally selected CRTH2 agonist also has this effect, showing that CRTH2 gathers Th2 lymphocytes and other white blood cells to allergic inflammation Important role ( Nat Rev Drug Discov. 2007 Apr ; 6 (4): 313-25 ). CRTH2-deficient mice further confirmed the importance of the PGD2-CRTH2 system for allergic skin symptoms, where these mice exhibited less skin reactions when exposed to allergens. ( J Immunol. 2006 Aug 15 ; 177 (4): 2621-9 ). Similarly, the correlation between the amount of CRTH2 in circulating T cells and the severity of atopic dermatitis has also been confirmed ( Int Immunol. 2004 Jul ; 16 (7): 947-59 ).

It is known that the presence of allergens triggers the production of PGD2 in sensitized individuals. In asthma patients, the test of bronchial allergens leads to the rapid generation of PGD2. The local antigen test also stimulates PGD2 production in the nasal mucosa of patients with allergic rhinitis and the skin of patients with atopic dermatitis ( Nat Rev Drug Discov. 2007 Apr ; 6 (4): 313-25 ).

CRTH2 activation seems to play a key role in mediating allergic reactions, so the use of CRTH2 receptor antagonists is an attractive method to treat the inflammatory components of allergic diseases such as asthma, rhinitis, and dermatitis.

Since 2006, several powerful and selective CRTH2 antagonists have been investigated as new compounds for clinical use in the treatment of allergy and asthma-related diseases ( Expert Opin Ther Pat. 2010 Nov ; 20 (11): 1505-30 ).

Despite the development of many CRTH2 antagonist compounds, there is still an unmet need to identify and develop novel compounds that exhibit desired efficacy and safety of CRTH2 antagonists.

WO2010083725 discloses a cephalosporin derivative containing a substituted nitrogen-containing fused heterocyclic ring, which has good antimicrobial activity and can be an active ingredient of an agent for treating infections.

WO2009108551 and WO2009023623 disclose that heteroarylamide analogs act as dopamine agonists and P2X7 receptor modulators.

WO2004022551 discloses furan and thiophene derivatives that act as PPAR regulators and GPR40 agonists. Similarly, WO2006060535 discloses compounds that are active against PPAR and can be used to treat PPAR-mediated diseases or symptoms, or the preparation of a medicament in which PPAR modulates a disease or symptom that can provide therapeutic benefits.

WO2003035005 discloses that the heteroindane analogue has affinity for cannabinoid receptors.

WO2014187928 discloses novel heterocyclic compounds as insect repellents.

The present invention provides novel substituted indazole compounds as CRTH2 antagonists that have been demonstrated to have desired effects and safety properties.

In a specific embodiment, the present invention provides novel compounds of formula (I), Structural formula -1, wherein n is independently selected from 1, 2 and 3; m is selected from 0-2; Y is -OZ; Z is selected from H and a cation; R and R 'are independently selected from hydrogen And (C ₁ -C ₃ ) alkyl; R ₁ is selected from (C ₁ -C ₆ ) alkyl and (C ₃ -C ₈ ) cycloalkyl; R ₂ is independently selected from hydrogen, (C _1- C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, aryl, heteroaryl, heterocycloalkyl, halogen, -NO ₂ , hydroxyl, CF ₃ , ( C ₁ -C ₆ ) alkoxy, -S- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₃ -C ₈ ) cycloalkane Group, -SO ₂ NR ₆ R ₇ , -NH ₂ , -NH-CO- (C ₁ -C ₆ ) alkyl group, -NH-CO- (C ₃ -C ₈ ) cycloalkyl group, -NH-CO- (C ₁ -C ₃ ) alkylaryl, -NH-CO- (C ₁ -C ₃ ) alkylheteroaryl, -NH-CO-aryl, -NH-CO-heteroaryl, -NHCO- Heterocycloalkyl, -NH-CO- (C ₁ -C ₆ ) alkoxy, -NH-COO- (C ₃ -C ₈ ) cycloalkyl, -NH-COO-aryl, -NH-COO- Heteroaryl, -NH-COO-heterocycloalkyl, -NH-COO- (C ₁ -C ₃ ) alkyl aryl, -NHCONHR ₇ , -NHCONR ₆ R ₇ , -NH-SO _2- (C ₁ -C ₈₎ alkyl, -NH-SO ₂ - aryl, -NH-SO ₂ - and _{heteroaryl-NH-SO 2 - (C 3} -C 8) cycloalkyl group; R ₃ is selected from hydrogen (C ₁ -C ₃₎ alkyl, halo, CF ₃ and (C ₁ -C ₃₎ alkoxy; -L-is selected from -SO ₂ - and -SO ₂ N (R ₅₎ - linker; Ring A is selected from (C ₃ -C ₈ ) cycloalkyl, aryl, heteroaryl and heterocycloalkyl; R ₄ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl,-(C ₁ -C ₆ ) alkylaryl,-(C ₁ -C ₆ ) alkylheteroaryl, aryl, heteroaryl, heterocycloalkyl, halogen, side Oxygen, CN, CF ₃ , hydroxyl, -NO ₂ , -NH ₂ , (C ₁ -C ₆ ) alkoxy, hydroxy- (C ₁ -C ₆ ) alkyl, -S- (C ₁ -C ₆ ) Alkyl, -SO _2- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₃ -C ₈ ) cycloalkyl, -SO ₂ (C ₁ -C ₆ ) alkylaryl, -SO ₂ -Aryl, -SO ₂ -heteroaryl, -CO- (C ₁ -C ₆ ) alkyl, -CO- (C ₁ -C ₆ ) alkylaryl, -CO- (C ₃ -C ₈ ) Cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, (C ₁ -C ₆ ) alkoxycarbonyl, -NR ₆ R ₇ , -NH-CO- ( C ₁ -C ₆ ) alkyl, -NH-CO- (C ₃ -C ₈ ) cycloalkyl, -NH-CO- (C ₁ -C ₃ ) alkylaryl, -NH-CO- (C ₁ -C ₃ ) alkylheteroaryl, -NH-CO-aryl, -NH-CO-heteroaryl, -NHCO-heterocycloalkyl, -NH-COO- (C ₁ -C ₆ ) alkyl, -NH-COO- (C ₃ -C ₈ ) cycloalkyl, -NH-COO-aryl, -NH-COO-heteroaryl, NH-COO-heterocycloalkyl, -NH-COO- (C ₁ -C ₃ ) alkylaryl , -NHCONR ₆ R ₇ , -NH-SO _2- (C ₁ -C ₆ ) alkyl, -NH-SO _2- (C ₃ -C ₈ ) cycloalkyl, -NH-SO ₂ -aryl,- NH-SO ₂ -heteroaryl, -C (O) OH, -C (O) OR ₆ , -CONH ₂ , -CONH-aryl, -CONH-heteroaryl, -SO ₂ NH- (C _1- C ₈ ) alkyl, -SO ₂ NH- (C ₃ -C ₈ ) cycloalkyl and -SO ₂ NH-aryl, wherein aryl, heteroaryl and heterocycloalkyl residues are optionally Up to 5 selected from-(C ₁ -C ₈ ) alkyl,-(C ₃ -C ₇ ) cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C ₁ -C ₆ ) alkoxy , -O-aryl, halogen, pendant oxygen, CN, -CF ₃ , -SO _2- (C ₁ -C ₈ ) -alkyl, -SO ₂ -aryl, -SO ₂ -heterocycloalkyl, -NH ₂ , -NR ₆ R ₇ , -NH-CO- (C ₁ -C ₈ ) alkyl, -NH-SO _2- (C ₁ -C ₈ ) alkyl, -NH-SO ₂ -aryl, -COOH, C (O) NH-alkyl, -CONH-aryl, -CONH-heteroaryl, -C (O)-(C ₁ -C ₈ ) alkyl, -C (O) O- (C ₁ -C ₈ ) alkyl, -C (O) O-aryl, -SO ₂ NH- (C ₁ -C ₈ ) alkyl, -SO ₂ NH-aryl, -SO ₂ NR ₆ R ₇ ,- SO ₂ NH-heteroaryl and hydroxyl groups Generation; R ₅ is selected from hydrogen, (C ₁ -C ₆ ) alkyl, aralkyl, (C ₃ -C ₈ ) cycloalkyl and aryl; R ₆ and R ₇ are independently selected from (C ₁ -C ₆ ) alkyl, aralkyl, (C ₃ -C ₈ ) cycloalkyl and aryl; or R ₆ and R ₇ may together form a heterocycloalkyl ring; its pharmaceutically acceptable salts and Its isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates or solvates.

In another specific embodiment, the present invention includes compounds as described above, but only pharmaceutically acceptable salts thereof.

In another specific embodiment, the present invention includes synthetic intermediates useful for preparing compounds of structural formula (1) and methods for preparing such intermediates.

Another specific embodiment of the present invention is a method for preparing a compound of structural formula (1) or an intermediate product as described in Schemes 1 to 5 herein.

Another specific embodiment of the present invention is a pharmaceutical composition containing a compound of formula (1), which is optionally mixed with a pharmaceutically acceptable adjuvant or carrier.

Another specific embodiment of the present invention provides a method for treating allergic or non-allergic inflammatory diseases selected from atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, eosinophilic esophagitis , Eosinophilia syndrome, nasal polyps, and chronic obstructive pulmonary disease. This method involves administering a therapeutically effective amount of a compound of formula (1) to mammals in need thereof, including humans.

Another specific embodiment of the present invention provides the use of a compound of formula (1) for the preparation of a medicament for the treatment of allergic or non-allergic inflammatory diseases selected from atopic dermatitis, asthma, allergic rhinitis , Allergic conjunctivitis, eosinophilic esophagitis, eosinophilia syndrome, nasal polyps, and chronic obstructive pulmonary disease.

In a specific embodiment, the present invention provides a novel compound of formula (1), Structural formula- 1 wherein R, R ', R ₁ , R ₂ , R ₃ , R ₄ , L, Y, A, m and n are as defined above, and their pharmaceutically acceptable salts and their isomers Compounds, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates or solvates.

In a preferred embodiment, the present invention provides a novel compound of formula (1), wherein, n is independently 1 or 2; m is 1; Y is -OZ; Z is selected from H and A cation; R ₁ is (C ₁ -C ₆ ) alkyl; R ₂ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl, halogen and CF ₃ ; R ₃ is selected from hydrogen and (C ₁ -C ₃ ) alkoxy; R ₄ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl,-(C ₁ -C ₆ ) alkylaryl, aryl, heteroaryl, heterocycloalkane Group, halogen, pendant oxygen, CF ₃ , hydroxy, hydroxy- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₁ -C ₆ ) alkyl, -SO ₂ -aryl, -CO- ( C ₁ -C ₆ ) alkyl, -CO-aryl, -CO-heteroaryl, -C (O) OR ₆ and -CONH ₂ ; where aryl, heterocycloalkyl and heteroaryl residues follow Optionally 1 to 5 are selected from-(C ₁ -C ₈ ) alkyl, (C ₁ -C ₆ ) alkoxy, -COOH, -C (O) NH-alkyl, -CF ₃ , -CN , -SO ₂ -heterocycloalkyl, -NHCO- (C ₁ -C ₈ ) alkyl, halogen, hydroxyl and pendant groups; R ₅ is selected from hydrogen and (C ₁ -C ₆ ) alkyl group; R ₆ is (C ₁ -C ₆₎ alkyl; R, R ', L and ring A system as defined above; pharmaceutically acceptable thereof Salts thereof and isomers, stereoisomers, configurational isomers (atropisomers), configurational isomers thereof (conformers), tautomeric, polytype, hydrate or solvate thereof.

A specific family of compounds of particular interest within the scope of the present invention consists of compounds like the following and pharmaceutically acceptable salts: definition:

Unless otherwise restricted in specific examples, the following definitions apply to the terms used throughout the specification:

The term "compound" as used herein means any compound included in the general structural formula disclosed herein. The compounds disclosed herein may contain one or more double bonds, and therefore may exist as isomers, stereoisomers such as geometric isomers, E and Z isomers, and may possess asymmetric carbon atoms (optical center ), And therefore may exist as mirror isomers and non-mirror isomers. Thus, the chemical structure described herein encompasses all possible stereoisomers of the exemplified compounds, including stereomerically pure forms (eg geometrically isomerically pure) and stereoisomeric mixtures (racemates). The compounds described herein may exist in a conformational isomer, such as a chair or boat. The compounds described herein can also exist as atropisomers. Compounds can also exist in several tautomeric forms (including enol, keto, and mixtures thereof). Therefore, the chemical structures described herein encompass all possible tautomeric forms of the exemplified compounds. The described compounds also include isotopically-calibrated compounds in which one or more atoms have an atomic weight different from the atomic weight traditionally found in nature. Examples of isotopes of compounds that can be incorporated into the present invention include, but are not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, and the like. The compounds can exist in unsolvated as well as solvated forms, including hydrated forms. In general, compounds can be hydrated or solvated. Certain compounds can exist in multiple crystalline or amorphous forms. In general, all physical forms are the same for the uses considered herein and are intended to be included within the scope of the present invention.

Unless otherwise indicated in this article or clearly contradicted by context, the terms "a" and "an" and "the" and similar terms are used in the context of describing the invention (especially in the following applications In the context of patent scope) are used to be interpreted to cover both singular and majority.

As indicated herein, the nomenclature of the compounds of the present invention is based on ACD Lab's / IUPAC nomenclature rules (version 12.0).

