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WO2024180520A1 - Novel atx inhibitors - Google Patents

Novel atx inhibitors Download PDF

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Publication number
WO2024180520A1
WO2024180520A1 PCT/IB2024/052000 IB2024052000W WO2024180520A1 WO 2024180520 A1 WO2024180520 A1 WO 2024180520A1 IB 2024052000 W IB2024052000 W IB 2024052000W WO 2024180520 A1 WO2024180520 A1 WO 2024180520A1
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Prior art keywords
oxo
chloro
indene
pyrazol
carboxylic acid
Prior art date
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PCT/IB2024/052000
Other languages
French (fr)
Inventor
Kumaragurubaran NAGASWAMY
Rajesh Bahekar
Vijay PRAJAPATI
Darshan Joshi
Harsh Desai
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Zydus Lifesciences Limited
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Publication of WO2024180520A1 publication Critical patent/WO2024180520A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/14—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 three or more hetero rings
    • 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
    • C07D471/10—Spiro-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
    • C07D487/10—Spiro-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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention describe novel compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs as ATX inhibitors for the treatment and prophylaxis of conditions or a disorder caused by autotaxin (ATX) activation or increased concentration of lysophosphatidic acid (LPA) and also a pharmaceutical composition containing the same.
  • ATX autotaxin
  • LPA lysophosphatidic acid
  • ATX enzyme is important for converting Lysophosphatidylcholine (LPC) into LPA, as a bioactive signaling molecule.
  • LPC Lysophosphatidylcholine
  • ATX is a secreted enzyme of the ectonucleotide phosphatase family, also known as Ectonucleotide Pyrophosphatase/ Phosphodiesterase 2 (ENPP-2 or NPP2).
  • ENPP-2 or NPP2 Ectonucleotide Pyrophosphatase/ Phosphodiesterase 2
  • LPA is a bioactive lipid that affects migration, proliferation and survival of various cell types. LPA mediates variety of cellular and biological actions through LPA receptors (LPAR).
  • the LPA shows broad tissue expression and it can couple to at least six distinct G proteins, known as LPAR1-6, which in turn, feed into multiple effector systems (Yung, Y.C. et al., J. Lipid Res. 2014, 55, 1192 and Kihara, Y. et al., Exp. Cell Res. 2015, 333, 171). Since the LPA level in plasma is highly related to the activity of ATX, it is believed that ATX is an important supply source of extracellular LPA.
  • LPA lymphocyte homing chronic inflammation
  • neuropathic pain fibrotic diseases
  • fibrotic diseases such as Idiopathic Pulmonary Fibrosis (IPF), thrombosis and cholestatic pruritus which caused and / or propagated by increased LPA levels and / or activation of ATX.
  • IPF Idiopathic Pulmonary Fibrosis
  • thrombosis thrombosis
  • IPF is characterized as a progressive scarring of lung tissue which leads to worsening lung function and is ultimately fatal within 3-5 years from the onset of symptoms.
  • LPAR1 has been identified to be the predominant LPA receptor (Tager, A. M. et al., Nat. Med. 2008, 14, 45 and Montesi, S. B. et al., BMC Pulm. Med. 2014). In the lung fibroblasts of an IPF patient, LPAR1 was found to be responsible for enhanced fibroblast cell migration and vascular leak.
  • LPAR1 antagonists will be a potential drug target for the treatment of IPF.
  • several LPAR1 antagonists have been reported, and some of these compounds are currently being evaluated for the treatment of IPF (Budd, D. C et al.., Future Med. Chem. 2013, 5, 1935; Qian, Y. et al., J. Med. Chem. 2012, 55, 7920 and Terakado, M. et al., ACS Med. Chem. Lett. 2016, 7, 913).
  • Fibrosis can develop in the liver, kidney, lung, dermis, vasculature, gut and other sites. Fibrosis develops due to action of pathways including growth factors, cytokines, integrin and lipids.
  • ATX, LPA and LPAR pathways have been implicated in fibrotic disease. Increased levels of ATX, LPA and LPARs observed in various rodent models of fibrosis and in patient fluids and biopsy tissues. LPA can induce proliferative, survival and chemotactic responses in cells known to be critical in fibrotic disease, including: fibroblasts, smooth muscle cells, macrophages, epithelial and endothelial cells and leukocytes.
  • Inhibitors of LPARs indicate that antagonism of receptors within this pathway blocked or reversed fibrosis in the lung, liver, kidney and skin in rodents. Accordingly in fibrotic diseases, it is desirable to lower LPA levels. This can be accomplished through inhibition of enzymes involved in LPA biosynthesis, such as ATX.
  • WO2022258693 W02022149010, W02022100727, WO2022074459, W02022003557, W02022003377, WO2021088957, WO2021078227, WO2021143753, WO2019228403, WO2019108943, WO 2019029620, WO2019223721, W02019158107, WO201815312, WO2017152062, W02017050791, W02017050792, W02017050747, W02017050732, WO2016144706, WO2016144704, WO2016028686, WO2015144605, W02015042053, W02015042052, WO2015154023, WO2015175171, W02015077503, W02015077502, W0201504830L WO2014139882.
  • ATX inhibitors for use in the treatment and / or prophylaxis of physiological and / or pathophysiological conditions such as cancer, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis which are caused, medicated and / or propagated by increased LPA levels and / or the activation of ATX.
  • the present invention describe novel compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs as ATX inhibitors for treatment and prophylaxis of conditions or a disorder caused by ATX activation or increased concentration of LPA and also a pharmaceutical composition containing the same.
  • Embodiments of the present invention include the compounds herein, pharmaceutically acceptable salts thereof, any physical forms thereof including solvates and hydrates, preparation of the compounds, intermediates and pharmaceutical compositions and formulations thereof.
  • An embodiment of the present invention provides novel compounds represented by the general formula (I), their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs and pharmaceutical compositions containing them or their mixtures thereof.
  • the use of novel compounds their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs of the present invention is use for the treatment of cancer, chronic inflammation, neuropathic pain, fibrotic diseases, by administering a therapeutically effective and non-toxic amount of novel compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals.
  • the present invention includes a method for the treatment of at least one of cancer, chronic inflammation, neuropathic pain, fibrotic diseases mediated in part by ATX comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the novel compound of formula (I).
  • the compound of formula (I) can be administered in combination with other therapeutic agents.
  • the present invention relates to the novel compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs represents below;
  • R 1 and R 2 are independently selected from -H, halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy, - (CH 2 ) q CF 3 , -CN, -O(CH 2 ) q CF 3 , -(CH 2 ) q OR a , -COOR a , -C(O)NR a R b , (C 3 -C 7 )cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl; E is selected from -CH 2 or -O-; when E is -O- then n is 1; when E is -CH 2 then n is 1 or 2;
  • Ring A is selected from aryl or heteroaryl
  • Ring B is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or heterocyclyl;
  • R 3 is selected from -H, halo, -(CH 2 ) r CF 3 , -CN, -O(CH 2 ) r CF 3 , -(CH 2 ) r OR d , - (CR d R e ) r NR d R e , or -NR d R e , -(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl , ( -C ⁇ alkoxy, (C C 6 )acyloxy, heterocyclyl wherein alkyl, cycloalkyl, alkoxy, acyloxy, heterocyclyl are substituted or unsubstituted;
  • R 4 and R 5 are independently selected from -H, halo, -(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, - (CH 2 ) S CF 3 , -CN, -O(CH 2 ) S CF 3 , -(CH 2 ) S OR S , or (C 3 -C 7 )cycloalkyl;
  • X, Y and Z are independently selected from -C or -N; m is selected from 1 or 2; p is selected from 0 or 1; q, r and s are independently selected from 0, 1, 2 or 3;
  • R a , R b , R c , R d , R e , R f , R s , R h and R 1 are independently selected from H, -OH, (Ci-C 6 )alkyl, haloalkyl, or (C 3 -C 7 )cycloalkyl
  • novel compounds of the general formula (I-a) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs represents below;
  • R 1 and R 2 are independently selected from -H, halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy, - (CH 2 ) q CF 3 , -CN, -O(CH 2 ) q CF 3 , -(CH 2 ) q OR a , -COOR a , -C(O)NR a R b , (C 3 -C 7 )cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;
  • E is selected from -CH 2 or -O-; when E is -O- then n is 1; when E is -CH 2 then n is 1 or 2;
  • Ring A is selected from aryl or heteroaryl
  • Ring B is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or heterocyclyl;
  • R 3 is selected from -H, halo, substituted or unsubstituted -(Ci-Ce)alkyl, (C 3 -C 7 )cycloalkyl , (Ci-C 6 )alkoxy, (Ci-C 6 )acyloxy, -(CH 2 ) r CF 3 , -CN, -O(CH 2 ) r CF 3 , -(CH 2 ) r OR d , - (CR d R e ) r NR d R e , or -NR d R e ;
  • R 4 and R 5 are independently selected from -H, halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy, - (CH 2 ) S CF 3 , -CN, -O(CH 2 ) S CF 3 , -(CH 2 ) S OR S , or (C 3 -C 7 )cycloalkyl;
  • X, Y and Z are independently selected from -C or -N; m is selected from 1 or 2; p is selected from 0 or 1; q, r and s are independently selected from 0, 1, 2 or 3;
  • R a , R b , R c , R d , R e , R f , R s , R h and R 1 are independently selected from -H, -OH, (Ci-Ce)alkyl, haloalkyl, or (C 3 -C 7 )cycloalkyl
  • R 1 and R 2 are independently selected from -H, halo, -COOR a , substituted or unsubstituted heteroaryl;
  • Ring A is selected from aryl
  • Ring B is selected from substituted or unsubstituted heteroaryl
  • R 3 is selected from -(CH 2 ) r OR d , -(Ci-Ce)alkyl;
  • R 4 and R 5 are independently selected from halo; p is selected form 0; q is selected from 2;
  • R a and R d are independently selected from -H.
