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WO2018042377A1 - Novel indazole compounds - Google Patents

Novel indazole compounds Download PDF

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Publication number
WO2018042377A1
WO2018042377A1 PCT/IB2017/055261 IB2017055261W WO2018042377A1 WO 2018042377 A1 WO2018042377 A1 WO 2018042377A1 IB 2017055261 W IB2017055261 W IB 2017055261W WO 2018042377 A1 WO2018042377 A1 WO 2018042377A1
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WO
WIPO (PCT)
Prior art keywords
methyl
phenyl
acetic acid
sulfonyl
indazol
Prior art date
Application number
PCT/IB2017/055261
Other languages
French (fr)
Inventor
Chaitanya Dutt
Deepa Joshi
Rameshchandra GUPTA
Laxmikant Chhipa
Sudhanshu PANDA
Vikrant Jagtap
Appaji Mandhare
Shailesh Deshpande
Siralee Munshi
Ram Gupta
Jaya Abraham
Vivek Mishra
Original Assignee
Torrent Pharmaceuticals Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Torrent Pharmaceuticals Limited filed Critical Torrent Pharmaceuticals Limited
Publication of WO2018042377A1 publication Critical patent/WO2018042377A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to substituted indazole compounds, their pharmaceutically acceptable salts, and their isomers, steroisomers, atropisomers, conformers, tautomers, polymorphs, hydrates and solvates.
  • the present invention also encompasses pharmaceutically acceptable compositions of said compounds and process for prepari ng novel compounds.
  • T he i nventi on further relates to the use of the above menti oned compounds for the preparation of medicament for use as pharmaceuticals.
  • Prostaglandin D2 isan acidic lipid mediator derived from arachidonic acid by the sequential action of cyclooxygenase(s) (COX) and PGD2 synthase(s). PGD2 is released largely by activated mast cells in addition to some contribution from other leukocytes such as dendritic cells and T-helper 2 (Th2) cells and plays a key role in inflammatory response in allergic conditions. PGD2 exerts its actions through interaction with G-protein-coupled receptors, which include prostanoid receptor DP1 and DP2 or CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) receptor.
  • G-protein-coupled receptors include prostanoid receptor DP1 and DP2 or CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) receptor.
  • the DP1 receptor largely mediates the vascular effects of PGD2 such as stimulation of vasodilation and inhibition of platelet aggregation, whereas the CRT H 2 receptor primarily mediates the inflammatory effects of PGD2.
  • CRTH2 receptors are typically highly expressed on eosinophils, basophils and T-helper 2 cells are known to be involved in chemotaxis and activation of these cells, which form the key events initiating the inflammatory response in allergic diseases(Clin Pharmacol Drug Dev.2016J ul; 5(4): 306- 13).
  • Presence of an allergen is known to trigger the production of PG D2 in sensitized individuals.
  • a bronchial allergen challenge leads to the rapid production of PG D2.
  • Local antigen challenge also stimulates PG D2 production in the nasal mucosa of patients with allergic rhinitis and in the skin of patients with atopic dermatitis (Nat Rev Drug Discov. 2007 Apr; 6(4): 313-25).
  • C RT H2 activation appears to have a crucial role in mediating allergic responses, and thus the use of antagonists of the C RT H2 receptor are an attractive approach to treat the inflammatory component of allergic diseases such as asthma, rhinitis, and dermatitis.
  • WO2010083725 discloses cephalosporin derivatives containing substituted nitrogen-containing fused heterocyclic ring having good anti microbial activities and can be effecti ve i ngredi ents of agents for treati ng i nf ecti ons.
  • WO2009108551 and W 02009023623 disclose heteroaryl amide analogues acting as dopami ne agonists and as P2X 7 receptor modulators.
  • W 02004022551 discloses furan and thiophene derivatives which act as PPAR regulators as well as G PR40 agonists.
  • W 02006060535 discloses compounds active on PPARs which can be used in the preparation of a medicament for the treatment of a PPA R-mediated disease or condition or a disease or condition i n which modulation of a PPA R provides a therapeutic benefit.
  • WO 2003035005 discloses heteroindane analogues having affinity to cannabinoid receptors.
  • WO2014187928 discloses novel heterocyclic compounds as pest control agents.
  • n is independently selected from 1, 2 and 3; m i s sel ected from 0-2; Y is-OZ;
  • Z is selected from H and a cation
  • R and R " are independently selected from hydrogen and (Ci-C 3 )alkyl
  • Ri is selected from (Ci-C6)alkyl and (C 3 -C8)cycloalkyl;
  • R 2 is independently selected from hydrogen, (Ci-Ce)alkyl, (C 2 -C6)alkenyl, (C 2 -C6)alkynyl, aryl, heteroaryl, heterocycloalkyl, halo, -N0 2 , hydroxyl, CF 3 , (Ci-Ce)alkoxy, -S-(Ci- C e )alkyl, -S0 2 -(CrC 6 )alkyl, -S0 2 -(C 3 -C 8 )cycloalkyl, -S0 2 NR 6 R 7 , -NH 2 , -NH-CO-(Ci- C e )alkyl, -NH-CO-(C 3 -C 8 )cycloalkyl, -NH-CO-(d-C 3 )alkylaryl, -
  • Ring A is selected from (C 3 -Cs)cycloalkyl, aryl, heteroaryl and heterocycloalkyl;
  • R 4 is independently selected from hydrogen, (CrC6)al kyl, (C 3 -C8)cycloalkyl, -(C i-C6)alkylaryl, -(Ci-C6)alkyl heteroaryl, aryl, heteroaryl, heterocycloalkyl, halo, oxo, CN, C F 3 , hydroxyl, - N0 2 , -NH 2 , (Ci-Ce)alkoxy, hydroxy-(C i-C 6 )alkyl, -S-(Ci-C 6 )al kyl, -S0 2 -(C i-C 6 )alkyl, - S0 2 -(C 3 -C8)cycloalkyl, -S0 2 (Ci-C6)alkylaryl, -S0 2 -aryl
  • R5 is selected from hydrogen, (Ci-Ce)alkyl, aralkyl, (C3-C 8 )cycloalkyl and aryl;
  • R6 and R 7 are independently selected from (CrC6)alkyl, aralkyl, (C3-C 8 )cycloalkyl and aryl; or
  • R6 and R 7 are taken together may form a heterocycloalkyl ring; their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates or solvates.
  • the present invention pertains to a compound as above, however only incl udi ng pharmaceutical ly acceptable salts thereof.
  • the present invention includes synthetic intermediates that are useful in preparing the compounds of formula (1) and process for preparing such intermediates.
  • Another embodiment of the present invention is a method for preparation of a compound of formula (1) or intermediates as herein described in Schemes 1 to 5.
  • Another embodi ment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (1), optionally in admixture with a pharmaceutically acceptabl e adj uvant or carri er.
  • Another embodiment of the present invention provides a method for treating allergic or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, nasal polyps and chronic obstructive pulmonary disease by administering a therapeutically effective amount of a compound of formula (1) to a mammal, including human bei ng, i n need thereof.
  • Another embodiment of the present invention provides the use of a compound of formula (1) for the preparation of a medicament for treating allergic or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhi nitis, allergic conjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, nasal polyps and chronic obstructive pulmonary disease.
  • allergic or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhi nitis, allergic conjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, nasal polyps and chronic obstructive pulmonary disease.
  • FIGURES are a diagrammatic representation of FIGURES.
  • F ig 1 Effect of treatment with Compound no.36 on ear thickness.
  • Fig 2 Histopathological analysis of ear of a) FITC control group mice; b) Compound no. 36 (2.2 % cream) treated mice.
  • the present invention provides novel compounds of formula (1),
  • R, R ⁇ Ri, R 2 , R 3 , R 4 , L, Y , A mand n areas defined above, their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates or solvates.
  • n is independently 1 or 2;
  • Z is selected from H and a cation
  • Ri is (Ci-Ce)alkyl
  • R 2 is independently selected from hydrogen, (Ci-C6)alkyl, haloand CF 3 ;
  • R 3 is selected from hydrogen and (Ci-C 3 )alkoxy
  • R 4 is independently selected from hydrogen, (Ci-Ce)alkyl, -(Ci-C6)alkylaryl, aryl, heteroaryl, heterocycloalkyi, halo, oxo, CF 3 , hydroxyl, hydroxy-(Ci-C6)alkyl, -S0 2 -(Ci- Ce)alkyl, -S0 2 -aryl, -CO-(CrC 6 )alkyl, -CO-aryl, -CO- heteroaryl, -C(0)OR 6 , and-CONH 2 ; wherein aryl, heterocycloalkyi and heteroaryl radicals are optionally substituted with one to five groups selected from -(Ci-Cs)alkyl, (Ci-Ce)alkoxy, -COOH, -C(0)NH-alkyl, -CF 3 , -CN, -S0 2 -heterocycloalkyl, -NHCO-(Ci-
  • R5 is selected from hydrogen and (Ci-Ce)alkyl
  • R 6 is (Ci-Ce)alkyl
  • R, R " , L andRingA are as defined above; their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates or solvates.
  • a family of specific compounds of particular interest within the scope of present invention consists of compound and pharmaceutically acceptable salts thereof as follows:
  • compound employed herein refers to any compound encompassed by the generic formula disclosed herein.
  • the compounds described 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 centres) and therefore may exi st as enanti omers, di astereoi somers.
  • the compound described herein may exist as a conformational isomer such as chair or boat form
  • the compound described herein may also exist as atropi somers.
  • T he compounds may al so exi st i n several tautomeri c forms i ncl udi ng the enol form, the keto form and mixtures thereof.
  • the chemical structures described herein encompass all possible tautomeric forms of the illustrated compounds.
  • the compounds described also include isotopi cally labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature.
  • E xampl es of i sotopes that may be i ncorporated i nto the compounds of the i nventi on i ncl ude, but are not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, etc.
  • Compounds may exist in unsolvated forms as well as solvated forms, i ncluding hydrated forms. In general, compounds may be hydrated or solvated. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contempl ated herei n and are i ntended to be withi n the scope of the present i nventi on.
  • “Pharmaceutically acceptable sal t_ refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with i norganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, isobutyric acid, hexanoic acid, cyclopentanepropionic acid, oxalic acid, glycol ic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, suberic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, phthalic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
  • polymorph pertains to compounds having the same chemical formula, the same salt type and having the same form of hydrate/sol vate but having different crystal I ographic properties.
  • hydrate pertains to a compound having a number of water molecules bonded to the compound.
  • solvate pertains to a compound having a number of solvent molecules bonded to the compound.
  • the present invention also encompasses compounds which are in a prodrug form
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemi cal changes under physi ol ogi cal condi ti ons ( i n vivo) to provi de the compounds of the present i nventi on.
  • a dditi onal ly, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, for example, transdermal patch reservoir with a suitable enzyme or chemical.
  • Prodrugs are, in some si tuati on, easi er to admi ni ster than the parent drug.
  • T hey may, for i nstance, be bi oavai I abl e by oral admi ni strati on whereas the parent drug i s not T he prodrug may al so have i mproved solubility in pharmacological composition over the parent drug.
  • Esters, peptidyl derivatives and the like, of the compounds are the examples of prodrugs of the present invention.
  • In vivo hydrolysable (or cleavable) ester of a compound of the present invention that contains a carboxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid.
  • substituted includes mono- and poly-substitution by a named substituent to the extent such si ngle and multiple substitution (including multiple substitution at the same site) is chemically allowed and which means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, for example, when a substituent is keto, then the two hydrogens on the atom are replaced.
  • a 11 substituents ( R i, R 2 ⁇ .) and thei r further substituents described herein may be attached to the main structure at any heteroatom or carbon atom whi ch results i n f ormati on of stabl e compound.
  • halo_ substituent is a monovalent halogen radical chosen from chloro, bromo, iodoandfluoro.
  • cation refers to an ion having a positive charge such as Na ⁇ K ⁇ Mg 2+ ,
  • alkyl _ used either alone or in attachment with another group refers to aliphatic hydrocarbon radical having the indicated number of carbon atoms and that is unsubstituted or substituted with groups or substituents attached at any available atom to produce a stable compound.
  • the subscri pt refers to the number of carbon atoms that group may contai n.
  • a "(C r C6)alkyl” would refer to any alkyl group containing one to six carbons in the structure.
  • Alkyl may be straight chain (for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl) or branched chain (for example, isopropyl, isobutyl, sec-butyl, tert-butyl).
  • the said (Ci-C6)alkyl may also contain (C3-C6)cycloalkyl ring in a spiro manner.
  • cycl oal kyl _ used either al one or i n attachment with another group refers to a cyclic ring system having the indicated number of carbon atoms and that is unsubstituted or substituted with groups or substituents attached at any available atom to produce a stable compound.
  • the subscript refers to the number of carbon atoms that group may contain.
  • (C3-C8)cycloalkyl_ would refer to a cyclic ring system having 3 to 8 carbon atoms and that is unsubstituted or substituted.
  • (C3-Cs)cycloalkyl_ means a cyclic ring system containing only carbon atom in the ring system backbone such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Cycloalkyl may include bi cyclic rings. Cycloalkyl may have any degree of saturation provided that at least one ring in the ring system is not aromatic.
  • alkenyl _ used either alone or in attachment with another group refers to aliphatic hydrocarbon having at least one carbon to carbon double bond having the indicated number of carbon atoms and that is unsubstituted or substituted with groups or substituents attached at any available atom to produce a stable compound.
  • the subscri pt refers to the number of carbon atoms that group may contain.
  • (C 2 -C6)alkenyl _ used either alone or in attachment with another group refers to al i phati c hydrocarbon radi cal havi ng 2 to 6 number of carbon atoms and having at least one carbon to carbon double bond. It can be straight chain or branched chain.
  • alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl and the I i ke.
  • al kynyl _ used either alone or i n attachment with another group refers to aliphatic hydrocarbon having at least one carbon to carbon triple bond having the indicated number of carbon atoms and that is unsubstituted or substituted with groups or substituents attached at any avai I abl e atom to produce a stabl e compound.
  • W hen a subscri pt i s used with reference to an al kynyl the subscri pt refers to the number of carbon atoms that group may contai n.
  • (C 2 -C6)al kynyl _ used either alone or i n attachment with another group refers to al i phati c hydrocarbon radi cal havi ng 2 to 6 number of carbon atoms and havi ng at least one carbon to carbon triple bond. It can be straight chain or branched. Examples of alkynyl groups include ethyny I, propynyl, butynyl, and the like.
  • aryl used either alone or i n attachment with another group refers to an aromatic group for example, which is a 6 to 14 membered monocyclic, bicyclic or tricyclic carbon-containing ring system
  • the aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, tetrahydronaphthyl and indane.
  • the said aryl may be optionally substituted with groups or substituents attached at any available atom to produce a stable compound.
  • heteroaryl used either alone or in attachment with another group refers to an aromatic group for example, which is a 5 to 14 membered monocyclic, bicyclic or tricyclic ring systenri which has at least one heteroatom
  • heteroatom as used herein includes 0, N, S.
  • heteroaryl groups include, but are not limited to pyrrolyl, furanyl (furyl), thiophenyl (thienyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (pyridyl), pyridazinyl, pyrimdinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl (benzothienyl), indazolyl, benzimidazol, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxal
  • heterocycl oal kyl used either al one or i n attachment with another group refers to a fully or partially saturated cyclic group, for example, which is a 3 to 14 membered monocyclic, bicycl ic or tricyclic ring systern which has at least one heteroatom and at least one ring is not aromatic.
  • heteroatom as used herein includes 0, N, S.
  • Heterocycl oal kyl groups include, but are not limited, oxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolidi nyl, dihydropyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, triazolidinyl, oxadiazolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, dioxanyl, morpholinyl, triazinanyl, azepanyl, diazepanyl, diazepinyi, oxepanyl, di
  • heterocycl oal kyl may be optionally substituted with groups or substituents attached at any available atom to produce a stable compound.
  • heterocycl oal kyl _ and heterocycle_ can be used interchangeably.
  • oxo_ refers to oxygen atom double bonded to carbon or sul phur.
  • aral kyl _ refers to an al kyl group substituted with one or more aryl groups at any available atom to produce a stable compound.
  • alkyl _ and aryl _ are as defined above.
  • alkoxy_ used either alone or in attachment with another group refers to any alkyl group having the indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge.
  • the subscript refers to the number of carbon atoms that group may contain.
  • a "(Ci-C6)alkoxy” would refer to any alkoxy group containing one to six carbon atoms in the structure.
  • the said (Ci-Ce)alkoxy may also contain (C3-C6)cycloalkyl ri ng in a spiro manner.
  • the alkyl group in said al koxy may be straight chain or branched and it may contain one or two double or triple bonds.
  • the said alkyl group may be further substituted with one or more substituents such as halo, aryl, heteroaryl, cycloalkyl or heterocycloalkyl.
  • substituents such as halo, aryl, heteroaryl, cycloalkyl or heterocycloalkyl.
  • substituted alkoxy group includes but not limited to OC H F 2 , -OC F3, -0-CH 2 -heteroaryl or -0-C H 2 -aryl.
  • room temperature refers to a temperature between 20 0 C and 30
  • mammal _ means a human or an ani mal such as monkeys, primates, dogs, cats, horses, cows, etc.
  • a therapeutically effective amount means the amount of a compound that when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, mode of administration, the disease and its severity and the age, weight, etc., of the pati ent to be treated.
  • present invention provides the process for preparing the compounds of formula (1).
  • the compounds of formula (1) of the present invention may be prepared as descri bed in the schemes below.
  • Illustrative embodiments of compounds of formula (1) include compounds of formula 1a, formula 1 b, formula 1 c, formula 1 d, formula 1e, formula 1f, formula 1g, formula 1 h, formula 1 i, formula 1j, formula 1 k, formula 11, formula 1 m, formula 1 n and 1 o, in which the substituents are as defined in connection with general formula (1) and schemes 1-5.
  • Scheme 1
  • R 2 can be (CrC6)alkyl, halo, -N0 2 , heterocycloalkyl, C F 3 , (Ci-Ce)alkoxy, -S-(Ci-C6)alkyl, - S0 2 -(CrC6)alkyl, -S0 2 N R6R? and R, R ⁇ Ri, R 3 , R 4 , R5, R6, R7, L, Ring A, m and n are as defined in formula (1), is represented in Scheme 1.
  • the compound of formula 1a wherein Ring A is heterocycloalkyl attached through hetero atom " N _ to ⁇ S0 2 (L), can be prepared by alkali ne hydrolysis of compound IX a in presence of a suitable base like alkali hydroxide such as sodium hydroxide or lithium hydroxide and a suitable solvent such as methanol, tetrahydrofuran, di methyl formamide, water or mixture thereof.
  • a suitable base like alkali hydroxide such as sodium hydroxide or lithium hydroxide and a suitable solvent such as methanol, tetrahydrofuran, di methyl formamide, water or mixture thereof.
  • the compound of formula IX a can be prepared from compound of formula VIII by amidation using a suitable amine of formula XV, in presence of a suitable base such as pyridi ne or tri ethyl ami ne and a suitable solvent such as tetrahydrofuran or dichloromethane or mixture thereof.
  • a suitable base such as pyridi ne or tri ethyl ami ne
  • a suitable solvent such as tetrahydrofuran or dichloromethane or mixture thereof.
  • the compound of formula 1 b can be prepared by amidation of compound of formula VIII using a suitable amine of formula XV I, in presence of a suitable base such as pyridi ne or triethylamine and a suitable solvent such as tetrahydrofuran or dichloromethane or mixture thereof which is followed by alkaline hydrolysis in presence of a suitable base like alkali hydroxide such as sodium hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethyl formamide, water or mixture thereof.
  • a suitable base such as pyridi ne or triethylamine
  • a suitable solvent such as tetrahydrofuran or dichloromethane or mixture thereof
  • alkaline hydrolysis in presence of a suitable base like alkali hydroxide such as sodium hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethyl formamide, water or mixture thereof.
  • the compound of formula VIII can be prepared by chlorosulfonation of compound of formula VII using mixture of chlorosulfonic acid and thionyl chloride in a suitable solvent
  • the compound of formula VII can be prepared by N-al kylation of compound of formula Via with suitable halo-derivative such as Br(CR R " )nCOOEt in presence of a suitable base like metal carbonate such as cesium carbonate and a suitable solvent such as tetrahydrofuran, di methyl formamide or mixture thereof.
  • T he compound of formula V la can be prepared by cyclization of compound of formula Va with hydrazine hydrate in a suitable solvent such as dimethyl formamide, di methyl acetamide, dimethylsufoxide or mixture thereof, under heating.
  • the compound of formula V a can be prepared by reacting compound of formula IV a with Lawesson s reagent i n a suitable solvent such as toluene under heating conditions.
  • T he compound of formula IV a can be prepared from compound of formula II using suitable compound of formula Ilia in presence of base such as triethylamine and a suitable inert solvent such as dichloromethane.
  • Ring A can be aryl, heteroaryl or cycloalkyl, L is S0 2 , R 2 can be (Ci-Ce)alkyl, halo, -N0 2 , heterocycloalkyl, C F 3 , (Ci- C 6 )alkoxy, -S-(Ci-C 6 )alkyl, -S0 2 -(Ci-C 6 )alkyl, -S0 2 NR 6 R7 and R, R " , Ri, R 3 , R 4 , R 6 , Ry, m and n are as defined in formula (1), can be prepared by alkaline hydrolysis of compound of formula IX b in presence of a suitable base li ke alkali hydroxide such as sodium hydroxide or lithium hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
  • a suitable base li ke alkali hydroxide such as sodium hydrox
  • a suitable base I ike alkali hydroxide such as sodium hydroxide or lithium h
  • the compound of formula X I can be prepared from formula X by reacting suitable acid chloride or suitable chloroformate or coupling of suitable carboxylic acid using coupling reagent in presence of base such as triethylamine in presence of a suitable solvent such as dichloromethane.
  • the compound of formula le where R6 and R 7 are as defined in formula (1); Ring A, R, R ⁇ R i, R 2 , R 3 , Y , mand n are as defined in formula 1 d, can be prepared by reacting compound of formula X with a suitable carbamoyl chloride in presence of a suitable base such as tri ethyl amine and a suitable solvent followed by alkaline hydrolysis in presence of a suitable base li ke alkali hydroxide such as sodium hydroxide or lithium hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
  • a suitable base such as tri ethyl amine
  • a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
  • T he compound of formula 1f where RingA, R, R ⁇ R i, R 2 , R 3 , Rs, Y , m and n are as def i ned in formula 1 d can be obtained by treating compound of formula X with a suitable sulfonyl chloride in presence of a suitable base such as triethylamine and pyridine and a suitable solvent, followed by alkaline hydrolysis in presence of a suitable base I ike alkali hydroxide such as sodium hydroxide or lithi um hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
  • a suitable base such as triethylamine and pyridine
  • a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
  • the compound of formula X where Ring A is aryl can be prepared by reduction of nitro group of compound of formula IX b where R 4 is nitro, n is 1 and Ring A is aryl using hydrogen and pal ladi um catalyst or usi ng ti n chl oh de i n a sui tabl e solvent such as methanol .
  • the compound of formula IX b can be prepared by N-alkylation of compound of formula VIb with suitable halo- derivative such as Br(CRR " )nCOOEt in presence of a suitable base like metal carbonate such as cesium carbonate and a suitable solvent such as tetrahydrof uran, di methylformami de or mixture thereof.
  • T he compound of formula V lb can be prepared by cyclization of compound of formula V b using hydrazine hydrate in a suitable solvent such as di methylformami de, dimethyl acetamide, dimethyl suf oxide or mixture thereof under heating conditions.
  • the compound of formula V b can be prepared from compound of formula IV b using Lawesson s reagent in presence of a suitable solvent such as toluene under heating conditions.
  • the compound of formula IV b can be prepared from compound of formula II usi ng compound of formula Illb i n presence of base such as tri ethyl amine and an inert solvent such as dichloromethane.
  • T he compound of formula 1 g, 1 h and 1 i can be prepared from compound of formula X II which is obtained by reduction of nitro group of compound of formula IX a where m is 1 and R 2 is nitro group, in presence of Palladium catalyst or tin chl oh de and a suitable solvent.