"Pharmaceutically acceptable salts" means salts of compounds having the pharmacological activity required by the parent compound. Such salts include: (1) Acid addition salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc .; or accompanied by organic acids such as acetic acid, propionic acid, isopropyl Butyric acid, caproic acid, cyclopentanepropionic acid, oxalic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, suberic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzene Formic acid, 3- (4-hydroxybenzoyl) benzoic acid, phthalic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid , Benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid , Glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glucuronic acid, galacturonic acid, glutamic acid, hydroxynaphthoic acid, water Formed by salicylic acid, stearic acid, adipic acid, etc .; or (2) formed when the acidic protons present in the parent compound are replaced by metal ions (eg, alkali metal ions, alkaline earth ions, or aluminum ions) Salt; or when Salts formed when the acidic protons of the parent compound are coordinated to, for example, the following organic bases: ethanolamine, diethanolamine, triethanolamine, tromethamine (1,3-dihydroxy-2- (hydroxymethyl) propane -2-amine), choline (2-hydroxy-N, N, N-trimethylethylamine), N-methyl reduced glucosamine, diethylamine (N-ethylethylamine), etc. Also included are amino acids, such as arginate (arginate) and other salts (see, for example, Berge, S.M., et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).

As used herein, the term "polymorph" refers to compounds that have the same chemical formula, the same salt type, and the same form of hydrate / solvate, but have different crystal properties.

As used herein, the term "hydrate" refers to a compound that has some water molecules bonded to the compound.

As used herein, the term "solvate" refers to a compound that has some solvent molecules bonded to the compound.

The invention also includes compounds in the form of prodrugs. The prodrugs of the compounds described in the present invention are those compounds that easily undergo chemical changes under physiological conditions (in vivo) to provide the compounds of the present invention. In addition, prodrugs can be converted into the compounds of the present invention by chemical or biochemical methods in an ex vivo environment (such as a transdermal patch reservoir accompanied by suitable enzymes or chemicals). In some cases, the prodrug is easier to administer than the original drug. For example, they can be bioavailable via oral administration, while the original drug is not. The prodrug may also have better solubility in the pharmacological components than the original drug. Compound esters and peptide derivatives are examples of prodrugs of the present invention. For example, the hydrolyzable (or cleavable) esters of the compounds of the present invention containing carboxyl groups are pharmaceutically acceptable esters, which are hydrolyzed in humans or animals to produce parent acids .

As used herein, the term "substituted" includes single or multiple substitutions of named substituents to the extent that such single and multiple substitutions (including multiple substitutions at the same position) are chemically allowed, and which It means that any one or more hydrogens on the specified atom are replaced by a choice of the specified group, which stipulates that the normal valence of the specified atom is not exceeded, and this substitution produces a stable compound. For example, when substituted When the group is a keto group, then two hydrogens on the atom are substituted. All substituents described herein (R ₁ , R ₂ ...) And their further substituents can be attached to any heteroatom or carbon atom on the main structure, which results in the formation of stable compounds.

As used herein, a "halogen" substituent is a monovalent halogen residue selected from chlorine, bromine, iodine, and fluorine.

The term "cation" means a positively charged ion, such as Na ⁺ , K ⁺ , Mg ²⁺ , Ca ²⁺ , 1,3-dihydroxy-2- (hydroxymethyl) propan-2-amine, 2-hydroxyl -N, N, N-trimethylethylamine, N-methyl reduced glucosamine, N-ethylethylamine, etc.

The term "alkyl", whether used alone or in conjunction with another group, means an aliphatic hydrocarbon group with the carbon atom of interest, which is unsubstituted or is attached to any available atom or Substituents are substituted to form a stable compound. When a subscript is used on an alkyl group, the subscript indicates the number of carbon atoms that the group can contain. For example, "(C ₁ -C ₆ ) alkyl" means any alkyl group having a structure of 1 to 6 carbon atoms. The alkyl group may be linear (for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl) or branched (for example, isopropyl, isobutyl, sec-butyl) Base, tert-butyl). The (C ₁ -C ₆ ) alkyl group may also contain a (C ₃ -C ₆ ) cycloalkyl ring in a spiro mode.

The term "cycloalkyl", whether used alone or in connection with another group, means a cyclic ring system having the indicated number of carbon atoms, and the cyclic ring system is not substituted or is on any available atom The attached groups or substituents are substituted to form a stable compound. When a subscript is used for cycloalkyl, the subscript indicates the number of carbon atoms that the group can contain. For example, the term "(C ₃ -C ₈ ) cycloalkyl" may mean a cyclic ring system having 3 to 8 unsubstituted or substituted carbon atoms. The "(C ₃ -C ₈ ) cycloalkyl" means a cyclic ring system containing only carbon atoms in the skeleton of the ring system, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may include a bicyclic ring structure. The cycloalkyl group can have any degree of saturation, specifying that at least one ring in the ring system is non-aromatic.

The term "alkenyl" whether used alone or in connection with another group means an aliphatic hydrocarbon group having at least one carbon-carbon double bond and having the indicated number of carbon atoms, and the aliphatic hydrocarbon group is unsubstituted or substituted Substitute any available groups or substituents on atoms to form a stable compound. When a subscript is used for alkenyl, the subscript indicates the number of carbon atoms that the group can contain. For example, the term "(C ₂ -C ₆ ) alkenyl" whether used alone or in conjunction with another group may mean an aliphatic having 2 to 6 unsubstituted or substituted carbon atoms It is a hydrocarbon group and has at least one carbon-carbon double bond. The alkenyl group can be linear or branched. Examples of alkenyl groups include vinyl, propenyl, isopropenyl, butenyl and the like.

The term "alkynyl", whether used alone or in connection with another group, means an aliphatic hydrocarbon group having at least one carbon-carbon triple bond and having the indicated number of carbon atoms, and the aliphatic hydrocarbon group is unsubstituted or substituted Substitute any available groups or substituents on atoms to form a stable compound. When a subscript is used for an alkynyl group, the subscript indicates the number of carbon atoms that the group can contain. For example, the term "(C ₂ -C ₆ ) alkynyl" whether used alone or in conjunction with another group may mean an aliphatic having 2 to 6 unsubstituted or substituted carbon atoms It is a hydrocarbon group and has at least one carbon-carbon triple bond. The alkynyl group may be linear or branched. Examples of alkynyl groups include ethynyl, propynyl, butynyl and the like.

The term "aryl" used regardless of whether it is alone or connected to another group means an aromatic group, for example, it is a 6 to 14-membered monocyclic, bicyclic, or tricyclic carbon-containing ring system. Aryl groups include but are not limited to phenyl, naphthyl, biphenyl, tetrahydronaphthyl and indane. The aryl group may be optionally substituted with a group or substituent attached to any available atom to form a stable compound.

The term "heteroaryl" whether used alone or in connection with another group means an aromatic group, for example, it is a 5- to 14-membered, monocyclic, bicyclic or tricyclic aromatic system having at least one heteroatom Group. As used herein, the term "heteroatom" includes O, N, and S. In a ring system that fused rings, the rings can be fused via bridged heteroatoms. Heteroaryl groups include but are not limited to pyrrolyl, furanyl (furyl), thiophenyl (thienyl), pyrazolyl, imidazolyl, oxazolyl ( oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (pyridyl)), pyridazinyl, pyrimdinyl, pyrazinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophene Benzothienyl, indazolyl, benzimidazol, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl (Quinolinyl), isoquinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, acridine ( acridine, phenothiazine, dibenzo [b, d] thiophene, dibenzo [b, d] thiophene, furopyridinyl, thienopyridinyl, pyrazolopyridinyl ) Or naphthyridinyl. The heteroaryl group can be optionally substituted by any group or substituent attached to any available atom to form a stable compound.

The term "heterocycloalkyl" whether used alone or in connection with another group means a fully or partially saturated cyclic group, for example it is a 3 to 14 membered, has at least one heteroatom and at least one ring is not an aromatic ring Single ring, double ring or triple ring system. As used herein, the term "heteroatom" includes O, N, and S. Heterocycloalkyl groups include but are not limited to ethylene oxide (oxiranyl), aziridinyl (aziridinyl), propylene oxide (oxetanyl), azetidinyl (azetidinyl), pyrrolidinyl (pyrrolidinyl), Dihydropyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrazolidinyl, imidazolidinyl ( imidazolidinyl), oxazolidinyl, isoxazoiidinyl, thiazoiidinyl, triazolidinyl, oxadiazolidinyl, piperidinyl , Tetrahydropyridinyl (tetrahydropyridinyl), dihydropyridinyl (dihydropyridinyl), piperazinyl (piperazinyl), tetrahydropyranyl (tetrahydropyranyl), dioxycyclohexyl (dioxanyl), morpholinyl (morpholinyl), triazine Alkyl (triazinanyl), azepanyl (azepanyl), diazepanyl (diazepanyl), di Diazepinyl, oxepanyl, dioxepanyl, oxazepanyl, oxazepinyl, dihydro Indolinyl, benzomorpholinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroisoquinolyl, dihydroisoquinolyl, dihydrothienopyridine Dihydrothienopyridinyl, tetrahydrothienopyridine, 2-azaadamantane, tryptoline, tetrahydrocarbazole, thiomorpholinedioxide or thioxo Morpholine (thiomorpholinyl). The heterocycloalkyl group can be optionally substituted with a group or substituent attached to any available atom to form a stable compound. The terms "heterocycloalkyl" and "heterocycle" are used interchangeably.

The term "hydroxyl" means the -OH group.

The term "pendant" means an oxygen atom connected to a carbon or sulfur atom by a double bond.

The term "aralkyl" means an alkyl group substituted with one or more aryl groups on any available atom to form a stable compound. The terms "alkyl" and "aryl" are as defined above.

The term "alkoxy", whether used alone or in connection with another group, means any alkyl group having the indexed carbon atom and connected to the parent molecular motif via an oxygen bridge. When a subscript is used on an alkoxy group, the subscript indicates the number of carbon atoms that the group can contain. For example, "(C ₁ -C ₆ ) alkoxy" means any alkoxy group having a structure of 1 to 6 carbon atoms. The (C ₁ -C ₆ ) alkoxy group may also contain a (C ₃ -C ₆ ) cycloalkyl ring in a spiro mode. The alkyl group in the alkoxy group may be linear, which may contain 1 or 2 double or triple bonds. The alkyl group may be further substituted with one or more substituents (eg halogen, aryl, heteroaryl, cycloalkyl or heterocycloalkyl). Examples of substituted alkoxy groups include, but are not limited to -OCHF ₂ , -OCF ₃ , -O-CH ₂ -heteroaryl or -O-CH ₂ -aryl.

As used herein, "room temperature" means a temperature between 20 ^o C and 30 ^o C.

As used herein, the term "mammal" means humans or animals, such as monkeys, primates, dogs, cats, horses, cattle, and so on.

As used herein, the term "treating" or "treatment" for any disease or disorder means completely or partially preventing or delaying the onset of the disease or disorder or its signs or symptoms; and / or part Or completely cure or ameliorate the disease or disorder and / or may be attributable to the adverse effects of the disorder.

The expression "therapeutically effective amount" means the amount of compound sufficient to achieve the treatment of a disease when administered to a patient who is treating the disease. The "therapeutically effective amount" will vary depending on the compound, the mode of administration, the disease and its severity, and the age and weight of the patient to be treated.

Throughout this specification and the scope of the attached patent applications, it is important to understand that unless the context stipulates otherwise, the terms "comprise" and "include" and the variations are "comprises" and "comprising" ) "," Includes "and" including "are all inclusively explained. In other words, the use of these terms may imply the inclusion of a single element or elements that are not specifically described.

In another specific embodiment, the present invention provides a method for preparing a compound of formula (1).

The following reaction scheme is provided to disclose the synthesis of compounds according to the present invention.

Therefore, the compound of the structural formula (1) of the present invention can be prepared by the following scheme.

Illustrative specific examples of the compound of structural formula (1) include structural formula 1a, structural formula 1b, structural formula 1c, structural formula 1d, structural formula 1e, structural formula 1f, structural formula 1g, structural formula 1h, structural formula 1i, The compounds of Structural Formula 1j, Structural Formula 1k, Structural Formula 11, Structural Formula 1m, Structural Formulas 1n and 1o, wherein the substituents are as defined in relation to the general structural formula (1) and Schemes 1-5. Solution – 1

The preparation method of the compounds of formula 1a and 1b is shown in Scheme 1, where Y is OZ and Z is H, and R ₂ may be (C ₁ -C ₆ ) alkyl, halogen, -NO ₂ , heterocycloalkyl , CF ₃ , (C ₁ -C ₆ ) alkoxy, -S- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₁ -C ₆ ) alkyl, -SO ₂ NR ₆ R ₇ and R, R ', R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , L, ring A, m and n are as defined in structural formula (1). Solution – 1 a) Triethylamine, methylene chloride, 1-6 hours; b) Lawesson's reagent, toluene, heated for 1-4 hours; c) Hydrazine hydrate, dimethylacetamide or dimethylsulfoxide, heated 6-80 Hours; d) Br (CRR ') nCOOEt, cesium carbonate, dimethylformamide THF, 2-4 hours; e) chlorosulfonic acid, chlorosulfinyl chloride, methylene chloride, 0 ˚С-room temperature, 2 -4 hours; f) suitable class, triethylamine, solvent (such as dichloromethane or THF), 0˚С-room temperature, 2-6 hours; g) sodium hydroxide or lithium hydroxide solution, solvent (such as MeOH, THF or DMF), 0˚С-room temperature, 0.5-2 hours.