  • novel compounds of the general formula (I-b) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and Dolvmorohs reoresents below;
  • R 1 and R 2 are independently selected from -H, halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy, - (CH 2 ) q CF 3 , -CN, -O(CH 2 ) q CF 3 , -(CH 2 ) q OR a , -COOR a , -C(O)NR a R b , (C 3 -C 7 )cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;
  • E is selected from -CH 2 or -O-; when E is -O- then n is 1; when E is -CH 2 then n is 1 or 2;
  • Ring A is selected from aryl or heteroaryl
  • Ring B is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or heterocyclyl;
  • R 3 is selected from -H, halo, substituted or unsubstituted -(Ci-C 6 )alkyl, (C 3 -C 7 )cycloalkyl , (Ci-C 6 )alkoxy, (Ci-C 6 )acyloxy, -(CH 2 ) r CF 3 , -CN, -O(CH 2 ) r CF 3 , -(CH 2 ) r OR d , - (CR d R e ) r NR d R e , or -NR d R e ;
  • R 4 and R 5 are independently selected from -H, halo, -(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, - (CH 2 ) S CF 3 , -CN, -O(CH 2 ) S CF 3 , -(CH 2 ) S OR S , or (C 3 -C 7 )cycloalkyl;
  • X, Y and Z are independently selected from -C or -N; m is selected from 1 or 2; p is selected from 0 or 1; q, r and s are independently selected from 0, 1, 2 or 3;
  • R a , R b , R c , R d , R e , R f , R s , R h and R 1 are independently selected from H, -OH, (Ci-Ce)alkyl, haloalkyl, or (C 3 -C 7 )cycloalkyl
  • R 1 and R 2 may be selected from -H, halo, -(Ci-Ce)alkyl, -COOR a , -C(O)NR a R b , substituted or unsubstituted aryl, (C 3 -C7)cycloalkyl, substituted or unsubstituted heteroaryl;
  • Preferred Ring A may be selected from aryl or heteroaryl
  • Preferred Ring B may be selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
  • Preferred R 3 may be selected from -H, -(Ci-Ce)alkyl, -(CH 2 ) r CF 3 , -(CH 2 ) r OR d , (C 3 - C7)cycloalkyl, or heterocyclyl;
  • R 4 and R 5 may be selected from -H, halo, -(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, - (CH 2 ) S CF 3 , -CN, -O(CH 2 ) S CF 3 ;
  • Preferred X, Y and Z may be selected from -C or -N;
  • R a , R b , R c , R d , R e , R f , R s , R h and R 1 may be selected from -H, (Ci-Ce)alkyl, -OH;
  • the groups, radicals described above may be selected from:
  • Alkyl as well as other groups having the prefix “alk”, such as alkoxy and alkanoyl, means carbon chain which may either be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise.
  • alkyl group include but not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert.-butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from C 3 .io, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures.
  • Cycloalkyl is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. A cycloalkyl group generally is monocyclic unless otherwise stated. Cycloalkyl groups are saturated unless and otherwise stated.
  • Haloalkyl group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
  • Aryl means a mono- or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
  • Heterocyclyl or “heterocyclic” group used either alone or in combination with other radicals, is selected from suitable saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 4- methylpiprrazinyl, 4-hydroxypiperidinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2- oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, 2- oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, o
  • Heteroaryl or “heteroaromatic” group used either alone or in combination with other radicals is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl,
  • Alkoxy group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbon attached to oxygen atom, selected from Methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, isobutoxy, pentyloxy, hexyloxy and the like;
  • “Acyloxy” group used either alone or in combination with other radicals is selected from groups containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, pentanoyl , benzoyl and the like; "Halo” or “halogen” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom;
  • Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Substitution selected from hydrogen, deuterium, hydroxy, cyano, halo, nitro, haloalkyl, oxo, (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aminoalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, alkylsulfonyloxy.
  • “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues.
  • Such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2- acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, eidetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, is
  • ‘optional’ or ‘optionally’ means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not.
  • ‘optionally substituted alkyl’ means either ‘alkyl’ or ‘substituted alkyl’. Further an optionally substituted group means unsubstituted.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • Particularly useful compounds may be selected from but not limited to the following; Table: 1
  • DIEA Diisopropyl ethyl amine
  • DMEDA 1,2-Dimethyl ethylene diamine
  • NaHCCh Sodium bicarbonate/sodium hydrogen carbonate
  • novel compounds of the present invention were prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art.
  • the reactions can be performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
  • Preferred methods include, but not limited to those described below, where all symbols are as defined earlier unless and otherwise defined below.
  • the compounds (IV) can be obtained by reacting compounds of the formula (II) with (III) inpresence of base such as Na 2 CO 3 , K 2 CO 3 Cs 2 CO 3 etc. in solvent such as THF, DMF etc.
  • base such as Na 2 CO 3 , K 2 CO 3 Cs 2 CO 3 etc.
  • solvent such as THF, DMF etc.
  • Step-1 Preparation of ethyl 6'-chloro-2'-oxo-F3-dihvdrospirolindene-2,3'-indoline1-5- carboxylate (3)
  • Step-2 ethyl 6'-chloro-2'-oxo-T-phenyl-l,3-dihvdrospirorindene-2,3'-indoline1-5- carboxylate (4)
  • Step-3 6'-chloro-2'-oxo-T-phenyl-L3-dihydrospirorindene-2,3'-indoline1-5-carboxylic acid
  • Compound 1 ethyl 6'-chloro-2'-oxo-T-phenyl-l,3-dihydrospiro[indene-2,3'-indoline]-5- carboxylate (0.21 g, 0.50 mmol) was dissolved in ethanol (2.1 mL) at room temperature. Aqueous NaOH solution (1.22 mL, 1.50 mmol) was dropwise added to the reaction mixture at room temperature and stirred for 5h.
  • Autotaxin activity was measured by determining the amount of Choline released from LPC 16:0 using Amplite® Choline Quantitation Kit (AAT Bioquest, 40007).
  • 5 pl of 20 nM purified recombinant human autotaxin (Echelon, E-4000) was mixed with lOpl of test compound (concentration range) in black 96 well plate in assay buffer (50 mM Tris-HCl pH 8.0, 500 mM NaCl, 5 mM KC1, 5 mM CaCl 2 , 0.1% Fatty acid free BSA) and incubated for 10 minutes at room temperature.
  • ATX inhibitory activity for representative compounds are listed in the Table 2.
  • the novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • the pharmaceutical compositions further comprise an effective amount of an ATX inhibitor.
  • the dosage of ATX inhibitors may vary within wide limits and should be adjusted, in each particular case, to the individual conditions.
  • the compounds of formula (I), or pharmaceutical compositions containing them are useful as a medicament for the inhibition of ATX activity and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
  • the quantity of active component, that is, the novel compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration.
  • composition comprising compound of general formula (I), their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.
  • the present invention includes a method for the treatment of at least one of cancer, chronic inflammation, neuropathic pain, fibrotic diseases mediated in part by ATX comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the novel compound of formula (I).
  • the compound of formula (I) may be used alone or in any combination with one or more therapeutic agents such as anti-inflammatory agents, antitumor agents, ant fibrotic agents, autotaxin inhibitors, immunomodulators and cardiovascular agents and other therapeutic agents which are known to skilled medical practitioner.
  • therapeutic agents such as anti-inflammatory agents, antitumor agents, ant fibrotic agents, autotaxin inhibitors, immunomodulators and cardiovascular agents and other therapeutic agents which are known to skilled medical practitioner.
  • the selection of such therapeutic agents may be depend upon the type of disease and its severity, condition of patient being treated, and other medications being taken by the patients, etc.
  • compound of formula (I) of the present invention may be used in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combination with tyrosine kinase inhibitors and pyridones class of therapeutic agents.
  • suitable pharmaceutically active agents selected from following therapeutic agents in any combination with tyrosine kinase inhibitors and pyridones class of therapeutic agents.
  • Nintedanib is tyrosine kinase inhibitors class of drug
  • Pirfenidone is pyridones class of drug.

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Abstract

The present invention relates to compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs. The invention also relates to processes for the preparation of the compounds of invention, pharmaceutical compositions containing the compounds and their use as ATX inhibitors. (I)

Description

NOVEL ATX INHIBITORS
FIELD OF INVENTION
The present invention describe novel compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs as ATX inhibitors for the treatment and prophylaxis of conditions or a disorder caused by autotaxin (ATX) activation or increased concentration of lysophosphatidic acid (LPA) and also a pharmaceutical composition containing the same.
