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WO2018109650A1 - Dérivés spiro[cyclopentane-1,3'-indolin]-2'-one utilisés en tant qu'inhibiteurs de bromodomaines - Google Patents

Dérivés spiro[cyclopentane-1,3'-indolin]-2'-one utilisés en tant qu'inhibiteurs de bromodomaines Download PDF

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Publication number
WO2018109650A1
WO2018109650A1 PCT/IB2017/057823 IB2017057823W WO2018109650A1 WO 2018109650 A1 WO2018109650 A1 WO 2018109650A1 IB 2017057823 W IB2017057823 W IB 2017057823W WO 2018109650 A1 WO2018109650 A1 WO 2018109650A1
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Prior art keywords
cyclopentane
indolin
oxospiro
benzenesulfonamide
optionally substituted
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Inventor
Ravi Kotrabasaiah Ujjinamatada
Susanta Samajdar
Subramanya Hosahalli
Chandrasekhar ABBINENI
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Aurigene Oncology Ltd
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Aurigene Discovery Technologies Ltd
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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
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel spiro[cyclopentane-l,3'-indolin]-2'-one derivatives of formula (I) which are useful as bromodomain inhibitors.
  • the invention also relates to the process for preparation of the compounds of the present invention thereof, pharmaceutical compositions comprising them, and their use for the treatment and prevention of diseases or disorder, their use in diseases or disorder associated with bromodomain containing proteins.
  • the acetylation of histone lysine is central to providing the dynamic regulation of chromatin-based gene transcription.
  • the bromodomain (BRD) which is the conserved structural module in chromatin-associated proteins and histone acetyl tranferases, is the sole protein domain known to recognize acetyl-lysine residues on proteins.
  • the BET family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t) which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction.
  • BRD2 and BRD3 are reported to associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al, Mol. Cell. 2008 30(1):51 -60), while BRD4 appears to be involved in the recruitment of the pTEF-[beta] complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al, Cell, 2009 138(1): 129-145).
  • BRD4 or BRD3 may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes, BRD4-NUT or BRD3-NUT, in a highly malignant form of epithelial neoplasia (French et al. Cancer Research, 2003, 63, 304-307 and French et al. Journal of Clinical Oncology, 2004, 22 (20), 4135-4139).
  • BRD-NUT fusion proteins contribute to carcinogenesis (Oncogene, 2008, 27, 2237-2242).
  • BRD-t is uniquely expressed in the testes and ovary.
  • Japanese patent application JP2008156311 discloses a benzimidazole derivative which is said to be a BRD2 bromodomain binding agent has utility with respect to virus infection / proliferation.
  • bromodomain inhibitors with desirable pharmaceutical properties.
  • Certain spiro[cyclopentane-l,3'-indolin]-2'-onederivatives have been found in the context of this invention to have a class of compounds that inhibit the binding of BET family bromodomains to acetylated lysine residues for controlling the gene expressions in human health and disease. Such compounds will hereafter be referred to as "bromodomain inhibitors".
  • the present invention provides a new class of spiro[cyclopentane-l,3'-indolin]-2'-one derivatives of the following formula (I) that inhibit the binding of BET family bromodomains to acetylated lysine residues.
  • Cy is a 3-12 membered monocyclic or bicyclic ring containing 0-4 hetero atoms or groups independently selected from N, O, S, NH or C(O);
  • L represents a linker selected from -NHS(0) 2 -, -S(0) 2 NH-, -NHS(0) 2 CH(R 3 )-,
  • -N S(0)(R 3 )- or -NHC(0)CH(R 3 )-;
  • Ri is hydrogen, cyano, nitro, halogen, Ci_ 7 alkyl, haloalkyl, -OR a , -COR a , -COOR a , - 0(CO)R a , -CONRaRb, -NHCORa, -NR a R b , -SR 3 , -S(0 2 )R 3 , optionally substituted alkylamino, optionally substituted C 3 _io cycloalkyl, optionally substituted C 3 _io cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; wherein the optional substitution at each occurrence is independently 1-3 substituents selected from halogen, Ci_ 7 alkyl, Ci_ 7 alkoxy, haloalkyl or C 3 _io cycloalkyl;
  • R 2 is halogen, Ci_ 7 alkyl, -OR a, haloalkyl, amino, alkylamino, cyano, nitro, -COOR 3 , -SR 3i -S(0 2 )R 3 , optionally substituted C 3 _io cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; wherein the optional substitution at each occurrence is independently 1- 3 substituents selected from halogen, cyano, nitro, amino, oxo, hydroxy, alkylamino, -COOR 3 , - SR 3i -S(0 2 )R 3 , Ci_ 7 alkyl, Ci_ 7 alkoxy, C 3 _io cycloalkyl, aryl or heterocyclyl;
  • R 3 is hydrogen or Ci_ 7 alkyl
  • R a and R b are independently selected from hydrogen, Ci_ 7 alkyl, haloalkyl, optionally substituted alkylamino, optionally substituted C 3 _io cycloalkyl, optionally substituted C 3 _io cycloalkylalkyl , optionally substituted heterocyclyl , optionally substituted heterocyclylalkyl, optionally substituted C 3 _i 2 spiroheterocyclyl, optionally substituted aryl or optionally substituted arylalkyl; wherein the optional substitution at each occurrence is independently 1 -3 substituents selected from halogen, cyano, nitro, amino, oxo, hydroxy, alkylamino, -COOR 3 , -SR 3i -S(0 2 )R 3 , Ci_ 7 alkyl, Ci_ 7 alkoxy, C 3 _io cycloalkyl, aryl or heterocyclyl; and
  • 'm' is 0, 1, 2 or 3.