Compounds of formula 1a (where ring A is a heterocycloalkyl group connected to —SO ₂ (L) via a heteroatom N atom) can be compound IXa in a suitable base (such as a base hydroxide, such as sodium hydroxide Lithium hydroxide) and suitable solvents (eg methanol, tetrahydrofuran, dimethylformamide, water or mixtures thereof) to prepare by alkaline hydrolysis. The compound of structural formula IXa can use the appropriate amine of structural formula XV from the compound of structural formula VIII, and in the presence of a suitable base (such as pyridine or triethylamine) and a suitable solvent (such as tetrahydrofuran or dichloromethane or mixtures thereof) The following is prepared by amidation. The compound of formula 1b can be used in the presence of a suitable base (such as pyridine or triethylamine) and a suitable solvent (such as tetrahydrofuran or dichloromethane or a mixture thereof), using a suitable amine of formula XVI Compound amidation, followed by base in the presence of a suitable base (such as alkali hydroxides, such as sodium hydroxide) and a suitable solvent (such as methanol, tetrahydrofuran, dimethylformamide, water, or mixtures thereof) Alkaline hydrolysis to prepare. The compound of formula VIII can be prepared by chlorosulfonation of the compound of formula VII using a mixture of chlorosulfonic acid and chlorosulfinyl chloride in a suitable solvent. The compound of structural formula VII can be formed by N-alkylation of the compound of structural formula VIa with a suitable halogen derivative (such as Br (CRR ') nCOOEt). Prepared in the presence of a solvent (such as tetrahydrofuran, dimethylformamide, or a mixture thereof). The compound of formula VIa can be passed through the ring of the compound of formula Va in a suitable solvent (such as dimethylformamide, dimethylacetamide, dimethylsulfoxide or a mixture thereof) under heating with hydrazine hydrate Preparation. The compound of formula Va can be prepared by reacting the compound of formula IVa with Lawesson's reagent in a suitable solvent (such as toluene) under heating conditions. Structural formula IVa can be prepared from compounds of structural formula II using appropriate compounds of structural formula IIIa in the presence of bases (such as triethylamine) and a suitable inert solvent (such as dichloromethane). Scheme -2

The preparation methods of the compounds of structural formulas 1c, 1d, 1e and 1f are shown in Scheme 2. Scheme -2 a) Triethylamine, methylene chloride, 1-6 hours; b) Lawesson's reagent, toluene, heated, 1-4 hours; c) Hydrazine hydrate, dimethylacetamide or dimethylsulfoxide, heated 6- 80 hours; d) Br (CRR ') nCOOEt, cesium carbonate, dimethylformamide, 2-4 hours; e) SnCl ₂ , methanol, hydrochloric acid, heating or Pd-C, H ₂ , methanol, room temperature, 2-4 hours; f) suitable R ₈ COCl or R8OCOCl, triethylamine, dichloromethane, 0˚С-room temperature, 2-6 hours; g) suitable R ₈ SO ₂ Cl, triethylamine or pyridine, di Chloromethane, 0˚С-room temperature, 2-6 hours; h) suitable R ₆ R ₇ NCOCl, triethylamine, dichloromethane, 0˚С-room temperature, 2-6 hours; i) sodium hydroxide or Lithium hydroxide solution, solvent (such as MeOH, THF or DMF), 0˚С-room temperature, 0.5-2 hours.

Compound of formula 1c (where Y is OZ, Z is H, ring A may be aryl, heteroaryl or cycloalkyl, L is SO ₂ , R ₂ may be (C ₁ -C ₆ ) alkyl, halogen , -NO ₂ , heterocycloalkyl, CF ₃ , (C ₁ -C ₆ ) alkoxy, -S- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₁ -C ₆ ) alkyl , -SO ₂ NR ₆ R ₇ and R, R ', R ₁ , R ₃ , R ₄ , R ₆ , R ₇ , m and n are as defined in structural formula (1)) can be a compound of structural formula IXb By alkaline in the presence of suitable bases (such as alkali gold hydroxides, such as sodium hydroxide or lithium hydroxide) and suitable solvents (such as methanol, tetrahydrofuran, dimethylformamide, water, or mixtures thereof) Prepared by hydrolysis.

Compound of formula 1d (where ring A may be aryl; R ₈ may be (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl, heteroaryl, heterocycloalkyl , O- (C ₁ -C ₆ ) alkyl, -O- (C ₃ -C ₈ ) cycloalkyl, -O-aryl, -O-heteroaryl, or -O-heterocycloalkyl; R, R ', R ₁ , R ₂ , R ₃ , Y, m, and n are as defined in Structural Formula 1c) The compound of Structural Formula XI where ring A is an aryl group in a suitable base (such as an alkali metal hydroxide) , Such as sodium hydroxide or lithium hydroxide) and a suitable solvent (such as methanol, tetrahydrofuran, dimethylformamide, water, or a mixture thereof) prepared by alkaline hydrolysis.

The compound of formula XI can be prepared from the compound of formula X by applying a suitable acid chloride or a suitable chloroformate, or using a coupling reagent to place a suitable carboxylic acid in the presence of a base (such as triethylamine) in a suitable solvent (such as dichloro Methane) prepared by coupling reaction.

Compound of structural formula 1e (wherein R ₆ and R ₇ are as defined in structural formula (1); rings A, R, R ′, R ₁ , R ₂ , R ₃ , Y, m and n are as structural formula (Defined in 1d) by reacting the compound of formula X with a suitable amine chloride in the presence of a suitable base (eg triethylamine) and a suitable solvent, followed by a suitable base (eg alkali metal hydroxide Prepared by alkaline hydrolysis in the presence of a substance such as sodium hydroxide or lithium hydroxide) and a suitable solvent (such as methanol, tetrahydrofuran, dimethylformamide, water, or a mixture thereof).

The compound of structural formula 1f (wherein rings A, R, R ', R ₁ , R ₂ , R ₃ , R ₈ , Y, m and n are as defined in structural formula 1d) can be Suitable sulfonyl chloride is treated in the presence of a suitable base (such as triethylamine and pyridine) and a suitable solvent, followed by a suitable base (such as an alkali metal hydroxide, such as sodium hydroxide or lithium hydroxide) and a suitable solvent It is obtained by alkaline hydrolysis in the presence of (for example, methanol, tetrahydrofuran, dimethylformamide, water, or a mixture thereof).

Compounds of formula X (where ring A is aryl) can use hydrogen and palladium catalysts or tin chloride in a suitable solvent (such as methanol) via compounds of formula IXb (where R ₄ is nitro and n is 1 and ring A is aryl) by the reduction reaction of the nitro group. The compound of structural formula IXb can be selected from the compound of structural formula VIb and suitable It is prepared by N-alkylation of halogen derivatives (such as Br (CRR ') nCOOEt). The compound of structural formula VIb may be a compound of structural formula Vb using hydrazine hydrate in a suitable solvent (such as dimethylformamide, dimethylacetamide, dimethylsulfoxide or a mixture thereof) under heating. Chemical preparation. The compound of structural formula Vb can be prepared by reacting the compound of structural formula IVb with Lawesson's reagent in a suitable solvent (such as toluene) under heating conditions. Structural formula IVb can be prepared from compounds of structural formula II using compounds of structural formula IIIb in the presence of bases (such as triethylamine) and a suitable inert solvent (such as dichloromethane). Scheme -3

The preparation methods of the compounds of structural formulas 1g, 1h, 1i, 1j and 1k are shown in Scheme 3. Scheme -3 a) SnCl ₂ and methanol, heated for 4-18 hours. Or Pd-C, H ₂ , methanol, room temperature, 2-4 hours; b) suitable for R ₈ COCl, triethylamine, dichloromethane, 0˚С-room temperature, 2-6 hours; c) suitable for R ₈ SO ₂ Cl, triethylamine or pyridine, dichloromethane, 0˚С-room temperature, 2-6 hours; d) suitable for NR ₆ R ₇ NCOCl, triethylamine, dichloromethane, 0˚С-room temperature, 2-6 hours; e) aryl or heteroaryl boronic acid, Pd catalyst, base, dimethoxyethane-water, heated or suitable ene derivative, Pd catalyst, base, dimethylformamide , Heating; f) phenylacetylene, Pd catalyst, Cul, triethylamine, dichloromethane, 2-6 hours; g) sodium hydroxide or lithium hydroxide solution, solvent (such as MeOH, THF or DMF), 0˚С -Room temperature, 0.5-2 hours.

Compounds of formula 1g, 1h and 1i can be prepared from compounds of formula XII, which are compounds of formula IXa in the presence of catalyst palladium or tin chloride and a suitable solvent (where m is 1 and R ₂ is nitro Group) obtained by the reduction of the nitro group.

Compound of formula 1g (where R ₈ can be (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl, heteroaryl, heterocycloalkyl, (C ₁ -C ₆ ) Alkoxy, -O- (C ₃ -C ₈ ) cycloalkyl, -O-aryl, -O-heteroaryl or -O-heterocycloalkyl; L is SO ₂ , Y is OZ and Z H, R, R ', R ₁ , R ₃ , R ₄ and n are as defined in structural formula (1)) can be used from the compound of structural formula XII through suitable acid chloride or suitable chloroformate Reaction, or through the use of a coupling agent in the presence of a suitable base (such as triethylamine) and a suitable solvent (such as tetrahydrofuran, dichloromethane, or a mixture thereof) with a suitable carboxylic acid coupling, followed by It is obtained by alkali hydrolysis in the presence of an alkali hydroxide, such as sodium hydroxide or lithium hydroxide, and a suitable solvent (such as tetrahydrofuran, methanol, water, or a mixture thereof).

Compound of formula 1i (wherein R ₆ and R ₇ are as defined in formula (1); L, Y, R, R ′, R ₁ , R ₃ , R ₄ and n are as defined in formula 1g )) By reacting the compound of formula XII with a suitable amine methyl chloride in the presence of a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane), followed by It is prepared by alkali hydrolysis in the presence. Similarly, the compound of structural formula 1h (where Y, R, R ', R ₁ , R ₃ , R ₄ , R ₈ and n are as defined in structural formula 1g) can Sulfonyl chloride is obtained by treatment in the presence of a suitable base (such as triethylamine or pyridine) and a suitable solvent (such as dichloromethane), followed by base hydrolysis.

The compound of formula 1k (wherein R ₂ can be aryl, heteroaryl or alkenyl; L, Y, R, R ′, R ₁ , R ₃ , R ₄ and n are as defined in formula 1g) By reacting a compound of formula IXa (where R ₂ is bromine and m is 1) under the Suzuki reaction conditions using a catalyst palladium with a suitable aryl or heteroaryl boric acid; or in a base and palladium catalyst and a suitable solvent (such as DMF ) In the presence of a suitable olefin derivative, followed by alkaline hydrolysis to prepare.

Compounds of structural formula 1j (wherein L, Y, R, R ', R ₁ , R ₃ , R ₄ and n are as defined in structural formula 1g) can be prepared by accommodating compounds of structural formula IXa with suitable acetylene derivatives, It is prepared by coupling the reaction conditions of prickly pear, reacting with palladium catalyst, and then hydrolyzing by alkali. Scheme -4

The preparation method of the compounds of structural formulas 11, 1m, 1n and 1o is shown in Scheme 4. Scheme -4 a) Triethylamine, methylene chloride, 0˚С-room temperature, 1-6 hours; b) Lawesson's reagent, toluene, heated, 1-4 hours; c) hydrazine hydrate, dimethylacetamide or dimethyl Chia, heated 6-80 hours; d) Br (CRR ') nCOOEt, cesium carbonate, dimethylformamide, 2-4 hours; e) TFA, dichloromethane, 0˚С-room temperature, 2 -4 hours; f) suitable alkanoic acid chloride, triethylamine, dichloromethane, 0˚С-room temperature, 2-6 hours; g) suitable alkanesulfonyl chloride, triethylamine or pyridine, dichloromethane , 0˚С-room temperature, 2-6 hours; h) Sodium hydroxide or lithium hydroxide solution, solvent (such as MeOH, THF or DMF), 0˚С-room temperature, 0.5-2 hours i) BBr ₃ CH ₂ Cl ₂ , 0˚С-room temperature, 2-4 hours.

Compound of formula 11 (where L is SO ₂ , Y is -OZ and Z is H, R ₂ may be (C ₁ -C ₆ ) alkyl, halogen, -NO ₂ , heterocycloalkyl, CF ₃ , ( C ₁ -C ₆ ) alkoxy, -S- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₁ -C ₆ ) alkyl; R, R ′, R ₁ , R ₃ , m and n as defined in formula (1)) by reacting the compound of formula XIII with a suitable acid chloride in the presence of a suitable base (such as triethylamine) and a suitable solvent (such as dichloromethane), It is then prepared by alkaline hydrolysis. Compounds of formula 1m (where L, Y, R, R ', R ₁ , R ₂ , R ₃ , m and n are as defined in formula 11) can use suitable sulfonyl chloride in suitable bases (e.g. In the presence of triethylamine or pyridine) and a suitable solvent (such as dichloromethane), it is prepared by the action of the amide of the compound of formula XIII followed by alkaline hydrolysis. The compound of formula XIII can be a compound of formula IXc (where ring A is piperazine (heterocycloalkyl) and R ₄ is a tert-butoxycarbonyl group, n is 1) via suitable acids (such as trifluoroacetic acid) and It is prepared by removing the tert-butoxycarbonyl group on the piperazine of the compound of formula IXc in the presence of a suitable solvent (such as dichloromethane).

Compound of formula 1n (where Y is -OZ and Z is H, L is SO ₂ , ring A is a heterocycloalkyl group connected to -SO ₂ via a heteroatom "N"; R, R ', R ₁ , R ₃ , R ₄ , m and n are as defined in structural formula (1)) can be obtained by combining the compound of structural formula IXc (where R ₂ is an alkoxy group) in the presence of a suitable solvent (such as dichloromethane) Boron tribromide reaction, followed by alkaline hydrolysis to prepare.

