TW202502735A - Novel atx inhibitors - Google Patents

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.

Description

New ATX Inhibitor

The present invention relates to novel compounds of general formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvent compounds, mirror image isomers, non-mirror image isomers and polymorphs thereof as ATX inhibitors for treating and preventing conditions or symptoms caused by activation of autotaxin (ATX) or increased concentration of lysophosphatidic acid (LPA), and pharmaceutical compositions containing the above compounds.

The enzyme ATX is important for the conversion of lysophosphatidylcholine (LPC) to LPA, a biologically active signaling molecule. ATX is a secreted enzyme of the ectonucleotide phosphatase family, also known as phosphodiesterase 2 (ectonucleotide pyrophosphatase, ENPP-2 or NPP2). ATX plays an important role in pathological conditions including fibrosis, arthritis inflammation, neurodegeneration, neuropathic pain, and cancer. LPA is a biologically active lipid that affects the migration, proliferation, and survival of various cell types. LPA mediates a variety of cellular and biological actions through the LPA receptor (LPAR). LPA is widely expressed in tissues and can couple to at least six different G proteins (called LPAR1-6) to enter multiple effector systems (Yung et al., J. Lipid Res. 2014, 55, 1192 and Kihara et al., Exp. Cell Res. 2015, 333, 171). Since the level of LPA in plasma is highly correlated with the activity of ATX, ATX is considered to be an important source of extracellular LPA.

Inhibition of ATX has been shown to reduce LPA levels in pathological settings. Reduction of LPA could provide therapeutic benefit in diseases with unmet needs, including cancer, chronic inflammation of lymphocyte homing, neuropathic pain, fibrotic diseases (e.g., idiopathic pulmonary fibrosis (IPF)), thrombosis, and cholestatic pruritus, which are caused and/or propagated by elevated LPA levels and/or ATX activation.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring of lung tissue, leading to worsening lung function and ultimately fatal within 3-5 years of symptom onset. IPF had no treatment options until 2014, when the FDA approved nintedanib (Ofev) and pirfenidone (Esbriet) (King et al., Lancet 2011, 378, 1949; Richeldi et al., N. Engl. J. Med. 2014, 370, 2071; Roth et al., J. Med. Chem. 2009, 52, 4466; J. Med. Chem. 2015, 58, 1053; Hilberg et al., Drugs Future 2010, 35, 5; and King et al., N. Engl. J. Med. 2014, 370, 2083). Despite this progress, additional drugs are still needed to treat IPF. IPF patients have elevated levels of LPA in bronchoalveolar lavage fluid (BALF) and exhaled breath condensate. LPAR1 has been identified as the main LPA receptor (Tager et al., Nat. Med. 2008, 14, 45 and Kihara et al., BMC. Med. 2014). In pulmonary fibroblasts of IPF patients, LPAR1 was found to be responsible for promoting fibroblast migration and vascular leakage; therefore, LPAR1 antagonists are expected to become potential drug targets for the treatment of IPF. In recent years, several LPAR1 antagonists have been discovered, some of which are currently being evaluated for the treatment of IPF (Budd et al., Future Med. Chem. 2013, 5, 1935; Qian et al., J. Med. Chem. 2012, 55, 7920 and Terakado et al., ACS Med. Chem. Lett. 2016, 7, 913).

Fibrosis may occur in the liver, kidney, lung, dermis, vascularization, intestine, and other sites. Fibrosis is mediated by growth factors, cytokines, integrins, and lipid pathways. The ATX, LPA, and LPAR pathways are associated with fibrotic diseases. Elevated levels of ATX, LPA, and LPAR have been observed in various rodent models of fibrosis, as well as in patient fluids and living tissues. LPA can induce proliferation, survival, and trending responses in cells known to be critical for fibrotic diseases, including: fibroblasts, smooth muscle cells, macrophages, epithelial cells, endothelial cells, and leukocytes. Antagonism of the receptors of LPAR inhibitors can block or reverse fibrosis in the lung, liver, kidney and skin of rodents in the inhibitory pathway. Therefore, it is necessary to reduce the level of LPA in fibrotic diseases. The aforementioned situation can be achieved by inhibiting enzymes involved in LPA biosynthesis (such as ATX).

Various prior art documents mention compounds capable of inhibiting ATX, including: WO2022258693, WO2022149010, WO2022100727, WO2022074459, WO2022003557, WO2022003377, WO2021088957, WO2021078227, WO2021143753, WO2019228403, WO2019108943, WO 2019029620, WO2019223721, WO2019158107, WO201815312, WO2017152062, WO2017050791, WO2017050792, WO2017050747, WO2017050732, WO2016144706, WO2016144704, WO2016028686, WO2015144605, WO2015042053, WO2015042052, WO2015154023, WO2015175171, WO2015077503, WO2015077502, WO2015048301, WO2014139882, WO2014139978, WO2014048865, WO2014202458. Therefore, there is an unmet need for the application of ATX inhibitors in the treatment and/or prevention of physiological and/or pathophysiological diseases such as cancer, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, etc., which are caused, mediated and/or propagated by elevated LPA levels and/or ATX activation.

The present invention relates to novel compounds of general formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates, mirror image isomers, non-mirror image isomers and polymorphs thereof as ATX inhibitors for treating and preventing conditions or symptoms caused by ATX activation or increased LPA concentration, and pharmaceutical compositions containing the above compounds. Embodiments of the present invention include the compounds of the present invention, pharmaceutically acceptable salts thereof, any physical form thereof (including solvates and hydrates), and methods for preparing the above compounds, intermediates, pharmaceutical compositions and formulations. Embodiments of the present invention

In one embodiment, the present invention provides novel compounds of formula (I), pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvents, mirror image isomers, non-mirror image isomers and polymorphs thereof, and pharmaceutical compositions comprising the above compounds or mixtures thereof.