  • spiro[cyclopentane-l,3'-indolin]-2'-one derivatives of formula (I) and processes for preparing thereof.
  • it provides use of spiro[cyclopentane-l,3'- indolin]-2'-one derivatives of formula (I) for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder for which a bromodomain inhibitor is indicated.
  • the invention relates to the use of substituted spiro[cyclopentane-l,3 '- indolin]-2'-one derivatives of formula (I) and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios as a medicament for which a bromodomain inhibitor is indicated.
  • alkyl alone or in combination with other term(s) means saturated aliphatic hydrocarbon chains, including Ci-Cio straight or Ci-Cio branched alkyl groups.
  • alkyl include but are not limited to methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl, sec -butyl, tert-butyl, isopentyl, neopentyl, and isohexyl and the like.
  • alkylamino refers to either a mono or a dialkylamino group in which the alkyl portion of the group may be straight or branched. Examples of such groups are methylamino, diethylamino, 2-propylamino and the like.
  • alkoxy refers to the group alkyl-O- or -O-alkyl, where alkyl groups are as defined above.
  • exemplary Ci-Cio alkyl group containing alkoxy- groups include but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy, t-butoxy and the like.
  • An alkoxy group can be unsubstituted or substituted with one or more suitable groups.
  • aryl alone or in combination with other term(s) means a carbocyclic aromatic system containing one or more rings wherein such rings may be fused.
  • fused means that the second ring is attached or formed by having two adjacent atoms in common with the first ring.
  • fused is equivalent to the term “condensed”.
  • an aryl group typically has from 6 to about 14 carbon atoms but the invention is not limited in that respect. Examples of aryl groups include but are not limited to phenyl, naphthyl, indanyl, and the like. Unless otherwise specified, all aryl groups described herein may be optionally substituted.
  • arylalkyl refers to an aryl moiety attached to the parent structure through C 1 -C5 alkyl group.
  • amino refers to an -NH 2 group.
  • nitro refers to an -N0 2 group.
  • cyano refers to -CN group.
  • hydroxyl refers to -OH group.
  • halogen alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with -F, -CI, -Br or -I.
  • Representative examples of an haloalkyl group include, but are not limited to -CH 2 F, -CCI 3 , - CF 3 , -CH 2 C1, -CH 2 CH 2 Br, -CH 2 CH 2 I, -CH 2 CH 2 CH 2 F, and -CH 2 CH(Br)CH 3 .
  • cycloalkyl alone or in combination with other term(s) means - C 3 -Cio saturated cyclic hydrocarbon ring.
  • a cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single -ring cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • heterocyclyl alone or in combination with other term(s) includes both “heterocycloalkyl” and “heteroaryl” groups which are as defined herein.
  • heterocyclyl include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, indolyl, benzimidazolyl, pyrazinyl, quinuclidine, 1,2,6-trimethylpiperidine, 4-methylmorpholine, tetrahydro-2H-thiopyran 1,1 -dioxide, pyrazolyl, imidazolyl, morpholinyl benzothiazolyl and the like.
  • heterocycloalkyl refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 15 members having at least one heteroatom or hetero group selected from O, N, S, S(O), S(0) 2 , NH or C(O).
  • heterocycloalkyl examples include, but are not limited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, 2,3-dihydrobenzo[b][l,4] dioxine,l,2,3,4-tetrahydroisoquinoline, 5,6-dihydropyridin-2(lH)-one, quinoline, 2-oxaspiro[3.3]
  • heteroaryl alone or in combination with other term(s) means a completely unsaturated ring system containing a total of 5 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms/groups being independently selected from the group consisting of carbon, oxygen, nitrogen or sulfur.
  • a heteroaryl may be a single -ring (monocyclic) or polycyclic ring system. Examples of “heteroaryl” include but are not limited to pyridyl, indolyl, benzimidazolyl, benzothiazolyl and the like.
  • heterocyclylalkyl refers to a heterocyclyl moiety attached to the parent structure through C 1 -C 5 alkyl group.
  • cycloalkylalkyl refers to a cycloalkyl moiety attached to the parent structure through C 1 -C 5 alkyl group.
  • monocyclic or bicyclic ring containing 0-4 heteroatoms/groups refers to monocyclic or bicyclic aromatic or non-aromatic cyclic ring with 3-12 ring atoms in which 0-4 of the ring carbon atoms have been independently replaced with C(O), N, NH, O, S, S(O) or S(0) 2 groups.