Compound of formula 1o (where R ₂ is alkyl, halogen, -NO ₂ , heterocycloalkyl, CF ₃ , (C ₁ -C ₆ ) alkoxy, -S- (C ₁ -C ₆ ) alkyl , -SO _2- (C ₁ -C ₆ ) alkyl; L, Y, ring A, R, R ′, R ₁ , R ₃ , R ₄ , m and n are as defined in Structural Formula 1n) The compound of formula IXc is prepared by alkaline hydrolysis. The compound of structural formula IXc can be prepared by N alkylation of the compound of structural formula VIc, which uses a suitable halogen derivative (eg Br (CRR ') _n COOEt) in a suitable base (eg metal carbonate, For example, cesium carbonate), in a suitable solvent (such as tetrahydrofuran, dimethylformamide) under appropriate conditions. The compound of structural formula VIc can be prepared by the cyclization of the compound of structural formula Vc by using hydrazine hydrate in a suitable solvent (such as dimethylformamide, dimethylacetamide or a mixture thereof) under heating conditions Next reaction. The compound of structural formula Vc can be prepared by reacting the compound of structural formula VIc with Lawesson's reagent in a suitable reagent (such as toluene) under heating conditions. The compound of structural formula IVc can be prepared by reacting the compound of structural formula II with the compound of structural formula IIIc in the presence of a suitable base (such as triethylamine) in a suitable solvent (such as dichloromethane). Option 5 Option 5 a) Triethylamine, methylene chloride, 1-6 hours; b) Lawesson's reagent, toluene, heated for 1-4 hours; c) Hydrazine hydrate, dimethylacetamide or dimethylsulfoxide, heated 6-80 Hours; d) Br (CRR ') nCOOEt, cesium carbonate, dimethylformamide, 2-4 hours. e) m-chloroperbenzoic acid, dichloromethane or H ₂ O ₂ , acetic acid, 0˚С-room temperature, 2-4 hours; f) sodium hydroxide or lithium hydroxide solution, solvent (such as MeOH, THF or DMF), 0˚С-room temperature, 0.5-2 hours.

The alternate preparation method of compound 1c is shown in Scheme 5, wherein ring A may be cycloalkyl or aryl; R ₂ may be (C ₁ -C ₆ ) alkyl, halogen, -NO ₂ , heterocycloalkyl, CF ₃ , (C ₁ -C ₆ ) alkoxy, -SO _2- (C ₁ -C ₆ ) alkyl, -SO ₂ NR ₆ R ₇ , Y is -OZ and Z is H; R, R ', R ₁ , R ₃ , R ₄ , m and n are as defined in structural formula (1). The compound of structural formula 1c can be obtained through the compound of structural formula IXb in a suitable base (such as alkali hydroxide, such as sodium hydroxide or lithium hydroxide) and a suitable solvent (such as methanol, tetrahydrofuran, dimethylformamide, It is prepared by alkaline hydrolysis in the presence of water or its mixture).

The compound of structural formula IXb can be prepared from the compound of structural formula XIV through the oxidation of a sulfur atom by using a suitable oxidizing agent (such as m-chloroperbenzoic acid) in a suitable solvent (such as dichloromethane). The compound of formula XIV can be accompanied by a suitable halogen derivative (such as Br (CRR ') nCOOEt) in the presence of a suitable base (such as a metal carbonate, such as cesium carbonate) in a suitable solvent (such as tetrahydrofuran, dimethyl Carboxymethylamine), prepared from the N-alkylation of compounds of structural formula VId. The compound of formula VId can be prepared by reacting the compound of formula IVd with Lawesson's reagent in the presence of a suitable solvent (such as toluene), and then using hydrazine hydrate in a suitable solvent (such as dimethylacetamide or dimethylsulfoxide or It is prepared by cyclization reaction in the presence of a mixture) under heating. The compound of structural formula IVd can be prepared by reacting the compound of structural formula II with the compound of structural formula IIId in the presence of a suitable base (such as triethylamine) and a suitable solvent (such as dichloromethane).

The compound of structural formula (1) (where Y is OZ and Z is a cation) can be easily prepared by a skilled person according to any one of Schemes 1 to 5.

In addition to the provided solutions, those skilled in the art will be able to easily synthesize the compounds according to the invention using conventional synthetic organic techniques according to the present invention, from suitable starting materials that are commercially available or can be easily synthesized.

It will be obvious to those skilled in the art that changes in reaction time, temperature, solvents and / or reagents may increase production.

The compounds of the present invention may have palm centers and occur as racemates, racemic mixtures and as individual diastereomers or mirror isomers and all their isomeric forms, all of which are included within the scope of the present invention. Therefore, palmitic compounds, and individual mirror isomers that do not substantially contain each other, are included within the scope of the present invention; all mixtures of two mirror isomers are further included.

In this specification, some common terms are used as they are well-known as defined below: APCI ionization technology (electrospray chemical free probe) or ESI or APCI thermal instrument technology Finnigan LXQ, using a single quadrupole (Single quadrupole) mass spectrometer (Water ZQ 2000 instrument) to measure the preparation of the present invention The mass spectrum of the compound.

The novel compounds of the present invention are prepared according to the protocol steps described above, using suitable materials, and are further illustrated by the following specific examples. These examples should not be viewed or interpreted as limiting the scope of the invention. Example: Example 1 : Synthesis of (5- fluoro- 3- { methyl [4- ( pyrrolidin- 1 -ylsulfonyl ) phenyl ] amino ] -1H- indazol- 1 -yl ) acetic acid (compound No. 5 ) Step -1 : Synthesis of 2, 5 -difluoro -N- methyl -N- phenylbenzamide

Triethylamine (172 ml, 1.7 mol) was added to a solution of N-toluidine (111 ml, 0.87 mol) in dichloromethane (750 ml), and the reaction mixture was cooled to 0 ° C. A solution of 2,5-difluorobenzyl chloride (150 gm, 0.85 mol) in dichloromethane (150 ml) was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 2N hydrochloric acid, and it was extracted with dichloromethane. The obtained organic layer was washed with water, followed by sodium bicarbonate solution. Dry over sodium sulfate and concentrate under reduced pressure to provide 195 gm of solid. ^{1 H-NMR (400 MHz,} DMSO-d 6): δ 7.06-7.26 (8H, m), 3.36 (3H, s) ESMS: 248.07 (M + +1) Step-2: 2,5-difluoro - Synthesis of N- Methyl -N -Phenylphenylthioformamide

Add Lawesson's reagent (222 gm, 0.55 mol) to a solution of 2,5-difluoro-N-methyl-N-phenylbenzamide (226 gm, 0.91 mol) in toluene (680 ml), and The mixture was heated to 100 ° C for 1 hour. Toluene was evaporated under reduced pressure, and 3.4 liters of isopropanol was added. The reaction mixture was heated at 85 ° C for 30 minutes and allowed to cool to room temperature with stirring. The obtained yellow crystalline solid was filtered, washed with isopropyl alcohol, and dried to obtain 180 gm of yellow crystalline solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 6.92-7.27 (8H, m), 3.81 (3H, s) ESMS: 264.01 (M ⁺ +1) Step -3 : 5- fluoro -N- A synthesis of phenyl group -N- -1H- indazol-3-amine the

Inject 99% hydrazine hydrate (332 ml) into 2,5-difluoro-N-methyl-N-phenylphenylthiomethanamide (180 gm, 0.68 mol) in dimethylacetamide (2160 ml) ) Solution, and the reaction mixture was heated at 120 ° C for 80 hours. The reaction mixture was cooled to room temperature, and poured into 6.6 liters of water and stirred for 1 hour. The obtained solid was filtered, washed with water and dried. The obtained solid material was suspended again in 720 ml of n-hexane and stirred for 30 minutes. It was filtered off and dried under vacuum to provide 142 gm of solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.63 (1H, s), 7.48-7.52 (1H, m), 7.18-7.26 (3H, m), 6.88-6.91 (3H, m), 6.70 -6.73 (1H, m), 3.57 (3H, s) ESMS: 242.07 (m + +1) step-4: {5-fluoro-3- [methyl (phenyl) amino] -1H- indazole - Synthesis of 1- yl } ethyl acetate

Add cesium carbonate (288 gm, 0.88 mol) to 5-fluoro-N-methyl-N-phenyl-1H-indazol-3-amine (142 gm, dimethylformamide (430 ml) 0.59 mol) Stir the solution and allow it to cool to 0-5 ° C. A solution of ethyl bromoacetate (88.5 ml, 0.77 mol) in dimethylformamide (80 ml) was added dropwise and stirred at room temperature for 3 hours. The reaction mass was filtered off and washed with ethyl acetate. 1.5 liters of water was added to the filtrate and extracted with ethyl acetate (2 liters). The organic layer was washed with water, dried over sodium sulfate and concentrated to provide 212 gm of crude material. The crude material obtained was redissolved in 215 ml of isopropanol and allowed to cool to 0-5 ° C. Add 280 ml of heptane and stir. The solid thus obtained was filtered off, washed with heptane and dried under vacuum to provide 140 gm of solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ7.64 (1H, m), 7.24-7.30 (3H, m), 6.95-6.99 (3H, m), 6.63 -6.66 (1H, m), 5.29 (2H, s), 4.15 (2H, q), 3.38 (3H, s), 1.19 (3H, t) ESMS: 328.1 (M ⁺ +1) Step- 5 : (5- fluoro- 3- { methyl [4- ( pyrrolidin- 1 -ylsulfonyl ) phenyl ] amino ] -1H- indazol- 1 -yl ) ethyl acetate synthesis step- 5a : (3-{[4- chlorosulfonyl ) Phenyl ] ( methyl ) amino } -5- fluoro -1H- indazol- 1 -yl ) ethyl acetate

Chlorosulfide (60 ml, 0.854 mol) was added to chlorosulfonic acid (45 ml, 0.676 mol) at 0-5 ° C, and the mixture was stirred for 15 minutes. Dichloromethane (30 ml) of {5-fluoro-3- [methyl (phenyl) amino] -1 H - indazol-1-yl} acetate (40 gm, 0.122 mol) solution of Slowly add to the preparation mixture and let it warm to room temperature. It was stirred for 3 hours. The reaction mixture was poured into 500 gm of crushed ice with stirring, and it was extracted with 1000 ml of dichloromethane. The organic phase was washed with water, dried over sodium sulfate and concentrated to provide 54 gm of viscous liquid. Step- 5b : Synthesis of (5- fluoro- 3- { methyl [4- ( pyrrolidin- 1 -ylsulfonyl ) phenyl ] amino ] -1H- indazol- 1 -yl ) ethyl acetate

Add triethylamine (27 ml, 0.19 mol) to a stirred solution of pyrrolidine (12.26 ml, 0.127 mol) in 200 ml of dichloromethane and let it cool to 0-5 ° C. Sulfonyl chloride (54 gm, 0.127 mol) in 100 ml of dichloromethane (product obtained in step 5a) was added to the preparation reaction mixture and stirred for 2 hours. The reaction mixture was poured into water and acidified by dilute hydrochloric acid, and extracted with 700 ml of dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated to provide a viscous liquid. The obtained viscous liquid was adsorbed on silica gel and extracted with ethyl acetate (1.5 L, twice). The ethyl acetate was distilled off under reduced pressure to provide a viscous liquid, which was crystallized from isopropanol to provide 32 gm of solid (5-fluoro-3- {methyl [4- (pyrrolidine- 1-ylsulfonyl) phenyl) amino] -1H-indazol-1-yl) ethyl acetate. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ7.76-7.79 (1H, m), 7.61 (2H, d), 7.34-7.39 (1H, m), 7.15-7.18 (1H, m), 6.95 (2H, d), 5.39 (2H, s), 4.13-4.18 (2H, q), 3.45 (3H, s), 3.06-3.10 (4H, m), 1.61-1.65 (4H, m), 1.19 ( 3H, t) ESMS: 461.1 (M ⁺ +1) Step- 6 : (5- fluoro- 3- { methyl [4- ( pyrrolidin- 1 -ylsulfonyl ) phenyl ] amino } -1H- Synthesis of indazol- 1 -yl ) acetic acid

Add sodium hydroxide (11.2 gm, 0.28 mol) aqueous solution to (5-fluoro-3- {methyl [4- (pyrrolidin-1-ylsulfonyl) benzene) in 190 ml of tetrahydrofuran at 15-20 ° C Yl] amino} -1H-indazol-1-yl) ethyl acetate (64 gm, 0.14 mol) in a stirred solution and stirred at room temperature for 30 minutes. The reaction mass was acidified with 2N hydrochloric acid and extracted with 1L of ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated to provide a foamy solid, which was triturated in isopropyl acetate to provide 44 gm of the title compound as a solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.75-7.79 (1H, m), 7.61 (2H, d), 7.33-7.38 (1H, m), 7.14 -7.17 (1H, m), 6.96 (2H, d), 5.26 (2H, s), 3.46 (3H, s), 3.09 (4H, m), 1.64 (4H, m) ESMS: 431.4 (M ⁺ -1) Example -2 : {5- fluoro 3- [methyl- (4 - {[4- (pyridin-2-yl) piperazin-1-yl] sulfonic yl} phenyl) amino] -1H- indazol-1-yl} acetic acid (Compound No. 36 ) Step -1 : {5- fluoro- 3- [ methyl (4-{[4- ( pyridin -2- yl ) piperazin- 1 -yl ] sulfonyl } phenyl ) amino ] -1H -indazole Synthesis of -1 -yl } ethyl acetate