  • the compound of formula 1g where Rs can be (CrC6)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl, heterocycloalkyl, (Ci-Ce)alkoxy, -0-(C3-Cs)cycloalkyl, -O-aryl, -O-heteroaryl or -O-heterocycloalkyl; L is S0 2 , Y is OZ and Z is H, R, R " , Ri, R 3 , R 4 , and n are as defined in formula (1) can be obtained from compound of formula X II by reacting with suitable acid chloride or suitable chloroformate or coupling of suitable carboxylic acid using coupling reagent in presence of a suitable base such as tri ethyl amine and a suitable solvent such as tetrahydrofuran, dichloromethane or mixture thereof, followed by alkaline hydrolysis in presence of suitable base like alkali hydroxide such as sodium hydroxide or lithium hydro
  • the compound of formula 1 i, where R6 and R 7 are as defined in formula (1); L, Y , R, R ⁇ Ri, R 3 , R 4 and n are as defined in formula 1g can be prepared by reacting compound of formula X II with a suitable carbamoyl chloride in presence of a suitable base such as triethylamine and a suitable solvent such as dichloromethane, followed by alkaline hydrolysis in presence of a suitable base and a suitable solvent Similarly, the compound of formula l h, whereY , R, R " , Ri, R 3 , R 4 , Rs and n are as defined in formula 1g can be obtained by treating the compound of formula X II with suitable sulfonyl chloride in presence of a suitable base such as triethylamine or pyridine and a suitable solvent such as dichloromethane, followed by alkaline hydrolysis.
  • a suitable base such as triethylamine or pyridine
  • a suitable solvent such as dichlor
  • the compound of formula 1 k, where R 2 can be aryl, heteroaryl or alkenyl; L, Y , R, R ⁇ Ri, R 3 , R 4 and n are as def i ned i n formula 1 g can be prepared by reacti ng compound of formula IX a where R 2 is bromo and m is 1, with suitable ary I or heteroaryl boronic acid under suzuki reaction conditions using palladium catalyst; or with suitable alkene derivative in presence of base and palladium catalyst and a suitable solvent such as DM F, followed by alkaline hydrolysis.
  • the compound of formula 1j where L, Y , R, R ⁇ Ri, R 3 , R 4 and n are as defined in formula 1g can be prepared by reacting compound of formula IX a with suitable acetylene derivative using palladium catalyst applying sonoghasira reaction conditions followed by alkaline hydrolysis.
  • R 2 can be (Ci-C6)alkyl, halo, -N0 2 , heterocycloalkyl, C F 3 , (Ci-Ce)alkoxy, -S-(CrC6)alkyl, -S0 2 -(CrC6)alkyl;
  • R, R Ri, R 3 , m and n are as defined in formula (1) can be prepared by reacting compound of formula X III with a suitable acid chloride in presence of a suitable base such as Triethylamine and a suitable solvent such as dichloromethane, followed by alkaline hydrolysis.
  • the compound of formula 1 m where L,Y , R, R ⁇ Ri, R 2 , R 3 , m and n are as defined i n formula 11, can be prepared by amidation of compound of formula X III using a suitable sulfonyl chloride in presence of a suitable base such as tri ethyl amine or pyridine and a suitable solvent such as dichloromethane, followed by alkaline hydrolysis.
  • a suitable base such as tri ethyl amine or pyridine
  • a suitable solvent such as dichloromethane
  • T he compound of formula X III can be prepared from compound of formula IX c where ri ng A is piperazine (Heterocycloalkyl) and R 4 is t-butyloxycarbonyl group, n is 1, by removal of t-butyl oxycarbonyl group from pi perazi ne of compound of formula IX c i n presence of a suitable acid such as trifluoroacetic acid and a suitable solvent such as dichloromethane.
  • a suitable acid such as trifluoroacetic acid
  • a suitable solvent such as dichloromethane
  • the compound of formula 1 n where Y is " OZ and Z is H, L is S0 2 , Ring A is heterocycloalkyl attached through hetero atom " N _ to " S0 2 ; R, R ⁇ R i, R 3 , R 4 , m and n are as defined in formula (1) can be prepared by reacting compound of formula IX c where R 2 is alkoxy, with boron tribromide in presence of a suitable solvent such as dichloromethane followed by alkaline hydrolysis.
  • a suitable solvent such as dichloromethane
  • R 2 can be alkyl, halo, -N0 2 , heterocycloalkyl, CF 3 , (C i-Ce)alkoxy, -S-(C i-C 6 )alkyl, -S0 2 -(C i-C 6 )alkyl;
  • L, Y , Ring A, R, R " , Ri, R 3 , R 4 , m and n are as def i ned i n f ormul a 1 n, can be prepared from compound of f ormul a IX c by al kal i ne hydrolysis.
  • the compound of formula IX c can be prepared by N-alkylation of compound of formula Vic using a suitable halo-derivative such as Br(C RR " )nCOOEt in presence of a suitable base l ike metal carbonate such as cesium carbonate in suitable solvent such as tetrahydrofuran, di methyl formamide under suitable conditions.
  • a suitable halo-derivative such as Br(C RR " )nCOOEt
  • a suitable base l ike metal carbonate such as cesium carbonate
  • suitable solvent such as tetrahydrofuran, di methyl formamide under suitable conditions.
  • the compound of formula Vic can be prepared by cyclization of compound of formula V c using hydrazine hydrate in a suitable solvent such as dimethyl formamide, dimethyl acetamide or mixture thereof under heating conditions.
  • T he compound of formula Vc can be prepared by reacting compound of formula IV c with Lawesson ' s reagent i n a suitable solvent such as tol uene under heati ng conditions.
  • the compound of formula IVc can be prepared by reacting compound of formula II with compound of formula IIIc in presence of a suitable base such as tri ethyl amine in a suitable solvent such as dichloromethane.
  • Ring A can be cycloalkyl or aryl
  • R 2 can be (Ci-C6)alkyl, halo, -N0 2 , heterocycloalkyl, CF 3 , (Ci-Ce)alkoxy, -S0 2 -(Ci- C6)alkyl, -S0 2 N R6R7, Y is -OZ and Z is H
  • R, R ⁇ Ri, R 3 , R 4 , m and n are as defined in formula (1), is represented in scheme 5.
  • the compound of formula 1 c can be prepared by alkaline hydrolysis of compound of formula IX b in presence of a suitable base like alkali hydroxide such as sodium hydroxide or lithi um hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
  • a suitable base like alkali hydroxide such as sodium hydroxide or lithi um hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
  • the compound of formula IX b can be prepared from compounds of formula X IV by oxidation of Sulphur atom using suitable oxidizing agent such as m-chloro perbenzoic acid in a suitable solvent such as dichloromethane.
  • suitable oxidizing agent such as m-chloro perbenzoic acid in a suitable solvent such as dichloromethane.
  • the compound of formula X IV can be prepared by N-alkylation of compound of formula VId with suitable halo-derivative such as Br(CRR " )nCOOEt in presence of a suitable base like metal carbonate such as cesium carbonate in suitable solvent such as tetrahydrofuran, dimethylformamide.
  • the compound of formula VId can be prepared by reacting compound of formula IV d with Lawesson s reagent in presence of a suitable solvent such as toluene, followed by cyclization reaction using hydrazine hydrate in presence of a suitable solvent such as dimethylacetamide or dimethylsulfoxide or mixture thereof under heating.
  • the compound of formula IV d can be prepared by reacting compound of formula II with compound of formula Hid in presence of a suitable base such as triethylamine and a suitable solvent such as dichloromethane.
  • Compounds of formula (1), wherein Y is OZ and Z is cation can be readily prepared by a ski 11 ed person by f ol I owi ng any of the schemes 1 to 5.
  • the compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers.
  • G 16 gene encoding a G protein alpha subunit
  • Mass of compounds prepared according to present invention is measured using Single quadrupole mass spectrometer (Water ZQ 2000 instrument) using A PCI ionization technique (E lectro spray chemical ionization Probe) or Finnigan LX Q, thermo instrument Technique using either ESI or A PCI.
  • a PCI ionization technique E lectro spray chemical ionization Probe
  • Finnigan LX Q thermo instrument Technique using either ESI or A PCI.
  • Triethylamine (172ml, 1.7mol) was added to a solution of N-methylaniline (111 ml, 0.87mol) in dichloromethane (750ml) and the reaction mixture was cooled to 0°C.
  • T he reacti on mixture was di I uted with 2N hydrochl ori c aci d and then it was extracted with dichloromethane. The obtained organic layer was washed with water, followed by sodium bicarbonate solution. It was dried over sodium sulphate and concentrated under reduced pressure to provi de 195 gm of sol i d.
  • Cesium carbonate (288gnri0.88mol) was added to a sti rred solution of 5-fl uoro-N- methyl - N-phenyl-1 H-indazole-3-amine (142 gm,0.59 mol) in dimethylformamide (430ml) and allowed to cool upto 0-5eC.
  • a solution of ethyl bromoacetate (88.5ml ,0.77mol) in dimethylformamide (80ml) was added dropwise and sti rred for 3 hours at room temperature. Reaction mass was filtered off and washed with ethyl acetate. To the filtrate, 1.5 liter of water was added and extracted with ethyl acetate (2 liters).
  • ST E P-5 Synthesis of ethyl (5-fluoro-3- ⁇ methyl[4-(pyrrolidin-1-ylsulfonyl)phenyl] ami no ⁇ -1 H -indazol-1-yl)acetate
  • ST E P 5a Synthesis of ethyl (3- ⁇ [4-chlorosulfonyl)phenyl](methyl)ami no ⁇ -5-fluoro- 1 H-indazol-1-yl)acetate
  • Tri ethyl amine (27 ml, 0.19mol) was added to a stirred solution of pyrrolidine (12.26ml, 0.127mol) in 200ml of dichloromethane and allowed to cool upto 0-5°C.
  • a solution of sulfonyl chloride (54gm, 0.127) (product obtained in the step 5a) in 100ml of dichloromethane was added to the prepared reaction mixture and stirred for 2 hours.
  • the reaction mixture was then poured into water and acidified by dilute hydrochloric acid and then extracted with 700ml of dichloromethane. T he organic layer was washed with water, dried over sodium sulphate and concentrated to provide viscous liquid.
  • the obtained viscous liquid was adsorbed on silica gel and then it is extracted with ethyl acetate (1.5 ⁇ t i ce ).
  • T he ethyl acetate was disti 11 ed off under reduce pressure to provi de a vi scous liquid which was crystallized from isopropyl alcohol to provide 32 gm of ethyl (5-fluoro-3- ⁇ methyl [4-(pyrrolidi n-1 -ylsulfonyl)phenyl] ami no ⁇ -1 H-i ndazol-1 -yl)acetate as sol id.
  • Aqueous solution of sodium hydroxide (11.2 gm ,0.28mol) was added to a stirred sol ution of ethyl (5-fluoro-3- ⁇ methyl[4-(pyrrolidin-1-ylsulfonyl)phenyl]amino ⁇ -1 H-indazol-1- yl)acetate (64gm ,0.14mol) in 190 ml of tetrahydrofuran at 15-20°C, and sti rred for 30 minutes at room temperature.
  • the reaction mass was acidified with 2N hydrochloric acid and extracted with 1.0 1 itre of ethyl acetate.
  • T he organi c layer was washed with water, dried over sodium sulphate and concentrated to provide foamy solid which was triturated in i sopropyl acetate to provi de a 44 gm of titl e compound as sol i d.
  • Triethylamine (27 ml ,0.19mol) was added to a solution of 1-(2-pyridyl)pi perazine (22gm,0.139mol) in 200ml of dichloromethane and allowed to cool at 0-5°C.
  • a solution of the ethyl (3- ⁇ [4-chlorosulfonyl)phenyl](methyl) amino ⁇ -5- fluoro-1 H-indazol-1-yl)acetate (obtained in the step 5a of example-1) in 300ml of dichloromethane was slowly added and stirred for 2 hours at room temperature.
  • the reaction mass was diluted with dilute hydrochloride and extracted with 700ml of dichloromethane. The organic layer was washed with water, dried over sodium sulphate and concentrated to provide viscous liquid. The obtained viscous liquid was adsorbed on silica gel and then extracted with ethyl acetate (1.01 ⁇ twice). The ethyl acetate was distil led off under reduced pressure to yield a viscous liquid which was crystallized from methanol (200ml) to provide 35 gm of white solid.
  • step-1 To a stirred solution of ethyl ester obtained in step-1 (29 gm ,52.4mmol) in 30 ml tetrahydrof uran and 90 ml methanol , 10 ml of aqueous sol uti on of sodi um hydroxi de (3gm ,75mmol) was slowly added at room temperature. The reaction mixture was stirred for 1 hour at room temperature and evaporated to dryness. The resulted residue was stirred in 900ml ethyl acetate and filtered to provide white powder which was dissolved in water and acidified with acetic acid. The precipitate thus obtained was filtered, washed well with water and dried to provide 23 gm of the title compound as solid.
  • Triethylamine (0.2 ml, 1.5mmol) was added to a stirred solution of N-Boc-piperazine
  • reaction mass was diluted with water and acidified with dilute hydrochloric acid which was then extracted with 20ml of dichloromethane.
  • the organic I ayer was washed with water, dri ed over sodi um sul phate and concentrated to obtai n crude mass which was purified by column chromatography to give 300mg of title compound.
  • the compound obtained i n step-2 was dissolved in 15 ml of ethanol and 2ml of aqueous lithium hydroxide (27mg, 1 mmol) was added. The reaction mixture was stirred, diluted with cold water and acidified with dilute hydrochloric acid. The solid thus obtained was filtered off, washed with water and suck dried to give 160 mg of title compound.
  • step-2 Synthesis of (5-chloro-3- ⁇ methyl [3-(morpholin-4-ylsulfonyl) phenyl] ami no ⁇ -1 H -indazol-1-yl) acetic acid
  • the compound obtained in step-2 (250nrg, 0.50mmol) was taken in 10 ml of methanol and 2ml of aqueous lithium hydroxide (30mg, 1.25mmol) was added. The reaction mixture was stirred and then diluted with cold water. The reaction mixture was acidified by dilute hydrochloric acid, a solid was obtained which was filtered off, washed well with water and suck dried to give 93 mg of title compound.
  • N,N-diisopropylethylamine (11 ml, 63.7mmol) was added to a stirred solution of 4- (Cyclopentylthio)anili ne (6.1gnri 31.6mmol) in 30ml dichloromethane and allowed to cool upto 0-5° C.
  • a solution of trifluoroacetic anhydride (4.8ml, 34.7mmol) in 10ml di chl oromethane was added to thi s sol uti on and sti rred for 1 hour at room temperature. T he reaction mixture was diluted with dilute hydrochloric acid and extracted with di chl oromethane.
  • reaction mixture was stirred for one hour, concentrated, diluted with water and then extracted with ethyl acetate. Organic layer was washed wi th water, dri ed over sodi um sul phate and concentrated under reduced pressure to provide 3.27gm of 4-(cyclopentylsulfanyl)-N-methylaniline as oily mass.
  • 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 sulphate and concentrated under reduced pressure to provide 5.6 gm of N-[4-(cyclopentylsulfanyl)phenyl]-2,5-difluoro-N-methyl benzamide.
  • present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound of formula (1). While it is possible to administer therapeutical ly effective quantity of compounds of formula (1) either individually or in combination, directly without any formulation, it is common practi ce to admi ni ster the compounds i n the form of pharmaceuti cal dosage forms comprising pharmaceutically acceptable exci pi ent(s)/adjuvant(s) or carrier and at least one active i ngredi ent T hese dosage forms may be admi ni stered by a vari ety of routes i ncl udi ng oral, topical, transdermal, subcutaneous, intramuscular, intravenous, intraperitoneal, intranasal, pulmonary etc.
  • O ral composi ti ons may be i n the form of sol i d or I i qui d dosage form
  • S ol i d dosage form may comprise pellets, pouches, sachets or discrete units such as tablets, multiparticulate units, capsules (soft & hard gelatin) etc.
  • L iquid dosage forms may be i n the form of elixirs, suspensions, emulsions, sol utions, syrups etc.
  • Composition intended for oral use may be prepared according to any method known in the art for the manufacture of the composition and such pharmaceutical compositions may contai n in addition to active ingredients, excipients such as diluents, disintegrating agents, binders, solubilizers, lubricants, glidants, surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavours, sweeteners, colours etc.
  • excipients such as diluents, disintegrating agents, binders, solubilizers, lubricants, glidants, surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavours, sweeteners, colours etc.
  • excipients include lactose, cellulose and its derivatives such as microcrystalline cel lulose, methyl cellulose, hydroxy propyl methyl cellulose & ethyl eel ly lose, di calcium phosphate, mannitol, starch, gelatin, polyvinyl pyrolidone, various gums like acacia, tragacanth, xanthan, alginates & its derivatives, sorbitol, dextrose, xylitol, magnesium stearate, talc, colloidal silicon dioxide, mineral oi l, glyceryl mono stearate, glyceryl behenate, sodium starch glycol ate, cross povidone, crosslinked carboxymethyl cellulose, various emulsifiers such as polyethylene glycol, sorbitol, fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyoxyethylene polyoxypropyl block copolymers, poly emulsifier
  • Topical pharmaceutical compositions according to the present invention can be in the form of cream, ointment gel, transdermal formulations, foam, spray, lotion, solution, emulsion or suspension.
  • Transdermal formulations refer to transdermal drug delivery system which may comprise a drug-containing composition, and, optionally, a backing layer and/or a release li ner layer. Such composition may contain 0.01% to 50% w/w orw/v of the drug.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, N - Methyl -2- Pyrrol i done, propylene glycol and other glycols, alcohols, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cotton seed oil or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, anti -oxidants, preservatives, complexing agents like cellulose derivatives, peptides, polypeptides and cyclodextrins and the like can be incorporated as required.
  • a vehicle such as water for injection, N - Methyl -2- Pyrrol i done, propylene glycol and other glycols, alcohols, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cotton seed oil or a synthetic fatty vehicle like ethyl oleate or the like.
  • T he dosage form can have a si ow, del ayed or control I ed rel ease of active i ngredi ents i n addi ti on to i mmedi ate rel ease dosage forms.
  • T he compounds of the invention may be administered by oral, inhalation, dermal or parenteral route at a dose of from 0.0005 to 100 mg/kg per day, preferably from 0.0005 to 50 mg/kg per day, more preferably from 0.0001 to 20 mg/kg per day, most preferably from 0.0001 to 10 mg/kg per day.
  • T he dose range for adult humans is general ly from 5 1 g to 5 g per day, preferably dose range is 10i g to 2 g per day.
  • Dosage forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for example units containing 5 1 g to 1000 mg.
  • present invention provides method of treating allergic and non-allergic inflammatory diseases by administering a therapeutically effective amount of a compound of formula (1) to a mammal, including human being, in need thereof. Besides these, the present invention also provides a method for treating impaired hair growth and alopecia.
  • present i nventi on provi des a method for treati ng al I ergi c or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, nasal polyps and chronic obstructive pulmonary disease, by administering a therapeutically effective amount of a compound of formula (1) to a mammal, including human being, in need thereof.
  • a preferred embodiment of the present invention is the use of a compound of formula (1) for the preparation of a medicament for treating allergic or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhi nitis, allergic conj unctivitis, eosinophilic esophagitis, hypereosinophi lic syndrome, nasal polyps and chronic obstructive pulmonary disease.
  • allergic or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhi nitis, allergic conj unctivitis, eosinophilic esophagitis, hypereosinophi lic syndrome, nasal polyps and chronic obstructive pulmonary disease.
  • Human Prostanoid Receptor DP2 (CRT H2) Aequorin Cell line from PerkinE lmer was employed. Cells contained the sequence coding for the human Prostanoid Receptor CRT H2 transfected in CHO-K 1 cells expressing G 16 and mitochondrial ly targeted Aequorin. Cells were cultured with antibiotics Zeocin (final conc.0.25mg/ml) and G418 (fi nal conc.0.4nrg/ml) in growth medium Ham s F-12.
  • Zeocin final conc.0.25mg/ml
  • G418 fi nal conc.0.4nrg/ml
  • mice In vivo efficacy evaluation in mice:
  • FITC Fluorescein isothiocyanate
  • Sensitization of mice by topical application of FITC results in increased IgE levels, as well as the development of FITC specific Th2 cells.
  • Antigen challenge by applying FITC to the ear 6 days post- sensitization results in cutaneous inflammation characterized by edema and large infiltration of inflammatory cells as mononuclear cells, eosinophils and neutrophils (Boehme SA et al., Int Immunol. 2009J an;21(1):81-93).
  • Efficacy of Compound no. 36 was evaluated in FITC-induced al lergic cutaneous inflammation in female BA L B/c mice. Mice were prepared for sensitization on day 0 by carefully removing hair from their bel ly using an electric hair clipper under isoflurane anesthesia. On day 1 and day 2, 400 ⁇ L of 0.5% FITC solution was painted on the shaved ventral skin (dissolved in acetone : di butyl phthalate, 1 :1 v/v). Further on day 8, the mice were challenged with 0.5% FITC on the right ear (20 ⁇ I volume). Mice in different treatment groups were treated with 100mg cream containing 1% or 2.2% Compound no.

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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
FIELD OF THE INVENTION:
The present invention relates to substituted indazole compounds, their pharmaceutically acceptable salts, and their isomers, steroisomers, atropisomers, conformers, tautomers, polymorphs, hydrates and solvates. The present invention also encompasses pharmaceutically acceptable compositions of said compounds and process for prepari ng novel compounds. T he i nventi on further relates to the use of the above menti oned compounds for the preparation of medicament for use as pharmaceuticals.
BACKGROUND OF THE INVENTION:
Prostaglandin D2(PGD2) isan acidic lipid mediator derived from arachidonic acid by the sequential action of cyclooxygenase(s) (COX) and PGD2 synthase(s). PGD2 is released largely by activated mast cells in addition to some contribution from other leukocytes such as dendritic cells and T-helper 2 (Th2) cells and plays a key role in inflammatory response in allergic conditions. PGD2 exerts its actions through interaction with G-protein-coupled receptors, which include prostanoid receptor DP1 and DP2 or CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) receptor. The DP1 receptor largely mediates the vascular effects of PGD2 such as stimulation of vasodilation and inhibition of platelet aggregation, whereas the CRT H 2 receptor primarily mediates the inflammatory effects of PGD2. CRTH2 receptors, are typically highly expressed on eosinophils, basophils and T-helper 2 cells are known to be involved in chemotaxis and activation of these cells, which form the key events initiating the inflammatory response in allergic diseases(Clin Pharmacol Drug Dev.2016J ul; 5(4): 306- 13).
In vivo, injection of PGD2 leads to the exacerbation of allergic responses in the lungs and skin of mice, an effect also demonstrated using DK-PGD2, natural selective CRTH2 agonist, indicating an important role CRTH2 in the recruitment of Th2 lymphocytes and other leukocytes to sites of allergic inflammation (Nat Rev Drug Discov. 2007 Apr; 6(4) : 313-25) . T he i importance ofPGD2-CRTH2 system i n al I ergi c ski n condi ti on is further demonstrated in CRTH2-deficient mice where these mice exhibit reduced skin responses upon exposure to allergen (J Immunol. 2006 Aug 15; 177(4): 2621 -9). Simi larly, correlation between CRT H2 levels on circulating T cells and the severity of atopic dermatitis has also been demonstrated (Int Immunol. 2004J ul; 16(7): 947-59).
Presence of an allergen is known to trigger the production of PG D2 in sensitized individuals. In asthmatics, a bronchial allergen challenge leads to the rapid production of PG D2. Local antigen challenge also stimulates PG D2 production in the nasal mucosa of patients with allergic rhinitis and in the skin of patients with atopic dermatitis (Nat Rev Drug Discov. 2007 Apr; 6(4): 313-25).
C RT H2 activation appears to have a crucial role in mediating allergic responses, and thus the use of antagonists of the C RT H2 receptor are an attractive approach to treat the inflammatory component of allergic diseases such as asthma, rhinitis, and dermatitis.
Several potent and selective C RT H2 antagonists are being investigated for clinical use si nee 2006 as new compounds for the treatment of diseases associated with al lergy and asthma (Expert Opin Ther Pat 2010 Nov; 20(11): 1505-30).