  • rings include, but are not limited to phenyl, pyridine, pyrimidine, morpholine, piperidine, piperazine, cyclohexyl, 2,3-dihydrobenzo[b][l,4] dioxine, 1,2,3,4-tetrahydroisoquinoline, 5,6-dihydropyridin-2(lH)-one, quinoline, 2-oxobicyclo [2.2.1]heptane, indazole, [1,2,4] triazolo[4,3-a]pyridine and tetrahydroisoquinoline.
  • heteroatom/group designates a C(O), N, NH, O, S, S(O) and
  • spiroheterocyclyl refers to a bicyclic heterocyclic ring as defined above wherein the two rings are joined through a common ring carbon atom.
  • optionally substituted refers to replacement of one or more hydrogen radicals in a given structure with a radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro,
  • the term 'compound(s)' comprises the compounds disclosed in the present invention.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • the term “prevents”, “preventing” and “prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent”, “preventing” and “prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease. As used herein, the term “therapeutically effective amount” refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
  • “Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salt” refers to the salts of the compounds, that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulf
  • stereoisomers refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of formula (I), (IA), (IB), (IC), (ID), (IE) and (IF); wherever they are chiral or when they bear one or more double bonds.
  • compounds of the formula (I), (IA), (IB), (IC), (ID), (IE) and (IF), and related formulae are chiral, they can exist in racemic or in optically active form. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as J-isomers and /-isomers and mixtures thereof.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds of the present invention may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • E Electronic Data
  • Z data isomers
  • the present invention provides spiro[cyclopentane-l,3'-indolin]-2'-one derivatives of formula (I) useful as bromodomain inhibitors.
  • the present invention further provides pharmaceutical compositions comprising the said spiro[cyclopentane-l,3'-indolin]-2'-one derivatives as therapeutic agents.
  • One of the embodiments of the present invention relates to compounds of formula (I):
  • Cy is a 3-12 membered monocyclic or bicyclic ring containing 0-4 hetero atoms or groups independently selected from N, O, S, NH or C(O);
  • L represents a linker selected from -NHS(0) 2 -, -S(0) 2 NH-, -NHS(0) 2 CH(R 3 )-,
  • -N S(0)(R 3 )- or -NHC(0)CH(R 3 )-;
  • Ri is hydrogen, cyano, nitro, halogen, Ci_ 7 alkyl, haloalkyl, -OR a , -COR a , -COOR a , - 0(CO)R a, -CONR a R b , -NHCOR a, -NR a R b , -SR 3, -S(0 2 )R 3 , optionally substituted alkylamino, optionally substituted C 3 _io cycloalkyl, optionally substituted C 3 _io cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; wherein the optional substitution at each occurrence is independently 1-3 substituents selected from halogen, Ci_ 7 alkyl, Ci_ 7 alkoxy, haloalkyl or C 3 _io cycloalkyl;
  • R 2 is halogen, Ci_ 7 alkyl, -OR a, haloalkyl, amino, alkylamino, cyano, nitro, -COOR 3 , -SR 3i -S(0 2 )R 3 , optionally substituted C 3 _io cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; wherein the optional substitution at each occurrence is independently 1- 3 substituents selected from halogen, cyano, nitro, amino, oxo, hydroxy, alkylamino, -COOR 3 , - SR 3i -S(0 2 )R 3 , Ci_ alkyl, Ci_ alkoxy, C 3 _io cycloalkyl, aryl or heterocyclyl;
  • R 3 is hydrogen or Ci_ alkyl
  • R a and R are independently selected from hydrogen, C 1-7 alkyl, haloalkyl, optionally substituted alkylamino, optionally substituted C 3 _io cycloalkyl, optionally substituted C 3 _io cycloalkylalkyl , optionally substituted heterocyclyl , optionally substituted heterocyclylalkyl, optionally substituted C 3-12 spiroheterocyclyl, optionally substituted aryl or optionally substituted arylalkyl; wherein the optional substitution at each occurrence is independently 1 -3 substituents selected from halogen, cyano, nitro, amino, oxo, hydroxy, alkylamino, -COOR 3 , -SR 3i -S(0 2 )R 3 , Ci_ alkyl, Ci_ alkoxy, C 3 _io cycloalkyl, aryl or heterocyclyl; and
  • 'm' is 0, 1, 2 or 3.
  • the compound of formula (I) is a compound of formula
  • R 1; R 2i L, Cy and 'm' are same as defined in formula (I).
  • the compound of formula (I) or (IA) is a compound of formula IB):
  • the compound of formula (I) or (IA) is a compound of formula (IC):
  • the compound of formula (I) or (IA) is a compound of formula ID):
  • the compound of formula (I) or (IA) is a compound of formula IE):
  • the compound of formula (I) or (IA) is a compound of formula (IF):
  • L is a linker selected from -NHS(0) 2 -, -S(0) 2 NH-, -NHS(0) 2 CH 2 -,
  • -N S(0)CH 3 - or -NHC(0)CHCH 3 -.
