WO2014155301A1 - Composés bicycliques substitués utilisés comme inhibiteurs d'ezh2 - Google Patents

Composés bicycliques substitués utilisés comme inhibiteurs d'ezh2 Download PDF

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WO2014155301A1
WO2014155301A1 PCT/IB2014/060157 IB2014060157W WO2014155301A1 WO 2014155301 A1 WO2014155301 A1 WO 2014155301A1 IB 2014060157 W IB2014060157 W IB 2014060157W WO 2014155301 A1 WO2014155301 A1 WO 2014155301A1
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methyl
oxo
dihydropyridin
pyridin
carboxamide
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PCT/IB2014/060157
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Rajiv Sharma
Amol Gupte
Abhijit Roychowdhury
Ravindra Dnyandev Jadhav
Shivaji Sadashiv KANDRE
Kishorkumar Shivajirao Kadam
Sambhaji CHAVAN
Pradip Keshavrao GADEKAR
Tandra GUHA
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Piramal Enterprises Limited
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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
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Definitions

  • the present invention relates to bicyclic compounds (the compounds of formula 1 ), processes for their preparation, pharmaceutical compositions containing them and their use as EZH2 (enhancer of zeste homolog 2) inhibitors, and methods of using said compounds in the treatment of diseases mediated by EZH2.
  • Histone methyl transferases are a family of enzymes, which control selective methylation at specific amino acid sites on histones. Covalent modification of histones such as methylation control changes of chromatin structure in eukaryotic cell DNA, which leads to heritable alteration in gene expression. These modifications are referred to as epigenetic modifications. Polycomb genes are an illustration of epigenetic effectors structured in multimeric repressive complexes. Aberrant expression and/or activity of enzymes responsible for histone modification result in disease states such as cancer. Therefore, epigenetic modifications can be reversed and consequently, treatment of diseases such as cancer may be effected through selective inhibition of the enzymes involved.
  • Histone-lysine N-methyltransferase EZH2 (enhancer of zeste homolog 2) is the catalytic subunit of Polycomb repressive complex 2 (PRC2), which methylates Lys27 of a specific histone H3 (H3K27) and is essential for the self-renewal of cancer stem cells.
  • PRC2 Polycomb repressive complex 2
  • H3K27 histone H3
  • EZH2 is capable of silencing several anti-metastatic genes, favoring cell-invasion and uncontrolled cell-growth. For instance, somatic mutations of tyrosine 641 of EZH2 are reported to be associated with follicular lymphoma and diffused B-cell lymphoma (Nature Genet., 2010, 42, 2, 181 -185).
  • Increased levels of trimethylated H3K27 resulting due to an increased expression of EZH2 contribute to cancer aggressiveness, metastasis, shorter disease free survival and increased death rate in many tumor types, for instance, in melanoma, prostate cancer, breast cancer and cancer of the endometrium (Bachmann et al, Journal of Clinical Oncology, 2006, 24, 4, 268-73). This is further substantiated in Oncogene, 2012, 31 , 3827-44, wherein EZH2 expression is reported to be deregulated in prostate cancer, breast cancer and endometrial cancer, B-cell non-Hodgkin's lymphoma and bladder carcinoma.
  • Increased expression of EZH2 also induces pulmonary artery smooth muscle proliferation (PLoS ONE, 2012, 7, 5, e37712). Increased expression of EZH2 has been further reported to have implication in myelofibrosis (Expert Review of Hematology, 2012, 5, 3, 313-324), HIV (PCT publication WO2012051492 A2), graft versus host diseases (GVHD) (Blood, 2012, 1 19. 5, 1274-1282), Weaver Syndrome (American Journal of Human Genetics, 2012, 90, 1 , 1 10-1 18), psoriasis vulgaris (European Journal of Dermatology, 201 1 . 21 , 4, 552-557) and liver fibrogenesis (PCT publication WO2010090723A2 ).
  • PCT patent publication WO201 1 140324A1 discloses indoles as inhibitors of EZH2 and use of said compounds for the treatment of cancer.
  • PCT patent publication WO20121 18812A2 discloses bicyclic heterocyclic compounds for inhibition of EZH2 and use of said compounds for the treatment of cancer.
  • compounds of formula 1 (as described herein), or isotopic forms, stereoisomers or tautomers thereof, or pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, S-oxides or N-oxides thereof.
  • compositions comprising one or more of the compounds of formula 1 or isotopic forms, stereoisomers or tautomers thereof, or pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, S-oxides or N-oxides thereof; and at least one pharmaceutically acceptable carrier or excipient.