Inspite of diverse CRT H2 antagonist compounds being developed, there remai ns an unmet need to identify and develop novel compounds acting as C RT H2 antagonists which demonstrate desired efficacy and safety profile.
WO2010083725 discloses cephalosporin derivatives containing substituted nitrogen-containing fused heterocyclic ring having good anti microbial activities and can be effecti ve i ngredi ents of agents for treati ng i nf ecti ons.
WO2009108551 and W 02009023623 disclose heteroaryl amide analogues acting as dopami ne agonists and as P2X 7 receptor modulators.
W 02004022551 discloses furan and thiophene derivatives which act as PPAR regulators as well as G PR40 agonists. Similarly, W 02006060535 discloses compounds active on PPARs which can be used in the preparation of a medicament for the treatment of a PPA R-mediated disease or condition or a disease or condition i n which modulation of a PPA R provides a therapeutic benefit.
WO 2003035005 discloses heteroindane analogues having affinity to cannabinoid receptors.
WO2014187928 discloses novel heterocyclic compounds as pest control agents.
Present invention provides novel substituted indazole compounds as CRT H2 antagonists which have demonstrated desired efficacy and safety profile. SUMMARY OF THE INVENTION:
In one embodiment the present invention provides novel compounds of formula
Figure imgf000004_0001
Formula-1
Wherein, n is independently selected from 1, 2 and 3; m i s sel ected from 0-2; Y is-OZ;
Z is selected from H and a cation;
R and R "are independently selected from hydrogen and (Ci-C3)alkyl;
Ri is selected from (Ci-C6)alkyl and (C3-C8)cycloalkyl; R2 is independently selected from hydrogen, (Ci-Ce)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, heterocycloalkyl, halo, -N02, hydroxyl, CF3, (Ci-Ce)alkoxy, -S-(Ci- Ce)alkyl, -S02-(CrC6)alkyl, -S02-(C3-C8)cycloalkyl, -S02NR6R7, -NH2, -NH-CO-(Ci- Ce)alkyl, -NH-CO-(C3-C8)cycloalkyl, -NH-CO-(d-C3)alkylaryl, -NH-CO-(Ci- C3)alky I heteroaryl, -NH-CO-aryl, -NH-CO-heteroaryl, -NHCO-heterocycloalkyl, -NH- CO-(C i-C6)alkoxy, -NH-COO-(C3-C8)cycloalkyl, -NH-COO-aryl, -NH-COO-heteroaryl, - NH-COO-heterocycloalkyl, -NH-C OO-(C i-C3)alkylaryl, -N HCON H R7, -NHCONR6R7, - NH-S02-(CrC8)alkyl, -NH-S02-aryl, -NH-S02-heteroaryl and -NH-S02-(C3- Ce) cycloalkyl; R3 is selected from hydrogen, (C i-C3)alkyl, halo, CF3 and (Ci-C3)al koxy; - L - i s I i nker sel ected from -S 02- and -S 02 N ( R 5)-;
Ring A is selected from (C3-Cs)cycloalkyl, aryl, heteroaryl and heterocycloalkyl; R4 is independently selected from hydrogen, (CrC6)al kyl, (C3-C8)cycloalkyl, -(C i-C6)alkylaryl, -(Ci-C6)alkyl heteroaryl, aryl, heteroaryl, heterocycloalkyl, halo, oxo, CN, C F3, hydroxyl, - N02, -NH2, (Ci-Ce)alkoxy, hydroxy-(C i-C6)alkyl, -S-(Ci-C6)al kyl, -S02-(C i-C6)alkyl, - S02-(C3-C8)cycloalkyl, -S02(Ci-C6)alkylaryl, -S02-aryl, -S02-heteroaryl, -CO-(C i- C6)alkyl, -CO-(Ci-C6)alkylaryl, -CO-(C3-C8)cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, - CO- heteroaryl, (C rC6)alkoxycarbonyl, -NR6Ry, -NH-CO-(C rC6)alkyl, -NH-CO-(C3- C8)cycloalkyl, -NH-CO-(C i-C3)alkylaryl, -NH-CO-(C i-C3)alkylheteroaryl, -NH-CO-aryl, -NH-CO-heteroaryl, -NHCO-heterocycloalkyl, -NH-COO-(C rC6)alkyl, -NH-COO-(C3- C8)cycloalkyl, -NH-COO-aryl, -NH-COO-heteroaryl, -NH-COO-heterocycloalkyl, -NH- COO-(CrC3)alkylaryl, -NHCONR6R7, -NH-S02-(C rC6)alkyl, -NH-S02-(C3- C8)cycloalkyl, -NH-S02-aryl, -NH-S02-heteroaryl, -C(0)OH, -C(0)OR6, -CONH2, - CONH-aryl, -CONH-heteroaryl, -S02NH-(Ci-C8)alkyl, -S02NH-(C3-C8)cycloalkyl and - S02NH-aryl wherein aryl, heteroaryl and heterocycloalkyl radicals are optionally substituted with one to five groups selected from -(C i-Cs)alkyl, -(C3-C7)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (Ci-Ce)alkoxy, -O-aryl, halo, oxo, C N, -CF3, -S02-(Ci- C8)-alkyl, -S02-aryl, -S02- heterocycloalkyl, -NH2, -NR6R7, -NH-CO-(C rC8)alkyl, -NH- S02-(Ci-C8)alkyl, -N H-S02-aryl, -COOH, -C(0)N H-alkyl, -CON H-aryl, -CON H- heteroaryl, -C(0)-(Ci-C8)alkyl, -C(0)0-(Ci-C8)alkyl, -C(0)0-aryl, -S02NH-(Ci-C8)alkyl, -S02NH-aryl, ~S02NR6R7,-S02NH-heteroaryl, and hydroxy I;
R5 is selected from hydrogen, (Ci-Ce)alkyl, aralkyl, (C3-C8)cycloalkyl and aryl; R6 and R7 are independently selected from (CrC6)alkyl, aralkyl, (C3-C8)cycloalkyl and aryl; or
R6 and R7 are taken together may form a heterocycloalkyl ring; their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates or solvates.
In another embodi ment the present invention pertains to a compound as above, however only incl udi ng pharmaceutical ly acceptable salts thereof.
In another embodiment the present invention includes synthetic intermediates that are useful in preparing the compounds of formula (1) and process for preparing such intermediates.
Another embodiment of the present invention is a method for preparation of a compound of formula (1) or intermediates as herein described in Schemes 1 to 5.
Another embodi ment of the present invention is a pharmaceutical composition comprising a compound of formula (1), optionally in admixture with a pharmaceutically acceptabl e adj uvant or carri er.
Another embodiment of the present invention provides a method for treating allergic or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, nasal polyps and chronic obstructive pulmonary disease by administering a therapeutically effective amount of a compound of formula (1) to a mammal, including human bei ng, i n need thereof.
Another embodiment of the present invention provides the use of a compound of formula (1) for the preparation of a medicament for treating allergic or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhi nitis, allergic conjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, nasal polyps and chronic obstructive pulmonary disease.
FIGURES:
F ig 1 : Effect of treatment with Compound no.36 on ear thickness. Fig 2: Histopathological analysis of ear of a) FITC control group mice; b) Compound no. 36 (2.2 % cream) treated mice.
DETAILED DESCRIPTION OF THE INVENTION:
In one embodiment the present invention provides novel compounds of formula (1),
Figure imgf000007_0001
Formula-1
wherein R, R ~ Ri, R2, R3, R4, L, Y , A, mand n areas defined above, their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates or solvates.
In a preferred embodiment the present invention provides novel compounds of formula (1),
Wherein,
n is independently 1 or 2;
m is 1; Y is-OZ;
Z is selected from H and a cation;
Ri is (Ci-Ce)alkyl;
R2 is independently selected from hydrogen, (Ci-C6)alkyl, haloand CF3;
R3 is selected from hydrogen and (Ci-C3)alkoxy;
R4 is independently selected from hydrogen, (Ci-Ce)alkyl, -(Ci-C6)alkylaryl, aryl, heteroaryl, heterocycloalkyi, halo, oxo, CF3, hydroxyl, hydroxy-(Ci-C6)alkyl, -S02-(Ci- Ce)alkyl, -S02-aryl, -CO-(CrC6)alkyl, -CO-aryl, -CO- heteroaryl, -C(0)OR6, and-CONH2; wherein aryl, heterocycloalkyi and heteroaryl radicals are optionally substituted with one to five groups selected from -(Ci-Cs)alkyl, (Ci-Ce)alkoxy, -COOH, -C(0)NH-alkyl, -CF3, -CN, -S02-heterocycloalkyl, -NHCO-(Ci-Cs)alkyl, halo, hydroxyl and oxo;
R5 is selected from hydrogen and (Ci-Ce)alkyl;
R6 is (Ci-Ce)alkyl;
R, R", L andRingA are as defined above; their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates or solvates.
A family of specific compounds of particular interest within the scope of present invention consists of compound and pharmaceutically acceptable salts thereof as follows:
Compd. Chemical Name
No. f5-chloro-3-{methy][4-(morphoiin-iyl suffonyF) phenyl] ami no} -Ϊ H-indazol-
1-yl)acetic acid (5-chloro-3-{ methyl[4-(pyrrolidin-1-yl sulfonyl)phenyl]amino}-1 H-indazol-
1-yl)acetic acid
(5-chl oro-3-{ methyl [3-( morphol i n-4-y I sul f ony I ) phenyl ] ami no} - 1 H - i ndazol -
1-yl)acetic acid
(5-chloro-3-{ methyl[4-(piperidin-1-yl sulfonyl)phenyl]amino}-1 H-indazol-
1-yl)acetic acid
(5-fl uoro-3-{ methyl [4-(pyrrol idi n-1 -yl sulfonyl) phenyl] ami no} -1 H-i ndazol -
1-yl)acetic acid
( 5-fl uoro-3-{ methyl [4-( pi peri di n- 1 -y I sulfonyl ) phenyl ] ami no} - 1 H - i ndazol -
1-yl)acetic acid
(5-fl uoro-3-{ methyl [4-(morphol i n-4-yl sulfonyl) phenyl] ami no} -1 H-i ndazol-
1-yl)acetic acid
(5-chl oro-3-{ ethyl [4-( morphol i n-4-y I sulfonyl ) phenyl ] ami no} - 1 H - i ndazol - 1 - yl)acetic acid
(5-chl oro-3-{ ethyl [4-( pi peri di n- 1 -y I sul f ony I ) phenyl ] ami no} - 1 H - i ndazol - 1 - yl)acetic acid
(5-chloro-3-{ ethyl [4-(pyrrolidi n-1 -yl sulfonyl)phenyl]amino}-1 H-indazol-1- yl)acetic acid
{ 5-fl uoro-3- [{ 4- [(4- hydroxy pi peri di n- 1 -y I ) sul f ony I ] phenyl }
( methy I ) ami no] - 1 H - i ndazol - 1 -y I } aceti c aci d
{3-[(4-{ [4-(tert-butoxycarbonyl)pi perazin-1-yl]sulfonyl} phenyl)(methyl) ami no] -5-fl uoro-1 H-i ndazol -1-yl} acetic acid
(5-fluoro-3-{ methyl[4-(piperazin-1-yl sulfonyl)phenyl]amino}-1 H-indazol-
1-yl)acetic acid
[5-fluoro-3-(methyl{4-[methyl(phenyl) sulfamoyl] phenyl} ami no)-1 H- indazol-1-yl]acetic acid
[3-{ methyl [4-( pyrrol i di n-1 -y I sulfonyl ) phenyl] ami no} -5-(trif I uoromethyl )-
1 H-indazol-1-yl]acetic acid
(3-{ [4-(cyclopropylsulfamoyl)phenyl] (methyl)amino}-5-fluoro-1 H-indazol-
1 -yl) acetic acid [3-{ methyl [4-(morpholin-4-y I sulfonyl)phenyl]amino}-5-(trifluoromethyl)-
1 H-indazol-1-yl]acetic acid
{ 3- [{ 4- [(4-acety I pi perazi n- 1 -y I) sulfonyl] phenyl} (methyl)ami no]-5-fluoro-
1 H-indazol-1-yl}acetic acid
{ 3-[{ 4-[(3,3-dif I uoropyrrol i di n-1 -yl)sulfonyl] phenyl} (methyl)ami no]-5- f I uoro- 1 H - i ndazol - 1 -y 1} aceti c aci d
{ 5-f 1 uoro-3-[{ 4-[(4-f 1 uorophenyl)
(methyl)sulfamoyl] phenyl} (methyl)amino]-1 H-indazol-1-yl} acetic acid
(3-{ [4-(3,4-dihydroisoqui noli n- 2(1 H)-yl sulfonyl)phenyl](methyl)amino}-5- f I uoro- 1 H - i ndazol - 1 -y I ) aceti c aci d
( 5- chl oro-3-{ methyl [2-( pyrrol i di n- 1 -y I sulfonyl ) phenyl ] ami no} - 1 H - i ndazol -
1-yl)acetic acid
{ 5-fluoro-3-[methyl(4-{ [4-(methylsulfonyl)pi perazi n-1 -yl] sulfonyl} phenyl) amino]-1 H-indazol-1-yl} acetic acid
(3-{ [4-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)phenyl](methyl) ami no} -5-f I uoro- 1 H - i ndazol - 1 -y I ) aceti c aci d
{ 5-chloro-3-[methyl(4-{ [4-(methylsulfonyl)piperazin-1-yl] sulfonyl} phenyl) amino]-1 H-indazol-1-yl} acetic acid
(3-{ [4-(azetidi n-1 -ylsulfonyl) phenyl](methyl)ami no} -5- I uoro-1 H-i ndazol-
1-yl)acetic acid
(3-{ [4-(azetidi n-1 -ylsulfonyl) phenyl](methyl)amino}-5-chloro-1 H-indazol-
1-yl)acetic acid
( 5- chl oro-3-{ [3- methoxy-4-( morphol i n-4-y I sul f ony I ) phenyl] ( methyl ) ami no} - 1 H - i ndazol - 1 -y I ) aceti c aci d
{ 5-f I uoro- 3-[(4-{ [(3R)-3- hydroxy pyrrol idi n-1 -yl]sulfonyl} phenyl)(methyl) ami no] - 1 H - i ndazol - 1 -y 1} aceti c aci d
(5-fluoro-3-{ methyl[4-(phenylsulfamoyl) phenyl] ami no} -1 H-i ndazol- 1- yl)acetic acid
(3-{ [4-(cyclopentylsulfonyl)phenyl] (methyl)ami no} -5- I uoro-1 H-i ndazol-1- yl) acetic acid { 5-f I uoro- 3-[(4-{ [(2S)-2-(hydroxymethyl)pyrrolidi n-1 -yl]sulfonyl} phenyl)
( methy I ) ami no] - 1 H - i ndazol - 1 -y I } aceti c aci d
[5- I uoro- 3-(methyl{4-[(4-methyl-1, 3- thiazol-2-yl)sulfamoyl] phenyl} ami no)-1 H -i ndazol -1 -yl] aceti c aci d
(3-{ [4-(2,3-di hydro-1 H-i ndol-1 -ylsulfonyl)phenyl](methyl)ami no} -5-fluoro-
1 H-indazol-1-yl)acetic acid
{3-[{4-[(1,1-dioxidothiomorpholin-4-yl) sulfonyl] phenyl} (methyl)amino]-5- f I uoro- 1 H - i ndazol - 1 -y 1} aceti c aci d
{ 5-fluoro-3-[methyl(4-{ [4-(pyridin-2-yl) pi perazin-1-yl]sulfonyl} phenyl) ami no] - 1 H - i ndazol - 1 -y 1} aceti c aci d
( 5-f 1 uoro-3-{ methyl [4-( thi omorphol i n-4-y 1 sul f ony 1 ) phenyl ] ami no} - 1 H - indazol-1-yl) acetic acid
(5-chloro-3-{ [4-(4,7-dihydrothieno[2,3-c] pyridi n-6(5H)-ylsulfonyl)phenyl]
( methy l)amino}-1 H-indazol-1-yl)acetic acid
3-[[4-[(4-benzoyl-1-piperazinyl)sulfonyl] phenyl] methylami no]-5-fluoro-
1 H-indazole-1-acetic acid
{ 5-f luoro-3-[methyl(4-{ [4-(trif I uoromethyl) pi peridi n-1 -yl] sulfonyl} phenyl) ami no] - 1 H - i ndazol - 1 -y 1} aceti c aci d
[5-f 1 uoro- 3-(methyl{4-[(4-methylpiperazi n-1 -yl)sulfonyl] phenyl} ami no)-
1 H-indazol-1-yl]acetic acid
{ 3-[(4-{ [4-(5-chl oropyri di n-2-y I ) pi perazin-1-yl]sulfonyl} phenyl)(methyl) ami no] -5-fluoro-1 H-i ndazol -1-yl} acetic acid
[5-f I uoro- 3-(methyl{4-[(4-methylpi peridi n-1 -yl)sulfonyl] phenyl} ami no)-1 H- indazol-1-yl]acetic acid
(7-methyl-3-{ methyl[4-(pyrrolidin-1-yl sulfonyl)phenyl]amino}-1 H-indazol-
1-yl)acetic acid
{ 3-[{ 4-[(4- benzyl pi perazi n-1 -yl) sulfonyl] phenyl} (methyl)ami no]-5-f I uoro-
1 H-indazol-1-yl}acetic acid
{ 5-fluoro-3-[methyl(4-{ [4-(pyrimidin-2-yl) pi perazin-1-yl]sulfonyl} phenyl) ami no] - 1 H - i ndazol -1-yl} aceti c aci d { 5-fluoro-3-[methyl(4-{ [4-(2-methoxyphenyl) pi perazin-1-y I] sulfonyl} phenyl )ami no] - 1 H - i ndazol - 1 -y I } aceti c aci d
{7-methyl-3-[methyl(4-{ [4-(pyridin-2-yl) pi perazin-1-y I] sulfonyl} phenyl) ami no] - 1 H - i ndazol - 1 -y 1} aceti c aci d
{ 5-fluoro-3-[methyl(4-{ [4-(2-oxo-2,3-dihydro-1 H-benzimidazol-1- y I ) pi peri di n- 1 -y I ] sulfonyl } pheny I )ami no] - 1 H - i ndazol - 1 -y I } aceti c acid
{ 3-[{ 4-[(4-carbamoyl pi peri di n-1 -yl) sulfonyl] phenyl} (methyl )ami no] -5- f I uoro- 1 H - i ndazol - 1 -y 1} aceti c aci d
{ 5-f 1 uoro- 3-[{4-[(3-hydroxyazetidi n-1 -yl) sulfonyl] phenyl} (methyl)ami no]-
1 H-indazol-1-yl}acetic acid
( 5-f I uoro-3-{ propan-2-y I [4-( pyrrol i di n- 1 -y I sulfonyl ) phenyl ] ami no} - 1 H - i ndaz ol - 1 -y I ) aceti c acid
{ 5-fluoro-3-[methyl(4-{ [4-(pyrimidin-2-yl) pi perazin-1-yl]sulfonyl} phenyl) amino]-1 H-indazol-1-yl} acetic acid, Sodium salt
{ 5-fluoro-3-[methyl(4-{ [4-(pyridin-2-yl) pi perazin-1-yl]sulfonyl} phenyl) amino]-1 H-indazol-1-yl} acetic acid, Sodium salt
{3-[(4-{ [4-(3,4-dichlorophenyl)pi perazin-1-yl]sulfonyl} phenyl)(methyl) ami no] -5-fluoro-1 H-i ndazol -1-yl} acetic acid
{3-[(4-{ [4-(3-chlorophenyl)pi perazin-1-yl]sulfonyl} phenyl)(methyl)amino]-
5-f I uoro- 1 H - i ndazol - 1 -y I } aceti c aci d
{3-[(4-{ [4-(2,3-dichlorophenyl)pi perazin-1-yl]sulfonyl} phenyl)(methyl) ami no] -5-fluoro-1 H-i ndazol -1-yl} acetic acid
{ 5-f I uoro- 3- [ propan-2-yl (4-{ [4-( py ri di n-2-y I ) pi perazi n- 1 -y I ] sulfonyl } pheny I )ami no] - 1 H - i ndazol - 1 -y I } aceti c aci d
{ 3-[{ 4-[(2,6-di methyl morphol i n-4-yl)sulfonyl] phenyl} (methyl)ami no] -5- f I uoro- 1 H - i ndazol - 1 -y 1} aceti c aci d
( 5-f 1 uoro-3-{ methyl [4-( 1 , 3-thi azol i di n-3-y I sulfonyl ) phenyl ] ami no} - 1 H - i ndaz ol - 1 -y I ) aceti c acid
{ 3-[{4-[(3-carbamoyl pi peri di n-1 -yl)sulfonyl] phenyl} (methyl)amino]-5- f I uoro- 1 H - i ndazol - 1 -y 1} aceti c aci d { 5-f I uoro-3- [(4-{ [4-(f uran-2-y I carbony I ) pi perazi n- 1 -y I ] sul f ony I } phenyl )
( methy I ) ami no] - 1 H - i ndazol - 1 -y I } aceti c aci d
{ 5-fluoro-3-[(4-{ [4-(methylsulfonyl)pi perazi n-1 -yl]sulfonyl} phenyl)
(propan-2-yl)amino]-1 H-indazol-1-yl} acetic acid
( 5-f I uoro-3-{ [4-( morphol i n-4-y I sul f ony I ) phenyl ] ( propan-2-y I )ami no} - 1 H - i ndaz ol - 1 -y I ) aceti c acid
(3-{ [4-({4-[(4-chlorophenyl)sulfonyl]piperazin-1-yl}sulfonyl)phenyl]
(propan-2-yl)amino}-5-fluoro-1 H-indazol-1-yl)acetic acid
2-(3-{ [4-(azeti di n-1 -ylsul f ony I) phenyl] (methyl)ami no} -5-f I uoro-1 H- indazol-1-yl)propanoic acid
3-( 5-f I uoro-3-{ methyl [4-(py rrol i di n-1 -y Isulf onyl ) phenyl] ami no} -1 H - indazol-1-yl)propanoic acid
Calci um bis({ 5-f I uoro-3- [methy I (4-{ [4-(pyridi n-2-yl) pi perazi n-1 - yl]sulfonyl} phenyl)ami no] -1 H-i ndazol -1-yl} acetate)
Calcium bis({5-fl uoro-3-[methyl(4-{ [4-(pyri mi din-2-yl)pi perazi n-1 - yl]sulfonyl} phenyl)ami no] -1 H-i ndazol -1-yl} acetate)
Calci um bis[(5-f I uoro-3-{ methyl [4-( pyrrol idi n-1 -ylsul f onyl) phenyl] ami no} -
1 H-indazol-1-yl)acetate]
{ 3-[(4-{ [4-(6-chl oropyri di n-2-y I ) pi perazin-1-yl]sulfonyl} phenyl)(methyl) ami no] -5-f I uoro-1 H-i ndazol -1-yl} acetic acid
{ 5-f I uoro-3-[(4-{ [4-(6-methoxypyridin-2-yl)pi perazin-1-yl]sulfonyl} phenyl)
( methy I ) ami no] - 1 H - i ndazol - 1 -y I } aceti c aci d
M agnesi um bi s({ 5-f I uoro-3- [ methyl (4-{ [4-( py ri di n-2-y I ) pi perazi n- 1 - yl]sulfonyl} phenyl)ami no] -1 H-i ndazol -1-yl} acetate)
1 ,3-di hydroxy- 2-(hydroxy methyl) propan-2-ami ni um { 5-f I uoro-3- [methyl (4-
{ [4-( py ri di n-2-y I ) pi perazi n- 1 -y I ] sul f ony I } phenyl ) ami no] - 1 H - i ndazol - 1 - yl} acetate
2- hydroxy- N , N , N -tri methyl ethanami ni um { 5-f I uoro-3- [ methyl (4-{ [4-
( py ri di n-2-y I ) pi peraz i n- 1 -y I] sul f ony I } phenyl ) ami no] - 1 H - i ndazol - 1 - yl} acetate 1 ,3-di hydroxy- 2-(hydroxymethyl)propan-2-ami ni um (5-fl uoro-3-{ methyl [4-
(pyrrolidin-1-ylsulfonyl)phenyl]amino}-1 H-indazol-1-yl)acetate
N-ethy I ethanami ni um (5-fl uoro-3-{ methyl [4-( pyrrol i di n- 1 - ylsulfonyl)phenyl]ami no}-1 H-indazol-1-yl)acetate
{ 5-fl uoro-3-[(4-{ [4-(6- hydroxy py ri di n-2-yl ) pi perazi n-1 - yl]sulfonyl} phenyl)(methyl)amino]-1 H-indazol-1-yl}acetic acid
{ 5-fl uoro-3- [(4-{ [4-(5- hydroxy py ri di n-2-yl ) pi perazi n-1 - yl]sulfonyl} phenyl)(methyl)amino]-1 H-indazol-1-yl}acetic acid
{ 5-fl uoro-3-[(4-{ [4-(4- hydroxy py ri di n-2-yl ) pi perazi n-1 - yl]sulfonyl} phenyl)(methyl)amino]-1 H-indazol-1-yl}acetic acid
{ 5-fl uoro-3-[(4-{ [4-(3- hydroxy py ri di n-2-yl ) pi perazi n-1 - yl]sulfonyl} phenyl)(methyl)amino]-1 H-indazol-1-yl}acetic acid
{ 5-fl uoro-3- [(4-{ [4-(4-methoxypyri di n-2-yl) pi perazi n-1 - yl]sulfonyl} phenyl)(methyl)amino]-1 H-indazol-1-yl}acetic acid
(5-fl uoro-3-{ methyl [4-({4-[6-(trifl uoromethyl)pyridi n-2-yl] pi perazi n-1 - y I } sul f ony I ) phenyl] ami no} - 1 H - i ndazol -1-yl)acetic acid
(5-fl uoro-3-{ methyl [4-({4-[5-(trifl uoromethyl)pyridi n-2-yl] pi perazi n-1 - y I } sul f ony I ) phenyl] ami no} - 1 H - i ndazol -1-yl)acetic acid
(5-fl uoro-3-{ methyl [4-({4-[5-(morphol i n-4-ylsulfonyl)pyridin-2- y I ] pi perazi n- 1 -y 1} sul f ony 1 ) phenyl] ami no} - 1 H - i ndazol - 1 -yl )aceti c aci d
2-{ 4-[(4-{ [1 -(carboxy methyl )-5-f I uoro- 1 H -i ndazol -3-y I] ( methyl ) amino} phenyl)sulfonyl] piperazin-1-yl} pyridine-4-carboxylic acid
(3-{ [4-({ 4-[3-(tert-buty I carbamoyl) pyri di n-2-y I] pi perazi n- 1 - yl}sulfonyl)phenyl](methyl)amino}-5-fluoro-1 H-indazol-1-yl)acetic acid
{ 5-fl uoro-3- [(4-{ [4-(f uro[3, 2-c] py ri di n-4-y I ) pi perazi n- 1 - yl]sulfonyl} phenyl)(methyl)amino]-1 H-indazol-1-yl}acetic acid
{ 5-fl uoro- 3-[methyl(4-{ [4-(4- methyl qui noli n-2-y I) pi perazi n-1 - y I ] sulf ony I } phenyl )ami no] - 1 H - i ndazol - 1 -y I } aceti c aci d
{ 5-f luoro-3-[methyl(4-{ [4-( 1 , 6- naphthy ri di n-5-yl) pi perazi n-1 - y I ] sulf ony I } phenyl )ami no] - 1 H - i ndazol - 1 -y I } aceti c aci d 91 (3-{ [4-({4-[1,3-dinnethyl-^(trifluoronnethyl)-1 H-pyrazolo[3,4-b] pyri di n-6- yl]piperazi n-1-yl}sulfonyl)phenyl](methyl)amino} -5-fluoro-1 H-indazol-1- yl)acetic acid
92 { 5-f I uoro-3- [ methyl (4-{ [4-(thi eno[3,2-c] py ri di n-4-y I ) pi perazi n- 1 - y I ] sulf ony I } phenyl )ami no] - 1 H - i ndazol - 1 -y I } aceti c aci d
93 { 5-fluoro-3-[methyl(4-{ [4-(4- methylfuro[3,2-c] pyri din- 6-yl)piperazin-1 - y I ] sulf ony I } phenyl )ami no] - 1 H - i ndazol - 1 -y I } aceti c aci d
94 { 5-f I uoro-3-[(4-{ [4-(isoqui noli n-1-yl) pi perazi n-1- yl]sulfonyl} phenyl)(methyl)amino]-1 H-indazol-1-yl}acetic acid
95 {3-[(4-{ [4-(1,3-benzothiazol-2-yl)pi perazin-1- yl]sulfonyl} phenyl)(methyl)amino]-5-fl uoro-1 H-indazol-1-yl} acetic acid
96 {3-[(4-{ [4-(3-cyano- 5,6, 7,8- tetrahydroqui noli n-2-yl)pi perazin-1- yl]sulfonyl} phenyl)(methyl)amino]-5-fl uoro-1 H-indazol-1-yl} acetic acid
97 (3-{ [4-({ 4-[5-(acetyl ami no) pyri di n-2-yl ] pi perazi n-1 - yl}sulfonyl)phenyl](methyl)amino}-5-fluoro-1 H-indazol-1-yl)acetic acid
DE FINITIONS:
The following definitions apply to the terms as used throughout this specification, unless otherwise limited i n specific instances:
The term "compound, employed herein refers to any compound encompassed by the generic formula disclosed herein. The compounds described 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 centres) and therefore may exi st as enanti omers, di astereoi somers. A ccordi ngly, the chemi cal structures described herein encompasses all possible stereoisomers of the illustrated compounds including the stereoisomer! cal ly pure form (e.g., geometrically pure) and stereoisomer! c mixtures (racemates). The compound described herein, may exist as a conformational isomer such as chair or boat form The compound described herein may also exist as atropi somers. T he compounds may al so exi st i n several tautomeri c forms i ncl udi ng the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures described herein encompass all possible tautomeric forms of the illustrated compounds. The compounds described also include isotopi cally labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. E xampl es of i sotopes that may be i ncorporated i nto the compounds of the i nventi on i ncl ude, but are not limited to 2H, 3H, 13C, 14C, 15N, 180, 170, etc. Compounds may exist in unsolvated forms as well as solvated forms, i ncluding hydrated forms. In general, compounds may be hydrated or solvated. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contempl ated herei n and are i ntended to be withi n the scope of the present i nventi on.