FIELD AND BACKGROUND
ATX enzyme is important for converting Lysophosphatidylcholine (LPC) into LPA, as a bioactive signaling molecule. ATX is a secreted enzyme of the ectonucleotide phosphatase family, also known as Ectonucleotide Pyrophosphatase/ Phosphodiesterase 2 (ENPP-2 or NPP2). ATX plays important role in driving pathological conditions, including fibrosis, arthritic inflammation, neurodegeneration, neuropathic pain and cancer. LPA is a bioactive lipid that affects migration, proliferation and survival of various cell types. LPA mediates variety of cellular and biological actions through LPA receptors (LPAR). The LPA shows broad tissue expression and it can couple to at least six distinct G proteins, known as LPAR1-6, which in turn, feed into multiple effector systems (Yung, Y.C. et al., J. Lipid Res. 2014, 55, 1192 and Kihara, Y. et al., Exp. Cell Res. 2015, 333, 171). Since the LPA level in plasma is highly related to the activity of ATX, it is believed that ATX is an important supply source of extracellular LPA.
Inhibition of ATX has been shown to reduce LPA levels in pathological settings. Reduction of LPA may provide therapeutic benefits in diseases with unmet need, including cancer, lymphocyte homing chronic inflammation, neuropathic pain, fibrotic diseases such as Idiopathic Pulmonary Fibrosis (IPF), thrombosis and cholestatic pruritus which caused and / or propagated by increased LPA levels and / or activation of ATX.
IPF is characterized as a progressive scarring of lung tissue which leads to worsening lung function and is ultimately fatal within 3-5 years from the onset of symptoms. There were no treatment options for IPF until 2014, when the FDA approved Nintedanib (Ofev) and Pirfenidone (Esbriet) (King, T, E. et al., Lancet 2011, 378, 1949; Richeldi, L. at el., N. Engl. J. Med. 2014, 370, 2071; Roth, G. J. et al., J. Med. Chem. 2009, 52, 4466; J. Med. Chem. 2015, 58, 1053; Hilberg, F. et al., Drugs Future 2010, 35, 5; and King, T. E. et al., N. Engl. J. Med. 2014, 370, 2083). Despite this advancement, there remains a need for additional medicines to treat IPF. Patients with IPF have elevated levels of LPA in their bronchoalveolar lavage fluid (BALF) and exhaled breath condensate. LPAR1 has been identified to be the predominant LPA receptor (Tager, A. M. et al., Nat. Med. 2008, 14, 45 and Montesi, S. B. et al., BMC Pulm. Med. 2014). In the lung fibroblasts of an IPF patient, LPAR1 was found to be responsible for enhanced fibroblast cell migration and vascular leak. It is therefore envisaged that LPAR1 antagonists will be a potential drug target for the treatment of IPF. In recent years, several LPAR1 antagonists have been reported, and some of these compounds are currently being evaluated for the treatment of IPF (Budd, D. C et al.., Future Med. Chem. 2013, 5, 1935; Qian, Y. et al., J. Med. Chem. 2012, 55, 7920 and Terakado, M. et al., ACS Med. Chem. Lett. 2016, 7, 913).
Fibrosis can develop in the liver, kidney, lung, dermis, vasculature, gut and other sites. Fibrosis develops due to action of pathways including growth factors, cytokines, integrin and lipids. ATX, LPA and LPAR pathways have been implicated in fibrotic disease. Increased levels of ATX, LPA and LPARs observed in various rodent models of fibrosis and in patient fluids and biopsy tissues. LPA can induce proliferative, survival and chemotactic responses in cells known to be critical in fibrotic disease, including: fibroblasts, smooth muscle cells, macrophages, epithelial and endothelial cells and leukocytes. Inhibitors of LPARs indicate that antagonism of receptors within this pathway blocked or reversed fibrosis in the lung, liver, kidney and skin in rodents. Accordingly in fibrotic diseases, it is desirable to lower LPA levels. This can be accomplished through inhibition of enzymes involved in LPA biosynthesis, such as ATX.
Various publications refer to compounds that are capable of inhibiting ATX, including: WO2022258693, W02022149010, W02022100727, WO2022074459, W02022003557, W02022003377, WO2021088957, WO2021078227, WO2021143753, WO2019228403, WO2019108943, WO 2019029620, WO2019223721, W02019158107, WO201815312, WO2017152062, W02017050791, W02017050792, W02017050747, W02017050732, WO2016144706, WO2016144704, WO2016028686, WO2015144605, W02015042053, W02015042052, WO2015154023, WO2015175171, W02015077503, W02015077502, W0201504830L WO2014139882. WO2014139978. WO2014048865. WO2014202458. Thus there is an unmet need for ATX inhibitors for use in the treatment and / or prophylaxis of physiological and / or pathophysiological conditions such as cancer, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis which are caused, medicated and / or propagated by increased LPA levels and / or the activation of ATX.
SUMMARY OF THE INVENTION
The present invention describe novel compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs as ATX inhibitors for treatment and prophylaxis of conditions or a disorder caused by ATX activation or increased concentration of LPA and also a pharmaceutical composition containing the same. Embodiments of the present invention include the compounds herein, pharmaceutically acceptable salts thereof, any physical forms thereof including solvates and hydrates, preparation of the compounds, intermediates and pharmaceutical compositions and formulations thereof.
Figure imgf000004_0001
EMBODIMENT(S) OF THE INVENTION
An embodiment of the present invention provides novel compounds represented by the general formula (I), their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs and pharmaceutical compositions containing them or their mixtures thereof.
In a further embodiment of the present invention is provided pharmaceutical compositions containing novel compounds of the general formula (I), their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions. In a still further embodiment is provided the use of novel compounds their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs of the present invention is use for the treatment of cancer, chronic inflammation, neuropathic pain, fibrotic diseases, by administering a therapeutically effective and non-toxic amount of novel compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals.
In some embodiments, the present invention includes a method for the treatment of at least one of cancer, chronic inflammation, neuropathic pain, fibrotic diseases mediated in part by ATX comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the novel compound of formula (I).
In a still further embodiment is provided a process for preparing the novel compounds of the present invention.
In some embodiments, the compound of formula (I) can be administered in combination with other therapeutic agents.
DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to the novel compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs represents below;
Figure imgf000005_0001
Formula (I)
Wherein,
R1 and R2 are independently selected from -H, halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy, - (CH2)qCF3, -CN, -O(CH2)qCF3, -(CH2)qORa, -COORa, -C(O)NRaRb, (C3-C7)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl; E is selected from -CH2 or -O-; when E is -O- then n is 1; when E is -CH2 then n is 1 or 2;
Ring A is selected from aryl or heteroaryl;
Ring B is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or heterocyclyl;
R3 is selected from -H, halo, -(CH2)rCF3, -CN, -O(CH2)rCF3, -(CH2)rORd, - (CRdRe)rNRdRe, or -NRdRe, -(C1-C6)alkyl, (C3-C7)cycloalkyl , ( -C^alkoxy, (C C6)acyloxy, heterocyclyl wherein alkyl, cycloalkyl, alkoxy, acyloxy, heterocyclyl are substituted or unsubstituted;
R4 and R5 are independently selected from -H, halo, -(Ci-C6)alkyl, (Ci-C6)alkoxy, - (CH2)SCF3, -CN, -O(CH2)SCF3, -(CH2)SORS, or (C3-C7)cycloalkyl;
X, Y and Z are independently selected from -C or -N; m is selected from 1 or 2; p is selected from 0 or 1; q, r and s are independently selected from 0, 1, 2 or 3;
Ra, Rb, Rc, Rd, Re, Rf, Rs, Rh and R1 are independently selected from H, -OH, (Ci-C6)alkyl, haloalkyl, or (C3-C7)cycloalkyl
In certain embodiments, the novel compounds of the general formula (I-a) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs represents below;
Figure imgf000006_0001
Wherein,
R1 and R2 are independently selected from -H, halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy, - (CH2)qCF3, -CN, -O(CH2)qCF3, -(CH2)qORa, -COORa, -C(O)NRaRb, (C3-C7)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;
E is selected from -CH2 or -O-; when E is -O- then n is 1; when E is -CH2 then n is 1 or 2;
Ring A is selected from aryl or heteroaryl;
Ring B is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or heterocyclyl;
R3 is selected from -H, halo, substituted or unsubstituted -(Ci-Ce)alkyl, (C3-C7)cycloalkyl , (Ci-C6)alkoxy, (Ci-C6)acyloxy, -(CH2)rCF3, -CN, -O(CH2)rCF3, -(CH2)rORd, - (CRdRe)rNRdRe, or -NRdRe;
R4 and R5 are independently selected from -H, halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy, - (CH2)SCF3, -CN, -O(CH2)SCF3, -(CH2)SORS, or (C3-C7)cycloalkyl;
X, Y and Z are independently selected from -C or -N; m is selected from 1 or 2; p is selected from 0 or 1; q, r and s are independently selected from 0, 1, 2 or 3;
Ra, Rb, Rc, Rd, Re, Rf, Rs, Rh and R1 are independently selected from -H, -OH, (Ci-Ce)alkyl, haloalkyl, or (C3-C7)cycloalkyl
In a preferred embodiments, R1 and R2 are independently selected from -H, halo, -COORa, substituted or unsubstituted heteroaryl;
Ring A is selected from aryl;
Ring B is selected from substituted or unsubstituted heteroaryl;
R3 is selected from -(CH2)rORd, -(Ci-Ce)alkyl;
R4 and R5 are independently selected from halo; p is selected form 0; q is selected from 2;
Ra and Rd are independently selected from -H.