In another embodiment, the present invention provides a pharmaceutical composition comprising a novel compound of formula (I), a pharmaceutically acceptable salt, a pharmaceutically acceptable solvent, a mirror image isomer, a non-mirror image isomer and a polymorph or a mixture thereof, wherein the pharmaceutical composition can be mixed with a suitable carrier, solvent, diluent and other media commonly used for preparing such compositions.

In another embodiment, the present invention further provides the use of the novel compound, its pharmaceutically acceptable salt, pharmaceutically acceptable solvent complex, mirror image isomer, non-mirror image isomer and polymorph thereof for treating cancer, chronic inflammation, neuropathic pain, fibrotic disease, by administering a therapeutically effective and non-toxic dose of the novel compound of formula (I) or its pharmaceutically acceptable composition to mammals.

In some embodiments, the present invention also includes at least one method for treating cancer, chronic inflammation, neuropathic pain, and fibrotic diseases mediated in part by ATX, comprising administering a therapeutically effective amount of a compound or salt of the novel compound of formula (I) to a subject in need thereof.

In another embodiment, the present invention also provides a method for preparing the novel compound.

In some embodiments, the novel compounds of formula (I) can be administered in combination with other therapeutic agents.

Therefore, the present invention relates to novel compounds of general formula (I), their pharmaceutically acceptable salts, pharmaceutically acceptable solvents, mirror image isomers, non-mirror image isomers and polymorphs, as shown below: wherein ^R1 and ^R2 are independently selected from -H, halogen, -( _C1 - _C6 )alkyl, ( _C1 - _C6 )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 heterocyclo; E is selected ^from _-CH2 or -O-; when E is -O-, n is 1; when E is _-CH2 , 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 heterocyclic group; ^R3 is ^selected from -H, halogen, -( _CH2 ) _rCF3 , -CN, ^-O ( _CH2 ) _rCF3 , _- ( _CH2 ) _rORd , - ^(CRdRe ₎ ^rNRdRe _, or ^-NRdRe , -( _C1 - _C6 ) ^alkyl , ( _C3 - _C7 )cycloalkyl, ( _C1 -C6)alkoxy, ( _C1 - _C6 )acyloxy, heterocyclic group, wherein alkyl, cycloalkyl, alkoxy, acyloxy, heterocyclic group is substituted or unsubstituted ^{; R4} and ^R5 are independently selected from -H, halogen, -( _C1 - _{C6 )} )alkyl, (C ₁ -C ₆ )alkoxy, -(CH ₂ ) _s CF ₃ , -CN, -O(CH ₂ ) _s CF ₃ , -(CH ₂ ) _s OR ^g 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; ^Ra , ^Rb , ^Rc , ^Rd , ^Re , ^Rf , ^Rg , ^Rh and ^Ri are independently selected from H, -OH, (C ₁ -C ₆ )alkyl, halogenalkyl or (C ₃ -C ₇ )cycloalkyl.

In certain embodiments, the novel compound of formula (Ia) , its pharmaceutically acceptable salt, pharmaceutically acceptable solvent complex, mirror image isomer, non-mirror image isomer and polymorph are represented as follows: wherein ^R1 and ^R2 are independently selected from -H, halogen, -( _C1 - _C6 )alkyl, ( _C1 - _C6 )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 heterocyclo; E is selected ^from _-CH2 or -O-; when E is -O-, n is 1; when E is _-CH2 , 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 heterocyclic; ^R3 is selected from -H, halogen, substituted or unsubstituted -( _C1 - _C6 )alkyl, ( _C3 - _C7 )cycloalkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )acyloxy _{, -(CH2)rCF3, -CN, -O(CH2)rCF3, -(CH2)rORd , - ( CRdRe ) rNRdRe or} ^{-NRdRe ; R4} and ^R5 are independently selected from -H, ^halogen , -( _C1 - ^C6 )alkyl, ( _C1 - _C6 )alkoxy, -(CH2 ⁾ sCF3 _, -CN, -O(CH2)rCF3, -( _{CH2 ) rORd} , - ^{( CRdRe} ) _rNRdRe or -NRdRe. ₂ ) _sCF3 , -( _CH2 ) _sORg 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 , Rg ^{, Rh} and ^Ri are independently selected from -H, -OH, ( _C1 - _C6 )alkyl, halogenalkyl or ( _C3 - _C7 )cycloalkyl.

In a preferred embodiment, R ¹ and R ² are independently selected from -H, halogen, -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 , -(C ₁ -C ₆ ) alkyl; R ⁴ and R ⁵ are independently selected from halogen; p is selected from 0; q is selected from 2; ^Ra and R ^d are independently selected from -H.