The use of the terms "a_ & "an_ & "the_ and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
The nomenclature of the compounds of the present invention as indicated herein is according to AC D Lab's/IU PAC name (Version 12.0).
"Pharmaceutically acceptable sal t_ refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with i norganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, isobutyric acid, hexanoic acid, cyclopentanepropionic acid, oxalic acid, glycol ic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, suberic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic 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, tri methyl acetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glucuronic acid, galactunoric acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanol amine, diethanol amine, tri ethanol amine, tromethamine (1,3-dihydroxy-2- (hydroxymethyl)propan-2-amine), choline (2-hydroxy-N,N,N-trimethylethanamine), N- methylglucamine, diethylamine (N-ethylethanamine) and the like. A lso included are salts of amino acids such as arginate and the like (see, for example, Berge, S.M., et al., "Pharmaceutical Salts_, J ournal of Pharmaceutical Science, 1977, 66, 1-19).
As used herein, the term "polymorph, pertains to compounds having the same chemical formula, the same salt type and having the same form of hydrate/sol vate but having different crystal I ographic properties.
As used herein, the term "hydrate, pertains to a compound having a number of water molecules bonded to the compound.
As used herein, the term "solvate, pertains to a compound having a number of solvent molecules bonded to the compound.
The present invention also encompasses compounds which are in a prodrug form Prodrugs of the compounds described herein are those compounds that readily undergo chemi cal changes under physi ol ogi cal condi ti ons ( i n vivo) to provi de the compounds of the present i nventi on. A dditi onal ly, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, for example, transdermal patch reservoir with a suitable enzyme or chemical. Prodrugs are, in some si tuati on, easi er to admi ni ster than the parent drug. T hey may, for i nstance, be bi oavai I abl e by oral admi ni strati on whereas the parent drug i s not T he prodrug may al so have i mproved solubility in pharmacological composition over the parent drug. Esters, peptidyl derivatives and the like, of the compounds are the examples of prodrugs of the present invention. In vivo hydrolysable (or cleavable) ester of a compound of the present invention that contains a carboxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid.
The term "substituted", as used herein, includes mono- and poly-substitution by a named substituent to the extent such si ngle and multiple substitution (including multiple substitution at the same site) is chemically allowed and which means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, for example, when a substituent is keto, then the two hydrogens on the atom are replaced. A 11 substituents ( R i, R2 ΰ .) and thei r further substituents described herein may be attached to the main structure at any heteroatom or carbon atom whi ch results i n f ormati on of stabl e compound.
As used herein, a "halo_ substituent is a monovalent halogen radical chosen from chloro, bromo, iodoandfluoro.
The term "cation, refers to an ion having a positive charge such as Na\ K\ Mg2+ ,
Ca2+, 1,3-di hydroxy-2-(hydroxymethyl)propan-2-amine, 2-hydroxy-N,N, N- tri methyl ethanamine, N-methylglucamine, N-ethylethanamine and the like.
The term "alkyl _ used either alone or in attachment with another group refers to aliphatic hydrocarbon radical having the indicated number of carbon atoms and that is unsubstituted or substituted with groups or substituents attached at any available atom to produce a stable compound. When a subscript is used with reference to an alkyl, the subscri pt refers to the number of carbon atoms that group may contai n. For example, a "(C r C6)alkyl" would refer to any alkyl group containing one to six carbons in the structure. Alkyl may be straight chain (for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl) or branched chain (for example, isopropyl, isobutyl, sec-butyl, tert-butyl). The said (Ci-C6)alkyl may also contain (C3-C6)cycloalkyl ring in a spiro manner.
T he term "cycl oal kyl _ used either al one or i n attachment with another group refers to a cyclic ring system having the indicated number of carbon atoms and that is unsubstituted or substituted with groups or substituents attached at any available atom to produce a stable compound. When a subscript is used with reference to a cycloalkyl, the subscript refers to the number of carbon atoms that group may contain. For example, the term "(C3-C8)cycloalkyl_ would refer to a cyclic ring system having 3 to 8 carbon atoms and that is unsubstituted or substituted. The said "(C3-Cs)cycloalkyl_ means a cyclic ring system containing only carbon atom in the ring system backbone such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Cycloalkyl may include bi cyclic rings. Cycloalkyl may have any degree of saturation provided that at least one ring in the ring system is not aromatic.
The term "alkenyl _ used either alone or in attachment with another group refers to aliphatic hydrocarbon having at least one carbon to carbon double bond having the indicated number of carbon atoms and that is unsubstituted or substituted with groups or substituents attached at any available atom to produce a stable compound. When a subscript is used with reference to an al kenyl, the subscri pt refers to the number of carbon atoms that group may contain. For example, the term "(C2-C6)alkenyl _ used either alone or in attachment with another group refers to al i phati c hydrocarbon radi cal havi ng 2 to 6 number of carbon atoms and having at least one carbon to carbon double bond. It can be straight chain or branched chain. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl and the I i ke.
T he term "al kynyl _ used either alone or i n attachment with another group refers to aliphatic hydrocarbon having at least one carbon to carbon triple bond having the indicated number of carbon atoms and that is unsubstituted or substituted with groups or substituents attached at any avai I abl e atom to produce a stabl e compound. W hen a subscri pt i s used with reference to an al kynyl , the subscri pt refers to the number of carbon atoms that group may contai n. T he term "(C2-C6)al kynyl _ used either alone or i n attachment with another group refers to al i phati c hydrocarbon radi cal havi ng 2 to 6 number of carbon atoms and havi ng at least one carbon to carbon triple bond. It can be straight chain or branched. Examples of alkynyl groups include ethyny I, propynyl, butynyl, and the like.
T he term "aryl" used either alone or i n attachment with another group refers to an aromatic group for example, which is a 6 to 14 membered monocyclic, bicyclic or tricyclic carbon-containing ring system The aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, tetrahydronaphthyl and indane. The said aryl may be optionally substituted with groups or substituents attached at any available atom to produce a stable compound.
The term "heteroaryl" used either alone or in attachment with another group refers to an aromatic group for example, which is a 5 to 14 membered monocyclic, bicyclic or tricyclic ring systenri which has at least one heteroatom The term "heteroatom" as used herein includes 0, N, S. In fused ring system, ring can be fused through a bridge heteroatom The heteroaryl groups include, but are not limited to pyrrolyl, furanyl (furyl), thiophenyl (thienyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (pyridyl), pyridazinyl, pyrimdinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl (benzothienyl), indazolyl, benzimidazol, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, acridine, phenothiazine, dibenzo[b,d]thiophene, furopyridi nyl, thienopyridinyl, pyrazolopyridinyl or naphthyridinyl. The said heteroaryl may be optionally substituted with groups or substituents attached at any avail able atom to produce a stable compound.
T he term " heterocycl oal kyl " used either al one or i n attachment with another group refers to a fully or partially saturated cyclic group, for example, which is a 3 to 14 membered monocyclic, bicycl ic or tricyclic ring systern which has at least one heteroatom and at least one ring is not aromatic. The term "heteroatom" as used herein includes 0, N, S. Heterocycl oal kyl groups include, but are not limited, oxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolidi nyl, dihydropyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, triazolidinyl, oxadiazolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, dioxanyl, morpholinyl, triazinanyl, azepanyl, diazepanyl, diazepinyi, oxepanyl, dioxepanyl, oxazepanyl, oxazepinyl, indol inyl, benzomorpholinyl, tetrahydroquinolyl tetrahydroi soqui noly I , di hy droi soqui nol i ny I , di hydrothi enopy ri di ny I , tetrahydrothienopyridine, 2-azaadamantane, tryptolines, tetrahydrocarbazole. thiomorpholinedi oxide or thiomorpholinyl. The said heterocycl oal kyl may be optionally substituted with groups or substituents attached at any available atom to produce a stable compound. The terms "heterocycl oal kyl _ and "heterocycle_ can be used interchangeably.
The term "Hydroxyl" or "hydroxy, refers to the group -OH.
T he term "oxo_ refers to oxygen atom double bonded to carbon or sul phur.
T he term "aral kyl _ refers to an al kyl group substituted with one or more aryl groups at any available atom to produce a stable compound. The meaning of terms "alkyl _ and "aryl _ are as defined above.
The term "alkoxy_ used either alone or in attachment with another group refers to any alkyl group having the indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. When a subscript is used with reference to an alkoxy, the subscript refers to the number of carbon atoms that group may contain. For example, a "(Ci-C6)alkoxy" would refer to any alkoxy group containing one to six carbon atoms in the structure. The said (Ci-Ce)alkoxy may also contain (C3-C6)cycloalkyl ri ng in a spiro manner. The alkyl group in said al koxy may be straight chain or branched and it may contain one or two double or triple bonds. The said alkyl group may be further substituted with one or more substituents such as halo, aryl, heteroaryl, cycloalkyl or heterocycloalkyl. Examples of substituted alkoxy group includes but not limited to OC H F2, -OC F3, -0-CH2-heteroaryl or -0-C H2-aryl.
As used herei n, "room temperature, refers to a temperature between 200 C and 30
° C.
As used herei n, the term "mammal _ means a human or an ani mal such as monkeys, primates, dogs, cats, horses, cows, etc.
The terms "treating, or "treatment, of any disease or disorder as used herein to mean completely or partially preventing or delaying the onset of a disease or disorder or sign or symptom thereof; and/or partially or completely curing or ameliorating a disease or di sorder and/or adverse effect attri butabl e to the di sorder.
The phrase "a therapeutically effective amount" means the amount of a compound that when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, mode of administration, the disease and its severity and the age, weight, etc., of the pati ent to be treated.
Throughout this specification and the appended claims, it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwi se. T hat i s, the use of these words may i mply the i ncl usi on of an el ement or el ements not specifically recited.
In another embodiment present invention provides the process for preparing the compounds of formula (1).
The followi ng reaction schemes are given to disclose the synthesis of the compounds accordi ng to the present i nventi on.
Accordingly, the compounds of formula (1) of the present invention may be prepared as descri bed in the schemes below.
Illustrative embodiments of compounds of formula (1) include compounds of formula 1a, formula 1 b, formula 1 c, formula 1 d, formula 1e, formula 1f, formula 1g, formula 1 h, formula 1 i, formula 1j, formula 1 k, formula 11, formula 1 m, formula 1 n and 1 o, in which the substituents are as defined in connection with general formula (1) and schemes 1-5. Scheme 1
Process for preparation of compounds of formula 1a and 1 b, where Y is OZ and Z is H, R2 can be (CrC6)alkyl, halo, -N02, heterocycloalkyl, C F3, (Ci-Ce)alkoxy, -S-(Ci-C6)alkyl, - S02-(CrC6)alkyl, -S02N R6R? and R, R ~ Ri, R3, R4, R5, R6, R7, L, Ring A, m and n are as defined in formula (1), is represented in Scheme 1.
Scheme-1
Figure imgf000022_0001
The compound of formula 1a, wherein Ring A is heterocycloalkyl attached through hetero atom "N _ to ~S02(L), can be prepared by alkali ne hydrolysis of compound IX a in presence of a suitable base like alkali hydroxide such as sodium hydroxide or lithium hydroxide and a suitable solvent such as methanol, tetrahydrofuran, di methyl formamide, water or mixture thereof. The compound of formula IX a can be prepared from compound of formula VIII by amidation using a suitable amine of formula XV, in presence of a suitable base such as pyridi ne or tri ethyl ami ne and a suitable solvent such as tetrahydrofuran or dichloromethane or mixture thereof. The compound of formula 1 b can be prepared by amidation of compound of formula VIII using a suitable amine of formula XV I, in presence of a suitable base such as pyridi ne or triethylamine and a suitable solvent such as tetrahydrofuran or dichloromethane or mixture thereof which is followed by alkaline hydrolysis in presence of a suitable base like alkali hydroxide such as sodium hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethyl formamide, water or mixture thereof. The compound of formula VIII can be prepared by chlorosulfonation of compound of formula VII using mixture of chlorosulfonic acid and thionyl chloride in a suitable solvent The compound of formula VII can be prepared by N-al kylation of compound of formula Via with suitable halo-derivative such as Br(CR R ")nCOOEt in presence of a suitable base like metal carbonate such as cesium carbonate and a suitable solvent such as tetrahydrofuran, di methyl formamide or mixture thereof. T he compound of formula V la can be prepared by cyclization of compound of formula Va with hydrazine hydrate in a suitable solvent such as dimethyl formamide, di methyl acetamide, dimethylsufoxide or mixture thereof, under heating. The compound of formula V a can be prepared by reacting compound of formula IV a with Lawesson s reagent i n a suitable solvent such as toluene under heating conditions. T he compound of formula IV a can be prepared from compound of formula II using suitable compound of formula Ilia in presence of base such as triethylamine and a suitable inert solvent such as dichloromethane.
Scheme-2 Process for preparati on of C ompounds of formula 1 c, 1 d, 1 e and 1 f i s represented i n scheme 2.
S cheme-2
Figure imgf000024_0001
20
25
The compound of formula 1c, where Y is OZ and Z is H, Ring A can be aryl, heteroaryl or cycloalkyl, L is S02, R2 can be (Ci-Ce)alkyl, halo, -N02, heterocycloalkyl, C F3, (Ci- C6)alkoxy, -S-(Ci-C6)alkyl, -S02-(Ci-C6)alkyl, -S02NR6R7 and R, R ", Ri, R3, R4, R6, Ry, m and n are as defined in formula (1), can be prepared by alkaline hydrolysis of compound of formula IX b in presence of a suitable base li ke alkali hydroxide such as sodium hydroxide or lithium hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
The compound of formula 1 d where Ring A can be aryl; Rs can be (CrC6)alkyl, (C3- C8)cycloalkyl, aryl, heteroaryl, heterocycloal kyl, 0-(C i-C6)alkyl, -0-(C3-C8)cycloalkyl, - O-aryl, -O-heteroaryl or -0- heterocycloalkyl; R, R R i, R2, R3, Y , m and n are as defined in formula 1c, can be prepared by alkal ine hydrolysis of compound of formula X I where RingA is aryl, in presence of a suitable base I ike alkali hydroxide such as sodium hydroxide or lithium hudroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
The compound of formula X I can be prepared from formula X by reacting suitable acid chloride or suitable chloroformate or coupling of suitable carboxylic acid using coupling reagent in presence of base such as triethylamine in presence of a suitable solvent such as dichloromethane.
The compound of formula le where R6 and R7are as defined in formula (1); Ring A, R, R ~ R i, R2, R3, Y , mand n are as defined in formula 1 d, can be prepared by reacting compound of formula X with a suitable carbamoyl chloride in presence of a suitable base such as tri ethyl amine and a suitable solvent followed by alkaline hydrolysis in presence of a suitable base li ke alkali hydroxide such as sodium hydroxide or lithium hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
T he compound of formula 1f where RingA, R, R ~ R i, R2, R3, Rs, Y , m and n are as def i ned in formula 1 d, can be obtained by treating compound of formula X with a suitable sulfonyl chloride in presence of a suitable base such as triethylamine and pyridine and a suitable solvent, followed by alkaline hydrolysis in presence of a suitable base I ike alkali hydroxide such as sodium hydroxide or lithi um hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
The compound of formula X where Ring A is aryl, can be prepared by reduction of nitro group of compound of formula IX b where R4 is nitro, n is 1 and Ring A is aryl using hydrogen and pal ladi um catalyst or usi ng ti n chl oh de i n a sui tabl e solvent such as methanol . The compound of formula IX b can be prepared by N-alkylation of compound of formula VIb with suitable halo- derivative such as Br(CRR ")nCOOEt in presence of a suitable base like metal carbonate such as cesium carbonate and a suitable solvent such as tetrahydrof uran, di methylformami de or mixture thereof. T he compound of formula V lb can be prepared by cyclization of compound of formula V b using hydrazine hydrate in a suitable solvent such as di methylformami de, dimethyl acetamide, dimethyl suf oxide or mixture thereof under heating conditions. The compound of formula V b can be prepared from compound of formula IV b using Lawesson s reagent in presence of a suitable solvent such as toluene under heating conditions. The compound of formula IV b can be prepared from compound of formula II usi ng compound of formula Illb i n presence of base such as tri ethyl amine and an inert solvent such as dichloromethane.
Scheme -3
Process for preparation of compounds of formula 1g, 1 h, 1 i, 1j and 1 k is represented in scheme 3.
Scheme-3
Figure imgf000027_0001
T he compound of formula 1 g, 1 h and 1 i can be prepared from compound of formula X II which is obtained by reduction of nitro group of compound of formula IX a where m is 1 and R2 is nitro group, in presence of Palladium catalyst or tin chl oh de and a suitable solvent.
The compound of formula 1g, where Rs can be (CrC6)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl, heterocycloalkyl, (Ci-Ce)alkoxy, -0-(C3-Cs)cycloalkyl, -O-aryl, -O-heteroaryl or -O-heterocycloalkyl; L is S02, Y is OZ and Z is H, R, R ", Ri, R3, R4, and n are as defined in formula (1) can be obtained from compound of formula X II by reacting with suitable acid chloride or suitable chloroformate or coupling of suitable carboxylic acid using coupling reagent in presence of a suitable base such as tri ethyl amine and a suitable solvent such as tetrahydrofuran, dichloromethane or mixture thereof, followed by alkaline hydrolysis in presence of suitable base like alkali hydroxide such as sodium hydroxide or lithium hydroxide and a suitable solvent such as tetrahydrofuran, methanol, water or mixture thereof.
The compound of formula 1 i, where R6 and R7 are as defined in formula (1); L, Y , R, R ~ Ri, R3, R4 and n are as defined in formula 1g can be prepared by reacting compound of formula X II with a suitable carbamoyl chloride in presence of a suitable base such as triethylamine and a suitable solvent such as dichloromethane, followed by alkaline hydrolysis in presence of a suitable base and a suitable solvent Similarly, the compound of formula l h, whereY , R, R ", Ri, R3, R4, Rs and n are as defined in formula 1g can be obtained by treating the compound of formula X II with suitable sulfonyl chloride in presence of a suitable base such as triethylamine or pyridine and a suitable solvent such as dichloromethane, followed by alkaline hydrolysis.