Add triethylamine (27 ml, 0.19 mol) to a solution of 1- (2-pyridyl) piperazine (22 gm, 0.139 mol) in 200 ml of dichloromethane and let it be at 0-5 ° C Under cooling. Add (3-{[4-chlorosulfonyl) phenyl] (methyl) amino} -5-fluoro-1H-indazol-1-yl) ethyl acetate (52 gm ) (Obtained in step 5a of Example-1) was slowly added to this reaction mass and stirred at room temperature for 2 hours. The reaction mass was diluted with dilute hydrochloric acid and extracted with 700 ml of dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated to provide a viscous liquid. The viscous liquid obtained was adsorbed on silica gel and extracted with ethyl acetate (1 L, twice). Ethyl acetate was distilled off under reduced pressure to provide a viscous liquid, which was crystallized from methanol (200 ml) to provide 35 gm of white solid. ¹ H-NMR (400MHz, DMSO-d ₆ ): δ 8.07-8.08 (1H, s), 7.76-7.79 (1H, m), 7.49-7.56 (3H, m), 7.34-7.39 (1H, m), 7.19-7.21 (1H, m), 6.95 (2H, d), 6.79-6.81 (1H, m), 6.63-6.66 (1H, m), 5.38 (2H, s), 4.15 (2H, q), 3.56- 3.58 (4H, m), 3.44 (3H, s), 2.90-2.92 (4H, m), 1.19 (3H, t) ESMS: 553.13 (M ⁺ +1) Step -2 : {5- fluoro- 3- [ methyl (4 - {[4- (pyridin-2-yl) piperazin-1-yl] sulfonic yl} phenyl) amino] -1H- indazol-1-yl} acetic acid

10 ml of an aqueous solution of sodium hydroxide (3 gm, 75 mmol) was slowly added to a stirred solution of the ethyl ester (29 gm, 52.4 mmol) obtained in step-1 in 30 ml of tetrahydrofuran and 90 ml of methanol at room temperature. The reaction mixture was stirred at room temperature for 1 hour and evaporated to dryness. The resulting residue was stirred in 900 ml of ethyl acetate and filtered to provide a white powder, which was dissolved in water and acidified with acetic acid. The precipitate thus obtained was filtered, carefully rinsed with water and dried to provide the title compound as a 23 gm solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ δ 13.14 (1H, bs) 8.07 (1H, m), 7.75-7.78 (1H, m), 7.51-7.56 (3H, m), 7.32-7.37 (1H, m), 7.17-7.20 (1H, m), 6.95 (2H, d), 6.81 (1H, d), 6.63-6.67 (1H, m), 5.26 (2H, s), 3.57 (4H, m ), 3.44 (3H, s), 2.92 (4H, m) ESMS: 525.3 (M ⁺ +1) Example -3 : {5- fluoro- 3- [ methyl (4-{[4- ( methylsulfonamide Yl ) piperazin- 1 -yl ] sulfonyl } phenyl ) amino ] -1H- indazol- 1 -yl } acetic acid (compound number 23 ) Step -1 : 4-[(4-{[1- (2- ethoxy -2 -oxoethyl ) -5- fluoro -1H- indazol- 3 -yl ] ( methyl ) amino } benzene Of phenyl ) sulfonyl ] piperazine- 1- carboxylic acid tert-butyl ester

Triethylamine (0.2 ml, 1.5 mmol) was added to a stirred solution of N-Boc-piperazine (130 mg, 76 mmol) in 20 ml of dichloromethane and allowed to cool to 0-5 ° C. 10ml of dichloromethane (3-{[4-chlorosulfonyl) phenyl] (methyl) amino} -5-fluoro-1H-indazol-1-yl) ethyl acetate (325mg, 0.76 mmol) (obtained in step-1a of Example-1) was added to this solution and stirred for 2 hours. The reaction mass was diluted with water and acidified with diluted hydrochloric acid, and then extracted with 50 ml of dichloromethane. The organic phase was washed with water, dried over sodium sulfate and concentrated to provide 400 mg of off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.77 -7.80 (1H, m), 7.54 (2H, d), 7.35 -7.40 (1H, m), 7.18-7.20 (1H, m), 6.96 (2H, d), 5.39 (2H, s), 4.16 (2H, q), 3.46 (3H, s), 3.38 (4H, m), 2.79 (4H, m), 1.35 (9H, s), 1.02 ( 3H, t). ESMS: 576.4 (M ⁺ +1) Step -2 : {5- fluoro- 3- [ methyl (4-{[4- ( methylsulfonyl ) piperazin- 1 -yl ] sulfonate Synthesis of Acetyl } phenyl ) amino ] -1H- indazol- 1 -yl } ethyl acetate

2 ml of trifluoroacetic acid was added to the stirred solution of the compound (400 mg) obtained in Step-1 in 2 ml of dichloromethane and stirred for 1 hour. The reaction mixture was basified with diluted sodium carbonate solution and extracted with dichloromethane. The organic layer was concentrated to provide 300 mg of white solid. The obtained solid was dissolved in 15 ml of dichloromethane, triethylamine (0.2 ml) was added and allowed to cool to 0-5 ° C. Mesyl chloride (0.1 ml) was added to the reaction mixture and stirred for 2 hours. The reaction mass was diluted with water and acidified with diluted hydrochloric acid, and then extracted with 20 ml of dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated to obtain a crude mass, which was purified via column chromatography to produce 300 mg of the title compound. ¹ H-NMR (400MHz, DMSO-d ₆ ): δ 7.77-7.80 (1H, m), 7.55 (2H, d), 7.35-7.40 (1H, m), 7.22-7.25 (1H, m), 6.97 ( 2H, d), 5.39 (2H, s), 4.15 (2H, q), 3.46 (3H, s), 3.16-3.20 (4H, m), 2.94 (4H, m), 2.88 (3H, s), 1.19 (3H, t) ESMS: 554 (M ⁺ +1) Step -3 : {5- fluoro- 3- [ methyl (4-{[4- ( methylsulfonyl ) piperazin- 1 -yl ] sulfonate acyl} phenyl) amino] -1H- indazol-1-yl} acetic acid

The compound obtained in Step-2 was dissolved in 15 ml of ethanol and 2 ml of aqueous lithium hydroxide solution (27 mg, 1 mmol) was added. The reaction mixture was stirred, diluted with cold water and acidified with diluted hydrochloric acid. The solid thus obtained was filtered off, rinsed with water and sucked dry to produce 160 mg of the title compound. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ δ 13.16 (1H, bs), 7.77 (1H, m), 7.55 (2H, m), 7.36 (1H, m), 7.23 (1H, m) , 6.97 (2H, m), 5.27 (2H, s), 3.46 (3H, s), 3.19 (4H, m), 2.88-2.94 (7H, m) ESMS: 526.2 (M ⁺ +1) Example -4 : Synthesis of (5- chloro- 3- { methyl [3- ( morpholin- 4 -ylsulfonyl ) phenyl ] amino ] -1H- indazol- 1 -yl ) acetic acid (Compound No. 3 ) Step -1 : Synthesis of 5- chloro -N- methyl -N- [3- ( morpholin- 4 -ylsulfonyl ) phenyl ] -1H- indazol- 3- amine

Add triethylamine (4 ml, 27.7 mmol) to a stirred solution of N -methyl-3- (morpholin-4-ylsulfonyl) aniline (2.2 gm, 8.6 mmol) in dichloromethane, let It is cooled to 0 ° C. A solution of 5-chloro-2-fluorobenzoyl chloride (1.8 gm, 9.3 mmol) in dichloromethane was added to the reaction mixture dropwise, and stirred at 30 ° C for 1 hour. The reaction mixture was diluted with 2N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water, followed by sodium bicarbonate solution, and dried over sodium sulfate. Concentrate under reduced pressure to provide 3.6 gm of 5-chloro-2-fluoro-N-methyl-N- [3- (morpholin-4-ylsulfonyl) phenyl] benzamide.

5-chloro-2-fluoro-N-methyl-N- [3- (morpholin-4-ylsulfonyl) phenyl] benzamide (3.6 gm, 8.7) previously obtained in 15 ml toluene mmol) solution, Lawesson's reagent (3.8 gm, 9.4 mmol) was added and heated to 100 ° C for 1 hour. Toluene was evaporated under reduced pressure. The obtained residue was diluted with water and extracted with ethyl acetate (50 ml). The organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure to produce a crude mass. The obtained crude mass was purified by column chromatography using ethyl acetate and hexane to provide 3.6 gm of solid 5-chloro-2-fluoro-N-methyl-N- [3- (morpholine-4 -Sulfosulfonyl) phenyl] phenylthioformamide.

The previously obtained 5-chloro-2-fluoro-N-methyl-N- [3- (morpholin-4-ylsulfonyl) phenyl] phenylthiocarbamoyl in 20 ml of dimethyl sulfoxide To a solution of amine (3.6 gm, 8.4 mmol) was added 99% hydrazine hydrate (4 ml, 84 mmol) and heated to 100 ° C for 6 hours. The reaction mixture was allowed to cool to room temperature and poured into 50 ml of water and stirred for 20 minutes. The solid obtained was filtered off, rinsed with water and dried under vacuum. The resulting solid was resuspended in isopropanol and stirred for 15 minutes. It was filtered off and dried to provide 1.2 gm of solid 5-chloro-N-methyl-N- [3- (morpholin-4-ylsulfonyl) phenyl] -1H-indazol-3-amine . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.47-7.59 (2H, m), 7.36-7.39 (1H, m), 7.32 (1H, m), 7.24-7.26 (1H, m), 7.14 -7.17 (1H, m), 7.05 (1H, m), 3.59-3.62 (4H, m), 2.80-2.81 (4H, m) ESMS: 404.9 (m + -1) step-2: (5-chloro - Synthesis of 3- { methyl [3- ( morpholin- 4 -ylsulfonyl ) phenyl ] amine } -1H- indazol- 1 -yl ) ethyl acetate

In 20 ml dimethylformamide solution of 5-chloro - N - methyl - N - [3- (morpholin-4-sulfonic acyl) phenyl] -1 H - indazol-3-amine ( 600 mg, 1.5 mmol) of the stirred solution was added cesium carbonate (720 gm, 2.2 mmol) and allowed to cool to 0-5 ° C. To this suspension was added dropwise a solution of ethyl bromoacetate (0.2 ml, 1.8 mmol) in 2 ml of dimethylformamide and stirred for 3 hours. The reaction mixture was filtered off and rinsed with ethyl acetate. The obtained organic phase was washed with water (twice with 50 ml), dried over sodium sulfate and concentrated. The resulting crude material was purified via column chromatography using ethyl acetate and hexane to provide 250 mg of the title compound. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.73- 7.75 (1H, d), 7.57 (1H, t), 7.44-7.46 (1H, m), 7.33 (2H, m), 7.20-7.22 (1H, m), 7.08 (1H, m), 5.35 (2H, s), 4.14 (2H, q), 3.59-3.60 (4H, m), 3.46 (3H, s), 2.79 (4H, m), 1.17 (3H, m) ESMS: 492.9 (M ⁺ +1) Step -3 : (5- chloro- 3- { methyl [3- ( morpholin- 4 -ylsulfonyl ) phenyl ] amino ] - Synthesis of 1H -indazol- 1 -yl ) acetic acid

The compound obtained in Step-2 (250 mg, 0.50 mmol) was added to 10 ml of methanol, and 2 ml of an aqueous solution of lithium hydroxide (30 mg, 1.25 mmol) was added. The reaction mixture was stirred and diluted with cold water. The reaction mixture was acidified with diluted hydrochloric acid to obtain a solid, which was filtered off, rinsed carefully with water and sucked dry to produce 93 mg of the title compound. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.75 (1H, d), 7.55 (1H, t), 7.43-7.45 (1H, m), 7.37 (1H, m), 7.30-7.32 (1H , m), 7.19 (1H, d), 7.09 (1H, m), 5.23 (2H, s), 3.60 (4H, m), 3.47 (3H, s), 2.80 (4H, m) ESMS: 462.9 (M ⁺ -1) Example- 5 : (3-{[4- ( cyclopentylsulfonyl ) phenyl ] ( methyl ) amino } -5- fluoro -1H- indazol- 1 -yl ) acetic acid (compound No. 31 ) Synthesis Step -1 : Synthesis of 4- ( cyclopentylsulfonyl ) -N -methylaniline

N, N-diisopropylethylamine (11 ml, 63.7 mmol) was added to a stirred solution of 4- (cyclopentylthio) aniline (6.1 gm, 31.6 mmol) in 30 ml of dichloromethane, and Let it cool down to 0-5 ⁰ C. Trifluoroacetic anhydride (4.8 ml, 34.7 mmol) in 10 ml of dichloromethane was added to this solution, and stirred at room temperature for 1 hour. The reaction mixture was diluted with dilute hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to provide 5 gm of oily mass N- [4- (cyclopentylthio) phenyl] -2, 2, 2 -Trifluoroacetamide, which is used directly in the next step.

In a stirred solution of N- [4- (cyclopentylthio) phenyl] -2, 2, 2-trifluoroacetamide (5 gm, 17.3 mmol) in 20 ml of dimethylformamide Add cesium carbonate (8.3 gm, 25.4 mmol) and let it cool to 0-5 ° C. Methyl iodide (1.6 ml, 25.4 mmol) was added to this suspension and stirred for 3 hours. The reaction mass was filtered and rinsed with ethyl acetate. The combined organic phase was washed with water (50 ml, twice), dried over sodium sulfate and concentrated under reduced pressure to provide 5.0 gm of oily material.