In certain embodiments, the novel compound of formula (Ib) , its pharmaceutically acceptable salt, pharmaceutically acceptable solvent complex, mirror image isomer, non-mirror image isomer and polymorph are represented as follows: wherein ^R1 and ^R2 are independently selected from -H, halogen, -( _C1 - _C6 )alkyl, ( _C1 - _C6 )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 heterocyclo; E is selected from _-CH2 or -O-; when E is -O-, n is ₁ ; when E is _-CH2 , 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 heterocyclic; ^R3 is selected from -H, halogen, substituted or unsubstituted -( _C1 - _C6 )alkyl, ( _C3 - _C7 )cycloalkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )acyloxy _{, -(CH2)rCF3, -CN, -O(CH2)rCF3, -(CH2)rORd , - ( CRdRe ) rNRdRe or} ^{-NRdRe ; R4} and ^R5 are independently selected from -H, ^halogen , -( _C1 - ^C6 )alkyl, ( _C1 - _C6 )alkoxy, -(CH2 ⁾ sCF3 _, -CN, -O(CH2)rCF3, -( _{CH2 ) rORd} , - ^{( CRdRe} ) _rNRdRe or -NRdRe. ₂ ) _sCF3 , -( _CH2 ) _sORg 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} , Rg ^{, Rh} and ^Ri are independently selected from H, -OH, ( _C1 - _C6 )alkyl, halogenalkyl or ( _C3 - _C7 )cycloalkyl.

Further preferred embodiments of the present invention are disclosed as follows: Preferably, ^R1 and ^R2 can be selected from -H, halogen, -( _C1 - _C6 )alkyl, ^-COORa , -C(O) ^{NRaRb ,} substituted or unsubstituted aryl, ( _C3 - _C7 )cycloalkyl, substituted or unsubstituted heteroaryl; Preferably, Ring A can be selected from aryl or heteroaryl; Preferably, Ring B can be selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; Preferably, ^R3 can be selected from -H, -( _C1 - _C6 ) _alkyl , -( _CH2 ) _rCF3 , -( _CH2 ) _rORd ^, ( _C3 - _C7 )cycloalkyl or heterocyclo; Preferably, ^R4 and R ⁵ can be selected from -H, halogen, -(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, -(CH ₂ ) _s CF ₃ , -CN, -O(CH ₂ ) _s CF ₃ ; Preferably, X, Y and Z can be selected from -C or -N; Preferably, Ra, ^Rb , ^Rc , ^Rd , ^Re , ^Rf , ^Rg , ^Rh and ^Ri can be selected from -H, (C ₁ -C ₆ ⁾ alkyl, -OH;

In further embodiments, the above-mentioned radicals may be selected from:

"Alkyl" and other groups with the prefix "alk", such as alkoxy and alkacyl, refer to straight or branched carbon chains and combinations thereof, unless the carbon chain is otherwise defined. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, dibutyl, tertiary butyl, pentyl, hexyl, and the like. Where a specific number of carbon atoms is permitted (e.g., C _3-10 ), the term alkyl also includes cycloalkyl groups, as well as combinations of straight or branched alkyl chains and cycloalkyl structures.

"Cycloalkyl" is a subset of alkyl and refers to a saturated carbon ring having a specific number of carbon atoms, preferably 3 to 6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Unless otherwise specified, cycloalkyl is generally monocyclic. Unless otherwise specified, cycloalkyl is saturated.

"Haloalkyl" groups are selected from alkyl groups as defined above, suitably substituted by one or more halogens; for example fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono- or poly-halogen-substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;

"Aryl" refers to a monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferably, aryl is a monocyclic or bicyclic 6- to 10-membered aromatic ring system. Preferably, aryl is phenyl and naphthyl.

"Heterocyclic" or "heterocyclic" groups can be used alone or in combination with other groups, and are selected from appropriate saturated, partially saturated or unsaturated aromatic or non-aromatic monocyclic, bicyclic or tricyclic groups, which have one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and are more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 4-methylpiprrazinyl, 4-hydroxypiperidinyl, 4-hydroxypiperidinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazophenyl, epinyl), oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothiophene benzodihydrothienyl), pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, etc. In one embodiment, the heterocyclic group (if applicable) may be composed of an appropriate number of carbon atoms and contain 1-4 heteroatoms, wherein the aforementioned heteroatoms are selected from N, O and S(O)p (p = 0-2) groups;

The "heterocyclic" or "heterocyclic" group can be used alone or in combination with other groups, and is selected from a suitable monocyclic or condensed monocyclic, bicyclic or tricyclic aromatic heterocyclic group having one or more heteroatoms selected from O, N and S. More preferably, the group can be selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isothiocyanate ... isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl razolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, trithionyl benzothiazolyl, benzoxazolyl, benzothiazolyl, etc.;

"Alkoxy" groups may be used alone or in combination with other groups and refer to straight or branched chain groups having 1 to 6 carbon atoms, wherein the aforementioned carbon atom is connected to an oxygen atom and may be selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, isobutoxy, pentyloxy, hexyloxy, etc.;

The "acyloxy" group can be used alone or in combination with other groups, and is selected from groups containing 1 to 8 carbon atoms, and is more preferably selected from formyl, acetyl, propionyl, butyryl, pentyl, benzoyl, etc.;

Unless otherwise stated, “halogen” or “halogen”, by itself or as part of another substituent, means a fluorine, chlorine, bromine or iodine atom;

Suitable groups and substituents on the groups can be selected from the groups and substituents described anywhere in the specification of the present invention.

The term "substituted" as used in the present specification means that any one or more hydrogen atoms on a specific atom are replaced by one of the specified groups, provided that the normal valency of the specified atom is not exceeded and that a stable compound is formed after the substitution. The substituent is selected from hydrogen, deuterium, hydroxyl, cyano, halogen, nitro, halogenalkyl, pendoxy, (C ₁ -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 disclosed compounds, wherein the acid salts or base salts thereof are prepared by modifying the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of 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, Hydroxyacetic acid (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 "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl". To further clarify, an optionally substituted group also means unsubstituted.