The compound of formula 1 k, where R2 can be aryl, heteroaryl or alkenyl; L, Y , R, R ~ Ri, R3, R4 and n are as def i ned i n formula 1 g can be prepared by reacti ng compound of formula IX a where R2 is bromo and m is 1, with suitable ary I or heteroaryl boronic acid under suzuki reaction conditions using palladium catalyst; or with suitable alkene derivative in presence of base and palladium catalyst and a suitable solvent such as DM F, followed by alkaline hydrolysis.
The compound of formula 1j, where L, Y , R, R ~ Ri, R3, R4 and n are as defined in formula 1g can be prepared by reacting compound of formula IX a with suitable acetylene derivative using palladium catalyst applying sonoghasira reaction conditions followed by alkaline hydrolysis.
Scheme-4 Process for preparation of compounds 11, 1 m, 1 n and 1 o is represented i n Scheme 4. -4
Figure imgf000029_0001
20
T he compound of formula 11, where L is S02,Y is 'OZ and Z is H, R2 can be (Ci-C6)alkyl, halo, -N02, heterocycloalkyl, C F3, (Ci-Ce)alkoxy, -S-(CrC6)alkyl, -S02-(CrC6)alkyl; R, R Ri, R3, m and n are as defined in formula (1) can be prepared by reacting compound of formula X III with a suitable acid chloride in presence of a suitable base such as Triethylamine and a suitable solvent such as dichloromethane, followed by alkaline hydrolysis. The compound of formula 1 m, where L,Y , R, R ~ Ri, R2, R3, m and n are as defined i n formula 11, can be prepared by amidation of compound of formula X III using a suitable sulfonyl chloride in presence of a suitable base such as tri ethyl amine or pyridine and a suitable solvent such as dichloromethane, followed by alkaline hydrolysis.
T he compound of formula X III can be prepared from compound of formula IX c where ri ng A is piperazine (Heterocycloalkyl) and R4 is t-butyloxycarbonyl group, n is 1, by removal of t-butyl oxycarbonyl group from pi perazi ne of compound of formula IX c i n presence of a suitable acid such as trifluoroacetic acid and a suitable solvent such as dichloromethane. The compound of formula 1 n, where Y is "OZ and Z is H, L is S02, Ring A is heterocycloalkyl attached through hetero atom "N _ to "S02; R, R ~ R i, R3, R4, m and n are as defined in formula (1) can be prepared by reacting compound of formula IX c where R2 is alkoxy, with boron tribromide in presence of a suitable solvent such as dichloromethane followed by alkaline hydrolysis.
The compound of formula 1 o, where R2 can be alkyl, halo, -N02, heterocycloalkyl, CF3, (C i-Ce)alkoxy, -S-(C i-C6)alkyl, -S02-(C i-C6)alkyl; L, Y , Ring A, R, R ", Ri, R3, R4, m and n are as def i ned i n f ormul a 1 n, can be prepared from compound of f ormul a IX c by al kal i ne hydrolysis. The compound of formula IX c can be prepared by N-alkylation of compound of formula Vic using a suitable halo-derivative such as Br(C RR ")nCOOEt in presence of a suitable base l ike metal carbonate such as cesium carbonate in suitable solvent such as tetrahydrofuran, di methyl formamide under suitable conditions. The compound of formula Vic can be prepared by cyclization of compound of formula V c using hydrazine hydrate in a suitable solvent such as dimethyl formamide, dimethyl acetamide or mixture thereof under heating conditions. T he compound of formula Vc can be prepared by reacting compound of formula IV c with Lawesson's reagent i n a suitable solvent such as tol uene under heati ng conditions. The compound of formula IVc can be prepared by reacting compound of formula II with compound of formula IIIc in presence of a suitable base such as tri ethyl amine in a suitable solvent such as dichloromethane.
Scheme 5 Scheme-5
Figure imgf000031_0001
1
1
15
An alternate process for preparation of compound 1 c where Ring A can be cycloalkyl or aryl; R2 can be (Ci-C6)alkyl, halo, -N02, heterocycloalkyl, CF3, (Ci-Ce)alkoxy, -S02-(Ci- C6)alkyl, -S02N R6R7, Y is -OZ and Z is H; R, R ~ Ri, R3, R4, m and n are as defined in formula (1), is represented in scheme 5. The compound of formula 1 c can be prepared by alkaline hydrolysis of compound of formula IX b in presence of a suitable base like alkali hydroxide such as sodium hydroxide or lithi um hydroxide and a suitable solvent such as methanol, tetrahydrofuran, dimethylformamide, water or mixture thereof.
The compound of formula IX b can be prepared from compounds of formula X IV by oxidation of Sulphur atom using suitable oxidizing agent such as m-chloro perbenzoic acid in a suitable solvent such as dichloromethane. The compound of formula X IV can be prepared by N-alkylation of compound of formula VId with suitable halo-derivative such as Br(CRR ")nCOOEt in presence of a suitable base like metal carbonate such as cesium carbonate in suitable solvent such as tetrahydrofuran, dimethylformamide. The compound of formula VId can be prepared by reacting compound of formula IV d with Lawesson s reagent in presence of a suitable solvent such as toluene, followed by cyclization reaction using hydrazine hydrate in presence of a suitable solvent such as dimethylacetamide or dimethylsulfoxide or mixture thereof under heating. The compound of formula IV d can be prepared by reacting compound of formula II with compound of formula Hid in presence of a suitable base such as triethylamine and a suitable solvent such as dichloromethane. Compounds of formula (1), wherein Y is OZ and Z is cation, can be readily prepared by a ski 11 ed person by f ol I owi ng any of the schemes 1 to 5.
Alternative to the given schemes, one of ordinary skill will readily synthesize the compounds according to the present invention using conventional synthetic organic techniques from suitable starting material which are either commercially available or may be readily prepared.
It would be obvious to one skilled in the art that variations in reaction time, temperature, solvents and/or reagents could increase the yields.
The compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers.
In present specification some general terms are used with their known intended meaning which are defined herein below:
T HF Tetrahydrofuran
DM F Dimethylformamide
MeOH Methanol
RT Room temperature
T FA Trifluoroacetic acid
DMSO Dimethyl sulfoxide
ESMS Electrospray Mass Spectrometry
ESI E I ectro spray i oni zati on
A PCI Atmospheric pressure chemical ionization NM R Nuclear magnetic resonance
FITC Fluorescein isothiocyanate
IgE Immunoglobulin E
Mg Milligram
L microlitre
A NOVA Analysis of variance
DP2 Prostaglandin D2 receptor 2
CHO-K1 Chinese hamster ovary " K1 cells
G 16 gene encoding a G protein alpha subunit
E DTA Ethylene diamine tetra acetic acid
DM E M Dulbecco's Modified Eagle's Medium
PBS Phosphate buffer sal i ne
H E PES 4-(2- hydroxyethy I ) - 1 - pi peraz i ne
ethanesulfonic acid
M micromolar
NA Not available
Mass of compounds prepared according to present invention is measured using Single quadrupole mass spectrometer (Water ZQ 2000 instrument) using A PCI ionization technique (E lectro spray chemical ionization Probe) or Finnigan LX Q, thermo instrument Technique using either ESI or A PCI.
The novel compounds of the present invention were prepared according to the procedure of the schemes as described herein above, using appropriate materials and are further exemplified by the following specific examples. The examples are not to be consi dered or construed as I i mi ti ng the scope of the i nventi on set forth. EXAM PL E S:
E xample 1 : Synthesis of (5-fluoro-3-{methyl [4-(pyr rolidin-1-ylsulfonyl) phenyl] ami no}-1 H -indaz -1-yl) acetic acid. (C ompound no. 5)
Figure imgf000034_0001
ST E P-1 : Synthesis of 2, 5-difluoro-N-methyl-N-phenylbenzamide
Triethylamine (172ml, 1.7mol) was added to a solution of N-methylaniline (111 ml, 0.87mol) in dichloromethane (750ml) and the reaction mixture was cooled to 0°C. A solution of 2, 5-dif I uorobenzoyl chloride (150gm, 0.85mol) in dichloromethane (150ml) was added drop wise and the reaction mixture was stirred for 1 hour at room temperature. T he reacti on mixture was di I uted with 2N hydrochl ori c aci d and then it was extracted with dichloromethane. The obtained organic layer was washed with water, followed by sodium bicarbonate solution. It was dried over sodium sulphate and concentrated under reduced pressure to provi de 195 gm of sol i d.
Ί Η-ΝΜ Ρ,(400 M Hz,DMSO-d6): 7.06-7.26 (8H,m),3.36(3H,s)
ESMS: 248.07 (M++1)
ST E P-2: Synthesis of 2,5-difluoro-N-methyl-N-phenyl benzene carbothioamide Lawesson s reagent (222gm, 0.55mol) was added to a solution of 2, 5-difluoro-N-methyl- N-phenylbenzamide (226gm, 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 then 3.4 liter of isopropyl alcohol was added. The reaction mixture was heated to 85°C for 30 minutes and allowed to cool at room temperature under stirring. A yellow crystalline solid was thus obtained, filtered off, washed with isopropyl alcohol and dried to obtain 180 gm of yellow crystalline sol id.
1 H-NM R(400 M Hz,DMSO-d6): 6.92-7.27 (8H, m), 3.81 (3H, s)
ESMS: 264.01 (M++1) ST E P-3: Synthesis of 5-fluoro-N-methyl-N-phenyl-1 H -indazol-3-amine
99% hydrazine hydrate (332 ml) was charged to a solution of 2, 5-difl uoro-N- methyl -N- phenyl benzenecarbothioamide (180gm, 0.68 mol) in di methyl acetamide (2160 ml) and the reaction mixture was heated at 120°C for 80 hours. The reaction mixture was cooled to room temperature and poured i nto 6.6 1 iter of water and sti rred for one hour. T he obtai ned solid was filtered off, washed with water and dried. The solid material obtained was then suspended i n 720 ml of n-hexane and stirred for 30 minutes. It was filtered off and dried under vacuum to provi de 142 gm sol i d.
1 H-NM R(400M Hz,D MSO-d6): 12.63(1 H,s), 7.48-7.52 (1 H,m), 7.18-7.26 (3H,m), 6.88- 6.91 (3H,m), 6.70-6.73 (1 H,m),3.57(3H,s)
ESMS: 242.07 (M++1)
ST E P-4: Synthesis of E thyl {5-fluoro-3-[methyl(phenyl)amino]-1 H -indazol-1- yl}acetate
Cesium carbonate (288gnri0.88mol) was added to a sti rred solution of 5-fl uoro-N- methyl - N-phenyl-1 H-indazole-3-amine (142 gm,0.59 mol) in dimethylformamide (430ml) and allowed to cool upto 0-5eC. A solution of ethyl bromoacetate (88.5ml ,0.77mol) in dimethylformamide (80ml) was added dropwise and sti rred for 3 hours at room temperature. Reaction mass was filtered off and washed with ethyl acetate. To the filtrate, 1.5 liter of water was added and extracted with ethyl acetate (2 liters). The organic layer was washed with water, dri ed over sodi um sul phate and concentrated to provi de 212 gm of crude material. T he obtained crude material was then dissolved in 215 ml of isopropyl al cohol and al I owed to cool upto 0-5°C . 280ml of heptane was added and sti rred. T he sol i d thus obtained was filtered off, washed with heptane and dried under vacuum to provide 140gm of solid.
Ί Η-ΝΜ Ρ,(400 MHz,DMSO-d6): 7.64(1 H,m), 7.24-7.30 (3H,m), 6.95-6.99(3H,m), 6.63 - 6.66 (1 H,m), 5.29(2H,s), 4.15 (2H,q), 3.38(3H,s), 1.19 (3H,t)
ESMS: 328.1 (M++1)
ST E P-5: Synthesis of ethyl (5-fluoro-3-{methyl[4-(pyrrolidin-1-ylsulfonyl)phenyl] ami no}-1 H -indazol-1-yl)acetate ST E P 5a: Synthesis of ethyl (3-{[4-chlorosulfonyl)phenyl](methyl)ami no}-5-fluoro- 1 H-indazol-1-yl)acetate
Thionyl chloride (60 ml, 0.854mol) was added to chlorosulfonic acid (45 ml, 0.676mol) at 0-5°C, and the mixture was stirred for 15 minutes. A solution of ethyl { 5-fluoro-3-[methyl (phenyl) amino]-1 H-indazol-1-yl} acetate (40 gm, 0.122mol) in dichloromethane (30 ml) was si owly added to the prepared mi xture and al I owed to warm to room temperature. It was stirred for 3 hours. The reaction mixture was poured into 500gm of crushed ice under stirring which was then extracted with 1000ml dichloromethane. The organic phase was washed with water, dried over sodium sulphate and concentrated to provide 54 gm of viscous liquid.
ST E P 5b: Synthesis of ethyl (5-fluoro-3-{methyl [4-(pyrrolidin-1 -ylsulfonyl) phenyl] ami no}-1 H -indazol-1-yl) acetate
Tri ethyl amine (27 ml, 0.19mol) was added to a stirred solution of pyrrolidine (12.26ml, 0.127mol) in 200ml of dichloromethane and allowed to cool upto 0-5°C. A solution of sulfonyl chloride (54gm, 0.127) (product obtained in the step 5a) in 100ml of dichloromethane was added to the prepared reaction mixture and stirred for 2 hours. The reaction mixture was then poured into water and acidified by dilute hydrochloric acid and then extracted with 700ml of dichloromethane. T he organic layer was washed with water, dried over sodium sulphate and concentrated to provide viscous liquid. The obtained viscous liquid was adsorbed on silica gel and then it is extracted with ethyl acetate (1.5Νζ t i ce ). T he ethyl acetate was disti 11 ed off under reduce pressure to provi de a vi scous liquid which was crystallized from isopropyl alcohol to provide 32 gm of ethyl (5-fluoro-3- { methyl [4-(pyrrolidi n-1 -ylsulfonyl)phenyl] ami no} -1 H-i ndazol-1 -yl)acetate as sol id. Ί Η-ΝΜ Ρ,(400 MHz,DMSO-d6): 7.76-7.79 (1 H,m), 7.61 (2H,d), 7.34-7.39 (1 H,m), 7.15- 7.18(11-1, 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)
ST E P-6: Synthesis of (5-fluoro-3-{ methyl [4-(pyrrolidin-1-ylsulfonyl) phenyl] ami no}-1 H -indazol-1-yl) acetic acid
Aqueous solution of sodium hydroxide (11.2 gm ,0.28mol) was added to a stirred sol ution of ethyl (5-fluoro-3-{ methyl[4-(pyrrolidin-1-ylsulfonyl)phenyl]amino}-1 H-indazol-1- yl)acetate (64gm ,0.14mol) in 190 ml of tetrahydrofuran at 15-20°C, and sti rred for 30 minutes at room temperature. The reaction mass was acidified with 2N hydrochloric acid and extracted with 1.0 1 itre of ethyl acetate. T he organi c layer was washed with water, dried over sodium sulphate and concentrated to provide foamy solid which was triturated in i sopropyl acetate to provi de a 44 gm of titl e compound as sol i d.
1 H-NM R(400 M Hz,DMSO-d6): 7.75-7.79 (1 H,m),7.61 (2H,d), 7.33-7.38 (1 H,m), 7.14 -7.17 (1 H,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) E xample-2: Synthesis of {5-fluoro-3-[methyl(4-{[4-(pyridin-2-yl)piperazin-1- yl]sulfonyl}phenyl)ami no]-1 H -indazol-1-yl}acetic acid (C ompound no. 36)
Figure imgf000037_0001
ST E P-1 : synthesis of ethyl {5-fluoro-3-[methyl (4-{[4-(pyridin-2-yl)piperazin-1- yl]sulfonyl}phenyl)ami no]-1 H -indazol-1-yl}acetate
Triethylamine (27 ml ,0.19mol) was added to a solution of 1-(2-pyridyl)pi perazine (22gm,0.139mol) in 200ml of dichloromethane and allowed to cool at 0-5°C. To this reaction mass, a solution of the ethyl (3-{ [4-chlorosulfonyl)phenyl](methyl) amino}-5- fluoro-1 H-indazol-1-yl)acetate (52gm) (obtained in the step 5a of example-1) in 300ml of dichloromethane was slowly added and stirred for 2 hours at room temperature. The reaction mass was diluted with dilute hydrochloride and extracted with 700ml of dichloromethane. The organic layer was washed with water, dried over sodium sulphate and concentrated to provide viscous liquid. The obtained viscous liquid was adsorbed on silica gel and then extracted with ethyl acetate (1.01 ίζ twice). The ethyl acetate was distil led off under reduced pressure to yield a viscous liquid which was crystallized from methanol (200ml) to provide 35 gm of white solid. 1 H-N R(400 Hz,D SO-d6): 8.07-8.08 (1 H,s), 7.76-7.79 (1 H,m), 7.49-7.56 (3H,m), 7.34-7.39 (1 H,m), 7.19-7.21 (1 H,m), 6.95 (2H,d), 6.79-6.81 (1 H,m), 6.63-6.66 (1 H,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 )
ST E P-2: Synthesis of {5-fluoro-3-[methyl(4-{[4-(pyridin-2-yl)piperazin-1- yl]sulfonyl} phenyl)amino]-1 H-i ndazol-1-yl}acetic acid
To a stirred solution of ethyl ester obtained in step-1 (29 gm ,52.4mmol) in 30 ml tetrahydrof uran and 90 ml methanol , 10 ml of aqueous sol uti on of sodi um hydroxi de (3gm ,75mmol) was slowly added at room temperature. The reaction mixture was stirred for 1 hour at room temperature and evaporated to dryness. The resulted residue was stirred in 900ml ethyl acetate and filtered to provide white powder which was dissolved in water and acidified with acetic acid. The precipitate thus obtained was filtered, washed well with water and dried to provide 23 gm of the title compound as solid.
1 H-NM R(400 M Hz,DMSO-d6): 13.14 (1 H, bs) 8.07 (1 H,m), 7.75-7.78 (1 H,m), 7.51-7.56 (3H,m), 7.32-7.37 (1 H,m), 7.17-7.20 (1 H,m), 6.95(2H,d), 6.81 (1 H,d), 6.63- 6.67(1 H,m), 5.26(2H,s), 3.57(4H,m), 3.44(3H,s),2.92(4H,m)
ESMS: 525.3(M++1) E xample-3 :Synthesis of {5-fluoro-3-[methyl (4-{[4-(methylsulfonyl) piperazin-1- yl]sulfonyl}phenyl)ami no]-1 H -indazol-1-yl}acetic acid (C ompound no. 23)
Figure imgf000038_0001
ST E P-1 : synthesis of tert-butyl 4-[(4-{[1-(2-ethoxy-2-oxoethyl)-5-fluoro-1 H-indazol-
3-yl](methyl)amino}phenyl)sulfonyl] pi perazine-1-carboxylate
Triethylamine (0.2 ml, 1.5mmol) was added to a stirred solution of N-Boc-piperazine
(130nrg, 76mmol) in 20ml of dichloromethane and allowed to cooled to 0-5°C. To this solution, a solution of ethyl (3-{ [4-chlorosulfonyl) phenyl](methyl)amino}-5-fluoro-1 H- indazol-1-yl)acetate (325mg, 0.76mmol) (obtained in step- 5a of example-1) in 10ml of dichloromethane was added and stirred for 2 hours. The reaction mass was diluted with water and acidified with dilute hydrochloric acid and then extracted with 50ml of dichloromethane. T he organic phase washed with water, dried over sodium sulphate and concentrated to provide 00mg of off white solid.
Ί Η-ΝΜ Ρ,(400 M Hz,DMSO-d6): 7.77 -7.80 (1 H,m), 7.54 (2H,d), 7.35 -7.40 (1 H,m), 7.18-7.20 (1 H,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)
ST E P-2: Synthesis of ethyl {5-fluoro-3-[methyl(4-{[4-(methylsulfonyl)pi perazin-1- yl]sulfonyl}phenyl)ami no]-1 H -indazol-1-yl}acetate
2ml of trif I uoroaceti c aci d was added to a sti rred sol uti on of compound obtai ned i n step-1 (400nrg) in 2ml of dichloromethane and stirred for one hour. The reaction mixture was basified with dilute sodium carbonate solution and extracted with dichloromethane. The organic layer was concentrated to provide 300mg of white solid. The obtained solid was dissolved in 15 ml of dichloromethane, triethylamine (0.2ml) was added to it and allowed to cool up to 0-5°. To the reaction mixture, methane sulfonyl chloride (0.1 ml) was added and stirred for 2 hours. The reaction mass was diluted with water and acidified with dilute hydrochloric acid which was then extracted with 20ml of dichloromethane. The organic I ayer was washed with water, dri ed over sodi um sul phate and concentrated to obtai n crude mass which was purified by column chromatography to give 300mg of title compound. 1 H-NM R(400M Hz,D MSO-d6): 7.77-7.80 (1 H,m), 7.55 (2H,d), 7.35-7.40 (1 H,m), 7.22- 7.25 (1 H,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)
ST E P 3: Synthesis of {5-fluoro-3-[methyl (4-{[4-(methylsulfonyl) piperazin-1-yl] sulfonyl}phenyl)amino]-1 H -indazol-1-yl}acetic acid
The compound obtained i n step-2 was dissolved in 15 ml of ethanol and 2ml of aqueous lithium hydroxide (27mg, 1 mmol) was added. The reaction mixture was stirred, diluted with cold water and acidified with dilute hydrochloric acid. The solid thus obtained was filtered off, washed with water and suck dried to give 160 mg of title compound.
1 H-N R(400 Hz,D SO-d6): 13.16(11-1, bs), 7.77(11-1, m), 7.55(21-1, m), 7.36(11-1, m), 7.23(1 H,m), 6.97(2H,m), 5.27(2H,s), 3.46(3H,s), 3.19(41-1, m), 2.88-2.94(7H,m)
ESMS: 526.2(M++1)
E xample-4: Synthesis of (5-chloro-3-{methyl[3-(morpholin-4- ylsulfonyl)phenyl]amino}-1 H -indazol-1-yl)acetic acid (C ompound no. 3)
Figure imgf000040_0001
ST E P-1 : Synthesis 5-chloro-N-methyl-N-[3-(morpholin-4-ylsulfonyl)phenyl]-1 H - indazol-3-amine
To a stirred solution of N-methyl-3-(morpholin-4-ylsulfonyl)aniline (2.2gm, 8.6mmol) in dichloromethane, tri ethyl amine (4 ml ,27.7mmol) was added and allowed to cool upto 0°C. To the reacti on mixture, a sol uti on of 5-chl oro-2-f I uorol benzoyl chl ori de ( 1.8gm, 9.3mmol ) in dichloromethane was added in drop wise manner and stirred for 1 hour at 30°C. The reaction mixture was diluted with 2N hydrochloric acid and extracted with dichloromethane. T he organic layer was washed with water, followed by sodium bicarbonate solution and then dried over sodium sulphate. It was concentrated under reduced pressure to provide 3.6 gm of 5-chloro-2-fluoro-N-methyl-N-[3-(morpholin-4- ylsulfonyl) phenyl] benzamide.
To a solution of obtained 5-chloro-2-fluoro-N-methyl-N-[3-(morphol in-4-yl sulfonyl) phenyl] benzamide (3.6gm, 8.7mmol) in 15 ml toluene, Lawesson s reagent (3.8gnri 9.4mmol) 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 (50ml). The organic phase was washed with water, dried over sodium sulphate and concentrated under reduced pressure to give a crude mass. The obtained crude mass was purif i ed by col umn chromatography usi ng ethyl acetate and hexane to provi de 3.6 gm sol i d of 5-chloro-2-fluoro-N-methyl-N-[3-(morpholin-4-ylsulfonyl)phenyl] benzene carbothioamide
To a solution of obtained 5-chloro-2-fluoro-N-methyl-N-[3-(morpholin-4- ylsulfonyl)phenyl] benzene carbothioamide (3.6gm, 8.4mmol) in 20 ml of dimethylsulfoxide, 99% hydrazine hydrate (4 ml, 84mmol) was added and heated to 100°C for 6 hours. T he reacti on mixture was al I owed to cool to room temperature and poured i nto 50ml of water and stirred for 20 minutes. The obtained solid was filtered off, washed with water and dri ed under vacuum. T he resul ted sol i d was agai n suspended i n i sopropy I al cohol and stirred for 15 minutes. It was filtered off and dried to provide 1.2 gm of 5-chloro-N- methy I - N - [ 3-( morphol i n-4-y I sul f ony I ) pheny I ] - 1 H - i ndazol - 3- ami ne as sol i d.