In certain embodiments, the novel compounds of the general formula (I-b) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and Dolvmorohs reoresents below;
Figure imgf000008_0001
Wherein,
R1 and R2 are independently selected from -H, halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy, - (CH2)qCF3, -CN, -O(CH2)qCF3, -(CH2)qORa, -COORa, -C(O)NRaRb, (C3-C7)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;
E is selected from -CH2 or -O-; when E is -O- then n is 1; when E is -CH2 then n is 1 or 2;
Ring A is selected from aryl or heteroaryl;
Ring B is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or heterocyclyl;
R3 is selected from -H, halo, substituted or unsubstituted -(Ci-C6)alkyl, (C3-C7)cycloalkyl , (Ci-C6)alkoxy, (Ci-C6)acyloxy, -(CH2)rCF3, -CN, -O(CH2)rCF3, -(CH2)rORd, - (CRdRe)rNRdRe, or -NRdRe;
R4 and R5 are independently selected from -H, halo, -(Ci-C6)alkyl, (Ci-C6)alkoxy, - (CH2)SCF3, -CN, -O(CH2)SCF3, -(CH2)SORS, or (C3-C7)cycloalkyl;
X, Y and Z are independently selected from -C or -N; m is selected from 1 or 2; p is selected from 0 or 1; q, r and s are independently selected from 0, 1, 2 or 3;
Ra, Rb, Rc, Rd, Re, Rf, Rs, Rh and R1 are independently selected from H, -OH, (Ci-Ce)alkyl, haloalkyl, or (C3-C7)cycloalkyl
Further preferred embodiments of the present invention are those disclosed below: Preferred R1 and R2 may be selected from -H, halo, -(Ci-Ce)alkyl, -COORa, -C(O)NRaRb, substituted or unsubstituted aryl, (C3-C7)cycloalkyl, substituted or unsubstituted heteroaryl;
Preferred Ring A may be selected from aryl or heteroaryl;
Preferred Ring B may be selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
Preferred R3 may be selected from -H, -(Ci-Ce)alkyl, -(CH2)rCF3, -(CH2)rORd, (C3- C7)cycloalkyl, or heterocyclyl;
Preferred R4 and R5 may be selected from -H, halo, -(Ci-C6)alkyl, (Ci-C6)alkoxy, - (CH2)SCF3, -CN, -O(CH2)SCF3;
Preferred X, Y and Z may be selected from -C or -N;
Preferred Ra, Rb, Rc, Rd, Re, Rf, Rs, Rh and R1 may be selected from -H, (Ci-Ce)alkyl, -OH;
In a further embodiment, the groups, radicals described above may be selected from:
“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy and alkanoyl, means carbon chain which may either be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl group include but not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert.-butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from C3.io, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures.
“Cycloalkyl” is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. A cycloalkyl group generally is monocyclic unless otherwise stated. Cycloalkyl groups are saturated unless and otherwise stated.
“Haloalkyl” group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
“Aryl” means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. “Heterocyclyl” or “heterocyclic” group used either alone or in combination with other radicals, is selected from suitable saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 4- methylpiprrazinyl, 4-hydroxypiperidinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2- oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, 2- oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, and the like; In one embodiment, the heterocycle group, wherever applicable, may consists of appropriate number of carbon atoms and include from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, p = 0-2;
“Heteroaryl” or “heteroaromatic” group used either alone or in combination with other radicals, is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl and the like;
Alkoxy” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbon attached to oxygen atom, selected from Methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, isobutoxy, pentyloxy, hexyloxy and the like;
“Acyloxy” group used either alone or in combination with other radicals, is selected from groups containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, pentanoyl , benzoyl and the like; "Halo" or "halogen" by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom;
Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Substitution selected from hydrogen, deuterium, hydroxy, cyano, halo, nitro, haloalkyl, oxo, (Ci-C6)alkyl, (C3-C6)cycloalkyl, aminoalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, alkylsulfonyloxy.
“Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues. Such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2- acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, eidetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.
The term ‘optional’ or ‘optionally’ means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not. For example, ‘optionally substituted alkyl’ means either ‘alkyl’ or ‘substituted alkyl’. Further an optionally substituted group means unsubstituted.
Unless otherwise stated in the specification, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
Particularly useful compounds may be selected from but not limited to the following; Table: 1
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Following is a list of abbreviations used in the description of the preparation of the compounds of the present invention:
ACN : Acetonitrile BOC : tert-Butyloxy carbonyl
Cs2CO3 : Cesium carbonate
Cui : Copper(I) iodide
DCM : Dichloro methane
DIEA : Diisopropyl ethyl amine DMEDA : 1,2-Dimethyl ethylene diamine
DMF : N,N-Dimethyl formamide
DMSO : Dimethyl sulfoxide
EtOH : Ethanol EtOAc : Ethyl acetate h : hours
HC1 : Hydrochloric acid
HPLC : High performance liquid chromatography
IPA : Isopropyl alcohol
K2CO3 : Pottasium carbonate
MeOH : Methanol
Na2CO3 : Sodium carbonate
NaOH : Sodium hydroxide
Na2SO4 : Sodium sulfate
NaHCCh : Sodium bicarbonate/sodium hydrogen carbonate
NMP : N-Methyl-2-pyrrolidone
Z-BuOK : Potassium /c/7-butoxide
TEA : Triethylamine
TFA : Trifluoro acetic acid
THF : Tetrahydrofuran
TLC : Thin layer chromatography
The novel compounds of the present invention were prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art.
The reactions can be performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Preferred methods include, but not limited to those described below, where all symbols are as defined earlier unless and otherwise defined below.
The compounds of the formula (I) can be prepared as described in general scheme-1 below along with suitable modifications/variations which are well within the scope of a person skilled in the art.
The compounds (IV) can be obtained by reacting compounds of the formula (II) with (III) inpresence of base such as Na2CO3, K2CO3 Cs2CO3 etc. in solvent such as THF, DMF etc. A copper mediated cross-coupling reaction of compounds of formula (IV) with (V) to provide compounds of formula (I). General Scheme-1:
Figure imgf000029_0001
General Methods
Melting points were recorded on a scientific melting point apparatus and are uncorrected. IR spectra were recorded as neat (for oils) or on KBr pellet (for solid) on FT-IR 8300 Shimadzu and are reported in wavenumbers v (cm'1). NMR spectra were measured on a Varian Unity 400 (' H at 400 MHz, 13C at 100 MHz), magnetic resonance spectrometer. Spectra were taken in the indicated solvent at ambient temperature. Chemical shifts (6) are given in parts per million (ppm) with tetramethyl silane as an internal standard. Multiplicities are recorded as follows: s = singlet, d = doublet, t = triplet, q = quartet, br = broad. Coupling constants (J values) are given in Hz. Mass spectra are recorded on Perkin- Elmer Sciex API 3000. ESI-Q-TOF-MS measurements were performed with a micrOTOF- Q II (Bruker Daltonics) mass spectrometer. HPLC analysis were carried out at km ax 220 nm using column ODS C-18, 150 mm x 4.6 mm x 4 pm on AGILENT 1100 series. Reactions were monitored using thin layer silica gel chromatography (TLC) using 0.25 mm silica gel 60F plates from Merck. Plates were visualized by treatment with UV, acidic p-anisaldehyde stain, KMnCf stain with gentle heating. Products were purified by column chromatography using silica gel 100-200 mesh and the solvent systems indicated. All reactions involving air or moisture sensitive compounds were performed under nitrogen atmosphere in flame dried glassware. Tetrahydrofuran (THF) and diethyl ether (Et2O) were freshly distilled from sodium/ benzophenone under nitrogen atmosphere. Other solvents used for reactions were purified according to standard procedures. Starting reagents were purchased from commercial suppliers and used without further purification unless otherwise specified.
Synthesis of Compound-1: 6'-chloro-2'-oxo-l'-phenyl-l,3-dihydrospiro[indene-2,3'- indoline]-5-carboxylic acid
Figure imgf000030_0001
Synthesis of compound- 6'-chloro-2'-oxo-l'-phenyl-l,3-dihydrospiro[indene-2,3'-indoline]- 5-carboxylic acid was carried out as shown in Scheme-2 and the stepwise procedure is depicted below:
Figure imgf000030_0002
Scheme-2:
Step-1 : Preparation of ethyl 6'-chloro-2'-oxo-F3-dihvdrospirolindene-2,3'-indoline1-5- carboxylate (3)
To a solution of 6-chloroindolin-2-one (4.7 g, 28.0 mmol) in DMF (70.5 mL) was added cesium carbonate (22.84 g, 70.1 mmol) at 0°C and stirred for 30 min. Solution of ethyl 3,4- bis(bromomethyl)benzoate (11.31 g, 33.7 mmol) in DMF (23.5 mL) was dropwise added in the reaction mixture 0°C and stirred for 2 h. Reaction was poured into cold water and stirred for 15 min. Solid crude product was precipitated, filtered and dried in vacuo, The crude product was purified using a combiflash column chromatography (Hexane: EtOAC=l :4) to give ethyl 6'-chloro-2'-oxo-l,3-dihydrospiro[indene-2,3'-indoline]-5- carboxylate (3) as a solid (5.85 g, 61.0 % yield). 'H NMR: (CDC13; 400 MHz): 5 8.16 (s, 1H), 8.00-7.97 (m, 2H), 7.36 (d, J=8.0 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 6.88 (dd, Ji=8.0 Hz, J2=2.0 HZ, 1H), 6.71 (d, J=8.0 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.67 (d, J=16.8 Hz, 2H), 3.15 (d, J=16.8 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); ESI-MS: (+ve mode) 342.10 (M)+ (100 %).