Unless otherwise stated in the specification of the present invention, structures depicted herein also include compounds that differ only in the presence of one or more isotopically enriched atoms.

In the following examples, unless otherwise stated, molecules with a single chiral center exist as racemic mixtures. Unless otherwise stated, the above molecules with two or more chiral centers exist as racemic mixtures of non-mirror image isomers. Single mirror image isomers/non-mirror image isomers can be obtained by methods known to those skilled in the art.

Particularly useful compounds may be selected from, but are not limited to, the following:

surface 1 Compound No. ( Compd No. ） Structure IUPAC Name 1 6'-Chloro-2'-oxo-1'-benzene-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 2 6'-Chloro-2'-oxo-1'-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 3 6'-Chloro-2'-oxo-1'-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 4 6'-Chloro-2'-oxo-1'-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 5 6'-Chloro-1'-(6-methylpyridin-3-yl)-2'-oxo-1,3-dihydrospiro-[indene-2,3'-indoline]-5-carboxylic acid; 6 6'-Chloro-2'-oxo-1'-(pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid; 7 6'-Chloro-1'-(6-methylindole-3-yl)-2'-oxo-1,3-dihydrospiro-[indole-2,3'-indoleline]-5-carboxylic acid 8 6'-Chloro-2'-oxo-1'-(thiophene-3-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 9 6'-Chloro-1'-(furan-3-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 10 6'-Chloro-2'-oxo-1'-(1H-pyrrol-3-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 11 6'-Chloro-1'-(1-methyl-1H-pyrrol-3-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 12 6'-Chloro-1'-(isothiazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 13 6'-Chloro-1'-(isoxazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 14 6'-Chloro-1'-(5-ethyl-1,2,4-oxadiazole-3-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid 15 6'-Chloro-1'-(3,5-dimethylisoxazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid 16 6'-Chloro-2'-oxo-1'-(1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 17 6'-Chloro-1'-(1-methyl-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid 18 6'-Chloro-1'-(1-ethyl-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid; 19 6'-Chloro-1'-(1-isopropyl-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid 20 6'-Chloro-1'-(1-isobutyl-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid twenty one 6'-Chloro-1'-(1-cyclopropyl-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid twenty two 6'-Chloro-1'-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid twenty three 6'-Chloro-2'-oxo-1'-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid twenty four 6'-Chloro-1'-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 25 6'-Chloro-1'-(1-(oxocyclobutyl-3-yl)-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 26 1'-(1-butyl-1H-pyrazol-4-yl)-6'-chloro-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid 27 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid 28 6'-Chloro-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro-[indene-2,3'-indolin]-2'-one 29 (R)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 30 (S)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 31 6'-Chloro-4-fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 32 (S)-6'-chloro-4-fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 33 (R)-6'-Chloro-4-fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 34 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid methyl ester; 35 (S)-6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid methyl ester; 36 (R)-6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid methyl ester 37 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxamide 38 (S)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxamide 39 (R)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxamide 40 6'-Chloro-N-hydroxy-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxamide 41 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carbonitrile 42 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydro-spiro[cyclopenta[b]pyridine-6,3'-indoline]-2-carboxylic acid 43 (S)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-2-carboxylic acid 44 (R)-6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-2-carboxylic acid 45 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydro-spiro[cyclopenta[b]pyridine-6,3'-indoline]-3-carboxylic acid 46 (R)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-3-carboxylic acid 47 (S)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-3-carboxylic acid 48 2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 49 6'-Fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid 50 6'-Methyl-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid 51 2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-6'-(trifluoromethyl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 52 6'-Methoxy-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid 53 2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-6'-(trifluoromethoxy)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 54 6'-Cyano-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid 55 6'-Chloro-7'-fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 56 6'-Chloro-5'-fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 57 6'-Chloro-5'-methyl-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 58 5',6'-Dichloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 59 6'-Chloro-7'-methyl-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid 60 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridine]-5-carboxylic acid 61 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[3,2-b]pyridine]-5-carboxylic acid 62 2'-Chloro-6'-oxo-7'-(1-propyl-1H-pyrazol-4-yl)-1,3,6',7'-tetrahydrospiro[indene-2,5'-pyrrolo[2,3-d]pyrimidine]-5-carboxylic acid 63 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-3H-spiro-[benzofuran-2,3'-indoline]-6-carboxylic acid 64 6'-Chloro-1'-(1-methyl-1H-pyrazol-4-yl)-2'-oxo-3H-spiro-[benzofuran-2,3'-indoline]-6-carboxylic acid 65 Methyl 7'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid methyl ester 66 7'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid 67 7'-Chloro-1'-(1-ethyl-1H-pyrazol-4-yl)-2'-oxo-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid 68 7'-Chloro-1'-(1-methyl-1H-pyrazol-4-yl)-2'-oxo-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid 69 7'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1',4',5,7-tetrahydro-2'H-spiro[cyclopenta[b]pyridine-6,3'-quinoline]-2-carboxylic acid 70 7'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1',4',5,7-tetrahydro-2'H-spiro[cyclopenta[b]pyridine-6,3'-quinoline]-3-carboxylic acid 71 7'-Fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid 72 7'-Methyl-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid 73 2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-7'-(trifluoromethyl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid 74 7'-Methoxy-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid 75 6'-Chloro-1'-(1-propyl-1H-pyrazol-4-yl)-5-(1H-tetrazolyl-5-yl)-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one 76 3-(6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indolin]-5-yl)-1,2,4-oxadiazol-5(4H)-one 77 3-(6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indolin]-5-yl)-1,2,4-thiadiazole-5(4H)-one 78 6'-Chloro-5-(3-hydroxyisoxazol-5-yl)-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one 79 6'-Chloro-5-(3-hydroxyisothiazol-5-yl)-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one 80 5-(6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indolin]-5-yl)-1,3,4-oxadiazol-2(3H)-one 81 6'-Chloro-5-(5-hydroxy-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one 82 6'-Chloro-1'-(1-propyl-1H-pyrazol-4-yl)-5-(1H-1,2,3-triazol-5-yl)-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one