Ί Η-ΝΜ Ρ,(400 M Hz,DMSO-d6): 7.47-7.59 (2H,m), 7.36-7.39 (1 H,m), 7.32(11-1, m), 7.24- 7.26 (1 H,m), 7.14-7.17 (1 H,m), 7.05(1 H,m), 3.59-3.62 (4H,m), 2.80-2.81 (4H,m).
ESMS: 404.9(M+-1)
ST E P-2: Synthesis of ethyl (5-chloro-3-{methyl[3-(morpholin-4-ylsulfonyl)phenyl] ami no}-1 H -indazol-1-yl)acetate
To a stirred solution of 5-chloro-N-methyl-N-[3-(morpholin-4-ylsulfonyl) phenyl]-1 H- i ndazol -3-amine (600nrg ,1.5mmol) in 20ml of dimethylformamide, cesium carbonate (720gm ,2.2mmol) was added and allowed to cool upto 0-5eC. To this suspension, a 2 ml solution of ethyl bromoacetate (0.2ml, 1.8mmol) in dimethylformamide was added drop wise and stirred for 3 hours. The reaction mixture was filtered off and washed with ethyl acetate. The obtained combined organic phase was washed with water (50ml,t ice), dried over sodi um sul phate and concentrated. T he resulted crude material was purified by col umn chromatography using ethyl acetate and hexane to provide 250mg of title compound. Ί Η-ΝΜ Ρ,(400 M Hz,DMSO-d6): 7.73- 7.75 (1 H,d), 7.57 (1 H,t), 7.44-7.46 (1 H,m), 7.33(2H,m), 7.20-7.22 (1 H,m), 7.08(11-1, 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)
ST E P-3: Synthesis of (5-chloro-3-{methyl [3-(morpholin-4-ylsulfonyl) phenyl] ami no}-1 H -indazol-1-yl) acetic acid The compound obtained in step-2 (250nrg, 0.50mmol) was taken in 10 ml of methanol and 2ml of aqueous lithium hydroxide (30mg, 1.25mmol) was added. The reaction mixture was stirred and then diluted with cold water. The reaction mixture was acidified by dilute hydrochloric acid, a solid was obtained which was filtered off, washed well with water and suck dried to give 93 mg of title compound.
1 H-NM R(400 M Hz,DMSO-d6): 7.75 (1 H,d), 7.55 (1 H,t),7.43-7.45 (1 H,m), 7.37(1 H,m), 7.30-7.32 (1 H,m), 7.19(1 H,d), 7.09(1 H,m), 5.23(2H,s), 3.60(4H,m), 3.47(3H,s),
2.80(4H,m)
ESMS: 462.9(M+-1)
E xample- 5: Synthesis of (3-{[4-(cyclopentylsulfonyl)phenyl](methyl)ami no}-5- fluoro-1 H-indazol-1- l)acetic acid (C ompound No. 31)
Figure imgf000042_0001
ST E P-1 : Synthesis of 4-(cyclopentylsulfanyl)-N-methylanil ine
N,N-diisopropylethylamine (11 ml, 63.7mmol) was added to a stirred solution of 4- (Cyclopentylthio)anili ne (6.1gnri 31.6mmol) in 30ml dichloromethane and allowed to cool upto 0-5° C. A solution of trifluoroacetic anhydride (4.8ml, 34.7mmol) in 10ml di chl oromethane was added to thi s sol uti on and sti rred for 1 hour at room temperature. T he reaction mixture was diluted with dilute hydrochloric acid and extracted with di chl oromethane. The organic layer was washed with water, dried over sodium sulphate and concentrated under reduced pressure to provide 5gm of N-[4-(cyclopentylsulfanyl) phenyl ] -2, 2, 2-trif I uoroacetami de as oi ly mass whi ch was di rectly taken for next step. To a sti rred solution of N-[4-(cyclopentylsulfanyl) phenyl]-2, 2, 2-tri f I uoroacetami de(5gm, 17.3mmol) in 20ml di methyl formamide, cesium carbonates (8.3gnri 25.4mmol) was added and all owed to cool upto O-5eC. To this suspension, methyl iodide (1.6ml, 25.4mmol) was added and sti rred for 3 hours. T he reacti on mass was f i I tered and washed wi th ethyl acetate. The combined organic phase was washed with water (50ml, twice), dried over sodium sulphate and concentrated under reduced pressure to provide 5.0gm oily material. T o the obtai ned oi I, 30 ml of tetrahydrof uran was added and then 10ml aqueous sol uti on of sodium hydroxide (1.62gm) was added. The reaction mixture was stirred for one hour, concentrated, diluted with water and then extracted with ethyl acetate. Organic layer was washed wi th water, dri ed over sodi um sul phate and concentrated under reduced pressure to provide 3.27gm of 4-(cyclopentylsulfanyl)-N-methylaniline as oily mass.
1 H-NM R(400 M Hz,DMSO-d6) : 7.15-7.17 (2H,m), 6.47-6.49 (2H,m), 5.82-5.83(1 H,m), 3.26-3.31 (1 H,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)
ST E P-2: Synthesis of N-[4-(cyclopentylsulfanyl)phenyl]-2,5-difluoro-N-methyl benzamide
To a stirred solution of 4-(cyclopentylsulfanyl)-N-methylaniline (2.7 gm,15.8 mmol) in dichloromethane, triethylamine (3.3 ml, 34mmol) was added and cooled to 0°C. To the reaction mixture, a solution of 2,5-difluorobenzoyl chloride (2.7gm ,15.3mol) in dichloromethane was added drop wise over 30-40 minutes and stirred for 1 hour at 30°C.
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 sulphate and concentrated under reduced pressure to provide 5.6 gm of N-[4-(cyclopentylsulfanyl)phenyl]-2,5-difluoro-N-methyl benzamide.
Ί Η-ΝΜ Ρ,(400 M Hz,DMSO-d6): 7.14-7.26 (7H,m), 3.63(1 H,s), 3.34(3H,s),1.96(2H,m), 1.54-1.64 (4H,m), 1.39(21-1, m).
ESMS: 348(M++1)
ST E P-3: Synthesis of N-[4-(cyclopentylsulfanyl)phenyl]-5-fluoro-N-methyl-1 H - indazol-3-amine
To a solution of obtained N-[4-(cyclopentylsulfanyl)phenyl]-2,5-difluoro-N-methyl benzamide (5.6gm, 16.1 mmol) in toluene (60 ml), Lawesson s reagent (3.9gm, 9.6mmol) was added and heated to 100°C for 1 hour. T ol uene was evaporated under reduced pressure. The reaction mixture was diluted with water and extracted with ethyl acetate (50ml). The organic phase was washed with water, dried over sodium sulphate and concentrated under reduced pressure to give a crude mass. The obtained crude mass was purified by column chromatography using ethyl acetate and hexane to provide 4.9gm of N-[4- (cycl opentyl sulfanyl ) phenyl] -2, 5-dif I uoro- N-methyl benzenecarbothi oami de.
To a solution of N-[4-(cyclopentylsulfanyl)phenyl]-2,5-difl uoro-N-methylbenzene carbothioamide (4.9gm ,13.5mmol) in 60 ml of dimethylsulfoxide, 99% hydrazine hydrate (5.4ml, 108mmol) was added and heated to120°C for 12 hours. The reaction mixture was cooled to room temperature and poured into 50ml of ice-water which was then extracted with ethyl acetate (100ml). The collected organic phase was washed with water, dried over sodium sulphate and concentrated under reduced pressure to give a crude material which was purified by column chromatography using ethyl acetate and hexane to give 4.1gm of N-[4-(cyclopentylsulfanyl)phenyl]-5-fl uoro-N-methyl-1 H-indazol-3-amine.
Ί Η-ΝΜ Ι (400 M Hz,DMSO-d6): 12.73(1 H,br), 7.50-7.54 (1 H,m), 7.20-7.28 (3H,m), 6.82-6.85 (2H,m), 3.46-3.50 (1 H,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)
ST E P-4: Synthesis of ethyl (3-{[4-(cyclopentylsulfanyl)phenyl] (methyl)amino}-5- f I uoro-1 H -i ndazol-1 -yl)acetate
To a stirred solution of N-[4-(cyclopentylsulfanyl)phenyl]-5-fluoro-N-methyl-1 H-indazol- 3-amine (4.1 gm ,12mmol) in 20ml of dimethyl formamide, cesium carbonate (5.9gm ,18mol) was added and cooled to 0-5eC. To this suspension, a solution of ethylbromo acetate (1.6ml, 14.4mmol) in 5 ml of dimethyl formamide was added drop wise and stirred for 3 hours. The reaction mixture was filtered off and washed with ethyl acetate. The combined organic layer was washed with 50ml of water, dried over sodium sulphate and concentrated. The obtained crude material was purified by column chromatography using ethyl acetate and hexane to give 1.5gm sol i d.
Ί Η-ΝΜ Ι (400 M Hz,DMSO-d6): 7.66-7.69 (1 H,m), 7.28-7.30 (3H,m), 6.90 (2H,d), 6.77- 6,79 (1 H,m), 5.30 (2H,s), 4.15 (2H,q), 3.50-3.55 (1 H,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) ST E P-5: Synthesis of ethyl (3-{[4-(cyclopentylsulfonyl)phenyl] (methyl)ami no}-5- f I uoro-1 H -i ndazol-1 -yl)acetate
To a stirred solution of compound obtained i n step-4 (1.5 gm, 3.5mmol) in 10ml acetic acid, 9ml of 30% hydrogen peroxide was added and stirred for 5 hours. The acetic acid distilled under reduced pressure and the residue thus obtained was diluted with water and extracted with 50ml of ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material which was purified by column chromatography using ethyl acetate and hexane to provide 1.4gm orange color liquid.
1 H-NM R(400 M Hz,DMSO-d6): 7.78-7.81 (1 H,m), 7.65 (2H,d,),
7.35-7.40 (1 H,m), 7.19-7.21 (1 H,m), 6.96 (2H,d), 5.40 (2H,s), 4.13- 4.19 (2H,q), 3.60- 3.68 (1 H,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) ST E P-6: Synthesis of (3-{[4-(cyclopentylsulfonyl)phenyl](methyl)amino}-5-fluoro- 1 H-indazol-1-yl)acetic acid
To a stirred solution of compound (470mg, LOmmol) obtained in step-5 in methanol and tetrahydrofuran (3:2,10ml), 2ml of aqueous lithium hydroxide (40mg, 1.7mmol) was added. The reaction mass was stirred at room temperature and then concentrated to give a residue. The obtained residue was diluted with cold water, acidified with dil ute hydrochloric acid and extracted with ethyl acetate (30ml). The organic layer was distilled to provide oil, which upon trituration with diisopropyl ether gave 230mg of title compound. 1 H-NM R(400 M Hz,DMSO-d6): 7.72(1 H,m), 7.64 (2H,d), 7.33 (1 H,m), 7.16-7.18 (1 H,m), 6.94 (2H,d), 5.16(2H,s), 3.62(1 H,m), 3.45(3H, partially overlapped by 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 analogous manner by using the synthetic schemes as described above:
T able 1 Comp. !H-NMR (400 MHz, DMSO-de) MASS No.
1 7.76- 7.79 (1 H,m), 7.55 (2H,d), 7.45-7.48 (2H,m), 6.99 465.0 (2H,d), 5.27 (2H,s), 3.61-3.63 (4H,m), 3.48 (3H,s), 2.81 (M++1) (4H,m)
2 7.77 (1H,d), 7.62 (2H,d), 7.44-7.47 (1H,m), 7.39 446.9 (1H,m), 6.98 (2H,d), 5.25 (2H,s), 3.47 (3H,s), 3.09 (M+-1) (4H,t), 1.63 (4H,t).
4 13.19 (1H,bs), 7.77 (1H,d), 7.53 (2H,d), 7.45-7.47 461.4
(1H,m), 7.42 (1H,m), 6.98 (2H,d), 5.26 (2H,s), 3.46 (M+-1) (3H,s), 2.82 (4H,m), 1.45 (4H,m), 1.35 (2H,m)
6 7.76-7.79 (1 H,m), 7.53(2H,d), 7.34-7.38 (1 H,m), 7.18- 447.2 7.20 (1H,m), 6.96 (2H,d), 5.27 (2H,s), 3.46 (3H,s), 2.83 (M++1) (4H,m), 1.53 (4H,m), 1.35 (2H,m)
7 7.76-7.79 (1H,m),7.54 (2H,d), 7.34-7.38 (1H,m),7.21- 449.3 7.23 (1 H,m), 6.98 (2H,d), 5.26 (2H,s), 3.62 (4H,m), 3.47 (M++1) (3H,s), 2.81 (4H,m)
8 7.77 (1H,d), 7.52(2H,d), 7.44 -7.47 (1H,m), 7.34 479.2 (1H,s), 6.91 (2H,d), 5.25 (2H,s), 3.92 (2H,q), 3.62 (M++1) (4H,m), 2.74 (4H,m), 1.21 (3H,t)
9 7.76 (1H,d), 7.51 (2H,d), 7.44 -7.46 (1H,m), 7.28 477.2 (1H,s), 6.90 (2H,d), 5.23(2H,s), 3.90 (2H,q), 2.83 (M++1) (4H,m), 1.53 (4H,m), 1.36 (2H,m), 1.20 (3H,t)
10 7.76 (1H,d), 7.60 (2H,d), 7.44 (1H,d), 7.25(1 H,s), 6.90 461.4 (2H,d), 5.23 (2H,s), 3.91 (2H,q), 3.09 (4H,m), 1.64 (M+-1) (4H,m), 1.20 (3H,t)
11 7.78(1 H,m), 7.52-7.54 (2H,m), 7.36 (1H,m), 7.22 461.4 (1H,m), 6.96 (2H,m), 5.27 (2H,s), 4.67 (1H,bs), 4.04 (M+-1) (1H,m), 3.46 (3H, partially overlapped by water signal),
3.11 (2H,m), 2.64 (2H,m), 1.72 (2H,m), 1.43 (2H,m)
12 13.14 (1H,bs), 7.75 -7.78 (1H,m), 7.53 (2H,d), 7.33- 546.4 7.38(1H,m), 7.16-7.19 (1H,m), 6.96(2H,d), 5.26(2H,s), (M+-1) 3.46 (3H,s), 3.38 (4H,m), 2.79 (4H,m), 1.34 (9H,s) 7.52-7.54 (3H,m), 7.29(1 H,m), 7.14-7.17 (1H,m), 6.97 448.2
(2H,d), 4.74 (2H,s), 3.46 (3H,s), 2.81 (8H,m) (M++1) 13.16 (1H,bs), 7.74 -7.77 (1H,m), 7.23-7.38 (6H,m), 467.3 7.11 -7.13 (3H,m), 6.88 (2H,d), 5.24 (2H,s), 3.61 (3H,s), (M+-1) 3.09 (3H,s)
13.38 (1H,bs), 7.92 (1H,d), 7.71 (2H,d), 7.63-7.65 481.3 (3H,m), 7.04 (1H,d), 5.29 (2H,s), 3.51 (3H,s), 3.09 (M+-1) (4H,m), 1.62 (4H,m)
13.16 (1H,bs), 7.75-7.78 (1H,dd), 7.60-7.62 (3H,m), 419.08 7.33-7.37 (1H,m), 7.11-7.13 (1H,m), 6.95 (2H,d), 5.26 (M++1) (2H,s), 3.46 (3H,s), 2.07 (1H,m), 0.35-0.48 (4H,m)
13.27 (1H,bs), 7.94(1 H,d), 7.72-7.74 (2H,m), 7.57 499.2 (2H,d), 7.06 (2H,d), 5.32 (2H,s), 3.69 (4H,m), 3.52 (M++1) (3H,s), 2.81 (4H,m) .
13.16 (1H,bs), 7.76-7.80 (1H,m), 7.52 (2H,d), 7.34- 488.3 7.39 (1H,m), 7.22 (2H,d), 6.96 (2H,d), 5.27 (2H,s), (M+-1) 3.41-3.49 (7H,m), 2.79-2.84 (4H,m), 1.93 (3H,s)
13.14 (1H,bs), 7.76-7.79 (1H,m), 7.64 (2H,d), 7.34- 467.1 7.38(11-1, m), 7.15-,7.17 (1H,m), 6.97(2H,d), 5.26 (M+-1) (2H,s), 3.47-3.54 (5H,m), 3.27-3.29 (2H,partially
overlapped by water signal), 2.26-2.37 (2H,m)
7.64-7.67 (1H,m), 7.26-7.32 (3H,m), 7.11-7.16 487.3 (5H,m), 6.88 (2H,d), 4.99 (2H,s), 3.44 (3H,s), 3.06 (M++1) (3H,s)
13.14 (1H,bs), 7.75-7.78 (1H,m), 7.62 (2H,d), 7.33- 495.2 7.37 (1H,m), 7.13-7.16 (5H,m), 6.94 (2H,d), 5.26 (M++1) (2H,s), 4.13 (2H,s), 3.44 (3H,s), 3.23 (2H,t), 2.84-2.86
(2H,m).
12.97 (1H,bs), 8.06(1 H,d), 7.69-7.73 (1H,m), 7.64 449.3 (1H,t), 7.50 (1H,d), 7.37 (1H,d), 7.24-7.26 (1 H,m), 5.83 (M++1) (1H,s), 5.09 (2H,s), 3.28 (3H,s), 3.12 (4H,m), 1.41
(4H,m)
7.73-7.76 (1H,m), 7.60 (2H,d), 7.31-7.37 (2H,m), 501.2
7.14-7.16 (1H,m), 6.93(2H,d), 6.85(1H,d), 5.22 (2H,s), (M++1) 4.08 (2H,s), 3.44 (3H,s), 3.30-3.34 (2H, hidden under
signal of water), 2.83 (2H,m)
7.76 (1 H,d), 7.55 (2H,d), 7.45-7.46 (2H,m), 6.99 542.08 (2H,d), 5.25 (2H,s), 3.47 (3H,s), 3.19 (4H,m), 2.94 (M++1) (4H,m), 2.88 (3H,s)
13.00 (1 H,bs), 7.77-7.80 (1 H,m), 7.60 (2H,d), 7.34- 419.2 7.39 (1 H,m), 7.21-7.24 (1 H,m), 7.00 (2H,d), 5.28 (M++1) (2H,s), 3.60 (4H,t), 3.48(3H,s), 1.95-1.99 (2H,m)
7.77 (1 H,d), 7.61 (2H,d), 7.45-7.48 (2H,m), 7.02 435.2 (2H,d), 5.26 (2H,s), 3.60 (4H,t), 3.49 (3H,s), 1.94-2.01 (M++1) (2H,m)
7.79 (1 H,d), 7.56 (1 H,s), 7.46-7.52 (2H,m), 6.61 495.1 (1 H,s), 6.46 (1 H,d), 5.27 (2H,s), 3.72 (3H,s), 3.58 (M++1) (4H,m), 3.48 (3H,s), 2.98 (4H,m)
7.75-7.78 (1 H,m), 7.59 (2H,d), 7.33-7.37 (1 H,m), 449.2 7.16-7.18 (1 H,m), 6.94 (2H,d), 5.25 (2H,s), 4.90 (M++1) (1 H,bs), 4.14 (1 H,bs), 3.45 (3H,s), 3.14-3.21 (3H,m),
2.92-2.95 (1 H,m), 1.61-1.72 (2H,m)
13.13 (1 H,br), 10.01 (1 H,s), 7.73-7.77 (1 H,m), 7.54 453.2 (2H,d), 7.32-7.36 (1 H,m), 7.19-7.23 (2H,m), 7.06-7.08 (M+-1) (3H,m), 6.97-7.01 (1 H,m), 6.85 (2H,d), 5.24 (2H,s),
3.39 (3H,s)
7.75-7.79 (1 H,m), 7.62 (2H,d), 7.33-7.38 (1 H,m), 463.2 7.12-7.14 (1 H,m), 6.96 (2H,d), 5.27 (2H,s), 4.79 (M++1) (1 H,m), 3.46-3.52 (7H,m), 3.00-3.02 (1 H,m), 1.75
(2H,m), 1.45 (2H,m)
12.49 (1 H,s), 7.74-7.77 (1 H,m), 7.60 (2H,d), 7.32-7.36 493.2 (1 H,m), 7.08-7.11 (1 H,m), 6.88 (2H,d), 6.34 (1 H,s), (M++1) 5.25 (2H,s), 3.42 (3H, hidden under signal of water),
2.06 (3H,s)
7.72-7.74 (1 H,m), 7.58 (2H,d), 7.44 (1 H,d), 7.31-7.35 479.4 (1 H,m), 7.13-7.17 (3H,m), 6.93-6.97 (1 H,m), 6.84 (M+-1) (2H,d), 5.18 (2H,s), 3.83 (2H,t), 3.39 (3H,partially
overlapped by water signal), 2.89 (3H,t) 7.75-7.78 (1 H,m), 7.60 (2H,d), 7.34-7.38 (1 H,m), 495.3
7.24-7.26 (1 H,m), 6.97 (2H,d), 5.24 (2H,s), 3.47 (7H, (M+-1) partially overlapped by water signal), 3.26 (4H, partially overlapped by water signal)
7.75-7.78 (1 H,m), 7.54 (2H,d), 7.33-7.38 (1 H,m), 463.2
7.19- 7.22 (1 H,m), 6.96 (2H,d), 5.25 (2H,s), 3.46 (3H,s), (M+-1) 3.14 (4H,m), 2.65 (4H,t)
13.17 (1 H,bs), 7.77 (1 H,d), 7.61 (2H,d), 7.40-7.46 515.2 (2H,m), 7.31-7.32 (1 H,m), 6.95 (2H,d), 6.84-6.85 (M+-1) (1 H,m), 5.27 (2H,s), 4.09 (2H,s), 3.45 (3H,s), 3.31-3.34
(2H, hidden under signal of water), 2.83 (2H,m).
7.76-7.77 (1 H,m), 7.53 (2H,d), 7.33-7.42 (6H,m), 550.5
7.20- 7.23 (1 H,m), 6.97 (2H,d), 5.24 (2H,s), 3.70 (M+-1) (4H,m), 3.47 (3H,m). 2.90 (4H,m).
7.73 (1 H,m), 7.54 (2H,d), 7.35(1 H,m), 7.18-7.20 514.3 (1 H,m), 6.95 (2H,d), 5.17 (2H,s), 3.66 (5H, partially (M++1) overlapped by water signal), 2.50 (1 H, hidden under
solvent signal), 2.25 (2H,m), 1.82-1.85 (2H,m), 1.42- 1.45 (2H,m).
7.70-7.73 (1 H,m), 7.52 (2H,d), 7.32 (1 H,t), 7.17 461.1 (1 H,d), 6.95 (2H,d), 5.13 (2H,s), 3.45 (3H,s), 2.83 (M++1) (4H,m), 2.35 (4H,m), 2.14 (3H,s).
8.08 (1 H,d), 7.75-7.78 (1 H,m), 7.53-7.60 (3H,m), 558.9 7.33-7.37 (1 H,m), 7.18-7.20 (1 H,m), 6.95 (2H,d), 6.85 (M++1) (1 H,d), 5.26 (2H,s), 3.57 (4H,m), 3.44 (3H,s), 2.91
(4H,m)
7.75-7.78 (1 H,m), 7.52 (2H,d), 7.33-7.37 (1 H,m), 461.1 7.16-7.18 (1 H,m), 6.95 (2H,d), 5.25 (2H,s), 3.52-3.55 (M++1) (2H,m), 3.45 (3H,s), 2.14 (2H,t), 1.61-1.64 (2H,m),
1.23-1.28 (1 H,m), 1.10-1.15 (2H,m), 0.85 (3H,d).
7.61 (2H,d), 7.14 (1 H,d), 7.06-7.08 (1 H,d), 6.92-6.95 426.8 (1 H,m), 6.74 (2H,d), 5.07 (2H, s), 3.36 (3H, hidden (M+-1) under signal of water), 3.07 (4H,m), 2.51 (3H, hidden
under solvent signal), 1.62 (4H,m) . DMSO-de : 7.79(1 H,m), 7.52(2H,d), 7.23-7.37 (7H,m), 537.9(M 6.96 (2H,d), 5.28(2H, s), 3.46(5H,m), 2.83(4H,m), ++1) 2.40(4H,m).