  • Cy is a 3-8 membered monocyclic ring or 8-12 membered bicyclic ring containing 0-3 heteroatoms independently selected from N, NH, O or C(O).
  • Cy is cyclohexyl, phenyl, piperidinyl, pyridinyl, 1,4-benzodioxanyl, 2-oxobicyclo [2.2.1] heptane, [1,2,4] triazolo[4,3-a] pyridine, 1,2,3,4-tetrahydroisoquinoline or quinoline.
  • Cy is phenyl.
  • R 2 is selected from halogen, Ci_ 7 alkyl, Ci_ 7 alkoxy, -OR a or 4-10 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH or C(O); wherein R a is selected from haloalkyl, heterocyclyl, Ci_ 7 alkyl substituted C 3 _i 2 spiroheterocyclyl; and 'm' is 0, 1, 2 or 3.
  • heterocyclic ring is optionally substituted with 1-2 substituents selected from halogen or Ci_ 7 alkyl;
  • Ri is hydrogen, cyano, halogen, Ci_ alkyl, -0R 3i -COR a , -0(C0)R 3i -CONR a R b , - NHC0R 3i -NR a R b , optionally substituted C 3 _io cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; wherein the optional substitution is selected from halogen or C 1-7 alkyl;
  • R a and R are independently selected from hydrogen, optionally substituted alkylamino, optionally substituted C 3 _io cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl or optionally substituted C 3-12 spiroheterocyclyl; wherein the optional substitution at each occurrence is independently 1-3 substituents selected from halogen, amino, oxo, -S(0 2 )R 3 , Ci_ alkyl or C 3 _io cycloalkyl;
  • heterocyclyl group is a 3-10 membered mono or bicyclic ring containing 1-3 heteroatoms independently selected from N, NH, O, S or C(O).
  • Ri is selected from one of the following groups or tautomers thereof hydrogen, hydroxyl, amino, bromo, chloro, cyano, methyl, CONH 2 , cyclopropyl,
  • Cy is cyclohexyl, phenyl, piperidinyl, pyridinyl, 1,4-benzodioxanyl, 2- oxobicyclo[2.2.1]heptane, [l,2,4]triazolo[4,3-a]pyridine, 1,2,3,4-tetrahydroisoquinoline or quinoline;
  • L is -NHS(0) 2 -
  • R 2 is halogen, C 1-7 alkyl or C 1-7 alkoxy
  • Ri is hydrogen, hydroxyl, amino, bromo, chloro, cyano, methyl, CONH 2 , cyclopropyl,
  • Ri is selected from halogen (such as chloro and bromo), Ci_ alkyl (such as methyl, ethyl and isopropyl) and C3-10 cycloalkyl (such as cyclopropyl).
  • halogen such as chloro and bromo
  • Ci_ alkyl such as methyl, ethyl and isopropyl
  • C3-10 cycloalkyl such as cyclopropyl
  • the present invention provides processes for preparing spiro[cyclopentane-l,3'-indolin]-2'-one derivatives of formula (I).
  • a pharmaceutical composition comprising the compound of formula (I) of the present invention and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • compounds of the present invention inhibit one or more of BRD2, BRD3, BRD4, BRDT, and/or another member of the bromodomain-containing proteins, or a mutant thereof.
  • compounds of the present invention inhibit two or more of BRD2, BRD3, BRD4, BRDT, and/or another member of the bromodomain-containing proteins, or a mutant thereof.
  • compounds of the present invention are inhibitors of one of more of the bromodomain-containing proteins, such as BRD2, BRD3, BRD4, and/or BRDT and are therefore useful for treating one or more disorders associated with activity of one or more of the bromodomain-containing proteins, such as BRD2, BRD3, BRD4, and/or BRDT.
  • the present invention provides a method for treating an bromodomain- containing protein-mediated disorder, such as a BET-mediated, a BRD2-mediated, a BRD3- mediated, a BRD4-mediated disorder, and/or a BRDT-mediated disorder comprising the step of inhibiting a bromodomain-containing protein, such as a BET protein, such as BRD2, BRD3, BRD4, and/or BRDT, or a mutant thereof, by administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable composition thereof.
  • an bromodomain-containing protein-mediated disorder such as a BET-mediated, a BRD2-mediated, a BRD3- mediated, a BRD4-mediated disorder, and/or a BRDT-mediated disorder
  • a bromodomain-containing protein such as a BET protein, such as BRD2, BRD3, BRD4, and/or BRDT, or a mutant thereof
  • bromodomain-containing protein-mediated As used herein, the terms "bromodomain-containing protein-mediated”, “BET- mediated”, “BRD2-mediated”, “BRD3 -mediated”, “BRD4-mediated”, and/or “BRDT-mediated” disorders or conditions means any disease or other deleterious condition in which one or more of the bromodomain-containing proteins, such as BET proteins, such as BRD2, BRD3, BRD4 and/or BRDT, or a mutant thereof, are known to play a role.
  • BET proteins such as BRD2, BRD3, BRD4 and/or BRDT, or a mutant thereof
  • another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which one or more of the bromodomain-containing proteins, such as BET proteins, such as BRD2, BRD3, BRD4, and/or BRDT, or a mutant thereof, are known to play a role.