The following is a list of abbreviations used in the preparation descriptions of the compounds of the present invention: ACN: acetonitrile BOC: tert-butyloxycarbonyl Cs ₂ CO ₃ : cesium carbonate CuI: cuprous (I) iodide DCM: dichloromethane DIEA: diisopropylethylamine DMEDA: 1,2-dimethylethylenediamine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide EtOH: ethanol EtOAc: ethyl acetate h: hour HCl: hydrochloric acid HPLC: high performance liquid chromatography IPA: isopropyl alcohol K ₂ CO ₃ : potassium carbonate MeOH: methanol Na ₂ CO ₃ : sodium carbonate NaOH: sodium hydroxide Na ₂ SO ₄ : sodium sulfate NaHCO ₃ : sodium bicarbonate NMP ：N-methyl-2-pyrrolidone t-BuOK ：Potassium tributylate TEA ：Triethylamine TFA ：Trifluoroacetic acid THF ：Tetrahydrofuran TLC ：Thin layer chromatography

The novel compounds of the present invention are prepared using the following reactions and techniques, as well as common techniques known to those skilled in the art of organic synthesis, or variations thereof as understood by those skilled in the art.

The above reactions can be carried out in appropriate solvents for the reagents and materials used and are suitable for the transformation being carried out. Preferred methods include but are not limited to those described below, in which all code abbreviations are as defined above, unless otherwise defined below.

The compounds of formula (I) of the present invention can be prepared as described in the following general scheme 1 , and those skilled in the art can make appropriate modifications/alterations within their capabilities.

In the presence of a base such as Na ₂ CO ₃ , K ₂ CO _{3 ,} Cs ₂ CO ₃ , the compound of formula (II) can be reacted with the compound of formula (III) in a solvent such as THF or DMF to obtain the compound of formula (IV). The copper-mediated cross-coupling reaction of the compound of formula (IV) with (V) produces the compound of formula (I) .

General process 1 :

General Methods

Melting points were recorded on a scientific melting point apparatus and are uncorrected. Infrared spectra were recorded on a FT-IR 8300 Shimadzu from neat (oil phase) or KBr pellets (solid phase) and are reported as (cm ^-1 ) . NMR spectra were measured on a Varian Unity 400 magnetic resonance spectrometer (400 MHz for ¹ H, 100 MHz for ¹³ C). Spectra were measured in the specified solvents at ambient temperature. Chemical shift ( ) are expressed in parts per million (ppm) with tetramethylsilane as the internal standard. Multiplicities are recorded as follows: s = singlet, d = doublet, t = triplet, q = quartet, br = broad. Coupling constants (J values) are in Hz. Mass spectra were recorded on a Perkin-Elmer Sciex API 3000. ESI-Q-TOF-MS measurements were performed using a micrOTOF-Q II (Bruker Daltonics) mass spectrometer. HPLC analyses were performed using an AGILENT 1100 series ODS C-18, 150 mm x 4.6 mm x 4 μm column at λmax 220 nm. The reaction was monitored by thin layer silica gel chromatography (TLC) using Merck thin layer silica gel sheets (0.25 mm silica gel 60F). The plates were visualized by treatment with UV light, acidic p-anisaldehyde stain, KMnO ₄ stain, and mild heat. The product was purified by column chromatography using 100-200 mesh silica gel and the indicated solvent system.

All reactions involving air- or moisture-sensitive compounds were performed in flame-dried glassware under a nitrogen atmosphere. Tetrahydrofuran (THF) and diethyl ether (Et ₂ O) were freshly distilled from sodium/benzophenone under a nitrogen atmosphere. Other solvents used in the reactions were purified according to standard procedures. Starting reagents were purchased from commercial suppliers and used without further purification unless otherwise stated.

Synthesis of Compound -1 : 6'-Chloro-2'-oxo-1'-benzene-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

Synthesis of Compound - 6'-Chloro-2'-oxo-1'-benzene-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

Follow the steps in process 2 as shown below:

Process 2 :

Step-1: Preparation of 6'-chloro-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid ethyl ester (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 minutes. A solution of ethyl 3,4-bis(bromomethyl)benzoate (11.31 g, 33.7 mmol) in DMF (23.5 mL) was added dropwise to the reaction mixture at 0°C and stirred for 2 hours. The reaction mixture was poured into cold water and stirred for 15 minutes. The solid crude product precipitated, filtered and dried in vacuo. The crude product was purified by Combiflash column chromatography (hexane: EtOAC = 1:4) to give solid 6'-chloro-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid ethyl ester (3) (5.85 g, 61.0% yield). ¹ H NMR : (CDCl ₃ , 400 MHz): 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, J ₁ =8.0 Hz, J ₂ =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: 6'-chloro-2'-oxo-1'-benzene-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid ethyl ester (4)