30 ml of tetrahydrofuran was added to this oil, and then 10 ml of sodium hydroxide (1.62 gm) aqueous solution was added. The reaction mixture was stirred for 1 hour, concentrated, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to provide 3.27 gm of oily mass of 4- (cyclopentylthio) -N -methylaniline. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.15-7.17 (2H, m), 6.47-6.49 (2H, m), 5.82-5.83 (1H, m), 3.26-3.31 (1H, m) , 2.62-2.65 (3H, m), 1.78-1.84 (2H, m), 1.63-1.65 (2H, m), 1.41-1.52 (4H, m) Mass: 208.2 (M ⁺ +1) Step -2 : N -[4- ( Cyclopentylthio ) phenyl ] -2,5 -difluoro -N- methylbenzylamide synthesis

Add triethylamine (3.3 ml, 34 mmol) to a stirred solution of 4- (cyclopentylthio) -N -methylaniline (2.7 gm, 15.8 mmol) in dichloromethane and cool to 0 ° C . A solution of 2,5-difluorobenzyl chloride (2.7 gm, 15.3 mol) in dichloromethane was added dropwise to the reaction mixture within 30-40 minutes and stirred at 30 ° C for 1 hour. The reaction mixture was diluted with 2N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water, followed by sodium bicarbonate solution. It was dried over sodium sulfate and concentrated under reduced pressure to provide 5.6 gm of N- [4- (cyclopentylthio) phenyl] -2,5-difluoro-N-methylbenzophenone amine. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.14-7.26 (7H, m), 3.63 (1H, s), 3.34 (3H, s), 1.96 (2H, m), 1.54-1.64 (4H , m), 1.39 (2H, m). ESMS: 348 (M ⁺ +1) Step -3 : Synthesis of N- [4- ( cyclopentylthio ) phenyl ] -5- fluoro - N - methyl - 1H - indazole- 3- amine

Add Lawesson's reagent (3.9 gm, 9.6 mmol) to toluene (60 ml) to the previously obtained N- [4- (cyclopentylthio) phenyl] -2,5-difluoro-N-methylbenzene A solution of formamide (5.6 gm, 16.1 mmol) and heated to 100 ° C for 1 hour. Toluene was evaporated under reduced pressure. The reaction mixture was diluted with water and extracted with ethyl acetate (50 ml). The organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure to produce a crude mass. The obtained crude mass was purified by column chromatography using ethyl acetate and hexane to provide 4.9 gm of N- [4- (cyclopentylthio) phenyl] -2,5-difluoro- N -Methyl phenyl thioformamide.

Add 99% hydrazine hydrate (5.4 ml, 108 mmol) to N- [4- (cyclopentylthio) phenyl] -2,5-difluoro- N -methyl in 60 ml of dimethyl sulfoxide A solution of phenylthioformamide (4.9 gm, 13.5 mmol) and heated to 120 ° C for 12 hours. The reaction mixture was cooled to room temperature, poured into 50 ml of ice water, and extracted with ethyl acetate (100 ml). The collected organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure to produce a crude material, which was purified via column chromatography using ethyl acetate and hexane to produce 4.1 gm of N -[4- (cyclopentylthio) phenyl] -5-fluoro- N -methyl- 1H -indazol-3-amine. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.73 (1H, br), 7.50-7.54 (1H, m), 7.20-7.28 (3H, m), 6.82-6.85 (2H, m), 3.46 -3.50 (1H, m), 3.39 (3H, s), 1.91-1.93 (2H, m), 1.65-1.67 (2H, m), 1.44 -1.55 (4H, m) ESMS: 342.3 (M ⁺ +1) Step -4 : Synthesis of ethyl (3-{[4- ( cyclopentylthio ) phenyl ] ( methyl ) amino } -5- fluoro -1H- indazol- 1 -yl ) ethyl acetate

Add cesium carbonate (5.9 gm, 18 mol) to N- [4- (cyclopentylthio) phenyl] -5-fluoro- N -methyl-1 H -in 20 ml of dimethylformamide Indazole-3-amine (4.1 gm, 12 mmol) in a stirred solution and cooled to 0-5 ° C. Ethyl bromoacetate (1.6 ml, 14.4 mmol) in 5 ml of dimethylformamide was added dropwise to this suspension and stirred for 3 hours. The reaction mixture was filtered off and rinsed with ethyl acetate. The combined organic layer was washed with 50 ml of water, dried over sodium sulfate and concentrated. The obtained crude material was purified by column chromatography using ethyl acetate and hexane to produce 1.5 gm solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.66-7.69 (1H, m), 7.28-7.30 (3H, m), 6.90 (2H, d), 6.77-6,79 (1H, m) , 5.30 (2H, s), 4.15 (2H, q), 3.50-3.55 (1H, m), 3.38 (3H, s), 1.89-1.99 (2H, m), 1.66-1.67 (2H, m), 1 , 45-1.56 (4H, m), 1.19 (3H, t) ESMS: 428.3 (M ⁺ +1) Step- 5 : ethyl (3-{[4- ( cyclopentylsulfonyl ) phenyl ] ( synthesis of methyl) amino} -5-fluoro -1H- indazol-1-yl) acetate of

9 ml of 30% hydrogen peroxide was added to the stirred solution of the compound (1.5 gm, 3.5 mmol) obtained in Step-4 in 10 ml of acetic acid, and stirred for 5 hours. Acetic acid was distilled under reduced pressure, and the residue thus obtained was diluted with water and extracted with 50 ml of ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography using ethyl acetate and hexane to provide 1.4 gm of orange liquid . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.78-7.81 (1H, m), 7.65 (2H, d,), 7.35-7.40 (1H, m), 7.19-7.21 (1H, m), 6.96 (2H, d), 5.40 (2H, s), 4.13- 4.19 (2H, q), 3.60-3.68 (1H, m), 3.46 (3H, s), 1.80-1.83 (4H, m), 1.52- 1.58 (4H, m), 1.20 (3H, t) ESMS: 460.2 (M ⁺ +1) Step- 6 : (3-{[4- ( cyclopentylsulfonyl ) phenyl ] ( methyl ) amino } -5- fluoro -1H- indazol- 1 -yl ) acetic acid synthesis

Add 2 ml of lithium hydroxide aqueous solution (40 mg, 1.7 mmol) to a stirred solution of the compound (470 mg, 1.0 mmol) obtained in step-5 in methanol and tetrahydrofuran (3: 2, 10 ml), and place the reaction mass in Stir at room temperature and then concentrate to produce a residue. The obtained residue was diluted with cold water, acidified with diluted hydrochloric acid and extracted with ethyl acetate (30 ml). The organic layer was distilled to provide an oil, which was triturated with diisopropyl ether to produce 230 mg of the title compound. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.72 (1H, m), 7.64 (2H, d), 7.33 (1H, m), 7.16-7.18 (1H, m), 6.94 (2H, d ), 5.16 (2H, s), 3.62 (1H, m), 3.45 (3H, partially overlapping with the water signal), 1.79 (4H, m), 1.56 (4H, m). ESMS: 432.3 (M ⁺ +1)

The following representative compounds of the present invention were prepared in a similar manner using the above synthetic scheme: Table 1 Pharmaceutical composition

In another specific embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (1). Although it is possible to administer a therapeutically effective amount of a compound of formula (1) alone or in combination (directly without any formula), to include a pharmaceutically acceptable excipient / adjuvant or carrier and at least one It is common practice to administer the compound in pharmaceutical dosage form of the active ingredient. These dosage forms can be administered by various routes, including oral, topical, transdermal, subcutaneous, intramuscular, intravenous, intraperitoneal, intranasal, pulmonary and the like.

The oral composition may be in solid or liquid dosage form. Solid dosage forms may contain pills, pouches, sachets or discrete units, such as tablets, multiparticulate units, capsules (soft and hard gelatin), etc. Liquid dosage forms may be in the form of elixirs, suspensions, emulsions, solutions, syrups, etc. Compositions intended for oral use can be prepared according to any method of making compositions known in the art, and such pharmaceutical compositions can contain excipients, such as diluents, disintegrating agents, adhesives, in addition to the active ingredients Solubilizers, lubricants, slip agents, surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavors, sweeteners, pigments, etc. Some examples of suitable excipients include lactose, cellulose and derivatives thereof (e.g. microcrystalline cellulose, methyl cellulose, hydroxypropyl methyl cellulose and ethyl cellulose), calcium hydrogen phosphate, mannitol, Starch, gelatin, polyvinyl alcohol pyrrolidone, various gums like gum arabic, tragacanth gum, xanthan gum, algae gum and their derivatives, sorbitol, glucose, xylitol, magnesium stearate, Talc, colloidal silica, mineral oil, glycerol monostearate, glycerol synthetic ester, sodium starch glycolate, cross povidone, croscarmellose, various emulsifiers such as polyethylene Glycol, sorbitol, fatty acid ester, polyethylene glycol alkyl ether, sugar ester, polyoxyethylene polyoxypropylene block copolymer, polyunsaturated fatty acid monoester, diester and mixtures thereof.

The topical pharmaceutical composition according to the present invention may have the following forms: cream, ointment, gel, transdermal preparation, foam, spray, emulsion, solution, emulsion or suspension. Transdermal formulation means a transdermal drug delivery system, which may include a drug-containing composition and optionally a backing layer and / or peelable liner. Such compositions may contain 0.01% to 50% w / w or w / v drugs.

Sterile composition for injection can be prepared according to the traditional medical practice by dissolving or suspending the active substance in a carrier, such as water for injection, N-methyl-2-pyrrolidone, propylene glycol and other glycols, ethanol , Natural vegetable oils (like sesame oil, coconut oil, peanut oil, cottonseed oil) or synthetic fat carriers (like ethyl oleate or the like). Buffers, antioxidants, preservatives, complexing agents such as cellulose derivatives, peptides, peptides and cyclodextrins and the like can also be added as needed.

In addition to immediate release dosage forms, there are also dosage forms of active ingredients that are slow, delayed or controlled to release.

The content of the active ingredient required to achieve the therapeutic effect can of course vary with the specific compound, the route of administration, the subject of treatment, the specific disorder or disease to be treated. The compound of the present invention can be administered orally, by inhalation, epidermal or parenterally at a dose of 0.0005 to 100 mg / kg daily, preferably at a dose of 0.0005 to 50 mg / kg daily, more preferably It is administered daily at a dose of 0.0001 to 20 mg / kg, preferably at a dose of 0.0001 to 10 mg / kg daily. The dosage for adults is generally in the range of 5 µg to 5 g per day, preferably in the range of 10 µg to 2 g per day.

Presented dosage forms provided in discrete units may conveniently contain an effective amount of the compound of the invention or a plurality of identical doses, for example, containing units from 5 µg to 1000 mg.

In another specific embodiment, the present invention provides a method of treating allergic and non-allergic inflammatory diseases by administering a therapeutically effective amount of a compound of formula (1) to those in need A mammal of humans. In addition, the present invention also provides a method for treating damaged hair growth and hair loss.

In a preferred embodiment, the present invention provides a method for treating an allergic or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhinitis, Allergic conjunctivitis, eosinophilic esophagitis, eosinophilia syndrome, nasal polyps, and chronic obstructive pulmonary disease. The method is to administer a therapeutically effective amount of the compound of formula (1) to a mammal including humans in need thereof.

A preferred embodiment of the present invention is the use of the compound of formula (1) in the preparation of a medicament for the treatment of allergic or non-allergic inflammatory diseases. The allergic or non-allergic inflammatory diseases are selected from Dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, eosinophilic esophagitis, eosinophilia syndrome, nasal polyps, and chronic obstructive pulmonary disease. Biological test: Biological example 1 : In vitro study of CRTH2 antagonistic activity in vitro

The human prostaglandin receptor DP2 (CRTH2) aequorin cell line from PerkinElmer was used. The cells contain a sequence encoding human prostaglandin receptor CRTH2, which is transfected into CHO-K1 cells expressing Gα16 and Aequorin targeting mitochondria.

Cells were cultured in Ham's F-12 growth medium with Zeocin (final concentration 0.25 mg / ml) and G418 (final concentration 0.4 mg / ml) antibodies.

The cells were grown in growth medium without antibiotics for 18 hours and gently desorbed with fresh PBS / 0.5 mM EDTA. After centrifugal recovery, the cells were resuspended in test buffer (DMEM / HAM's-F12 with HEPES without phenol red + 0.1% BSA) at a concentration of 9 × ^{10 5} cells / ml. Under sterile conditions, add "coelenterazine h" at a final concentration of 5 µM. The cells were cultured at 21 ° C in the dark and kept stirring gently overnight. The next day, the cells were diluted with test buffer to obtain a final concentration of 3 × 10 ⁵ cells / ml and incubated for 60 minutes as described above.

For the measurement of compound activity, 25 μl of cells were divided into 384-well plates (7500 cells / well) and 25 μl of the compound solution of the invention was added. After 15 minutes of incubation, 25μl of PGD2 was injected into the syringe using the Envision (Perkin Elmer) automatic dispensing system to obtain the same final concentration as EC80 (PGD2 and the compound stock system were prepared with DMSO and diluted with test buffer to Make the final concentration of DMSO in the well <1%). Immediately after the addition of PGD2, the calcium release per well was measured with an Envision Multilabel reader by recording the relative light emission (RLU) within 70 seconds.