8.33 (2H,d), 7.70-7.72 (1 H,m), 7.53 (2H,d), 7.29-7.34 525.9 (1 H,m), 7.15-7.17 (1 H,m), 6.94 (2H,d), 6.62-6.65 (M++1) (1 H,m), 5.14 (2H,s), 3.79-3.82 (4H,m), 3.43 (3H,s),
2.88- 2.90 (4H,m).
7.76-7.79 (1 H,m), 7.57 (2H,d), 7.34-7.38 (1 H,m), 553.8 7.22-7.25 (1 H,m), 6.85-7.00 (6H,m), 5.27 (2H, s), 3.71 (M++1) (3H,s), 3.47 (3H,s), 296-2.99 (8H,m)
8.08 (1 H,m), 7.54-7.56 (3H,m), 7.04-7.11 (2H,m), 521.1
6.89- 6.91 (1 H,m), 6.74-6.81 (3H,m), 6.65 (1 H,m), 5.06 (M++1) (2H, s), 3.57 (4H,m), 3.46 (3H, hidden under signal of water), 2.90.(4H,m).
10.82(1 H,s), 7.77-7.80 (1 H,m), 7.61 (2H,d), 7.35-7.39 579.06 (1 H,m), 7.23-7.25 (1 H,m), 6.94-7.01 (6H,m), 5.28(2H, (M++1) s), 4.17(1 H,m), 3.76-3.79(2H,m), 3.49 (3H,s), 2.45
(2H,m), 2.31-2.34 (2H,m), 1.68-1.71 (2H,m)
7.75-7.79 (1 H,m), 7.52 (2H,d), 7.34-7.38 (1 H,m),7.18- 489.9 7.22 (2H,m), 6.95 (2H,d), 6.79 (1 H,m), 5.25 (2H, s), (M++1) 3.41-3.52 (5H,m), 2.21 (2H,t),2.03(1 H,m), 1.73-1.76
(2H,m), 1.51-1.57 (2H,m)
7.76 -7.79 (1 H,m), 7.59 (2H,d), 7.34-7.38 (1 H,m), 434.8 7.22-7.24 (1 H,m), 7.00 (2H,d), 5.70 (1 H,bs), 5.27 (M++1) (2H,s), 4.25 (1 H,m), 3.78-3.82 (2H,m), 3.48 (3H,s),
3.26-3.29 (2H, partially overlapped by water signal)
7.78-7.80 (1 H,m), 7.53 (2H,d), 7.32-7.36 (1 H,m), 7.09 460.9 -7.11 (1 H,m), 6.69 (2H,d), 5.28 (2H,s), 4.49-4.53 (M++1) (1 H,m), 3.05 (4H,m), 1.62 (4H,m), 1.14 (6H,d)
8.33 (2H,d),7.50-7.54 (3H,m), 7.19-7.24 (1 H,m), 7.09- 524.1 7.12 (1 H,m), 6.90 (2H,d), 6.64 (1 H,t), 4.62 (2H, s), (M+-1) 3.79-3.82 (4H,m), 3.41 (3H,s), 2.87-2.90 (4H,m).
8.087-8.088 (1 H,m), 7.49 -7.54 (4H,m), 7.22-7.24 523.2
(1 H,m), 7.11-7.13 (1 H,m), 6.91 (2H,d), 6.79-6.81 (M+-1) (1 H,m), 6.62-6.65 (1 H,m), 4.62 (2H,s), 3.55-3.58
(4H,m), 3.42 (3H,s), 2.89-2.91 (4H,m) 7.67 (1 H,m), 7.54-7.56 (2H,m), 7.37-7.39 (1 H,m), 591.8 7.32 (1 H,m), 7.20 (1 H,m), 7.11 (1 H,m), 6.94-6.96 (M++1) (3H,m), 5.07 (2H,s), 3.45 (3H,s), 3.25 (4H,partially
overlapped by water signal), 2.93 (4H,m).
7.74-7.77 (1 H,m), 7.56 (2H,d), 7.33-7.37 (1 H,m), 557.8 7.17-7.21 (2H,m), 6.92-6.98 (3H,m), 6.85-6.87 (1 H,m), (M++1) 6.79-6.81 (1 H,m), 5.23 (2H,s), 3.45 (3H,s), 3.24 (4H, partially overlapped by water signal), 2.94 (4H,m).
7.74-7.77 (1 H,m), 7.56 (2H,d), 7.31-7.38 (3H,m), 591.8
7.16- 7.22 (2H,m) , 6.98-7.01 (2H,d), 5.23 (2H,s), 3.47 (M++1) (3H,s), 3.01-3.04 (8H,m).
8.02 (1 H,m), 7.81(2H,m), 7.48 (2H,d), 7.35 (1 H,m), 553.1 7.14 (2H,m), 6.84 (1 H,m), 6.69 (2H,d), 5.32 (2H,s) , (M++1) 4.51 (1 H,m), 3.69 (4H,m), 2.96 (4H,m), 1.13 (6H,d).
7.75-7.78 (1 H,m), 7.53 (2H,d), 7.33-7.37 (1 H,m), 7.19- 475.1 7.21 (1 H,m), 6.97 (2H,d), 5.24 (2H,s), 3.42-3.58 (M+-1) (7H,m), 1.75-1.81 (2H,m), 1.035 (6H,d).
7.75-7.78 (1 H,m), 7.67 (2H,d), 7.33-7.37 (1 H,m), 450.8 7.12-7.14 (1 H,m) , 6.93 (2H,d), 5.25 (2H,s), 4.40 (2H,s), (M++1) 3.54 (2H,t), 3.46 (3H,s), 2.68 (2H,t).
7.75-7.79 (1 H,m), 7.52 (2H,d), 7.33-7.40 (2H,m), 489.9 7.22-7.24 (1 H,m), 6.95-6.97 (2H,m), 6.90 (1 H,m), 5.26 (M++1) (2H,s), 3.46-3.58 (4H,m), 2.35 (1 H,m), 2.05-2.16
(2H,m), 1.69-1.73 (2H,m), 1.42-1.45 (1 H,m), 1.20-1.28
(2H,m).
7.74-7.81 (2H,m), 7.53 (2H,d), 7.34 (1 H,m), 7.22 542.1 (1 H,m), 6.94-6.96 (3H,m), 6.59 (1 H,m), 5.22 (2H,s), (M++1) 3.72 (4H,m), 3.45 (3H,s), 2.91 (4H,m)
7.78-7.82 (1 H,m), 7.46 (2H,d), 7.32-7.37 (1 H,m), 553.8
7.17- 7.19 (1 H,m), 6.70 (2H,d), 5.29 (2H,s), 4.51-4.54 (M++1) (1 H,m), 3.18 (4H,m), 2.92 (4H,m), 2.88 (3H,s), 1.15
(6H,d). 13.27 (1 H,bs), 7.80-7.83 (1 H,m), 7.46 (2H,d), 7.33- 476.9 7.37 (1 H,m), 7.16-7.18 (1 H,m), 6.71 (2H,d), 5.31(2H,s), (M++1) 4.51-4.54 (1 H,m), 3.60 (4H,m), 2.78 (4H,m), 1.15
(6H,d).
7.78 (1 H,m),7.71 (4H,m), 7.35-7.43 (3H,m),7.16-7.18 649.9 (1 H,m), 6.68 (2H,d), 5.28 (2H,s), 4.52 (1 H,m), 3.01 (M++1) (4H,m), 2.89 (4H,m), 1.15 (6H,d)
7.79-7.82 (1 H,m), 7.59 (2H,d), 7.34-7.38 (1 H,m), 431.3 7.23-7.26 (1 H,m), 6.99 (2H,d), 5.68 (1 H,q), 3.58-3.61 (M+-1) (4H,m), 3.48 (3H,s), 1.95-1.99 (2H,m), 1.76 (3H,d).
7.80-7.82 (1 H,m),7.72 (2H,d), 7.32-7.37 (1 H,m), 7.13 447.05 -7.15 (1 H,m) , 6.93 (2H,d), 4.59 (2H,t), 3.44(3H,s), (M++1) 3.09-3.18(4H,m), 2.85(2H,t),1.62-1.65(4H,m)
8.07 (1 H,d), 7.49-7.57 (4H,m), 7.20-7.24 (1 H,m), 523.16 7.13 (1 H,d), 6.91 (2H,d), 6.79(1 H,d), 6.64 (1 H,t), (M+-1) 4.75(2H,s), 3.56(4H,m), 3.41(3H,s),2.90(4H,m).
8.33 (2H,d),7.49-7.56(3H,m), 7.21 (1 H,t), 7.11(1 H,d), 524.14 6.91(2H,d), 6.61-6.64(1 H,m), 4.77(2H, s), 3.80(4H,m), (M+-1) 3.41(3H,s),2.87(4H,m).
7.54-7.59 (3H,m),7.22 (1 H,t), 7.11 (1 H,d), 6.92 431.12 (2H,d), 4.77(2H,s), 3.43(3H,s), 3.07(4H,t), 1.62(4H,t) . (M+-1) 7.73-7.76 (1 H,m), 7.52-7.56 (3H,m), 7.31-7.36 556.9 (1 H,m), 7.18-7.20 (1 H,m), 6.95(2H,d), 6.76 (1 H,d), (M+-1) 6.67(1 H,d), 5.21(2H,s), 3.57(4H,m), 3.44(3H,s),
2.91(4H,m).
7.64-7.68 (1 H,m), 7.53 (2H,d), 7.42 (1 H,t), 7.27-7.29 555.01 (1 H,m),7.15-7.18 (1 H,m), 6.93(2H,d), 6.27 (1 H,d), (M++1) 6.03(1 H,d), 5.00(2H,s),3.73(3H,s) 3.55(4H,m),
3.43(3H,s), 2.90(4H,m).
8.07 (1 H,d), 7.48-7.55 (4H,m), 7.20-7.24 (1 H,m), 7.12 523.16 (1 H,d), 6.92 (2H,d), 6.78(1 H,d), 6.63 (1 H,t), (M+-1) 4.77(2H,s), 3.55(4H,m), 3.41(3H,s),2.89(4H,m). 74 8.07 (1 H,d), 7.49-7.60 (4H,m), 7.23-7.27 (1 H,m), 523.16
7.13-7.16 (1 H,m), 6.92(2H,d), 6.79 (1 H,d), 6.62-6.65 (M+-1)
(1 H,m), 4.78(2H,s), 3.56(4H,m), 3.42(9H,m ),
2.90(4H,m).
75 8.09 (1 H,m),7.51-7.53 (4H,m), 7.20-7.24 (1 H,m), 7.11 522.98
-7.13 (1 H,m) , 6.91 (2H,d), 6.80(1 H,d), 6.63- (M+-1)
6.66(1 H,m), 4.59(2H,s), 3.83(2H,m), 3.57 (4H,m),
3.38-3.51 (5H, hidden under signal of water), 3.10
(9H,s), 2.91(4H,m).
76 7.57-7.59 (3H,m),7.26 (1 H,t), 7.13 (1 H,d), 6.92 430.99
(2H,d), 4.80(2H,s), 3.43-3.44(9H, partially overlapped (M+-1)
by water signal),3.07(4H,t), 1.63(4H,t).
77 7.56-7.59 (3H,m),7.23-7.28 (1 H,t), 7.12-7.14 (1 H,d), 430.99
6.91 -6.93 (2H,d), 4.76(2H,s), 3.43(3H,s), 3.05-3.09 (M+-1)
(4H,t), 2.79-2.84(4H,q), 1.61-1.64(4H,t), 1.10-1.13
(6H,t)
Pharmaceutical compositions
In another embodiment present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound of formula (1). While it is possible to administer therapeutical ly effective quantity of compounds of formula (1) either individually or in combination, directly without any formulation, it is common practi ce to admi ni ster the compounds i n the form of pharmaceuti cal dosage forms comprising pharmaceutically acceptable exci pi ent(s)/adjuvant(s) or carrier and at least one active i ngredi ent T hese dosage forms may be admi ni stered by a vari ety of routes i ncl udi ng oral, topical, transdermal, subcutaneous, intramuscular, intravenous, intraperitoneal, intranasal, pulmonary etc.
O ral composi ti ons may be i n the form of sol i d or I i qui d dosage form S ol i d dosage form may comprise pellets, pouches, sachets or discrete units such as tablets, multiparticulate units, capsules (soft & hard gelatin) etc. L iquid dosage forms may be i n the form of elixirs, suspensions, emulsions, sol utions, syrups etc. Composition intended for oral use may be prepared according to any method known in the art for the manufacture of the composition and such pharmaceutical compositions may contai n in addition to active ingredients, excipients such as diluents, disintegrating agents, binders, solubilizers, lubricants, glidants, surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavours, sweeteners, colours etc. Some example of suitable excipients include lactose, cellulose and its derivatives such as microcrystalline cel lulose, methyl cellulose, hydroxy propyl methyl cellulose & ethyl eel ly lose, di calcium phosphate, mannitol, starch, gelatin, polyvinyl pyrolidone, various gums like acacia, tragacanth, xanthan, alginates & its derivatives, sorbitol, dextrose, xylitol, magnesium stearate, talc, colloidal silicon dioxide, mineral oi l, glyceryl mono stearate, glyceryl behenate, sodium starch glycol ate, cross povidone, crosslinked carboxymethyl cellulose, various emulsifiers such as polyethylene glycol, sorbitol, fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyoxyethylene polyoxypropyl block copolymers, poly ethoxy I ated fatty acid monoesters, di esters and mixtures thereof.
Topical pharmaceutical compositions according to the present invention can be in the form of cream, ointment gel, transdermal formulations, foam, spray, lotion, solution, emulsion or suspension. Transdermal formulations refer to transdermal drug delivery system which may comprise a drug-containing composition, and, optionally, a backing layer and/or a release li ner layer. Such composition may contain 0.01% to 50% w/w orw/v of the drug.
Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, N - Methyl -2- Pyrrol i done, propylene glycol and other glycols, alcohols, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cotton seed oil or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, anti -oxidants, preservatives, complexing agents like cellulose derivatives, peptides, polypeptides and cyclodextrins and the like can be incorporated as required.
T he dosage form can have a si ow, del ayed or control I ed rel ease of active i ngredi ents i n addi ti on to i mmedi ate rel ease dosage forms.
The amount of active ingredient which is required to achieve a therapeutic effect wi 11 , of course, vary with the parti cul ar compound, the route of admi ni strati on, the subj ect under treatment and the parti cul ar di sorder or di sease bei ng treated. T he compounds of the invention may be administered by oral, inhalation, dermal or parenteral route at a dose of from 0.0005 to 100 mg/kg per day, preferably from 0.0005 to 50 mg/kg per day, more preferably from 0.0001 to 20 mg/kg per day, most preferably from 0.0001 to 10 mg/kg per day. T he dose range for adult humans is general ly from 5 1 g to 5 g per day, preferably dose range is 10i g to 2 g per day.
Dosage forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for example units containing 5 1 g to 1000 mg.
In another embodiment present invention provides method of treating allergic and non-allergic inflammatory diseases by administering a therapeutically effective amount of a compound of formula (1) to a mammal, including human being, in need thereof. Besides these, the present invention also provides a method for treating impaired hair growth and alopecia.
In a preferred embodi ment, present i nventi on provi des a method for treati ng al I ergi c or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, nasal polyps and chronic obstructive pulmonary disease, by administering a therapeutically effective amount of a compound of formula (1) to a mammal, including human being, in need thereof.
A preferred embodiment of the present invention is the use of a compound of formula (1) for the preparation of a medicament for treating allergic or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhi nitis, allergic conj unctivitis, eosinophilic esophagitis, hypereosinophi lic syndrome, nasal polyps and chronic obstructive pulmonary disease.
Biological testing:
Biological example 1 : in-vitro studies
In-vitro assay for C RT H 2 antagonistic activity
Human Prostanoid Receptor DP2 (CRT H2) Aequorin Cell line from PerkinE lmer was employed. Cells contained the sequence coding for the human Prostanoid Receptor CRT H2 transfected in CHO-K 1 cells expressing G 16 and mitochondrial ly targeted Aequorin. Cells were cultured with antibiotics Zeocin (final conc.0.25mg/ml) and G418 (fi nal conc.0.4nrg/ml) in growth medium Ham s F-12.
Cells were grown in antibiotic free growth medium for 18 hours and detached gently with fresh PBS/D.5mM E DTA. After recovering by centrifugation, cells were resuspended in assay buffer (DM E M/HA M "s-F12 with HE PES without phenol red + 0.1 % BSA) at concentration of 9X 105 cells /ml. Under sterile condition, "coelenterazine h_ was added at a final concentration of 5i M. These eel Is were i ncubated at 21 eC protected from light and with constant gentle agitation overnight. Next day cells were diluted in assay buffer to get final concentration 3X 105 cells/ml and incubated as described above for 60 minutes. For measurement of activity of compounds, _25 ι I cells were dispended in 384 optiplate (7500 eel I s Wei I ) and 25 1 I sol uti on of compound(s) of present i nventi on was added. After 15 min of incubation, 25i I PG D2 was injected by injector to get final concentration equivalent to EC80 using E nvision (Perkin E lmer) automatic injection system (Stock of PG D2 and compounds were prepared in DMSO and diluted in assay buffer so that final cone, of DMSO <1% in well.) Immediately after PG D2 addition, calcium released was measured by recording relative light emission (R LU) for 70 seconds for each well in E nvision Multilabel Reader.
Area under curve was obtained and % inhibition was calculated by considering agonist control as 100%. Results are summarized in the table given below. T able 2
Compound 100nM 20nM
No
++++ NA
2 ++++ NA
4 ++++ NA
5 ++++ ++++
6 ++++ +++
7 ++++ +++ 8 ++++ NA
9 +++ NA
10 ++++ ++++
11 +++ ++
12 ++++ ++++
13 ++ NA
14 ++++ +++
15 ++++ +++
16 +++ ++
17 +++ +++
18 ++++ +++
19 ++++ +++
20 ++++ +++
21 ++++ ++++
23 ++++ ++++
24 ++++ ++++
25 ++++ ++++
26 ++++ ++++
27 ++++ ++++
28 ++++ +++
29 ++++ +++
30 ++++ +++
31 ++++ +++
32 +++ ++
33 +++ ++
34 NA ++++ 35 NA ++++
36 NA ++++
37 NA ++++
38 NA ++++
39 NA ++++
40 NA ++++
41 NA ++
42 NA ++++
43 NA +++
45 NA ++++
46 NA ++++
47 ++++ +++
48 NA ++
49 ++++ +++
50 +++ ++
51 NA ++++
52 ++++ +++
53 ++++ ++++
54 ++++ ++++
55 ++++ ++++
56 ++++ +++
57 ++++ ++++
58 ++++ ++++
59 +++ NA
60 ++++ NA
61 ++++ NA
62 ++++ NA 63 ++++ NA
64 ++++ NA
65 ++++ NA
66 ++++ NA
67 W NA
68 NA NA*
69 ΛΑΑΑ' NA
70 ΛΑΑΑ' NA
Criteria: ++++ = Inhibition Ti80%††I00%; +++ = Inhibition fi50% <80%;
++ = Inhibition fi20% <50%; + = Inhibition <20%; NA- Not Available
*- Compound no 68 shows inhibition in the range of ++++ at 5nM concentration Observati on: In-vitro data shows that compounds of present i nventi on si gnif i cantly i nhi bits C RT H2 receptor activity.
Biological example 2: in-vivo studies
In vivo efficacy evaluation in mice:
Animal model Mouse model for FITC (Fluorescein isothiocyanate)- induced allergic cutaneous inflammation bear resemblance with acute atopic dermatitis lesions. Sensitization of mice by topical application of FITC results in increased IgE levels, as well as the development of FITC specific Th2 cells. Antigen challenge by applying FITC to the ear 6 days post- sensitization results in cutaneous inflammation characterized by edema and large infiltration of inflammatory cells as mononuclear cells, eosinophils and neutrophils (Boehme SA et al., Int Immunol. 2009J an;21(1):81-93).
In-vivo efficacy studies in mice:
Efficacy of Compound no. 36 was evaluated in FITC-induced al lergic cutaneous inflammation in female BA L B/c mice. Mice were prepared for sensitization on day 0 by carefully removing hair from their bel ly using an electric hair clipper under isoflurane anesthesia. On day 1 and day 2, 400 ι L of 0.5% FITC solution was painted on the shaved ventral skin (dissolved in acetone : di butyl phthalate, 1 :1 v/v). Further on day 8, the mice were challenged with 0.5% FITC on the right ear (20 ι I volume). Mice in different treatment groups were treated with 100mg cream containing 1% or 2.2% Compound no. 36 applied topically on right ear 2 hours before and 5 hours after the FITC challenge. Mice in FITC control group were applied placebo cream. 24 hours after the FITC challenge, the right ear thickness was determined using digital V ernier caliper in anesthetized mice and histopathological analysis of formalin fixed right ear sections was performed after Hematoxylin and eosin staining (Fig 2). The results of change in ear thickness measurement has been represented graphically in Figure 1 (Data represent mean e standard error of mean). * denotes p<0.05 versus FITC control group using one way A NOV A followed by Dunnetfs post hoc analysis.
Observations: Prominent inflammatory cell infiltration was observed in FITC control group mi ce whereas attenuati on i n the i nf I ammatory eel I i nf i Itrati on was observed i n mi ce treated wi th C ompound of present i nventi on.

Claims

C LAIMS
1. A compound of formula (1),
Figure imgf000061_0001
Formula-1
Wherein,
n is i ndependently sel ected 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 (Ci-C3)alkyl;
Ri is selected from (Ci-C6)alkyl and (C3-C8)cycloalkyl;
R2 is i ndependently sel ected from hydrogen, (Ci-Ce)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, heterocycloalkyl, halo, -N02, hydroxyl, C F3, (Ci-Ce)alkoxy, -S-(Ci- Ce)alkyl, -S02-(CrC6)alkyl, -S02-(C3-C8)cycloalkyl, -S02NR6R7, -NH2, -NH-CO-(Ci- Ce)alkyl, -NH-CO-(C3-C8)cycloalkyl, -NH-CO-(CrC3)alkylaryl, -NH-CO-(Ci- C3)alky I heteroaryl, -NH-CO-aryl, -NH-CO-heteroaryl, -NHCO-heterocycloalkyl, -NH- CO-(Ci-C6)alkoxy, -NH-COO-(C3-C8)cycloalkyl, -NH-COO-aryl, -NH-COO-heteroaryl, - NH-COO-heterocycloalkyl, -NH-COO-(CrC3)alkylaryl, -N HCON H R7, -NHCONR6R7, - NH-S02-(Ci-C8)alkyl, -NH-S02-aryl, -NH-S02-heteroaryl and -NH-S02-(C3- Cs) cycloalkyl;
R3 is selected from hydrogen, (Ci-C3)alkyl, halo, CF3 and (Ci-C3)alkoxy;
- L - i s I i nker sel ected from -S 02- and -S 02 N ( R 5)-; Ring A is selected from (C3-C8)cycloalkyl, aryl, heteroaryl and heterocycloalkyl; R4 is independently selected from hydrogen, (CrC6)alkyl, (C3-C8)cycloalkyl, -(Ci-C6)alkylaryl, -(Ci-C6)alkyl heteroaryl, aryl, heteroaryl, heterocycloalkyl, halo, oxo, CN, CF3, hydroxyl, - N02, -NH2, (Ci-C6)alkoxy, hydroxy-(CrC6)alkyl, -S-(Ci-C6)alkyl, -S02-(Ci-C6)alkyl, - S02-(C3-C8)cycloalkyl, -S02(Ci-C6)alkylaryl, -S02-aryl, -S02-heteroaryl, -CO-(Ci- Ce)alkyl, -CO-(Ci-C6)alkylaryl, -CO-(C3-C8)cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, - CO- heteroaryl, (CrC6)alkoxycarbonyl, -NR6Ry, -NH-CO-(CrC6)alkyl, -NH-CO-(C3- C8)cycloalkyl, -NH-CO-(Ci-C3)alkylaryl, -NH-CO-(Ci-C3)alkylheteroaryl, -NH-CO-aryl, -NH-CO-heteroaryl, -NHCO-heterocycloalkyl, -NH-COO-(Ci-C6)alkyl, -NH-COO-(C3- C8)cycloalkyl, -NH-COO-aryl, -NH-COO-heteroaryl, -NH-COO-heterocycloalkyl, -NH- COO-(CrC3)alkylaryl, -NHCONR6R7, -NH-S02-(CrC6)alkyl, -NH-S02-(C3- C8)cycloalkyl, -NH-S02-aryl, -NH-S02-heteroaryl, -C(0)OH, -C(0)OR6, -CONH2, - CONH-aryl, -CONH-heteroaryl, -S02NH-(Ci-C8)alkyl, -S02NH-(C3-C8)cycloalkyl and - S02NH-aryl wherein aryl, heteroaryl and heterocycloalkyl radicals are optionally substituted with one to five groups selected from -(Ci-Cs)alkyl, -(C3-C7)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (Ci-Ce)alkoxy, -O-aryl, halo, oxo, CN, -CF3, -S02-(Ci- C8)-alkyl, -S02-aryl, -S02- heterocycloalkyl, -NH2, -NR6R7, -NH-CO-(CrC8)alkyl, -NH- S02-(Ci-C8)alkyl, -NH-S02-aryl, -COOH, -C(0)NH-alkyl, -CONH-aryl, -CONH- heteroaryl, -C(0)-(CrC8)alkyl, -C(0)0-(Ci-C8)alkyl, -C(0)0-aryl, -S02NH-(d-C8)alkyl, -S02NH-aryl, "S02NR6R7, -S02NH-heteroaryl, and hydroxyl;
R5 is selected from hydrogen, (Ci-Ce)alkyl, aralkyi, (C3-C8)cycloalkyl and aryl;
R6 and R7 are independently selected from (CrC6)alkyl, aralkyi, (C3-C8)cycloalkyl and aryl; or
R6 and R7 are taken together may form a heterocycloalkyl ring; their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates or solvates.