Toluene (5 mL), iodobenzene (0.179 g, 0.88 mmol), N, N-dimethylethylenediamine (0.052 g, 0.58 mmol), K 2 CO 3 (0.178 g, 1.28 mmol) and copper (I) iodide (0.056 g, 0.293) were added to ethyl 6'-chloro-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline] mixture _-5- carboxylate ( ₃ ) (0.2 g, 0.58 mmol) at room temperature under inert conditions, and the reaction mixture was stirred at 110°C. The reaction mixture was cooled to room temperature, filtered through celite, rinsed with ethyl acetate, and the combined organic layers were concentrated and dried in vacuo. The crude product was used in the next step without purification. (0.21 g, 86 % yield). ESI-MS : (+ve mode) 418.2 (M) ⁺ (100 %).

Step-3: 6'-chloro-2'-oxo-1'-benzene-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid ( Compound 1 )

Ethyl 6'-chloro-2'-oxo-1'-benzene-1,3-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 (1.22 mL, 1.50 mmol) was added dropwise to the reaction mixture at room temperature and stirred for 5 hours. The reaction mixture was concentrated in a rotavapour, the residue was dissolved in water (10 mL), acidified with 1M HCl (aq), filtered and dried, and purified by preparative HPLC to give the title compound 6'-chloro-2'-oxo-1'-benzene-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid (Compound 1). (0.124 g, 63.3% yield). ¹ H NMR : (DMSO-D ₆ , 400 MHz): 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%).

The specific novel compounds of the general formula (I) of the present invention are prepared by the method shown in General Scheme 1 .

Compound -3 : 6'-chloro-2'-oxo-1'-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (DMSO-D ₆ , 400 MHz): 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-1'-(pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (DMSO-d ₆ , 400 MHz): 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-1'-(thiophen-3-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (DMSO-d ₆ , 400 MHz): 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-1'-(1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (DMSO-d ₆ , 400 MHz): 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-1'-(1-methyl-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (DMSO-d ₆ , 400 MHz): 12.90 (bs, 1H), 8.14 (s, 1H), 7.87-7.85 (m, 2H), 7.73 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.09-7.03 (m, 2H), 6.96 (s, 1H), 3.96 (s, 3H), 3.50-3.45 (m, 2H) 3.31-3.17 (m, 2H); ESI-MS: (+ve mode) 394.1 (M) + (100%).

Compound -18 : 6'-chloro-1'-(1-ethyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (DMSO-d ₆ , 400 MHz): 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-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (CDCL ₃ , 400 MHz): 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-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (DMSO-d ₆ , 400 MHz): 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-1'-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (CDCL ₃ , 400 MHz): 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-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one

¹ H NMR : (CDCL ₃ , 400 MHz): 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-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (DMSO-d ₆ , 400 MHz): 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-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (CDCL _{3 ,} 400 MHz): 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=1.6 Hz, 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); ESI-MS: (+ve mode) 422.13 (M) + (100%).

Compound -30 : (S)-6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (CDCL _{3 ,} 400 MHz): 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=1.6 Hz, 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); ESI-MS: (+ve mode) 422.12 (M) + (100%).

Compound -31 : 6'-chloro-4-fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (CDCL _{3 ,} 400 MHz): 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 : 6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro-[indene-2,3'-indoline]-5-carboxylic acid methyl ester

¹ H NMR : (CDCL _{3 ,} 400 MHz): 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-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxamide

¹ H NMR : (CDCL _{3 ,} 400 MHz): 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-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carbonitrile

¹ H NMR : (CDCL _{3 ,} 400 MHz): 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-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro-[indene-2,3'-indoline]-5-carboxylic acid

¹ H NMR : (DMSO-d _{6 ,} 400 MHz): 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-1'-(1-propyl-1H-pyrazol-4-yl)-5-(2H-tetrazolyl-5-yl)-1,3-dihydro-spiro[indene-2,3'-indolin]-2'-one

¹ H NMR : (CDCL _{3 ,} 400 MHz): 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%). Test biological studies of the compounds of the present invention: ATX inhibitory activity ( IC ₅₀ assay):

Autotaxin activity was measured by measuring the amount of choline released from LPC 16:0 using the Amplite® Choline Quantitation Kit (AAT Bioquest, 40007). For inhibitor screening, 5 µl of 20 nM purified recombinant human autotaxin (Echelon, E-4000) was mixed with 10 µl of the test compound (concentration range) in assay buffer (50 mM Tris-HCl pH 8.0, 500 mM NaCl, 5 mM KCl, 5 mM CaCl ₂ , 0.1% fatty acid-free BSA) in a black 96-well plate and incubated for 10 min at room temperature. To start the reaction, 10 µl of 375 μM LPC 16:0 in methanol (Millipore Sigma, L5254) was added to the plate and incubated at 37°C for 30 minutes. Then 25 µl of choline assay working solution was added and incubated at 37°C for 30 minutes to measure the amount of choline released. Finally, the fluorescence intensity was measured using a Hidex sense reader with excitation and emission wavelengths of 540 nm and 590 nm, respectively. In this assay, the fluorescence intensity is proportional to the amount of choline released and, subsequently, to the enzyme activity. For _IC50 determination, the residual activity of autotaxin relative to vehicle (100% activity) was measured over a range of inhibitor concentrations and the data were analyzed by nonlinear regression using Graph Pad Prism to obtain the _IC50 .