  • BET proteins such as BRD2, BRD3, BRD4, and/or BRDT
  • diseases and conditions treatable according to the methods of this invention include, but are not limited to, cancer and other proliferative disorders, inflammatory diseases, sepsis, autoimmune disease, and viral infection.
  • the disorder or disease is an inflammatory disorder or disease. In certain embodiments, the disorder or disease is an autoimmune disorder or disease.
  • the disorder or disease is cancer.
  • a method of treating a subject is having a disease, disorder, or symptom thereof comprising administration of a therapeutically effective amount of a compound or composition of the present invention to the subject.
  • the present invention provides use of a compound of formula
  • the subject is a human.
  • the present invention provides compounds for use as a medicament.
  • the invention provides the use of the compounds of the present invention in the manufacture of a medicament.
  • the invention provides the use of the compounds of the present invention in the manufacture of a medicament for the treatment of immune or inflammatory disorder or disease.
  • the present invention provides compounds for use as a medicament for the treatment of immune or inflammatory disorder or disease.
  • the medicament is for treating a disease or disorder mediated by bromodomain containing proteins.
  • the present invention provides a method of modulating the function of a bromodomain in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of formula (I).
  • the present invention provides compounds of formula (I) for use in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by bromodomain containing proteins.
  • Bromodomain inhibitors are believed to be useful in the treatment of a variety of diseases or conditions related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and in the prevention and treatment of viral infections.
  • Bromodomain inhibitors may be useful in the treatment of a wide variety of chronic autoimmune and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes and
  • Bromodomain inhibitors may be useful in the treatment of a wide variety of acute inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritisnodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organ involvement and acute rejection of transplanted organs.
  • acute inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritisnodosa, Behcet's disease, Kawasaki disease
  • Bromodomain inhibitors may be useful in the prevention or treatment of diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex and coronavirus.
  • diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS),
  • Bromodomain inhibitors may be useful in the prevention or treatment of conditions associated with ischaemia-reperfusion injury such as myocardial infarction, cerebro- vascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
  • ischaemia-reperfusion injury such as myocardial infarction, cerebro- vascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
  • Bromodomain inhibitors may be useful in the treatment of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.
  • Bromodomain inhibitors may be useful in the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.
  • Bromodomain inhibitors may be useful in the prevention and treatment of viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses.
  • Bromodomain inhibitors may be useful in the treatment of cancer, including hematological, epithelial including lung, breast and colon carcinomas, midline carcinomas, mesenchymal, hepatic, renal and neurological tumors.
  • the disease or condition for which a bromodomain inhibitor is indicated is selected from diseases associated with systemic inflammatory response syndrome, such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia.
  • the bromodomain inhibitor would be administered at the point of diagnosis to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injury and mortality.
  • the bromodomain inhibitor would be administered prior to surgical or other procedures associated with a high risk of sepsis, haemorrhage, extensive tissue damage, SIRS or MODS (multiple organ dysfunction syndrome).
  • the disease or condition for which a bromodomain inhibitor is indicated is sepsis, sepsis syndrome, septic shock and endotoxaemia.
  • the bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis.
  • the bromodomain is indicated for the treatment of burns.
  • the disease or condition for which a bromodomain inhibitor is indicated is selected from herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus.
  • a bromodomain inhibitor is indicated for the treatment of Human papilloma virus infections of skin or cervical epithelia.
  • a compound of formula (I) as well as pharmaceutically acceptable salts thereof may be administered as the raw chemical, it is common to present the active ingredient as a pharmaceutical composition.
  • the compounds and pharmaceutically compositions of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention may be useful.
  • Such other drugs may be administered, by a route and in an amount commonly used there for, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention may also be preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • a pharmaceutical composition of the invention may be formulated as being compatible with its intended route of administration, which may preferably be an oral administration.
  • the pharmaceutical compositions of the invention may be formulated for administration by inhalation, such as aerosols or dry powders; for oral administration, such in the form of tablets, capsules, gels, syrups, suspensions, emulsions, elixirs, solutions, powders or granules; for rectal or vaginal administration, such as suppositories; or for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion) such as a sterile solution, suspension or emulsion.
  • the compounds of the present invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethyl cellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • the spiro[cyclopentane-l,3'-indolin]-2'-one derivatives of formula (I) according to the present invention may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. The specifics of the processes according to the present invention are detailed in the example section mentioned below.
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H ("D"), 3 H, U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the microwave chemistry was performed on a CEM Explorer.
  • the procedure for the compounds of Formula (I) are detailed herein below stepwise including the general synthesis of various intermediates involved in process of manufacture of the compounds according to the present invention.
  • Step-b Synthesis of tert-butyl 5-nitro-2-oxoindoline-l-carboxylate:
  • Step-d Synthesis of tert-butyl 5'-amino-2'-oxospiro [cyclopentane -l ⁇ '-indolinel-l'-carboxylate:
  • Step-b Synthesis of spiro[cyclopentane-l,3'-indolinl-2'-one:
  • step-d of intermediate- 1 The process for this step was depicted in step-d of intermediate- 1 by using 5'- nitrospiro[cyclopentane-l,3'-indolin]-2'-one as starting material.