  • a compound of formula 1 for use as an EZH2 inhibitor.
  • a compound of formula 1 or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or a disorder mediated by EZH2.
  • a method for the treatment of a disease or disorder mediated by EZH2 comprising administering to a subject in need thereof; a therapeutically effective amount of the compound of formula 1 or a stereoisomer or a tautomer thereof; or a pharmaceutically acceptable salt thereof.
  • the present invention relates to use of a compound of formula 1 or a stereoisomer or tautomer; or a pharmaceutically acceptable salt thereof; in combination with at least one further therapeutically active agent.
  • a compound of formula 1 or a stereoisomer or tautomer for the manufacture of a medicament for the treatment of diseases or disorders mediated by EZH2.
  • the present invention relates to a compound of formula 1 :
  • Xi and X 2 are independently selected from CRi and N, such that ring A is a phenyl, pyridyl or pyrimidinyl ring;
  • n and n are integers independently selected from 0 and 1 ; such that ring B is a 5-7 membered ring;
  • L is --C(0)NR 5 --, --NRsC(O)--, -NR 5 S(0) r -, --S(0) r NR 5 --, --CH(halo-(C r C 8 )- alkyl)NR 5 --, --NR 5 CH(halo-(CrC 8 )-alkyl)--, --C(halo-(Ci-C 8 )-alkyl) 2 NR5--, --
  • p is an integer from 0 to 3;
  • r is an integer from 0 to 2;
  • Ri and R 2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (C C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C C 8 )- alkoxy, (C3-Ci 2 )-cycloalkyl, (C5-C 8 )-cycloalkenyl, heterocyclyl, halo(CrC 8 )alkyl, NR a Rb, COORa, CONRgRb, S(0)q(C r C 6 )-alkyl and S(0) q NR a R b ; or Ri and R 2 may form a 3 to 7 membered ring optionally containing 1 -3 heteroatoms selected from the group consisting of O, N and S;
  • R3, R5 and R11 are independently selected from the group consisting of hydrogen
  • R 4 , R 6 , R 7 , Rs, R9 and R 0 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH) 2 , (CrC 8 )-alkyl, halo(C r C 8 )alkyl, (CrC 8 )-alkoxy, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -Ci 4 )-aryl, ar- (CrCs)-alkyl, heteroaryl, heterocyclyl, COR a , C0 2 R a , CONR a R b , CON(R) a NR a Rb, OC(0)NR a R b , S(0) q R a , S(0) q NR a R b , NR
  • R a and R b are independently selected from the group consisting of hydrogen, (C r C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 3 -Ci 2 )-cycloalkyl, (C 5 -C 8 )-cycloalkenyl, (C 6 -Ci 4 )-aryl, heterocyclyl and heteroaryl; or
  • R a and R b together with the nitrogen to which they are attached form a 5 to 8 membered saturated or unsaturated ring, optionally containing another heteroatom selected from oxygen, nitrogen, and sulphur;
  • each of the (CrC 8 )-alkyl, (CrC 8 )alkoxy and halo(CrC 8 )alkyl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (C r C 8 )-alkoxy-(R c )i- 2 , (C 3 - Ci 2 )-cycloalkyl-(R c )i- 2 , (C 6 -Ci 4 )-aryl-(R c )i- 2 , 0-(C 6 -Ci 4 )-aryl-(R c )i.
  • heterocyclyl refers to a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from the group consisting of a nitrogen (N), a sulphur (S) and an oxygen (O) atom;
  • the heteroaryl refers to a 5-10 membered aromatic monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from the group consisting of a nitrogen (N), a sulphur (S) and an oxygen (O) atom; each of the (C-2-C-8)-alkenyl, (C-2-C-8)-alkynyl, (C-3-Ci2)-cycloalkyl, (C-3-C-8)-cycloalkenyl, (C-6-Ci 4 )-aryl, heteroaryl and heterocyclyl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (CrC 8 )-alkyl-(R c ) 1 .2, (Ci -C 8 )-alkoxy-(R c )i-2, (C3-C12)- cycloalkyl-( R c
  • R c is hydrogen, halogen, hydroxy, cyano, nitro, (d-CsJ-alkyl, halo(d- Cs)alkyl, (C
  • substitution means that one or more hydrogens of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
  • (CrC 8 )-alkyl or “alkyl” as used herein; alone or as part of a substituent group, refers to the radical of saturated aliphatic groups, including straight or branched-chain alkyl groups.
  • (CrC 8 )-alkyl refers to an alkyl group having 1 to 8 (both inclusive) carbon atoms.