Step-2: ethyl 6'-chloro-2'-oxo-T-phenyl-l,3-dihvdrospirorindene-2,3'-indoline1-5- carboxylate (4)
To an ethyl 6'-chloro-2'-oxo-l,3-dihydrospiro[indene-2,3'-indoline] mixture -5- carboxylate (3) (0.2 g, 0.58 mmol) was added toluene (5 mL) along with iodobenzene (0.179 g, 0.88 mmol), N,N'-dimethylethylenediamine (0.052 g, 0.58 mmol), K2CO3 (0.178 g, 1.28 mmol), and copper(I) iodide (0.056 g, 0.293) at room temperature under inert condition, the reaction mixture was stirred at 110 °C. The reaction mixture was cooled to room temperature, filtered through celite, washed with ethyl acetate, and the combined organic layer was concentrated and dried in vacuo. The obtained crude product is taken to the next step without any purification. (0.21 g, 86 % yield). ESI-MS: (+ve mode) 418.2 (M)+ (100 %).
Step-3: 6'-chloro-2'-oxo-T-phenyl-L3-dihydrospirorindene-2,3'-indoline1-5-carboxylic acid (Compound 1) ethyl 6'-chloro-2'-oxo-T-phenyl-l,3-dihydrospiro[indene-2,3'-indoline]-5- carboxylate (0.21 g, 0.50 mmol) was dissolved in ethanol (2.1 mL) at room temperature. Aqueous NaOH solution (1.22 mL, 1.50 mmol) was dropwise added to the reaction mixture at room temperature and stirred for 5h. The reaction mixture was concentrated in rotavapour, the residue was dissolved in water (10 mL), acidified with 1 M HC1 (aq. ), and the solid was filtrated, dried, and purified using a preparative HPLC to yield the title compound 6'-chloro-2'-oxo-l'-phenyl-l,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid (Compound 1) as a white solid. (0.124 g, 63.3% yield). 1H NMR: (DMSO-D6J 400 MHz): 5 12.9 (bs, 1H), 7.88-7.85 (m, 2H), 7.58-7.62 (m, 2H), 7.52-7.43 (m 4H), 7.11-7.06 (m, 2H), 6.72 (s, 1H), 3.55-3.51 (m, 2H), 3.43-3.33 (m, 2H); ESI-MS: (+ve mode) 390.10 (M)+ (100 %).
Following specific novel compounds of general formula (I) of the present invention are prepared by using methods depicted in general scheme-1
Compound-3: 6'-chloro-2'-oxo-l'-(pyridin-3-yl)-l,3-dihydrospiro[indene-2,3'-indoline]-5- carboxylic acid
Figure imgf000033_0001
'H NMR: (DMSO-D6; 400 MHz): 5 13.0 (bs, 1H), 8.89 (d, J=2.0 Hz, 1H), 8.70 (s, 1H), 8.08-8.05 (m, 1H), 7.89-7.85 (m 2H), 7.69-7.66 (m, 1H), 7.45-7.43 (m 1H), 7.24-7.10 (m,
2H), 6.84 (s, 1H), 3.57-3.53 (m, 2H), 3.39-3.35 (m, 2H); ESI-MS: (+ve mode) 391.3 (M)+ (100 %).
Compound-6: 6'-chloro-2'-oxo-r-(pyrimidin-5-yl)-l,3-dihydrospiro[indene-2,3'- indoline]-5-carboxylic acid
Figure imgf000033_0002
'H NMR: (DMSO-d6, 400 MHz): 5 12.87 (bs, 1H), 9.28 (s, 1H), 9.07 (s, 2H), 7.89-7.85 (m, 2H), 7.44 (d, J=7.6 Hz, 1H), 7.19-7.12 (m, 2H), 7.06 (s, 1H), 3.58-3.54 (m, 2H), 3.40- 3.36 (m, 2H); ESI-MS: (+ve mode) 392.1 (M)+ (100 %).
Compound-8: 6'-chloro-2'-oxo-r-(thiophen-3-yl)-l,3-dihydrospiro[indene-2,3'-indoline]- 5-carboxylic acid
Figure imgf000034_0001
'H NMR: (DMSO-d6, 400 MHz): 5 12.93 (bs, 1H), 7.88-7.75 (m, 4H), 7.44 (d, J=7.6 Hz, 1H), 7.33-7.32 (m, 1H), 7.13 (s, 2H), 6.95 (s, 1H), 3.55-3.52 (m, 2H), 3.41-3.38 (m, 2H);
ESI-MS: (+ve mode) 396.1 (M)+ (100 %).
Compound-16: 6'-chloro-2'-oxo-l'-(lH-pyrazol-4-yl)-l,3-dihydrospiro[indene-2,3'- indoline]-5-carboxylic acid
Figure imgf000034_0002
'H NMR: (DMSO-d6, 400 MHz): 5 13.04 (bs, 1H), 8.07-7.98 (m, 2H), 7.88-7.85 (m, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.08-7.03 (m, 2H), 6.89 (s, 1H), 3.99 (d, J=7.2 Hz, 2H), 3.51-3.46 (m, 2H), 3.32-3.28 (m, 2H); ESI-MS: (+ve mode) 380.1 (M)+ (100 %).
Compound-17: 6'-chloro-l'-(l-methyl-lH-pyrazol-4-yl)-2'-oxo-l,3-dihydrospiro[indene- 2,3'-indoline]-5-carboxylic acid
Figure imgf000035_0001
'H NMR: (DMSO-d6, 400 MHz): 5 12.88 (bs, 1H), 8.19 (s, 1H), 7.87-7.85 (m, 2H), 7.75 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.09-7.03 (m, 2H), 6.97 (s, 1H), 4.21 (q, J=7.2 Hz, 2H),
3.50-3.46 (m, 2H) 3.31-3.27 (m, 2H), 1.43 (t, J=7.2 Hz, 3H) ; ESI-MS: (+ve mode) 408.1 (M)+ (100 %).
Compound-19: 6'-chloro- 1'-( 1 -isopropyl- lH-pyrazol-4-yl)-2'-oxo- 1,3- dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid
Figure imgf000036_0001
'H NMR: (CDCL3; 400 MHz): 5 8.08-8.06 (m, 2H), 7.85 (s, 1H), 7.80 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.96-6.93 (m, 1H), 6.79 (d, J=8.0 Hz, 1H), 4.65-4.58 (m, 1H) 3.77-3.73 (m, 2H), 3.25-3.20 (m, 2H), 1.61 (d, J=6.4 Hz, 6H); ESI-MS: (+ve mode) 422.1 (M)+ (100 %).
Compound-20: 6'-chloro- 1'-( 1 -isobutyl- lH-pyrazol-4-yl)-2'-oxo- 1 ,3 -dihydrospirofindene- 2,3'-indoline]-5-carboxylic acid
Figure imgf000036_0002
'H NMR: (DMSO-d6, 400 MHz): 5 12.90 (bs, 1H), 8.18 (s, 1H), 7.87-7.85 (m, 2H), 7.77 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.09-7.03 (m, 2H), 6.92 (s, 1H), 3.99 (d, J=7.2 Hz, 2H), 3.50-3.46 (m, 2H) 3.32-3.27 (m, 2H), 2.20-2.13 (m, 1H), 1.43 (t, J=7.2 Hz, 3H), 0.88 (d, J=6.8 Hz, 6H); ESI-MS: (+ve mode) 436.2 (M)+ (100 %). Compound-24: 6'-chloro-l'-(l-(2-hydroxyethyl)-lH-pyrazol-4-yl)-2'-oxo-l,3-dihydro- spiro[indene-2,3'-indoline]-5-carboxylic acid
Figure imgf000037_0001
'H NMR: (CDCL3; 400 MHz): 5 8.07-8.04 (m, 2H), 7.96 (s, 1H), 7.90 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.03-6.95 (m, 2H), 6.80-6.78 (m, 1H), 4.45-4.43 (m, 2H) 4.39-4.37 (m, 2H), 3.77-3.72 (m, 2H), 3.25-3.21 (m, 2H); ESI-MS: (+ve mode) 424.10 (M)+ (100 %).
Compound-27 : 6'-chloro- 1 '-(1 -propyl- lH-pyrazol-4-yl)- 1 ,3 -dihydrospiro[indene-2,3'- indolin]-2'-one
Figure imgf000037_0002
'H NMR: (CDCL3 400 MHz): 5 7.81 (d, J= 7.6 Hz, 2H), 7.32-7.27 (s, 5H), 7.01 (s, 1H), 6.94-6.91(m, 1H), 6.81-6.78 (m, 1H), 4.21-4.17 (m, 2H), 3.73-3.65 (m, 2H), 3.56-3.51 (m, 2H), 2.03-1.94 (m, 2H), 1.03-0.99 (m, 3H); ESI-MS: (+ve mode) 378.3(M)+ (100 %).
Compound-28: 6'-chloro-2'-oxo- 1'-( 1 -propyl- 1 H-pyrazol-4-yl)- 1 ,3 -dihydrospirofindene-
2,3'-indoline]-5-carboxylic acid
Figure imgf000038_0001
'H NMR: (DMSO-d6, 400 MHz): 5 12.87 (bs, 1H), 8.19 (s, 1H), 7.87-7.81 (m, 2H), 7.76 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.09-7.03 (m, 2H), 6.93 (s, 1H), 4.15-4.11 (m, 2H) 3.55- 3.50 (m, 2H), 3.32-3.27 (m, 2H), 1.88-1.78 (m, 2H), 0.88-0.83 (m, 3H); ESI-MS: (+ve mode) 422.1 (M)+ (100 %)
Compound-29: (R)-6'-chloro-2'-oxo-l'-(l-propyl-lH-pyrazol-4-yl)-l,3- dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid
Figure imgf000038_0002
'H NMR: (CDCL3; 400 MHz): 5 8.08-8.05 (m, 2H), 7.80 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.03 (d, J=1.6Hz, 1H), 6.96-6.93 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 4.20-4.17 (m, 2H) 3.78-3.73 (m, 2H), 3.24-3.21 (m, 2H), 2.04-1.94 (m, 2H), 1.04-0.99 (m, 3H); ESIMS: (+ve mode) 422.13 (M)+ (100 %).