  • the desired product obtained as a white solid (0.1 g, 21%).
  • N-Bromosuccinamide (1.265 g, 7.1 mmol) was added in portions to 5'-nitrospiro [cyclo pentane-l,3'-indolin]-2'-one (1.1 g, 4.7 mmol, step-c product of intermediate-2) in 10 mL of Con.H 2 S0 4 .
  • the reaction mixture was stirred for 5h at room temperature and poured into 200 mL of cold water. The precipitated solid was filtered, and then the solid was washed with 50 mL water and dried under reduced pressure to afford the title compound as a white solid (1.4 g, 95%).
  • Step-b Synthesis of 5'-amino-7'-bromospiro[cyclopentane-l,3'-indolinl-2'-one:
  • step-d of Intermediate- 1 The process for this step was depicted in step-d of Intermediate- 1 by using 7'-bromo-5'- nitrospiro[cyclopentane-l,3'-indolin]-2'-one as starting material.
  • the desired product obtained as white solid (1.1 g, 87%).
  • Step-a Synthesis of 7'-chloro-5'-nitrospiro[cyclopentane-l,3'-indolinl-2'-one:
  • step-a of intermediate-3 The process for this step was depicted in step-a of intermediate-3 by using 5'- nitrospiro[cyclopentane-l,3'-indolin]-2'-one (step-c product of intermediate-2) as starting material.
  • step-c product of intermediate-2 The desired product obtained as an off-white solid.
  • Step-b Synthesis of 5'-amino-7'-chlorospiro[cyclopentane-l,3'-indolinl-2'-one:
  • step-d of intermediate- 1 The process for this step was depicted in step-d of intermediate- 1 by using 7'-chloro-5'- nitrospiro[cyclopentane-l,3'-indolin]-2'-one as starting material.
  • the desired product obtained as an off-white (0.33 g, 90%).
  • 1H-NMR 300 MHz, DMSO-d 6 ) ⁇ 10.1 (s, 1H), 6.48 (m, 1H), 6.39 (m, 1H), 4.94 (s, 2H), 1.99-1.87 (m, 6H), 1.69-1.67 (m, 2H); LC-MS: m/z 237 (M+H) + .
  • Step-d Synthesis of 7'-methyl-5'-nitrospiro[cyclopentane-l,3'-indolinl-2'-one: To a stirred solution of 7-methyl-5-nitroindolin-2-one (0.5g, 2.0 mmol) in dry THF was added potassium teri-butoxide (0.683 g, 6.0 mmol) in portions at -15 °C and stirred for 30 min. Subsequently 1,4 dibromobutane (0.521 g, 2.04 mmol) was added and the reaction mixture was stirred at 0 °C for lh. The reaction mixture was quenched with IN HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure.
  • potassium teri-butoxide 0.683 g, 6.0 mmol
  • Step-e Synthesis of 5'-amino-7'-methyl spiro[cyclopentane-l,3'-indolinl-2'-one:
  • step-d of Intermediate- 1 The process for this step was depicted in step-d of Intermediate- 1 by using 7'-methyl-5'- nitrospiro[cyclopentane-l,3'-indolin]-2'-one as starting material.
  • the desired product obtained as brown solid (0.150 g, 90%).
  • Step-a Synthesis of 7'-cvclopropyl-5'-nitrospiro[cyclopentane-l,3'-indolinl-2'-one:
  • step-d of intermediate- 1 The process for this step was depicted in step-d of intermediate- 1 by using 7'- cyclopropyl-5'-nitrospiro[cyclopentane-l,3'-indolin]-2'-one as starting material.
  • the desired product obtained as pale-yellow solid (0.8g, 89.9%).
  • Step-a Synthesis of 2-(2'-oxospirorcyclopentane-L3'-indolinl-5'-yl)isoindoline-L3-dione:
  • Step-b Synthesis of 2-(7'-nitro-2'-oxospirorcyclopentane-L3'-indolinl-5'-yl)isoindoline-L3- dione:
  • Step-c Synthesis of 5'-amino-7'-nitrospiro[cyclopentane-l,3'-indolinl-2'-one: To a stirred solution of 2-(7'-nitro-2'-oxospiro[cyclopentane-l,3'-indolin]-5'- yl)isoindoline-l,3-dione (3.2 g, 8.48 mmol) in EtOH (30 mL) was added hydrazine hydrate (6 mL) and heated to 100 °C for 2h. Then the reaction mixture was poured into crushed ice and the solid formed was filtered off, washed with water and dried under reduced pressure to afford title compound as orange solid (1.9 g).
  • Step-a Synthesis of 7'-bromo-r-(4-methoxybenzyl)-5'-nitrospiro[cyclopentane-l,3'-indolinl-2'- one:
  • reaction mixture was cooled to RT, quenched with saturated ammonium chloride solution, extracted into ethyl acetate, the organic layer was dried over sodium sulfate and concentrated to get the title compound (3.2 g, 46.3%).