2. The compound according to claim 1, wherein
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 (Ci-C3)alkyl;
Ri is (Ci-Ce)alkyl;
R2 is independently selected from hydrogen, (CrC6)alkyl, haloand CF3;
R3 is selected from hydrogen and (Ci-C3)alkoxy;
- L - i s I i nker sel ected from -S 02- and -S 02 N ( R 5)-;
Ring A is selected from (C3-C8)cycloalkyl, aryl, heteroaryl and heterocycloalkyi;
R4 is independently selected from hydrogen, (Ci-Ce)alkyl, -(Ci-C6)alkylaryl, aryl, heteroaryl, heterocycloalkyi, halo, oxo, CF3, hydroxyl, hydroxy-(Ci-C6)alkyl, -S02-(Ci- Ce)alkyl, -S02-aryl, -CO-(CrC6)alkyl, -CO-aryl, -CO- heteroaryl, -C(0)OR6, and-CONH2; wherein aryl, heterocycloalkyi and heteroaryl radicals are optionally substituted with one to five groups selected from -(Ci-Cs)alkyl, (Ci-Ce)alkoxy, -COOH, -C(0)NH-alkyl, -CF3, -CN, -S02-heterocycloalkyl, -NHCO-(Ci-Cs)alkyl, halo, hydroxyl and oxo;
R5 is selected from hydrogen and (Ci-C6)alkyl;
R6 is (Ci-C6)alkyl.
3. T he compound accordi ng to clai m 1 , sel ected from the group consi sti ng of
(5-chloro-3-{methyl[4-(morpholin-4-yl sulfonyl)phenyl]amino}-1H-indazol-1-yl) acetic acid;
(5-chloro-3-{methyl[4-(pyrrolidin-1-yl sulfonyl)phenyl]amino}-1H-indazol-1-yl) acetic acid;
(5-chloro-3-{methyl[3-(morpholin-4-yl sulfonyl)phenyl]amino}-1H-indazol-1-yl) acetic acid; ( 5-chl oro-3-{ methyl [4-( pi peri di n- 1 -y I sulfonyl ) phenyl ] ami no} - 1 H -i ndazol - 1 -yl ) acetic acid;
(5-fluoro-3-{ methyl[4-(pyrrolidin-1-yl sulfonyl)phenyl]amino}-1 H-indazol-1-yl) acetic acid;
( 5-f I uoro-3-{ methyl [4-( pi peri di n- 1 -y I sulfonyl ) phenyl] ami no} - 1 H - i ndazol - 1 -y I ) acetic acid;
(5-f I uoro-3-{ methyl [4-(morphol i n-4-yl sulfonyl) phenyl] ami no} -1 H - i ndazol-1 -yl) acetic acid;
(5-chloro-3-{ ethyl[4-(morphol in-4-yl sulfonyl)phenyl]amino}-1 H-indazol-1-yl) acetic acid;
(5-chl oro-3-{ ethyl [4-(pi peridi n-1 -yl sulfonyl)phenyl]amino}-1 H-indazol-1-yl) acetic acid;
(5-chl oro-3-{ ethyl [4-( pyrrol i di n- 1 -y I sul f ony I ) phenyl ] ami no} - 1 H - i ndazol - 1 -y I ) acetic acid;
{ 5-fluoro-3-[{4-[(4-hydroxypiperidin-1-yl) sulfonyl] phenyl} (methyl)ami no]-1 H- i ndazol -1-yl} acetic acid;
{3-[(4-{ [4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl} phenyl )( methyl) amino]- 5-f I uoro- 1 H - i ndazol - 1 -y I } aceti c aci d;
( 5-f I uoro-3-{ methyl [4-( pi perazi n- 1 -y I sulfonyl ) phenyl ] ami no} - 1 H -i ndazol - 1 -yl ) acetic acid;
[5-fluoro-3-(methyl{4-[methyl(phenyl) sulfamoyl] phenyl} ami no)-1 H-i ndazol-1 - y I] acetic acid;
[3-{ methyl [4-( pyrrol idi n-1 -yl sulfonyl) phenyl] ami no} -5-(trifl uoromethyl)-1 H- i ndazol -1-yl] acetic acid;
(3-{ [4-(cyclopropylsulfamoyl)phenyl] (methyl)amino}-5-fluoro-1 H-indazol-1-yl) acetic acid;
[ 3-{ methy I [4- ( morphol i n-4-y I sul f ony I ) pheny I ] ami no} - 5-( tri f I uoromethy I ) - 1 H - i ndazol -1-yl] acetic acid;
{3-[{4-[(4-acetyl pi perazi n-1 -yl) sulfonyl] phenyl} (methyl)ami no] -5- f I uoro- 1 H- i ndazol -1-yl} acetic acid;
{3-[{4-[(3,3-difluoropyrrol idi n-1-yl)sulfonyl] phenyl} ( methyl )ami no] -5-f I uoro-1 H- i ndazol -1-yl} acetic acid; { 5-fluoro-3-[{4-[(4-fluorophenyl) (methyl)sulfamoyl] phenyl} (methyl)amino]-1 H- indazol-1-yl} acetic acid;
(3-{ [4-(3,4-di hydroisoqui nol i n-2( 1 H )-y I sulfonyl)phenyl](methyl)ami no}-5- f I uoro- 1 H - i ndazol - 1 -y I ) aceti c aci d;
(5-chloro-3-{ methyl[2-(pyrrolidin-1-yl sulfonyl)phenyl]amino}-1 H-indazol-1-yl) acetic acid;
{ 5-fluoro-3-[methyl(4-{ [4-(methylsulfonyl)piperazin-1-yl]sulfonyl} phenyl) amino]-1 H- indazol-1-yl} acetic acid;
(3-{ [4-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)phenyl](methyl) ami no} -5- f I uoro- 1 H - i ndazol - 1 -y I ) aceti c aci d;
{ 5-chloro-3-[methyl(4-{ [4-(methylsulfonyl)piperazin-1-yl] sulfonyl} phenyl)
amino]-1 H-indazol-1-yl} acetic acid;
(3-{ [4-(azetidin-1-ylsulfonyl) phenyl](methyl)amino} -5-fluoro-1 H-indazol-1-yl) acetic acid;
(3-{ [4-(azetidin-1-ylsulfonyl) phenyl](methyl)amino} -5-chloro-1 H-indazol-1-yl) acetic acid;
(5-chloro-3-{ [3-methoxy-4-(morpholin-4-yl sulfonyl) phenyl] (methyl) amino}- 1 H-indazol-1-yl)acetic acid;
{ 5-fluoro-3-[(4-{ [(3R)-3-hydroxypyrrolidin-1-yl]sulfonyl} phenyl)(methyl) ami no]-1 H- i ndazol -1-yl} acetic acid;
(5-fluoro-3-{ methyl[4-(phenylsulfamoyl) phenyl]amino}-1 H-indazol-1-yl)acetic Acid;
(3-{ [4-(cyclopentylsulfonyl)phenyl] (methyl)amino}-5-fluoro-1 H-indazol-1-yl acetic acid;
{ 5-f I uoro-3-[(4-{ [(2S)-2-( hydroxymethyl ) pyrrol i di n-1 -y I] sulfonyl} phenyl)
(methyl)amino]-1 H-indazol-1-yl}acetic acid;
[5-fl uoro- 3-(methyl{4-[(4-methyl-1,3-thiazol-2-yl)sulfamoyl] phenyl} amino)-1 H- i ndazol -1-yl] acetic acid;
(3-{ [4-(2,3-dihydro-1 H-indol-1-ylsulfonyl)phenyl](methyl)amino}-5-fluoro-1 H-indazol- 1-yl)acetic acid;
{3-[{4-[(1,1-dioxidothiomorpholin-4-yl) sulfonyl] phenyl} ( methyl ) ami no]- 5- f I uoro- 1 H - i ndazol - 1 -y I } aceti c aci d; { 5-fluoro-3-[methyl(4-{ [4-(pyridin-2-yl) pi perazin-1-yl]sulfonyl} phenyl) amino]- 1 H-i ndazol-1 -yl} acetic acid;
(5-f I uoro-3-{ methyl [4-(thiomorphol i n-4-ylsulfonyl) phenyl] ami no} -1 H-i ndazol-1 -yl) acetic acid;
(5-chloro-3-{ [4-(4,7-di hydrothieno[2,3-c]pyridi n-6(5H)-ylsulfonyl)phenyl]
(methyl)ami no} -1 H-i ndazol-1 -yl)acetic acid;
3-[[4-[(4-benzoyl-1-piperazinyl)sulfonyl] phenyl] methyl ami no] -5-fl uoro-1 H - indazole-1 -acetic acid;
{ 5-fluoro-3-[methyl(4-{ [4-(trifluoromethyl) pi peridi n-1-yl]sulfonyl} phenyl) ami no] - 1 H - i ndazol - 1 -y I } aceti c aci d;
[5-fl uoro-3-(methyl{ 4-[(4- methyl pi perazi n-1 -yl)sulfonyl] phenyl} ami no)-1 H -i ndazol-1 y I] acetic acid;
{3-[(4-{ [4-(5-chloropyridin-2-yl)piperazin-1-yl]sulfonyl} phenyl)(methyl) amino] f I uoro- 1 H - i ndazol - 1 -y I } aceti c aci d;
[5-fl uoro-3-(methyl{4-[(4-methylpi peridi n-1 -yl)sulfonyl] phenyl} ami no)-1 H-indazol-1 y I] acetic acid;
(7-methyl-3-{ methyl[4-(pyrrolidin-1-yl sulfonyl)phenyl]amino}-1 H-indazol-1- yl)acetic acid;
{ 3-[{4-[(4- benzyl pi perazi n-1 -yl) sulfonyl] phenyl} (methyl)ami no]-5-f I uoro-1 H- i ndazol -1-yl} acetic acid;
{ 5-fluoro-3-[methyl(4-{ [4-(pyrimidin-2-yl) pi perazi n-1 -yl]sulfonyl} phenyl) ami no]-1 H-indazol-1-yl} acetic acid;
{ 5-f luoro-3-[methyl(4-{ [4-(2-methoxyphenyl) pi perazi n-1 -yl] sulfonyl}
phenyl)amino]-1 H-indazol-1-yl}acetic acid;
{7-methyl-3-[methyl(4-{ [4-(pyridin-2-yl) pi perazin-1-yl]sulfonyl} phenyl) ami no]-1 H-indazol-1-yl} acetic acid;
{ 5-fl uoro- 3-[methyl(4-{ [4-(2-ox o- 2, 3-dihydro-1 H-benzimidazol-1-yl)pi peridi n-1 - yl]sulfonyl} phenyl)amino]-1 H-indazol-1-yl}acetic acid;
{3-[{4-[(4-carbamoylpi peridi n-1-yl) sulfonyl] phenyl} ( methyl )ami no] -5-f I uoro- 1 H-i ndazol-1 -yl} acetic acid;
{ 5-fluoro-3-[{4-[(3-hydroxyazetidi n-1-yl) sulfonyl] phenyl} (methyl)amino]-1 H- i ndazol -1-yl} acetic acid; (5-fluoro-3-{ propan-2-yl[4-(pyrrolidin-1-ylsulfonyl)phenyl]amino}-1 H-indazol-1- yl)acetic acid;
{ 5-fluoro-3-[methyl(4-{ [4-(pyrimidin-2-yl) pi peraz i n- 1 -y I ] sul f ony I } phenyl)
ami no]-1 H-indazol-1-yl} acetic acid, Sodium salt;
{ 5-fluoro-3-[methyl(4-{ [4-(pyridin-2-yl) pi peraz i n- 1 -y I ] sul f ony I } phenyl) amino]- 1 H-indazol-1-yl} acetic acid, Sodium salt;
{3-[(4-{ [4-(3,4-dichlorophenyl)piperazin-1-yl]sulfonyl} phenyl)(methyl) amino]- 5-f I uoro- 1 H - i ndazol - 1 -y I } aceti c aci d;
{3-[(4-{ [4-(3-chlorophenyl)piperazin-1-yl]sulfonyl} phenyl)(methyl)amino]-5-fl uoro-1 H- indazol-1-yl}acetic acid;
{3-[(4-{ [4-(2,3-dichl orophenyl)pi perazin-1-yl]sulfonyl} phenyl)(methyl)amino]-5-fluoro- 1 H-indazol-1-yl} acetic acid;
{ 5-fluoro-3-[propan-2-yl(4-{ [4-(pyridin-2-yl)piperazin-1-yl]sulfonyl} phenyl)amino]-1 H- i ndazol -1-yl} acetic acid;
{3-[{4-[(2,6-dimethylmorpholi n-4-yl)sulfonyl] phenyl} ( methyl) ami no] -5-f luoro-1 H- i ndazol -1-yl} acetic acid;
(5-f I uoro- 3-{ methyl [4-(1,3-thiazol idin-3-ylsulfonyl)phenyl]ami no} -1 H-indazol-1 - yl)acetic acid;
{3-[{4-[(3-carbamoylpiperidin-1-yl)sulfonyl] phenyl} (methyl)ami no]-5-fl uoro-1 H- i ndazol -1-yl} acetic acid;
{ 5-fluoro-3-[(4-{ [4-(furan-2-ylcarbonyl)piperazin-1-yl]sulfonyl} phenyl) ( methyl ) ami no] - 1 H-indazol-1-yl} acetic acid;
{ 5-fluoro-3-[(4-{ [4-(methylsulfonyl)piperazin-1-yl]sulfonyl} phenyl) (propan-2- yl)amino]-1 H-indazol-1-yl}acetic acid;
(5-f luoro-3-{ [4-( morpholin-4-ylsulfonyl)phenyl](propan-2-yl)amino}-1 H-i ndazol-1 - yl)acetic acid;
(3-{ [4-({4-[(4-chlorophenyl)sulfonyl] piperazi n-1-yl}sulfonyl)phenyl] (propan-2- yl)amino}-5-fluoro-1 H-indazol-1-yl)acetic acid;
2- (3-{ [4-(azeti di n- 1 -y I sul f ony I ) phenyl ] ( methyl)ami no} -5-f luoro-1 H-indazol-1 - y propanoic acid;
3- (5-fl uoro- 3-{ methyl[4-(pyrrolidin-1-ylsulfonyl)phenyl]ami no} -1 H-indazol-1 - y propanoic acid; Calcium bis({ 5-fl uoro-3-[methyl(4-{ [4-(pyridin-2-yl)pi perazin-1-yl]sulfonyl} phenyl )ami no] -1 H-i ndazol -1 -yl} acetate);
Calcium bis({ 5-fl uoro-3-[methyl(4-{ [4-(pyrimidin-2-yl)pi perazin-1-yl]sulfonyl} phenyl )ami no] -1 H-i ndazol -1 -yl} acetate);
Calcium bis[(5-fluoro-3-{ methyl[4-(pyrrolidi n-1-ylsulfonyl)phenyl]amino}-1 H- indazol-1-yl)acetate];
{3-[(4-{ [4-(6-chloropyridin-2-yl)piperazin-1-yl]sulfonyl} phenyl)(methyl)ami no]-5- f I uoro- 1 H - i ndazol - 1 -y I } aceti c aci d;
{ 5-fluoro-3-[(4-{ [4-(6-methoxypyridi n-2-yl)pi peraz i n- 1 -y I ] su I f ony I } phenyl) (methyl)amino]-1 H-indazol-1-yl}acetic acid;
Magnesi um bis({ 5-fl uoro-3-[methyl(4-{ [4-(pyridin-2-yl)pi peraz i n- 1 -y I ] su I f ony I } phenyl )ami no] -1 H-i ndazol -1 -yl} acetate);
1 ,3-dihydroxy-2-(hydroxymethyl)propan-2-ami ni um { 5-f I uoro-3-[methyl(4-{ [4-
(pyridi n-2-yl)pi perazin-1-yl]sulfonyl} phenyl)amino]-1 H-indazol-1-yl}acetate;
2-hydroxy-N,N,N-tri methyl ethanaminium { 5-fl uoro- 3-[methyl(4-{ [4-(pyridin-2- yl) pi perazi n-1 -yl] sulfonyl} phenyl)ami no]-1 H -i ndazol -1 -yl} acetate;
1 ,3-dihydroxy-2-(hydroxymethyl)propan-2-ami ni um (5-f I uoro-3-{ methyl [4-
( pyrrol i di n-1 -y I sulfonyl) phenyl] ami no} -1 H-i ndazol -1 -yl)acetate;
N-ethyl ethanami ni um (5-f I uoro-3-{ methyl [4-(pyrrol idi n-1 -ylsulf onyl) phenyl] ami no} - 1 H - i ndazol - 1 -y I ) acetate;
{ 5-fluoro-3-[(4-{ [4-(6-hydroxypyridi n-2-y I ) pi perazi n-1 -y I ] sul f ony I } phenyl ) (methyl)amino]-1 H-indazol-1-yl}acetic acid;
{ 5-fluoro-3-[(4-{ [4-(5-hydroxypyridi n-2-y I ) pi perazi n-1 -y I ] sul f ony I } phenyl ) (methyl)amino]-1 H-indazol-1-yl}acetic acid;
{ 5-f I uoro- 3- [(4-{ [4-(4- hy droxy py ri di n-2-y I ) pi perazi n- 1 -y I ] sul f ony I } phenyl ) (methyl)amino]-1 H-indazol-1-yl}acetic acid;
{ 5-fluoro-3-[(4-{ [4-(3-hydroxypyridi n-2-y I ) pi perazi n-1 -y I ] sul f ony I } phenyl ) (methyl)amino]-1 H-indazol-1-yl}acetic acid;
{ 5-fluoro-3-[(4-{ [4-(4-methoxypyridi n-2-yl)pi perazi n-1-yl]sulfonyl} phenyl) (methyl)amino]-1 H-indazol-1-yl}acetic acid;
(5-fluoro-3-{ methyl[4-({4-[6-(trifluoromethyl)pyridin-2-yl] pi perazin-1-yl} sul f ony I ) pheny I ] ami no} - 1 H - i ndazol - 1 -y I ) aceti c ac i d; (5-fluoro-3-{ methyl[4-({4-[5-(trifluoromethyl)pyridin-2-yl] pi perazin-1-yl}
sul f ony I ) pheny I ] ami no} - 1 H - i ndazol - 1 -y I ) aceti c ac i d;
( 5-f I uoro-3-{ methyl [4-({ 4- [5-( morphol i n-4-y I sulf ony I ) py ri di n-2-y I ] pi perazi n- 1 - yl} sulfonyl)phenyl]amino}-1 H-indazol-1-yl)acetic acid;
2-{4-[(4-{ [1-(carboxymethyl)-5-fl uoro-1 H-indazol-3-yl](methyl)ami no} phenyl) sulfonyl] pi perazi n-1-yl} pyridine-4-carboxyl ic acid;
(3-{ [4-({4-[3-(tert-butyl carbamoyl) pyridi n-2-yl] pi perazin-1-yl} sulfonyl)
phenyl ]( methyl )ami no} -5-f I uoro-1 H-indazol-1-yl)acetic acid;
{ 5-f I uoro-3-[(4-{ [4-(furo[3,2-c]pyridin-4-yl)piperazin-1-yl]sulfonyl} phenyl)
(methyl)amino]-1 H-indazol-1-yl}acetic acid;
{ 5-f I uoro-3- [ methyl (4-{ [4-(4- methyl qui nol i n-2-y I ) pi perazi n- 1 -y I ] sul f ony I}
phenyl)amino]-1 H-indazol-1-yl}acetic acid;
{ 5-f I uoro-3-[methyl(4-{ [4-(1 ,6-naphthyridi n-5-yl) pi perazi n-1 -yl]sulf onyl}
phenyl)amino]-1 H-indazol-1-yl}acetic acid;
(3-{ [4-({4-[1 -dimethyl-4-(trifluoromethyl)-1 H-pyrazolo[3,4-b] pyridin-6-yl] piperazin-1 yl} sulfonyl)phenyl](methyl)amino}-5-fl uoro-1 H-indazol-1-yl)acetic acid;
{ 5-fluoro-3-[methyl(4-{ [4-(thieno[3,2-c]pyridi n-4-yl)pi perazi n-1 -yl]
sulfonyl} phenyl)amino]-1 H-indazol-1-yl}acetic acid;
{ 5-fluoro-3-[methyl(4-{ [4-(4-methylfuro[3,2-c] pyridin-6-yl) pi perazi n-1 -yl]
sulfonyl} phenyl)amino]-1 H-indazol-1-yl}acetic acid;
{ 5-f I uoro-3-[(4-{ [4-(isoqui nol i n-1 -yl) pi perazi n-1 -yl] sulfonyl} phenyl) (methyl)ami no] 1 H-indazol-1-yl} acetic acid;
{3-[(4-{ [4-(1,3-benzothiazol-2-yl)piperazi n-1 -yl]sulfonyl} phenyl) (methyl)amino]-5 f I uoro- 1 H - i ndazol - 1 -y I } aceti c aci d;
{ 3-[(4-{ [4-(3-cyano-5,6,7,8-tetrahydroqui nol i n-2-yl)pi perazin-1- y I ] su I f ony I } pheny I ) ( methyl ) ami no] - 5-f I uoro- 1 H - i ndazol - 1 -y I } aceti c ac i d;
(3-{ [4-({4-[5-(acetylamino)pyridin-2-yl] piperazin-1-yl}sulfonyl)phenyl] ( methyl )ami no}
5-f I uoro- 1 H - i ndazol - 1 -y I )aceti c aci d;
and pharmaceutically acceptable salts thereof.
4. A pharmaceuti cal compositi on compri si ng one or more compound(s) accordi ng to any of preceding claims, optionally in admixture with a pharmaceutically acceptable adjuvant or carrier.
5. A method for treating allergic or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, nasal polyps and chronic obstructive pulmonary disease in a mammal, by administering a therapeutically effective amount of a compound according to claims 1, 2 or 3.
6. Use of a compound as clai med i n clai ms 1 , 2 or 3 f or the preparati on of a medi cament for treating allergic or non-allergic inflammatory disease selected from atopic dermatitis, asthma, allergic rhinitis, allergic conj unctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, nasal polyps and chronic obstructive pulmonary disease.
7. A compound of formula (1), its process for the preparation and pharmaceutical composition, as herein described with reference to the examples accompanying the specification.
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