Compound-30: (S)-6'-chloro-2'-oxo-l'-(l-propyl-lH-pyrazol-4-yl)-l,3- dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid
Figure imgf000039_0001
'H NMR: (CDCL3; 400 MHz): 5 8.08-8.05 (m, 2H), 7.80 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.03 (d, J=1.6Hz, 1H), 6.95-6.93 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 4.20-4.17 (m, 2H) 3.78-3.73 (m, 2H), 3.24-3.20 (m, 2H), 2.04-1.94 (m, 2H), 1.04-0.99 (m, 3H); ESIMS: (+ve mode) 422.12 (M)+ (100 %).
Compound-31 : 6'-chloro-4-fluoro-2'-oxo- 1 '-( 1 -propyl- lH-pyrazol-4-yl)- 1 ,3 -dihydro- spiro[indene-2,3'-indoline]-5-carboxylic acid
Figure imgf000039_0002
'H NMR: (CDCL3; 400 MHz): 5 8.04-8.00 (m, 2H), 7.81 (s, 1H), 7.80 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.03-6.98 (m, 2H), 6.87 (d, J=8.0 Hz, 1H), 4.22-4.18 (m, 2H) 3.78-3.71 (m, 2H), 3.36-3.21 (m, 2H), 2.04-1.94 (m, 2H), 1.03-0.99 (m, 3H); ESI-MS: (+ve mode) 440.12 (M)+ (100 %).
Compound-34: methyl -6'-chloro-2'-oxo-l'-(l -propyl- IH-pyrazol -4-yl)- 1,3 -dihydrospiro-
[indene-2,3'-indoline]-5-carboxylate
Figure imgf000040_0001
'H NMR: (CDCL3, 400 MHz): 5 8.00-7.98 (m, 2H), 7.81-7.79 (m, 2H), 7.38 (d, J= 7.6 Hz, 1H), 7.02 (s, 1H), 6.94-6.92 (m, 1H), 6.76 (d, J=8.0 Hz, 1H), 4.21-4.17 (m, 2H), 4.17 (s, 3H), 3.75-3.71 (m, 2H), 3.21-3.17 (m, 2H), 2.04-1.94 (m, 2H), 1.03-0.99 (m, 3H); ESI- MS: (+ve mode) 436.0 (M)+ (100 %).
Compound-37 : 6'-chloro-2'-oxo- 1'-( 1 -propyl- 1 H-pyrazol-4-yl)- 1 ,3 -dihydrospirofindene- 2,3'-indoline]-5-carboxamide
Figure imgf000040_0002
'H NMR: (CDCL3, 400 MHz): 5 8.19 (s, 1H), 7.95 (s, 1H), 7.82-7.76 (m, 3H), 7.38 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.08-7.03 (m, 2H), 6.93 (s, 1H), 4.18-4.11 (m, 2H), 3.54-3.40 (m, 2H), 3.28-3.17 (m, 2H), 1.88-1.76 (m, 2H), 0.88-0.85 (m, 3H); ESI-MS: (+ve mode) 421.3 (M)+ (100 %). Compound-41 : 6'-chloro-2'-oxo- 1'-( 1 -propyl- 1 H-pyrazol-4-yl)- 1 ,3 -dihydrospirofindene-
2,3'-indoline]-5-carbonitrile
Figure imgf000041_0001
'H NMR: (CDCL3; 400 MHz): 5 7.81 (s, 2H), 7.61-7.60 (m, 2H), 7.43-7.41 (m, 1H), 7.03- 6.96 (m, 2H), 6.79 (d, J=8.0 Hz, 1H), 4.22-4.18 (m, 2H) 3.75-3.69 (m, 2H), 3.26-3.20 (m, 2H), 2.03-1.94 (m, 2H), 1.02-0.99 (m, 3H); ESI-MS: (+ve mode) 403.12 (M)+ (100 %).
Compound-55: 6'-chloro-7'-fluoro-2'-oxo-l'-(l-propyl-lH-pyrazol-4-yl)-l,3- dihydrospiro-[indene-2,3'-indoline]-5-carboxylic acid
Figure imgf000041_0002
'H NMR: (DMSO-d6, 400 MHz): 5 12.87 (bs, 1H), 8.06 (s, 1H), 7.87-7.81 (m, 2H), 7.64 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.21-7.17 (m, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.15-4.09 (m,
2H) 3.52-3.47 (m, 2H), 3.35-3.31 (m, 2H), 1.85-1.76 (m, 2H), 0.88-0.82 (m, 3H); ESI-MS: (+ve mode) 440.1 (M)+ (100 %).
Compound-75: 6'-chloro-l'-(l -propyl- lH-pyrazol-4-yl)-5-(2H-tetrazol-5-yl)-l, 3-dihydro- spiro[indene-2,3'-indolin]-2'-one
Figure imgf000042_0001
'H NMR: (CDCL3; 400 MHz): 5 7.85-7.82 (m, 2H), 7.32-7.28 (m, 1H), 7.03-7.01 (m, 2H), 6.96-6.94 (m, 1H), 4.24-4.20 (m, 2H) 3.70-3.63 (m, 2H), 3.31-3.27 (m, 2H), 2.03-1.94 (m, 2H), 1.02-0.98 (m, 3H); ESI-MS: (+ve mode) 446.6 (M)+ (100 %).
Testins of Compounds of the invention
Biological studies:
ATX Inhibitory activity (IC50 determination):
Autotaxin activity was measured by determining the amount of Choline released from LPC 16:0 using Amplite® Choline Quantitation Kit (AAT Bioquest, 40007). For inhibitor screening, 5 pl of 20 nM purified recombinant human autotaxin (Echelon, E-4000) was mixed with lOpl of test compound (concentration range) in black 96 well plate in assay buffer (50 mM Tris-HCl pH 8.0, 500 mM NaCl, 5 mM KC1, 5 mM CaCl2, 0.1% Fatty acid free BSA) and incubated for 10 minutes at room temperature. To initiate the reaction, 10 pl of 375pM LPC 16:0 in methanol (Millipore Sigma, L5254) was added to the wells and the plate was incubated for 30 min at 37°C. The amount of choline released was measured by the addition of 25 pl of a choline assay working solution followed by incubation of the plate for 30 minutes at 37°C. Finally, fluorescence intensity was measured using excitation and emission wavelength of 540 nm and 590 nm respectively, using Hidex sense reader. In this assay, fluorescence intensity is directly proportional with the amount of Choline release and subsequently to the enzyme activity. For the IC50 determination, residual activity of Autotaxin was measured across the concentration range of inhibitor with respect to the vehicle (100% activity) and IC50 was derived by nonlinear regression analysis of the data using Graph Pad prism version. ATX inhibitory activity (IC50) for representative compounds are listed in the Table 2.
Figure imgf000043_0001
The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known. The pharmaceutical compositions further comprise an effective amount of an ATX inhibitor. The dosage of ATX inhibitors may vary within wide limits and should be adjusted, in each particular case, to the individual conditions. The compounds of formula (I), or pharmaceutical compositions containing them are useful as a medicament for the inhibition of ATX activity and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
The quantity of active component, that is, the novel compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration.
Pharmaceutical composition comprising compound of general formula (I), their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.
Use of the general formula (I) for the treatment of diseases selected from cancer, chronic inflammation, neuropathic pain, fibrotic diseases.
In some embodiments, the present invention includes a method for the treatment of at least one of cancer, chronic inflammation, neuropathic pain, fibrotic diseases mediated in part by ATX comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the novel compound of formula (I).
In an embodiment, the compound of formula (I), may be used alone or in any combination with one or more therapeutic agents such as anti-inflammatory agents, antitumor agents, ant fibrotic agents, autotaxin inhibitors, immunomodulators and cardiovascular agents and other therapeutic agents which are known to skilled medical practitioner. The selection of such therapeutic agents may be depend upon the type of disease and its severity, condition of patient being treated, and other medications being taken by the patients, etc.