  • Step-b Synthesis of r-(4-methoxybenzyl)-5'-nitro-2'-oxospiro[cyclopentane-l,3'-indolinel-7'- carbonitrile:
  • Step-c Synthesis of 5'-amino-r-(4-methoxybenzyl)-2'-oxospiro[cyclopentane-l,3'-indolinel-7'- carbonitrile:
  • Step-a Synthesis of 7'-bromo-5'-nitrospiro[cyclopentane-l,3'-indolinl-2'-one:
  • Step-c Synthesis of 7'-hvdroxy-r-(4-methoxybenzyl)-5'-nitrospiro[cyclopentane-l,3'-indolinl- 2'-one:
  • reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc, washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure and purified by CombiFlash® to afford title compound as pale brown solid (0.8 g, 67 %).
  • Step-e Synthesis of 5'-amino-r-(4-methoxybenzyl)-7'-((l-methylpiperidin-4-yl)oxy)spiro
  • reaction mixture was cooled to room temperature, filtered through Celite ®, washed with EtOAc, combined filtrate was concentrated, and the residue was diluted with water and extracted with EtOAc, washed with brine, dried over sodium sulphate and concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as pale yellow solid (0.2 g, 35 %).
  • the present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds according to the invention.
  • reaction mixture was diluted with DCM (50 mL), washed with saturated sodium bicarbonate solution, brine solution and dried over Na 2 S0 4i the organic layer was concentrated to obtain the crude compound.
  • the obtained crude was purified by silica gel chromatography using a mixture of 50% ethyl acetate/hexane as an eluent to get the title compound as white solid (0.020g, 25%).
  • Example-II with appropriate variations in reactants, quantities of reagents and reaction conditions.
  • the physiochemical characteristics of the compounds are summarized herein below table.
  • Step-a Synthesis of 6-hvdrazinyl-N-(2'-oxospiro[cyclopentane-l,3'-indolinl-5'-yl)pyridine-3- sulfonamide:
  • Step-b Synthesis of N-(2'-oxospiro[cvclopentane-l,3'-indolinl-5'-yl)-[l,2,41triazolo[4,3-al pyridine-6-sulfonamide:
  • Step-a Synthesis of N-((2,4-difluorophenyl)sulfonyl)-2,4-difluoro-N-(7'-nitro-2'-oxospiro
  • Step-b Synthesis of 2,4-difluoro-N-(7'-nitro-2'-oxospirorcyclopentane-L3'-indolinl-5'-yl) benzenesulfonamide :
  • Step-c Synthesis of N-(7'-amino-2'-oxospiro[cyclopentane-l,3'-indolinl-5'-yl)-2,4-difluoro benzenesulfonamide :
  • reaction mixture was cooled to room temperature, filtered through Celite ®, washed with EtOAc the combined filtrate was concentrated to obtain the residue, the residue was diluted with water, extracted with EtOAc (200 mL X 2), washed with brine solution (200 mL), dried over sodium sulphate, concentrated under reduced pressure and purified by column chromatography to afford the title compound as pale brown solid (1.0 g, 53%).
  • Step-a Synthesis of 2-methoxy-N-(7'-nitro-2'-oxospiro[cyclopentane-l,3'-indolinl-5'-yl) benzenesulfonamide :
  • step-c of example-IV The process for this step was depicted in step-c of example-IV by using 2-methoxy-N-(7'- nitro-2'-oxospiro[cyclopentane-l,3'-indolin]-5'-yl)benzenesulfonamide as starting material.
  • the desired product obtained as brown solid.
  • reaction mixture was diluted with EtOAc (100 mL) washed with aqueous ammonia (100 mL), water (100 mL), dried over sodium sulphate and concentrated under reduced pressure to obtain the crude compound.
  • the crude compound was purified by column chromatography to afford the title compound as brown solid (0.04 g, 21%).
  • Example-VII Synthesis of N-(7'-cvano-2'-oxospirorcyclopentane-L3'-indolinl-5'-yl)-2,4- difluorobenzenesulfonamide (Compound-29) & 5'-(2,4-difluorophenylsulfonamido)-2'- oxospiro[cyclopentane-l,3'-indolinel-7'-carboxamide: (Compound-30)
  • Step-a Synthesis of N-(7'-cvano-r-(4-methoxybenzyl)-2'-oxospiro[cyclopentane-l,3'-indolinl- 5'-yl)-2,4-difluorobenzenesulfonamide:
  • Step-b Synthesis of N-(7'-cvano-2'-oxospiro[cyclopentane-l,3'-indolinl-5'-yl)-2,4-difluoro benzene sulfonamide & 5'-((2,4-difluorophenyl) sulfonamido)-2'-oxospiro[cyclopentane-l,3'- indolinel-7'-carboxamide:
  • Step-a Synthesis of 5'-amino-7'-hvdroxy-r-(4-methoxybenzyl) spiro[cyclopentane-l,3'-indolinl- 2'-one:
  • Step-b Synthesis of N-(7'-hvdroxy-r-(4-methoxybenzyl)-2'-oxospiro[cyclopentane-l,3'- indolinl -5 '-yl)-2-methoxybenzenesulfonamide :
  • Step-c Synthesis of N-(7'-hvdroxy-2'-oxospiro[cyclopentane-l,3'-indolinl-5'-yl)-2-methoxy benzenesulfonamide :
  • reaction mixture was slowly poured in to aqueous NaHC0 3 and extracted with DCM, the organic layer was dried over Na 2 S0 4 , concentrated under reduced pressure and purified by CombiFlash® to afford title compound as white solid (0.015 g, 32%).