Obtain the area under the curve and treat the agonist control group as 100% to calculate% inhibition. The results are summarized in the table below. Form 2 Standard: ++++ = inhibition ≥80% ≤100%; +++ = inhibition ≥50% ＜ 80%; ++ = inhibition ≥20% ＜ 50%; + = inhibition ＜ 20%; NA- not available * -Compound No. 68 showed inhibitory in the range of ++++ at a concentration of 5 nM. Observation: In vitro data show that the compounds of the present invention significantly inhibit CRTH2 receptor activity. Biological Example 2 : Evaluation of the efficacy of in vivo studies in mice: animal models

FITC (fluorescent isothiocyanate) -induced allergic skin inflammation is similar to acute atopic dermatitis lesions. The sensitization of mice locally administered FITC caused an increase in the amount of IgE and an increase in FITC-specific Th2 cells. The application of FITC antigens to the ear test resulted in skin inflammation characterized by edema and massive infiltration of inflamed cells (such as monocytes, eosinophils, and neutrophils) after 6 days of sensitization ( Boehme SA et al. , Int Immunol. 2009 Jan ; 21 (1): 81-93 ). Study on the effect of mice:

The effect of Compound No. 36 was evaluated on FITC-induced allergic skin inflammation in female BALB / c mice. On day 0, the sensitized mice were prepared, and the abdominal hair was removed by electric shears under careful isoflurane anesthesia. On Day 1 and Day 2, apply 400 µL of 0.5% FITC solution (dissolved in acetone: dibutyl phthalate at a ratio of 1: 1 v / v) to the abdomen skin where the hair is shaved. Further on the 8th day, 0.5% FITC was applied to the right ear to test the mice (volume 20 µl). Mice in different treatment groups were treated with 100 mg cream containing 1% or 2.2% Compound No. 36, and the cream was topically applied to the right ear 2 hours before and 5 hours after the FITC test. Placebo cream was administered to mice in the FITC control group. Twenty-four hours after the FITC test, the thickness of the right ear of the anesthetized mouse was measured using a digital vernier caliper, and after hematoxylin and eosin staining, the formalin-fixed right ear section was subjected to histopathological analysis (Figure 2).

The measurement results of ear thickness changes are shown graphically in Figure 1 (the data represent the mean ± the standard deviation of the mean). * Indicates the use of one-way ANOVA followed by Dunnett ’s post hoc analysis (p <0.05 vs. FITC control group).

Observation: Protruding inflammatory cell infiltration was observed in mice in the FITC control group, while mice treated with the compound of the present invention observed a decrease in inflammatory cell infiltration.

FITC‧‧‧fluorescein isothiocyanate

FIG 1: the therapeutic effect to Compound No. 36 pairs of ear thickness. FIG 2: in a) FITC control mice; b) to Compound No. 36 (mouse ear histopathology 2.2% cream) Healing Analysis.

Claims (7)