In one of the embodiments compound of formula (I) of the present invention may be used in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combination with tyrosine kinase inhibitors and pyridones class of therapeutic agents. In other embodiments, Nintedanib is tyrosine kinase inhibitors class of drug and Pirfenidone is pyridones class of drug.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

Claim:
1. Novel compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers and diastereomers
Figure imgf000046_0001
Wherein,
R1 and R2 are selected from -H, halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy, -(CH2)qCF3, - CN, -O(CH2)qCF3, -(CH2)qORa, -COORa, -C(O)NRaRb, (C3-C7)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;
E is selected from -CH2 or -O-; when E is -O- then n is 1; when E is -CH2 then n is 1 or 2;
Ring A is selected from aryl or heteroaryl;
Ring B is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl;
R3 is selected from -H, halo, -(CH2)rCF3, -CN, -O(CH2)rCF3, -(CH2)rORd, - (CRdRe)rNRdRe, or -NRdRe, -(Ci-C6)alkyl, (C3-C7)cycloalkyl , (Ci-C6)alkoxy, (Ci- Ce)acyloxy, heterocyclyl wherein alkyl, cycloalkyl, alkoxy, acyloxy, heterocyclyl are substituted or unsubstituted;
R4 and R5 are selected from -H, halo, -(Ci-C6)alkyl, (Ci-C6)alkoxy, -(CH2)SCF3, - CN, -O(CH2)SCF3, -(CH2)SORS, or (C3-C7)cycloalkyl;
X, Y and Z are selected from -C or -N; m is selected from 1 or 2; p is selected from 0 or 1; q, r and s are selected from 0, 1, 2 or 3; Ra, Rb, Rc, Rd, Re, Rf, Rs, Rh and R1 are selected from H, -OH, (Ci-C6)alkyl, haloalkyl, or (C3-C7)cycloalkyl
2. The novel compounds of the general formula (I) as claimed in claim 1, wherein
R1 and R2 are selected from -H, halo, -(Ci-Ce)alkyl, -COORa, -C(O)NRaRb, substituted or unsubstituted aryl, (C3-C7)cycloalkyl, substituted or unsubstituted heteroaryl;
R3 is selected from -H, -(Ci-Ce)alkyl, -(CH2)rCF3, -(CH2)rORd, (C3-C7)cycloalkyl, or heterocyclyl; R4 and R5 is selected from -H, halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy, -(CH2)SCF3, -CN, -O(CH2)SCF3; X, Y and Z may be selected from -C or -N; Ra, Rb, Rc, Rd, Re, Rf, Rs, Rh and R1 is selected from -H, (C C6)alkyl, -OH.
3. The novel compounds of the general formula (I) are selected from: 6'-chloro-2'-oxo- 1 '-phenyl- 1 ,3 -dihydrospiro[indene-2,3 '-indoline]-5-carboxylic acid;
6'-chloro-2'-oxo-r-(pyridin-2-yl)-l,3-dihydrospiro[indene-2,3'-indoline]-5- carboxylic acid;
6'-chloro-2'-oxo-r-(pyridin-3-yl)-l,3-dihydrospiro[indene-2,3'-indoline]-5- carboxylic acid;
6'-chloro-2'-oxo-r-(pyridin-4-yl)-l,3-dihydrospiro[indene-2,3'-indoline]-5- carboxylic acid;
6'-chloro-r-(6-methylpyridin-3-yl)-2'-oxo-l,3-dihydrospiro-[indene-2,3'-indoline]- 5-carboxylic acid;
6'-chloro-2'-oxo- 1 '-(pyrimidin-5-yl)- 1 ,3 -dihydrospiro[indene-2,3 '-indoline]-5- carboxylic acid;
6'-chloro-r-(6-methylpyridazin-3-yl)-2'-oxo-l,3-dihydrospiro-[indene-2,3'- indoline]-5-carboxylic acid;
6'-chloro-2'-oxo- 1 '-(thiophen-3 -yl)- 1 ,3 -dihydrospiro[indene-2,3 '-indoline]-5- carboxylic acid;
6'-chloro-l'-(furan-3-yl)-2'-oxo-l,3-dihydrospiro[indene-2,3'-indoline]-5- carboxylic acid;
6'-chloro-2'-oxo- 1 '-(1 H-pyrrol-3 -yl)- 1 ,3 -dihydrospiro[indene-2,3 '-indoline]-5- carboxylic acid;
6'-chloro-l'-(l -methyl- lH-pyrrol-3-yl)-2'-oxo-l,3-dihydro-spiro[indene-2, 3'- indoline]-5-carboxylic acid; 6'-chloro-l'-(isothiazol-4-yl)-2'-oxo-l,3-dihydrospiro[indene-2,3'-indoline]-5- carboxylic acid;
6'-chloro-l'-(isoxazol-4-yl)-2'-oxo-l,3-dihydrospiro[indene-2,3'-indoline]-5- carboxylic acid;
6'-chloro-l'-(5-ethyl-l,2,4-oxadiazol-3-yl)-2'-oxo-l,3-dihydro-spiro[indene-2,3'- indoline]-5-carboxylic acid;
6'-chloro-r-(3,5-dimethylisoxazol-4-yl)-2'-oxo-l,3-dihydro-spiro[indene-2,3'- indoline]-5-carboxylic acid;
6'-chloro-2'-oxo-r-(lH-pyrazol-4-yl)-l,3-dihydrospiro[indene-2,3'-indoline]-5- carboxylic acid;
6'-chloro-l'-(l -methyl- lH-pyrazol-4-yl)-2'-oxo-l,3-dihydro-spiro[indene-2, 3'- indoline]-5-carboxylic acid;
6'-chloro-l'-(l-ethyl-lH-pyrazol-4-yl)-2'-oxo-l,3-dihydro-spiro[indene-2,3'- indoline]-5-carboxylic acid;
6'-chloro-l'-(l -isopropyl- lH-pyrazol-4-yl)-2'-oxo-l,3-dihydro-spiro[indene-2, 3'- indoline]-5-carboxylic acid;
6'-chloro-l'-(l -isobutyl- lH-pyrazol-4-yl)-2'-oxo- 1, 3-dihydro-spiro[indene-2, 3'- indoline]-5-carboxylic acid;
6'-chloro- 1'-( 1 -cyclopropyl- lH-pyrazol-4-yl)-2'-oxo- 1 ,3 -dihydrospiro[indene-2,3 '- indoline]-5-carboxylic acid;
6'-chloro-l'-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)-2'-oxo-l,3- dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid;
6'-chloro-2'-oxo-r-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)-l,3- dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid;
6'-chloro-l'-(l-(2-hydroxyethyl)-lH-pyrazol-4-yl)-2'-oxo-l,3-dihydrospiro[indene- 2,3'-indoline]-5-carboxylic acid;
6'-chloro-r-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)-2'-oxo-l,3-dihydrospiro[indene-2,3'- indoline]-5-carboxylic acid;
1 '-( 1 -butyl- lH-pyrazol-4-yl)-6'-chloro-2'-oxo- 1 ,3 -dihydro-spiro[indene-2,3 '- indoline]-5-carboxylic acid;
6'-chloro-2'-oxo-l'-(l-propyl-lH-pyrazol-4-yl)-l,3-dihydro-spiro[indene-2,3'- indoline]-5-carboxylic acid; 6'-chloro-l'-(l -propyl- lH-pyrazol-4-yl)-l,3-dihydrospiro-[indene-2, 3 '-indolin]-2'- one;
(R)-6'-chloro-2'-oxo- 1 '-(1 -propyl- IH-pyrazol -4-yl)- 1 ,3 -dihydrospiro[indene-2,3 '- indoline]-5-carboxylic acid;
(S)-6'-chloro-2'-oxo- 1 '-(1 -propyl- lH-pyrazol-4-yl)- 1 ,3 -dihydrospiro[indene-2,3 '- indoline]-5-carboxylic acid;
6'-chloro-4-fluoro-2'-oxo- 1 '-(1 -propyl- lH-pyrazol-4-yl)- 1 ,3 -dihydrospirofindene- 2,3'-indoline]-5-carboxylic acid;
(S)-6'-chloro-4-fluoro-2'-oxo- 1'-( 1 -propyl- lH-pyrazol-4-yl)- 1,3- dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid;
(R)-6'-chloro-4-fluoro-2'-oxo- 1'-( 1 -propyl - 1 H-pyrazol-4-yl)- 1,3- dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid; methyl 6'-chloro-2'-oxo- 1 '-(1 -propyl- lH-pyrazol-4-yl)- 1 ,3 -dihydrospirofindene-
2,3'-indoline]-5-carboxylate; methyl (S)-6'-chloro-2'-oxo-l'-(l -propyl- lH-pyrazol-4-yl)-l, 3- dihydrospiro[indene-2,3'-indoline]-5-carboxylate; methyl (R)-6'-chloro-2'-oxo-l'-(l -propyl- lH-pyrazol-4-yl)- 1,3- dihydrospiro[indene-2,3'-indoline]-5-carboxylate;
6'-chloro-2'-oxo-l'-(l-propyl-lH-pyrazol-4-yl)-l,3-dihydro-spiro[indene-2,3'- indoline]-5-carboxamide;
(S)-6'-chloro-2'-oxo- 1 '-(1 -propyl- lH-pyrazol-4-yl)- 1 ,3 -dihydrospiro[indene-2,3 '- indoline]-5-carboxamide;
(R)-6'-chloro-2'-oxo- 1 '-(1 -propyl- IH-pyrazol -4-yl)- 1 ,3 -dihydrospiro[indene-2,3 '- indoline]-5-carboxamide;