  • a straight-chain or branched chain alkyl has eight or fewer carbon atoms in its backbone, for instance, CrCs for straight- chain and C 3 -C 8 for branched chain.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl and 3-methylbutyl.
  • alkyl groups can be unsubstituted or substituted with one or more substituents.
  • a substituted alkyl refers to a (CrC 8 )- alkyl substituted with 1 -7 groups, preferably 1 -3 groups independently selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (C r C 8 )-alkoxy-(R c )i- 2 , (C 3 -Ci2)-cycloalkyl-(R c )i-2, (C 6 -Ci 4 )-aryl-(R c ) 1 . 2 , 0-(C 6 -Ci 4 )-aryl-(R c ) 1 .
  • R c is hydrogen, halogen, hydroxy, cyano, nitro, (CrC 8 )-alkyl, halo(CrC 8 )alkyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -Ci 4 )- aryl, ar-(C
  • halogen refers to a fluorine, chlorine, bromine, or iodine atom.
  • alkyl group When the alkyl group is substituted with one or more halogens, it is specifically referred to as "halo(CrC 8 )alkyl" or haloalkyl.
  • a monohalo(CrC 8 )alkyl radical for example, can have a chlorine, bromine, iodine or fluorine atom.
  • Dihalo and polyhalo(CrC 8 )alkyl radicals can have two or more of the same or different halogen atoms.
  • halo(CrC 8 )alkyl examples include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl or the like groups.
  • alkenyl or "(C 2 -C 8 )-alkenyr', as used herein; alone or as part of a substituent group, refers to a straight or branched chain hydrocarbon radical containing the indicated number of carbon atoms and at least one carbon- carbon double bond (two adjacent sp 2 carbon atoms).
  • (C 2 -Cs)-alkenyl refers to an alkenyl group having 1 to 8 (both inclusive) carbon atoms.
  • the geometry of the double bond may be
  • E Delta
  • Z rocking
  • alkenyl include, but are not limited to, vinyl, allyl and 2-propenyl.
  • the alkenyl groups can be unsubstituted or substituted with 1 -7 groups, preferably 1 -3 groups independently selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (Ci-C 8 )-alkyl-(R c ) 1 . 2 , (Ci-C 8 )-alkoxy-(Rc)i-2, (C 3 -Ci 2 )-cycloalkyl-(Rc)i-2, (C 6 -Ci 4 )-aryl-(R c )i.
  • 1 -7 groups preferably 1 -3 groups independently selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (Ci-C 8 )-alkyl-(R c ) 1 . 2 , (Ci-C 8 )-alkoxy-(Rc)i-2, (C 3 -Ci 2 )-cycloalkyl-(Rc)i-2, (
  • alkynyl or "(C 2 -C8)-alkynyl” whether used alone or as part of a substituent group, refers to a straight or branched chain hydrocarbon radical containing the indicated number of carbon atoms and at least one carbon- carbon triple bond (two adjacent sp carbon atoms).
  • (C 2 -Cs)alkynyl refers to an alkynyl group having 1 to 8 (both inclusive) carbon atoms.
  • Examples of (C 2 -C 8 )-alkynyl include, but are not limited to, ethynyl, 1 -propynyl, 3-propynyl and 3- butynyl.
  • alkynyl can be unsubstituted or substituted with 1 -7 groups, preferably 1 -3 groups independently selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (CrC8)-alkyl-(R c )i-2, (CrC 8 )- alkoxy-(R c )i-2, (C 3 -Ci 2 )-cycloalkyl-(R c ) 1 . 2 , (C 6 -Ci 4 )-aryl-(R c ) 1 . 2 , 0-(C 6 -Ci 4 )-aryl-(R c ) 1 .
  • alkoxy or "(d-C 8 )-alkoxy” refers to a (C C 8 )-alkyl having an oxygen radical attached thereto.
  • Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy.
  • An alkoxy group can be unsubstituted or substituted with one or more substituents.
  • a substituted alkoxy refers to an (CrC 8 )-alkoxy group in which the alkyl is substituted with one or more groups as explained in the definition of 'substituted alkyl' herein above.
  • Representative examples of substituted (CrC 8 )-alkoxy include, but are not limited to, chloromethoxy, 2-cyanoethoxy, trifluoromethoxy and benzyloxy group.
  • a benzyloxy group refers to a benzyl having an oxygen radical attached thereto.
  • cycloalkyl or " (C3-Ci 2 )cycloalkyl” whether used alone or as part of a substituent group, refers to a saturated or partially unsaturated cyclic hydrocarbon radical including 1 , 2 or 3 rings and including a total of 3 to 12 carbon atoms forming the rings.