A compound of formula (1), Structural formula (1) wherein, n is independently selected from 1, 2 and 3; m is selected from 0-2; Y is -OZ; Z is selected from H and a cation; R and R 'are independently selected from Hydrogen and (C ₁ -C ₃ ) alkyl; R ₁ is selected from (C ₁ -C ₆ ) alkyl and (C ₃ -C ₈ ) cycloalkyl; R ₂ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, aryl, heteroaryl, heterocycloalkyl, halogen, -NO ₂ , hydroxyl, CF _{3 ,} (C ₁ -C ₆ ) alkoxy, -S- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₃ -C ₈ ) ring Alkyl, -SO ₂ NR ₆ R ₇ , -NH ₂ , -NH-CO- (C ₁ -C ₆ ) alkyl, -NH-CO- (C ₃ -C ₈ ) cycloalkyl, -NH-CO -(C ₁ -C ₃ ) alkylaryl, -NH-CO- (C ₁ -C ₃ ) alkylheteroaryl, -NH-CO-aryl, -NH-CO-heteroaryl, -NHCO -Heterocycloalkyl, -NH-CO- (C ₁ -C ₆ ) alkoxy, -NH-COO- (C ₃ -C ₈ ) cycloalkyl, -NH-COO-aryl, -NH-COO -Heteroaryl, -NH-COO-heterocycloalkyl, -NH-COO- (C ₁ -C ₃ ) alkyl aryl, -NHCONHR ₇ , -NHCONR ₆ R ₇ , -NH-SO _2- (C ₁ -C ₈₎ alkyl, -NH-SO ₂ - aryl, -NH-SO ₂ - and _{heteroaryl-NH-SO 2 - (C 3} -C 8) cycloalkyl group; R ₃ is selected from , (C ₁ -C ₃₎ alkyl, halo, CF ₃ and (C ₁ -C ₃₎ alkoxy; -L-is selected from -SO ₂ - linker - and -SO ₂ N (R ₅₎ ; Ring A is selected from (C ₃ -C ₈ ) cycloalkyl, aryl, heteroaryl and heterocycloalkyl; R ₄ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl,-(C ₁ -C ₆ ) alkylaryl,-(C ₁ -C ₆ ) alkylheteroaryl, aryl, heteroaryl, heterocycloalkyl, halogen, Pendant, CN, CF ₃ , hydroxyl, -NO ₂ , -NH ₂ , (C ₁ -C ₆ ) alkoxy, hydroxy- (C ₁ -C ₆ ) alkyl, -S- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₃ -C ₈ ) cycloalkyl, -SO ₂ (C ₁ -C ₆ ) alkylaryl,- SO ₂ -aryl, -SO ₂ -heteroaryl, -CO- (C ₁ -C ₆ ) alkyl, -CO- (C ₁ -C ₆ ) alkylaryl, -CO- (C ₃ -C ₈ ) Cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, (C ₁ -C ₆ ) alkoxycarbonyl, -NR ₆ R ₇ , -NH-CO- (C ₁ -C ₆ ) alkyl, -NH-CO- (C ₃ -C ₈ ) cycloalkyl, -NH-CO- (C ₁ -C ₃ ) alkylaryl, -NH-CO- (C ₁ -C ₃ ) alkylheteroaryl, -NH-CO-aryl, -NH-CO-heteroaryl, -NHCO-heterocycloalkyl, -NH-COO- (C ₁ -C ₆ ) alkyl , -NH-COO- ( C ₃ -C ₈ ) cycloalkyl, -NH-COO-aryl, -NH-COO-heteroaryl, NH-COO-heterocycloalkyl, -NH-COO- (C ₁ -C ₃ ) alkyl Aryl, -NHCONR ₆ R ₇ , -NH-SO _2- (C ₁ -C ₆ ) alkyl, -NH-SO _2- (C ₃ -C ₈ ) cycloalkyl, -NH-SO ₂ -aryl , -NH-SO ₂ -heteroaryl, -C (O) OH, -C (O) OR ₆ , -CONH ₂ , -CONH-aryl, -CONH-heteroaryl, -SO ₂ NH- (C ₁ -C ₈ ) alkyl, -SO ₂ NH- (C ₃ -C ₈ ) cycloalkyl and -SO ₂ NH-aryl, of which aryl, heteroaryl and heterocycloalkyl groups are optionally selected Substituted from 1 to 5 groups selected from:-(C ₁ -C ₈ ) alkyl,-(C ₃ -C ₇ ) cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C ₁ -C ₆ ) alkoxy, -O-aryl, halogen, pendant, CN, -CF ₃ , -SO _2- (C ₁ -C ₈ ) -alkyl, -SO ₂ -aryl,- SO ₂ -heterocycloalkyl, -NH ₂ , -NR ₆ R ₇ , -NH-CO- (C ₁ -C ₈ ) alkyl, -NH-SO _2- (C ₁ -C ₈ ) alkyl,- NH-SO ₂ -aryl, -COOH, C (O) NH-alkyl, -CONH-aryl, -CONH-heteroaryl, -C (O)-(C ₁ -C ₈ ) alkyl,- C (O) O- (C ₁ -C ₈ ) alkyl, -C (O) O-aryl, -SO ₂ NH- (C ₁ -C ₈ ) alkyl, -SO ₂ NH-aryl, – _{SO 2 NR 6 R 7, -SO} 2 NH- Aryl group and a hydroxyl group; R ₅ is selected from hydrogen, (C ₁ -C ₆₎ alkyl, aralkyl, (C ₃ -C ₈₎ cycloalkyl and aryl; R ₆ R ₇ are independently selected and (C ₁ -C ₆ ) alkyl, aralkyl, (C ₃ -C ₈ ) cycloalkyl and aryl; or R ₆ and R ₇ may together form a heterocycloalkyl ring; which is pharmaceutically acceptable Salts and their isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates or solvates. Compounds as described in item 1 of the patent application, where n is independently 1 or 2; m is 1; Y is -OZ; Z is selected from H and a cation; R and R 'are independently selected from hydrogen And (C ₁ -C ₃ ) alkyl; R ₁ is (C ₁ -C ₆ ) alkyl; R ₂ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl, halogen and CF ₃ ; R ₃ Is selected from hydrogen and (C ₁ -C ₃ ) alkoxy; -L- is a linker selected from -SO ₂ -and -SO ₂ N (R ₅ )-; ring A is selected from (C ₃ -C ₈ ) Cycloalkyl, aryl, heteroaryl and heterocycloalkyl; R ₄ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl,-(C ₁ -C ₆ ) alkylaryl, Aryl, heteroaryl, heterocycloalkyl, halogen, pendant oxygen, CF ₃ , hydroxy, hydroxy- (C ₁ -C ₆ ) alkyl, -SO _2- (C ₁ -C ₆ ) alkyl,- SO ₂ -aryl, -CO- (C ₁ -C ₆ ) alkyl, -CO-aryl, -CO-heteroaryl, -C (O) OR ₆ and -CONH ₂ ; where aryl, heterocycle The alkyl and heteroaryl residues are optionally selected from 1 to 5 selected from-(C ₁ -C ₈ ) alkyl, (C ₁ -C ₆ ) alkoxy, -COOH, -C (O) NH -Alkyl, -CF ₃ , -CN, -SO ₂ -heterocycloalkyl, -NHCO- (C ₁ -C ₈ ) alkyl, halogen, hydroxyl and pendant groups are substituted; R ₅ It is selected from hydrogen and (C ₁ -C ₆ ) alkyl; R ₆ is (C ₁ -C ₆ ) alkyl. If the compound mentioned in item 1 of the patent application scope, the compound is selected from the group consisting of: (5-chloro-3- {methyl [4- (morpholin-4-ylsulfonyl) phenyl ] Amino} -1H-indazol-1-yl) acetic acid; (5-chloro-3- {methyl [4- (pyrrolidin-1-ylsulfonyl) phenyl] amino} -1H-ind Oxazol-1-yl) acetic acid; (5-chloro-3- {methyl [3- (morpholin-4-ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) acetic acid; (5-chloro-3- {methyl [4- (piperidin-1-ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) acetic acid; (5-fluoro-3- { Methyl [4- (pyrrolidin-1-ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) acetic acid; (5-fluoro-3- {methyl [4- (piperidine -1-ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) acetic acid; (5-fluoro-3- {methyl [4- (morpholin-4-ylsulfonyl) Phenyl] amino} -1H-indazol-1-yl) acetic acid; (5-chloro-3- {ethyl [4- (morpholin-4-ylsulfonyl) phenyl] amino} -1H -Indazol-1-yl) acetic acid; (5-chloro-3- {ethyl [4- (piperidin-1-ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) Acetic acid; (5-chloro-3- {ethyl [4- (pyrrolidin-1-ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) acetic acid; {5-fluoro-3 -[{4-[(4-hydroxypiperidin-1-yl) sulfonyl] phenyl} (methyl) Group] -1H-indazol-1-yl} acetic acid; {3-[(4-{[4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl} phenyl) (methyl) Amino] -5-fluoro-1H-indazol-1-yl} acetic acid; (5-fluoro-3- {methyl [4- (piperazin-1-ylsulfonyl) phenyl] amino}- 1H-indazol-1-yl) acetic acid; [5-fluoro-3- (methyl {4- [methyl (phenyl) sulfamoyl] phenyl} amino) -1H-indazol-1- Yl] acetic acid; [3- {methyl [4- (pyrrolidin-1-ylsulfonyl) phenyl] amino] -5- (trifluoromethyl) -1H-indazol-1-yl] acetic acid ; (3-{[4- (cyclopropylaminosulfonyl) phenyl] (methyl) amino} -5-fluoro-1H-indazol-1-yl) acetic acid; [3- {methyl [ 4- (morpholin-4-ylsulfonyl) phenyl] amino] -5- (trifluoromethyl) -1H-indazol-1-yl] acetic acid; {3-[{4-[(4 -Acetylpiperazin-1-yl) sulfonyl] phenyl} (methyl) amino] -5-fluoro-1H-indazol-1-yl} acetic acid; {3-[{4-[(3 , 3-difluoropyrrolidin-1-yl) sulfonyl] phenyl} (methyl) amino] -5-fluoro-1H-indazol-1-yl} acetic acid; {5-fluoro-3- [ {4-[(4-fluorophenyl) (methyl) aminosulfonyl] phenyl} (methyl) amino] -1H-indazol-1-yl} acetic acid; (3-{[4- ( 3,4-dihydroisoquinolinyl-2 (1H) -ylsulfonyl) phenyl] (methyl) amino} -5-fluoro-1H-indazol-1-yl) acetic acid; (5- Chloro-3- {A [2- (pyrrolidin-1-ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) acetic acid; {5-fluoro-3- [methyl (4-{[4- ( Methylsulfonyl) piperazin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid; (3-{[4- (6,7-dihydrothiophene [3,2-c] pyridine-5 (4H) -ylsulfonyl) phenyl] (methyl) amino} -5-fluoro-1H-indazol-1-yl) acetic acid; {5-chloro -3- [methyl (4-{[4- (methylsulfonyl) piperazin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid; ( 3-{[4- (Acridin-1-ylsulfonyl) phenyl] (methyl) amino} -5-fluoro-1H-indazol-1-yl) acetic acid; (3-{[4 -(Acridin-1-ylsulfonyl) phenyl] (methyl) amino} -5-chloro-1H-indazol-1-yl) acetic acid; (5-chloro-3-{[3- Methoxy-4- (morpholin-4-ylsulfonyl) phenyl] (methyl) amino} -1H-indazol-1-yl) acetic acid; {5-fluoro-3-[(4- {[(3R) -3-hydroxypyrrolidin-1-yl] sulfonyl} phenyl) (methyl) amino] -1H-indazol-1-yl} acetic acid; (5-fluoro-3- { Methyl [4- (phenylaminosulfonyl) phenyl] amino] -1H-indazol-1-yl) acetic acid; (3-{[4- (cyclopentylsulfonyl) phenyl] ( Methyl) amino} -5-fluoro-1H-indazol-1-ylacetic acid; {5-fluoro-3-[(4-{[(2S) -2- (hydroxymethyl) pyrrolidine-1- (Yl) sulfonyl} phenyl) (Methyl) amino] -1H-indazol-1-yl} acetic acid; [5-fluoro-3- (methyl {4-[(4-methyl-1,3-thiazol-2-yl) amine Sulfonyl] phenyl} amino) -1H-indazol-1-yl] acetic acid; (3-{[4- (2,3-dihydro-1H-indol-1-ylsulfonyl) benzene Group] (methyl) amino} -5-fluoro-1H-indazol-1-yl) acetic acid; {3-[{4-[(1,1-dithiothiomorpholin-4-yl) sulfonyl ] Phenyl} (methyl) amino] -5-fluoro-1H-indazol-1-yl} acetic acid; {5-fluoro-3- [methyl (4-{[4- (pyridin-2-yl ) Piperazin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid; (5-fluoro-3- {methyl [4- (thiomorpholin-4 -Ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) acetic acid; (5-chloro-3-{[4- (4,7-dihydrothieno [2,3-c ] Pyridine-6 (5H) -ylsulfonamido) phenyl] (methyl) amino} -1H-indazol-1-yl) acetic acid; 3-[[4-[(4-benzoylamino- 1-piperazinyl) sulfonyl] phenyl] methylamino] -5-fluoro-1H-indazole-1-acetic acid; {5-fluoro-3- [methyl (4-{[4- ( Trifluoromethyl) piperidin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid; [5-fluoro-3- (methyl {4-[(4 -Methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1H-indazol-1-yl] acetic acid; {3-[(4-{[4- (5-chloropyridine-2 -Yl) piperazin-1-yl] sulfonyl} Group) (methyl) amino] -5-fluoro-1H-indazol-1-yl} acetic acid; [5-fluoro-3- (methyl {4-[(4-methylpiperidin-1-yl ) Sulfonyl] phenyl} amino) -1H-indazol-1-yl] acetic acid; (7-methyl-3- {methyl [4- (pyrrolidin-1-ylsulfonyl) phenyl ] Amino} -1H-indazol-1-yl) acetic acid; {3-[{4-[(4-benzylpiperazin-1-yl) sulfonyl] phenyl} (methyl) amino] -5-fluoro-1H-indazol-1-yl} acetic acid; {5-fluoro-3- [methyl (4-{[4- (pyrimidin-2-yl) piperazin-1-yl] sulfonyl } Phenyl) amino] -1H-indazol-1-yl} acetic acid; {5-fluoro-3- [methyl (4-{[4- (2-methoxyphenyl) piperazine-1- Yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid; {7-methyl-3- [methyl (4-{[4- (pyridin-2-yl) piper Azin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid; {5-fluoro-3- [methyl (4-{[4- (2-side oxygen Yl-2,3-dihydro-1H-benzimidazol-1-yl) piperidin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid; {3 -[{4-[(4-Aminomethylpyridin-1-yl) sulfonyl] phenyl} (methyl) amino] -5-fluoro-1H-indazol-1-yl} acetic acid; {5-fluoro-3-[{4-[(3-hydroxyacridin-1-yl) sulfonyl] phenyl} (methyl) amino] -1H-indazol-1-yl} acetic acid; (5-fluoro-3- {prop-2-yl [4- ( Pyrrolidine-1-ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) acetic acid; {5-fluoro-3- [methyl (4-{[4- (pyrimidine-2- Yl) piperazin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid, sodium salt; {5-fluoro-3- [methyl (4-{[4 -(Pyridin-2-yl) piperazin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid, sodium salt; {3-[(4-{[4 -(3,4-dichlorophenyl) piperazin-1-yl] sulfonyl} phenyl) (methyl) amino] -5-fluoro-1H-indazol-1-yl} acetic acid; {3 -[(4-{[4- (3-chlorophenyl) piperazin-1-yl] sulfonyl} phenyl) (methyl) amino] -5-fluoro-1H-indazol-1-yl } Acetic acid; {3-[(4-{[4- (2,3-dichlorophenyl) piperazin-1-yl] sulfonyl} phenyl) (methyl) amino] -5-fluoro- 1H-indazol-1-yl} acetic acid; {5-fluoro-3- [prop-2-yl (4-{[4- (pyridin-2-yl) piperazin-1-yl] sulfonyl} benzene Yl) amino] -1H-indazol-1-yl} acetic acid; {3-[{4-[(2,6-dimethylmorpholin-4-yl) sulfonyl] phenyl} (methyl ) Amino] -5-fluoro-1H-indazol-1-yl} acetic acid; (5-fluoro-3- {methyl [4- (1,3-tetrahydrothiazol-3-ylsulfonyl) benzene Yl] amino} -1H-indazol-1-yl) acetic acid; {3-[{4-[(3-aminomethylpyridin-1-yl) sulfonyl] phenyl} (methyl) Amino] -5-fluoro-1H-indazol-1-yl} acetic acid; {5-fluoro-3-[(4-{[4- (furan-2-ylcarbonyl) piperazin-1-yl] sulfonyl} phenyl) (methyl) amino] -1H-indazole- 1-yl} acetic acid; {5-fluoro-3-[(4-{[4- (methylsulfonyl) piperazin-1-yl] sulfonyl} phenyl) (prop-2-yl) amine Group] -1H-indazol-1-yl} acetic acid; (5-fluoro-3-{[4- (morpholin-4-ylsulfonyl) phenyl]] (prop-2-yl) amino}- 1H-indazol-1-yl) acetic acid; (3-{[4-({4-[(4-chlorophenyl) sulfonyl] piperazin-1-yl} sulfonyl) phenyl) (propylene -2-yl) amino} -5-fluoro-1H-indazol-1-yl) acetic acid; 2- (3-{[4- (acridin-1-ylsulfonyl) phenyl) phenyl] (methyl Yl) amino} -5-fluoro-1H-indazol-1-yl) propanoic acid; 3- (5-fluoro-3- {methyl [4- (pyrrolidin-1-ylsulfonyl) phenyl ] Amino} -1H-indazol-1-yl) propionic acid; bis ({5-fluoro-3- [methyl (4-{[4- (pyridin-2-yl) piperazin-1-yl] Sulfonyl} phenyl) amino] -1H-indazol-1-yl} calcium acetate); bis ({5-fluoro-3- [methyl (4-{[4- (pyrimidin-2-yl) Piperazin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} calcium acetate); bis [(5-fluoro-3- {methyl [4- (pyrrolidine- 1-ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) calcium acetate]; {3-[(4-{[4- (6-chloropyridin-2-yl) piperazine -1-yl] sulfonyl} phenyl) (methyl) amino] -5-fluoro-1H -Indazol-1-yl} acetic acid; {5-fluoro-3-[(4-{[4- (6-methoxypyridin-2-yl) piperazin-1-yl] sulfonyl} phenyl ) (Methyl) amino] -1H-indazol-1-yl} acetic acid; bis ({5-fluoro-3- [methyl (4-{[4- (pyridin-2-yl) piperazine-1 -Yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} magnesium acetate); 1,3-dihydroxy-2- (hydroxymethyl) propan-2-amine onium salt {5 -Fluoro-3- [methyl (4-{[4- (pyridin-2-yl) piperazin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} ethyl Ester; 2-hydroxy-N, N, N-trimethylethylammonium {5-fluoro-3- [methyl (4-{[4- (pyridin-2-yl) piperazin-1-yl] sulfonate Acetyl} phenyl) amino] -1H-indazol-1-yl} acetate; 1,3-dihydroxy-2- (hydroxymethyl) propan-2-ammonium (5-fluoro-3- { Methyl [4- (pyrrolidin-1-ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) acetate; N-diethylamine (5-fluoro-3- {methyl [4- (pyrrolidin-1-ylsulfonyl) phenyl] amino] -1H-indazol-1-yl) acetate; {5-fluoro-3-[(4-{[4- ( 6-hydroxypyridin-2-yl) piperazin-1-yl] sulfonyl} phenyl) (methyl) amino] -1H-indazol-1-yl} acetic acid; {5-fluoro-3- [ (4-{[4- (5-hydroxypyridin-2-yl) piperazin-1-yl] sulfonyl} phenyl) (methyl) amino] -1H-indazol-1-yl} acetic acid; {5-fluoro- 3-[(4-{[4- (4-Hydroxypyridin-2-yl) piperazin-1-yl] sulfonyl} phenyl) (methyl) amino] -1H-indazol-1-yl } Acetic acid; {5-fluoro-3-[(4-{[4- (3-hydroxypyridin-2-yl) piperazin-1-yl] sulfonyl} phenyl) (methyl) amino]- 1H-indazol-1-yl} acetic acid; {5-fluoro-3-[(4-{[4- (4-methoxypyridin-2-yl) piperazin-1-yl] sulfonyl} benzene Group) (methyl) amino] -1H-indazol-1-yl} acetic acid; (5-fluoro-3- {methyl [4-({4- [6- (trifluoromethyl) pyridine-2 -Yl] piperazin-1-yl} sulfonyl) phenyl] amino] -1H-indazol-1-yl) acetic acid; (5-fluoro-3- {methyl [4-({4- [ 5- (trifluoromethyl) pyridin-2-yl] piperazin-1-yl} sulfonyl) phenyl] amino] -1H-indazol-1-yl) acetic acid; (5-fluoro-3- {Methyl [4-({4- [5- (morpholin-4-ylsulfonyl) pyridin-2-yl] piperazin-1-yl} sulfonyl) phenyl] amino} -1H- Indazol-1-yl) acetic acid; 2- {4-[(4-{[1- (carboxymethyl) -5-fluoro-1H-indazol-3-yl] (methyl) amino} phenyl ) Sulfonyl] piperazin-1-yl} pyridine-4-carboxylic acid; (3-{[4-({4- [3- (tert-butylaminemethylacetyl) pyridin-2-yl] piperazine -1-yl} sulfonyl) phenyl] (methyl) amino} -5-fluoro-1H-indazol-1-yl) acetic acid; {5-fluoro-3-[(4-{[4- (Furan [3,2-c] pyridin-4-yl) piperazin-1-yl] sulfonyl} benzene ) (Methyl) amino] -1H-indazol-1-yl} acetic acid; {5-fluoro-3- [methyl (4-{[4- (4-methylquinolin-2-yl) piper Azin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid; {5-fluoro-3- [methyl (4-{[4- (1,6- Naphthyridin-5-yl) piperazin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid; (3-{[4-({4- [1, 3-Dimethyl-4- (trifluoromethyl) -1H-pyrazolo [3,4-b] pyridin-6-yl] piperazin-1-yl} sulfonyl) phenyl] (methyl ) Amino} -5-fluoro-1H-indazol-1-yl) acetic acid; {5-fluoro-3- [methyl (4-{[4- (thieno [3,2-c] pyridine-4 -Yl) piperazin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid; {5-fluoro-3- [methyl (4-{[4- ( 4-methylfuran [3,2-c] pyridin-6-yl) piperazin-1-yl] sulfonyl} phenyl) amino] -1H-indazol-1-yl} acetic acid; {5- Fluoro-3-[(4-{[4- (isoquinolinyl-1-yl) piperazin-1-yl] sulfonyl} phenyl) (methyl) amino] -1H-indazole-1 -Yl} acetic acid; {3-[(4-{[4- (1,3-benzothiazol-2-yl) piperazin-1-yl] sulfonyl} phenyl) (methyl) amino] -5-fluoro-1H-indazol-1-yl} acetic acid; {3-[(4-{[4- (3-cyano-5,6,7,8-tetrahydroquinolin-2-yl) Piperazin-1-yl] sulfonyl} phenyl) (methyl) amino] -5-fluoro-1H-indazol-1-yl} acetic acid; (3-{[4-({4- [5- (acetamido) pyridin-2-yl] piperazin-1-yl} sulfonyl) phenyl] (methyl) amino} -5- Fluoro-1H-indazol-1-yl) acetic acid, and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising one or more compounds as described in any of the aforementioned patent applications, optionally mixed with a pharmaceutically acceptable adjuvant or carrier. A method for treating an allergic or non-allergic inflammatory disease in a mammal selected from atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, eosinophilic esophagitis, eosinophilia syndrome, For nasal polyps and chronic obstructive pulmonary diseases, this method is by administering a therapeutically effective amount of a compound as described in item 1, item 2, or item 3 of the patent application. For example, the use of the compound of item 1, item 2 or item 3 of the patent application scope is for the treatment of allergic or non-allergic inflammatory diseases. The allergic or non-allergic inflammatory diseases are selected from Atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, eosinophilic esophagitis, eosinophilia syndrome, nasal polyps, and chronic obstructive pulmonary disease. A compound of formula (1), its preparation method and its pharmaceutical composition refer to the examples attached to this specification as described herein.