6'-chloro-N-hydroxy-2'-oxo- 1'-( 1 -propyl- lH-pyrazol-4-yl)- 1,3- dihydrospiro[indene-2,3'-indoline]-5-carboxamide;
6'-chloro-2'-oxo-l'-(l-propyl-lH-pyrazol-4-yl)-l,3-dihydro-spiro[indene-2,3'- indoline]-5-carbonitrile;
6'-chloro-2'-oxo-l'-(l-propyl-lH-pyrazol-4-yl)-5,7-dihydro- spiro[cyclopenta[b]pyridine-6,3'-indoline]-2-carboxylic acid;
(S)-6'-chloro-2'-oxo-l'-(l -propyl- lH-pyrazol-4-yl)-5, 7- dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-2-carboxylic acid; (R)-6'-chloro-2'-oxo-l'-(l -propyl- lH-pyrazol-4-yl)-5, 7- dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-2-carboxylic acid;
6'-chloro-2'-oxo-l'-(l-propyl-lH-pyrazol-4-yl)-5,7-dihydro- spiro[cyclopenta[b]pyridine-6,3'-indoline]-3-carboxylic acid;
(R)-6'-chloro-2'-oxo-l'-(l -propyl- lH-pyrazol-4-yl)-5, 7- dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-3-carboxylic acid;
(S)-6'-chloro-2'-oxo-l'-(l -propyl- lH-pyrazol-4-yl)-5, 7- dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-3-carboxylic acid;
2'-oxo- 1 '-( 1 -propyl- lH-pyrazol-4-yl)- 1 ,3 -dihydrospiro[indene-2,3 '-indoline]-5- carboxylic acid;
6'-fluoro-2'-oxo- 1'-( 1 -propyl- 1 H-pyrazol-4-yl)- 1 , 3 -dihydro-spiro[indene-2, 3 '- indoline]-5-carboxylic acid;
6'-methyl-2'-oxo- 1 '-(1 -propyl- lH-pyrazol-4-yl)- 1 ,3 -dihydro-spiro[indene-2,3 '- indoline]-5-carboxylic acid;
2'-oxo-l'-(l -propyl-lH-pyrazol-4-yl)-6'-(tri fluoromethyl)- l,3-dihydrospiro[indene- 2,3'-indoline]-5-carboxylic acid;
6'-methoxy-2'-oxo- 1'-( 1 -propyl- 1 H-pyrazol-4-yl)- 1 ,3 -dihydro-spiro[indene-2,3 '- indoline]-5-carboxylic acid;
2'-oxo-r-(l-propyl-lH-pyrazol-4-yl)-6'-(trifluoromethoxy)-l,3- dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid;
6'-cyano-2'-oxo- 1 '-( 1 -propyl- IH-pyrazol -4-yl)- 1 ,3 -dihydro-spiro[indene-2,3 '- indoline]-5-carboxylic acid;
6'-chloro-7'-fluoro-2'-oxo- 1 '-(1 -propyl- lH-pyrazol-4-yl)- 1 ,3 -dihydrospirofindene-
2,3'-indoline]-5-carboxylic acid;
6'-chloro-5'-fluoro-2'-oxo-r-(l -propyl- lH-pyrazol-4-yl)-l, 3-dihydrospiro[indene-
2,3'-indoline]-5-carboxylic acid;
6'-chloro-5'-methyl-2'-oxo- 1 '-(1 -propyl- lH-pyrazol-4-yl)- 1 ,3 -dihydrospirofindene-
2,3'-indoline]-5-carboxylic acid;
5\6'-dichloro-2'-oxo-l'-(l -propyl- lH-pyrazol-4-yl)-l,3-dihydrospiro[indene-2, 3'- indoline]-5-carboxylic acid;
6'-chloro-7'-methyl-2'-oxo- 1 '-(1 -propyl- lH-pyrazol-4-yl)- 1 ,3 -dihydrospirofindene- 2,3'-indoline]-5-carboxylic acid; 6'-chloro-2'-oxo-l'-(l-propyl-lH-pyrazol-4-yl)-l,r,2',3-tetra-hydrospiro[indene- 2,3'-pyrrolo[2,3-b]pyridine]-5-carboxylic acid;
6'-chloro-2'-oxo-r-(l-propyl-lH-pyrazol-4-yl)-l,l',2',3-tetra-hydrospiro[indene- 2,3'-pyrrolo[3,2-b]pyridine]-5-carboxylic acid;
2'-chloro-6'-oxo-7'-(l -propyl-lH-pyrazol-4-yl)- 1,3,6', 7'-tetrahydrospiro[indene- 2,5'-pyrrolo[2,3-d]pyrimidine]-5-carboxylic acid;
6'-chloro-2'-oxo-l'-(l-propyl-lH-pyrazol-4-yl)-3H-spiro-[benzofuran-2,3'- indoline]-6-carboxylic acid;
6'-chloro- 1'-( 1 -methyl- lH-pyrazol-4-yl)-2'-oxo-3H-spiro-[benzofuran-2, 3 '- indoline]-6-carboxylic acid; methyl 7'-chloro-2'-oxo- 1 '-( 1 -propyl- lH-pyrazol-4-yl)- 1 , 1 ',3 ,4'-tetrahydro-2'H- spiro[indene-2,3'-quinoline]-5-carboxylate;
7'-chloro-2'-oxo-r-(l-propyl-lH-pyrazol-4-yl)-l,l',3,4'-tetra-hydro-2'H- spiro[indene-2,3'-quinoline]-5-carboxylic acid;
7'-chloro-r-(l-ethyl-lH-pyrazol-4-yl)-2'-oxo-l,l',3,4'-tetra-hydro-2'H- spiro[indene-2,3'-quinoline]-5-carboxylic acid;
7'-chloro-l'-(l -methyl- lH-pyrazol-4-yl)-2'-oxo-l,l', 3, 4'-tetra-hydro-2'H- spiro[indene-2,3'-quinoline]-5-carboxylic acid;
7'-chloro-2'-oxo-r-(l-propyl-lH-pyrazol-4-yl)-l',4',5,7-tetra-hydro-2'H- spiro[cyclopenta[b]pyridine-6,3'-quinoline]-2-carboxylic acid;
7'-chloro-2'-oxo-r-(l-propyl-lH-pyrazol-4-yl)-l',4',5,7-tetrahydro-2'H- spiro[cyclopenta[b]pyridine-6,3'-quinoline]-3-carboxylic acid;
7'-fluoro-2'-oxo-r-(l-propyl-lH-pyrazol-4-yl)-l,r,3,4'-tetrahydro-2'H- spiro[indene-2,3'-quinoline]-5-carboxylic acid;
7'-methyl-2'-oxo- 1 '-(1 -propyl- lH-pyrazol-4-yl)- 1 , 1 ',3 ,4'-tetrahydro-2'H- spiro[indene-2,3'-quinoline]-5-carboxylic acid;
2'-oxo-r-(l-propyl-lH-pyrazol-4-yl)-7'-(trifluoromethyl)-l,r,3,4'-tetrahydro-2'H- spiro[indene-2,3'-quinoline]-5-carboxylic acid;
7'-methoxy-2'-oxo- 1'-( 1 -propyl- 1 H-pyrazol-4-yl)- 1 , 1 ',3 ,4'-tetrahydro-2'H- spiro[indene-2,3'-quinoline]-5-carboxylic acid;
6'-chloro-l'-(l -propyl- lH-pyrazol-4-yl)-5-(lH-tetrazol-5-yl)- 1,3- dihydrospiro[indene-2,3'-indolin]-2'-one; 3 -(6'-chloro-2'-oxo- 1 '-(1 -propyl- 1 H-pyrazol-4-yl)- 1 ,3 -dihydro-spiro[indene-2,3 '- indolin]-5-yl)-l,2,4-oxadiazol-5(4H)-one;
3 -(6'-chloro-2'-oxo- 1 '-(1 -propyl- 1 H-pyrazol-4-yl)- 1 ,3 -dihydro-spiro[indene-2,3 '- indolin]-5-yl)-l,2,4-thiadiazol-5(4H)-one;
6'-chloro-5-(3-hydroxyisoxazol-5-yl)-l'-(l -propyl -IH-pyrazol -4-yl)- 1,3- dihydrospiro[indene-2,3'-indolin]-2'-one;
6'-chloro-5-(3 -hydroxyisothiazol-5-yl)- 1 '-( 1 -propyl- lH-pyrazol-4-yl)- 1,3- dihydrospiro[indene-2,3'-indolin]-2'-one;
5-(6'-chloro-2'-oxo-T-(l-propyl-lH-pyrazol-4-yl)-l,3-dihydro-spiro[indene-2,3'- indolin]-5-yl)-l,3,4-oxadiazol-2(3H)-one;
6'-chloro-5-(5-oxo-4,5-dihydro-lH-l, 2, 4-triazol-3-yl)-l'-(l -propyl- lH-pyrazol-4- yl)-l,3-dihydrospiro[indene-2,3'-indolin]-2'-one;
6'-chl oro-l'-(l -propyl- lH-pyrazol-4-yl)-5-(lH-l, 2, 3-triazol-5-yl)- 1,3- dihydrospiro[indene-2,3'-indolin]-2'-one.
4. The pharmaceutical composition comprising novel compounds of general formula (I) as claimed in claim 1, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers and diastereomers having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.
5. Use of the novel compounds of general formula (I) as claimed in claim 1 for the treatment of diseases selected from cancer, chronic inflammation, neuropathic pain, fibrotic diseases.
6. Method of treating cancer, chronic inflammation, neuropathic pain, fibrotic diseases mediated in part by ATX comprising administering to a subject in need thereof a therapeutically effective amount of the novel compound of formula (I) as claimed in claim 1 or its suitable pharmaceutical composition.
PCT/IB2024/052000 2023-03-02 2024-03-01 Novel atx inhibitors WO2024180520A1 (en)

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Citations (3)

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WO2022149010A1 (en) * 2021-01-05 2022-07-14 Cadila Healthcare Limited Novel inhibitors of autotaxin

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Publication number Priority date Publication date Assignee Title
WO1993012786A1 (en) * 1986-07-10 1993-07-08 Howard Harry R Jr Indolinone derivatives
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