  • TR-FRET time- resolved fluorescence resonance energy transfer
  • Bet bromodomain TR-FRET assay has been used to identify compounds that bind to bet bromodomain and prevent its interaction with acetylated histone peptides.
  • the reaction mixture was further incubated for 30mins at room temperature on a plate shaker.
  • 1 nM of Europium labeled streptavidn and 5nM of XL-665 labeled antibody diluted in detection buffer 50 mM HEPES, pH: 7.5, 50 mM NaCl, 500 ⁇ CHAPS and 800 mM KF) were added to all the wells excluding the buffer blank wells.
  • the reaction plate was incubated for additional 60mins at room temperature on plate shaker.
  • the plate was read in Perkin Elmer WALLAC 1420 Multilabel Counter Victor 5 (Ex: 340 nm Em: 615 and 665 nm).
  • the amount of displacement of the peptide was measured as ratio of specific 665 nm energy transfer signal to 615 nm signals.
  • the compounds IC 50 was determined by fitting the dose response data to sigmoid curve fitting equation using Graph Pad Prism software V7.

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Abstract

La présente invention concerne des dérivés de spiro[cyclopentaneane-1,3'-indolin]-2'-one de formule (I), qui sont thérapeutiquement utiles, plus particulièrement en tant qu'inhibiteurs de bromodomaines. Dans la formule (I), Cy, R1, R2, L et 'm' ont la signification donnée dans la description, ainsi que des sels ou des stéréoisomères pharmaceutiquement acceptables de ceux-ci, qui sont utiles dans le traitement et la prévention de maladies ou de troubles, en particulier leur utilisation en tant qu'inhibiteurs de bromodomaines dans le traitement et la prévention des maladies ou des troubles associés. L'invention concerne également la préparation de composés et de formulations pharmaceutiques comprenant au moins l'un des dérivés de spiro[cyclopentane-1,3'-indolin]-2'-one de formule (I), associés à un vecteur, un diluant, ou un excipient pharmaceutiquement acceptables.
PCT/IB2017/057823 2016-12-14 2017-12-12 Dérivés spiro[cyclopentane-1,3'-indolin]-2'-one utilisés en tant qu'inhibiteurs de bromodomaines Ceased WO2018109650A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111018772A (zh) * 2019-11-21 2020-04-17 天津科技大学 一类具有抗肿瘤活性的5-磺酰胺基取代的靛红类衍生物
EP4326696A4 (fr) * 2021-04-22 2025-06-25 Kayothera Inc. Composés hétérocycliques et leurs utilisations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009124692A1 (fr) * 2008-04-11 2009-10-15 Almirall, S.A. Nouveaux dérivés substitués de spiro[cycloalkyl-1,3’-indol]-2’(1’h)-one et leur utilisation en tant qu’inhibiteurs de la kinase activée par le mitogène p38
WO2009132774A1 (fr) * 2008-04-28 2009-11-05 Almirall, S. A. Nouveaux dérivés substitués indolin-2-one et utilisation de ces derniers en tant qu'inhibiteurs de kinase activés par le mitogène p39
WO2015092118A1 (fr) * 2013-12-17 2015-06-25 Orion Corporation Dérivés spiro[cyclobutane-1,3'-indolin]-2'-ones en tant qu'inhibiteurs de bromodomaine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009124692A1 (fr) * 2008-04-11 2009-10-15 Almirall, S.A. Nouveaux dérivés substitués de spiro[cycloalkyl-1,3’-indol]-2’(1’h)-one et leur utilisation en tant qu’inhibiteurs de la kinase activée par le mitogène p38
WO2009132774A1 (fr) * 2008-04-28 2009-11-05 Almirall, S. A. Nouveaux dérivés substitués indolin-2-one et utilisation de ces derniers en tant qu'inhibiteurs de kinase activés par le mitogène p39
WO2015092118A1 (fr) * 2013-12-17 2015-06-25 Orion Corporation Dérivés spiro[cyclobutane-1,3'-indolin]-2'-ones en tant qu'inhibiteurs de bromodomaine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111018772A (zh) * 2019-11-21 2020-04-17 天津科技大学 一类具有抗肿瘤活性的5-磺酰胺基取代的靛红类衍生物
EP4326696A4 (fr) * 2021-04-22 2025-06-25 Kayothera Inc. Composés hétérocycliques et leurs utilisations

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