Table 2 lists the ATX inhibitory activities (IC ₅₀ ) of representative compounds. Table 2 : ATX inhibitory activity (IC ₅₀ ) of representative compounds Sample (Example No.) _IC50 (nM) 1 600 3 382 6 1000 8 228 16 206.3 17 183.2 18 60.7 19 115.3 20 147 twenty four 48.3 27 253.4 28 36 29 108 30 22.9 31 59.7 34 261.7 37 91.5 41 313.4 55 25.7 75 55.1

The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with appropriate excipients, and the techniques, processes and concentrations thereof are well known. The above-mentioned pharmaceutical compositions also contain an effective amount of an ATX inhibitor. The dosage of the ATX inhibitor can vary within a wide range and should be individually adjusted according to the specific circumstances.

The compound of formula (I) or a pharmaceutical composition containing the same can be used as a drug for inhibiting ATX activity and is suitable for humans and other warm-blooded animals and can be administered orally, externally or by injection.

The amount of active ingredient (i.e., the novel compound of formula (I) of the present invention) in a pharmaceutical composition and its unit dosage form can be widely varied or adjusted depending on a variety of factors, such as the specific method of administration, the potency of the particular compound, and the desired concentration.

A pharmaceutical composition comprising a novel compound of general formula (I), a pharmaceutically acceptable salt, a pharmaceutically acceptable solvent complex, a mirror image isomer, a non-mirror image isomer and a polymorph thereof, and a pharmaceutically acceptable carrier, solvent, diluent, excipient and other medium for its production.

The general formula (I) is used to treat a disease selected from the group consisting of cancer, chronic inflammation, neuropathic pain and fibrotic diseases.

In some embodiments, the present invention also includes at least one method for treating cancer, chronic inflammation, neuropathic pain, and fibrotic diseases mediated in part by ATX, the aforementioned method comprising administering a therapeutically effective amount of a compound or salt of the novel compound of formula (I) to an individual in need thereof.

In one embodiment, the compound of formula (I) can be used alone or in any combination with one or more therapeutic agents, such as anti-inflammatory agents, anti-tumor agents, anti-fibrotic agents, autocrine motility factor inhibitors, immunomodulators and cardiovascular agents, as well as other therapeutic agents known to medical practitioners. The selection of such therapeutic agents may depend on the type and severity of the disease, the condition of the patient being treated, and other drugs taken by the patient.

In one embodiment, the compound of formula (I) of the present invention can be used in combination with one or more suitable pharmaceutically active agents of the following therapeutic agents, which can be combined with tyrosine kinase inhibitors and pyridone therapeutic agents.

In other embodiments, Nintedanib is a tyrosine kinase inhibitor and Pirfenidone is a pyridone.

Although the present invention has been described in terms of specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be encompassed within the scope of the present invention.

without

without

without

Claims (6)

A novel compound of general formula (I), its pharmaceutically acceptable salt, pharmaceutically acceptable solvent complex, mirror image isomer and non-mirror image isomer, wherein ^R1 and ^R2 are selected from -H, halogen, -( _C1 - _C6 )alkyl, ( _{C1 - C6} )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 heterocyclo; E is selected ^from _-CH2 or -O-; when E is -O-, n is 1; when E is -CH2, 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 heterocyclic group; ^R3 is selected from -H, halogen, -( _CH2 ) _rCF3 , -CN ^, -O( _CH2 ) _rCF3 , -( _{CH2 )rORd ,} -( ^CRdRe ) _rNRdRe , or ^-NRdRe , -( _C1 - ^C6 ) ^alkyl , ( _C3 -C7) ^cycloalkyl , ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )acyloxy, heterocyclic group, wherein alkyl _, cycloalkyl, alkoxy, acyloxy, heterocyclic group is substituted or unsubstituted; ^R4 and _R5 are selected from -H, halogen, -( _C1 -C6)alkyl, ( _C3 - _C7 )cycloalkyl, (C1- _C6 )alkoxy, (C1-C6)acyloxy, heterocyclic group. _{wherein R a , R} b , R _c , _{R d} , Re , R _{f , R g , R h and R i are selected from H, -OH , ( C 1} -C ₆ ) _alkyl, ^halogenalkyl or (C ₃ -C ₇ )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 , ^Rg , ^Rh and ^Ri are selected from H, -OH, (C ₁ -C ₆ )alkyl, halogenalkyl or (C ₃ -C ₇ )cycloalkyl. The novel compound of general formula (I) as described in claim 1, wherein ^R1 and ^R2 are selected from -H, halogen, -( _C1 - _C6 )alkyl, ^-COORa , -C(O) ^NRaRb , substituted or unsubstituted ^aryl , ( _C3 - _C7 )cycloalkyl, substituted or unsubstituted heteroaryl; ^R3 is selected from -H, -( _C1 - _C6 )alkyl, -( _CH2 ) _rCF3 , -(CH2) _rORd ^, ( _C3 - _C7 )cycloalkyl or heterocyclo; ^R4 and ^R5 are selected _{from -H, halogen, -(C1-C6)alkyl, (C1-C6 ) alkoxy , - ( CH2 ) sCF3 ,} -CN, -O( _CH2 ) _sCF3 ; X, Y and Z may be selected from -C or -N; ^Ra , ^Rb , ^Rc , ^Rd , ^Re , ^Rf , ^Rg , ^Rh and ^Ri are selected from -H, ( _C1 - _C6 )alkyl, -OH. The novel compound of general formula (I) is selected from the following: 6'-chloro-2'-oxo-1'-benzene-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-chloro-2'-oxo-1'-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-chloro-2'-oxo-1'-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-chloro-2'-oxo-1'-(pyridin-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(6-methylpyridin-3-yl)-2'-oxo-1,3-dihydrospiro-[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-2'-oxo-1'-(pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(6-methylthiazol-3-yl)-2'-oxo-1,3-dihydrospiro-[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-2'-oxo-1'-(thiophene-3-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(furan-3-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-2'-oxo-1'-(1H-pyrrol-3-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(1-methyl-1H-pyrrol-3-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(isothiazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(isoxazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(5-ethyl-1,2,4-oxadiazol-3-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(3.5-dimethylisoxazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-2'-oxo-1'-(1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(1-methyl-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(1-ethyl-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(1-isopropyl-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(1-isobutyl-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(1-cyclopropyl-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-2'-oxo-1'-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(1-(oxocyclobutyl-3-yl)-1H-pyrazol-4-yl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 1'-(1-butyl-1H-pyrazol-4-yl)-6'-chloro-2'-oxo-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro-[indene-2,3'-indole]-2'-one; (R)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; (S)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-4-fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; (S)-6'-Chloro-4-fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; (R)-6'-Chloro-4-fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid methyl ester; (S)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid methyl ester; (R)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid methyl ester; 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxamide; (S)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxamide; (R)-6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxamide; 6'-Chloro-N-hydroxy-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxamide; 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indole]-5-carbonitrile; 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydro-spiro[cyclopenta[b]pyridine-6,3'-indole]-2-carboxylic acid; (S)-6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-2-carboxylic acid; (R)-6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-2-carboxylic acid; 6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-3-carboxylic acid; (R)-6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-2-carboxylic acid; (S)-6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-indoline]-3-carboxylic acid; 2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indoline]-5-carboxylic acid; 6'-Fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-methyl-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-6'-(trifluoromethyl)-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Methoxy-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-6'-(trifluoromethoxy)-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-cyano-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-7'-fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-5'-fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-Chloro-5'-methyl-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 5',6'-dichloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-chloro-7'-methyl-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-5-carboxylic acid; 6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridine]-5-carboxylic acid; 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[3,2-b]pyridine]-5-carboxylic acid; 2'-Chloro-6'-oxo-7'-(1-propyl-1H-pyrazol-4-yl)-1,3,6',7'-tetrahydrospiro[indene-2,5'-pyrrolo[2,3-d]pyrimidine]-5-carboxylic acid; 6'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-3H-spiro-[benzofuran-2,3'-indoline]-6-carboxylic acid; 6'-Chloro-1'-(1-methyl-1H-pyrazol-4-yl)-2'-oxo-3H-spiro-[benzofuran-2,3'-indoline]-6-carboxylic acid; 7'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid methyl ester; 7'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid; 7'-Chloro-1'-(1-ethyl-1H-pyrazol-4-yl)-2'-oxo-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid; 7'-Chloro-1'-(1-methyl-1H-pyrazol-4-yl)-2'-oxo-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid; 7'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1',4',5,7-tetrahydro-2'H-spiro[cyclopenta[b]pyridine-6,3'-quinoline]-2-carboxylic acid; 7'-Chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1',4',5,7-tetrahydro-2'H-spiro[cyclopenta[b]pyridine-6,3'-quinoline]-3-carboxylic acid; 7'-Fluoro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid; 7'-Methyl-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid; 2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-7'-(trifluoromethyl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid; 7'-methoxy-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,1',3,4'-tetrahydro-2'H-spiro[indene-2,3'-quinoline]-5-carboxylic acid; 6'-chloro-1'-(1-propyl-1H-pyrazol-4-yl)-5-(1H-tetrazolyl-5-yl)-1,3-dihydrospiro[indene-2,3'-indole]-2'-one; 3-(6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indolin]-5-yl)-1,2,4-thiadiazole-5(4H)-one; 3-(6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2,3'-indolin]-5-yl)-1,2,4-thiadiazole-5(4H)-one; 6'-chloro-5-(3-hydroxyisoxazol-5-yl)-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indene-2 ,3'-indolin]-2'-one; 6'-chloro-5-(3-hydroxyisothiazol-5-yl)-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indolin-2,3'-indolin]-2'-one; 5-(6'-chloro-2'-oxo-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-spiro[indolin-2,3'-indolin]-5-yl)-1,3,4-oxadiazol-2(3H)-one; 6'-Chloro-5-(5-hydroxy-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1'-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydrospiro[indene-2,3'-indole]-2'-one; 6'-Chloro-1'-(1-propyl-1H-pyrazol-4-yl)-5-(1H-1,2,3-triazol-5-yl)-1,3-dihydrospiro[indene-2,3'-indole]-2'-one. A pharmaceutical composition comprising a novel compound of the general formula (I) as described in claim 1, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvent complex, a mirror image isomer and a non-mirror image isomer thereof, and having a pharmaceutically acceptable carrier, solvent, diluent, excipient and other media commonly used in its preparation. A use of the novel compound of general formula (I) as described in claim 1 for treating a disease selected from the following: cancer, chronic inflammation, neuropathic pain and fibrotic disease. A method for treating cancer, chronic inflammation, neuropathic pain, and fibrotic diseases mediated in part by ATX, comprising administering to a subject in need thereof a therapeutically effective amount of a novel compound of the general formula (I) as described in claim 1 or a suitable pharmaceutical composition thereof.