  • the term cycloalkyl includes bridged, fused and spiro ring systems.
  • (C-3-Ci 2 )-cycloalkyl refers to a cycloalkyl group having 3 to 8 (both inclusive) carbon atoms.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1 .0]pentane, bicyclo[2.2.1 ]heptyl, bicyclo[2.2.1 ]hept- 2-ene, spiro[3.3]heptane and 1 ,2,3,3a-tetrahydropentalene.
  • (C 5 -C 8 )-cycloalkenyl refers to a non-aromatic monocyclic carboxycyclic ring having the specified number of carbon atoms and up to 3 carbon- carbon double bonds.
  • Examples of cycloalkenyl include, but are not limited to cyclopentenyl and cyclohexenyl.
  • the "cycloalkyl” and "(C 5 -C 8 )-cycloalkenyr' can be unsubstituted or substituted with 1 -7 groups, preferably 1 -3 identical or different groups selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (Ci-C 8 )-alkyl-(R c )i-2, (Ci-C 8 )-alkoxy-(R c )i- 2 , (C 3 -Ci 2 )-cycloalkyl-(Rc)i-2, (C 6 -Ci 4 )- aryl-(R c )i-2, 0-(C 6 -Ci 4 )-aryl-(Rc)i-2, heterocyclyl-(R c )i- 2 , heteroaryl-(R c )i-2, halo(C C 8 )alkyl, halo(C C 8 )alkoxy,
  • aryl or "(C 6 -Ci 4 )-aryl” as used herein refers to a monocyclic or bicyclic hydrocarbon group having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system.
  • Examples of (C-6-Ci 4 )-aryl residues are phenyl, naphthyl, fluorenyl or anthracenyl.
  • Representative examples of (C 6 -Ci 4 )-aryl residues are phenyl or naphthyl.
  • Aryl groups can be unsubstituted or substituted by one or more, for example 1 , 2, 3, 4 or 5, identical or different substituents selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (CrC8)-alkyl-(R c )i- 2 , (d-Cs)- alkoxy-(R c )i-2, (C 3 -Ci2)-cycloalkyl-(R c )i-2, (C 6 -Ci 4 )-aryl-(R c )i. 2 , 0-(C 6 -Ci 4 )-aryl-(R c )i.
  • the substituent can be located in the 2-position, the 3-position or the 4-position. If the phenyl carries two substituents, they can be located in 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4- position or 3, 5-position.
  • Representative examples of monosubstituted phenyl groups include, but are not limited to, 3-trifluoromethylphenyl, 4-chlorophenyl and 4- cyanophenyl.
  • disubstituted phenyl groups include, but not limited to, 3, 5-difluorophenyl and 3, 4-dimethoxyphenyl.
  • aryloxy refers to an "(C 6 -Ci 4 )-aryl” group having an oxygen radical attached thereto.
  • the "aryl” of the aryloxy group can be unsubstituted or substituted as explained in the definition of substituted (C-6-Ci 4 )-aryl herein above.
  • Examples of aryloxy groups include, but not limited to, phenoxy, 4-chlorophenoxy, and 3, 4-dimethoxyphenoxy.
  • aralkyl refers to an alkyl group substituted with an (C-6-Ci 4 )-aryl group, wherein the terms alkyl and aryl are as defined above.
  • exemplary aralkyl groups include (CH 2 ) p- phenyl, wherein p is an integer from 1 to 6, such as benzyl wherein p is 1 .
  • the aryl of the (C 6 -Ci 4 )-aralkyl group can be unsubstituted or substituted as explained in the definition of substituted aryl herein above.
  • heteroatom as used herein, includes nitrogen (N), oxygen (O) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency.
  • heterocyclyl or “heterocyclic” whether used alone or as part of a substituent group, refers to a saturated, partially unsaturated, monocyclic or polycyclic ring system containing 1 to 1 0 carbon atoms and 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • heterocyclyl primarily refers to a 3- to 1 0- membered ring system which can be a monocyclic or a bicyclic ring.
  • heterocyclyls include, but are not limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyrazinyl, piperazinyl, oxazolyl, oxadiazolyl, isoxazolyl, triaziolyl, thiazolyl, tetrazolyl, furyl, thienyl, purinyl, pyridinyl, pyridazinyl, pyrimidinyl, piperidyl, benzoxazolyl, benzothiazolyl, benzofuranyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, indazolyl, isoindolyl, isothiazolyl, isoquinolyl, isoquinolyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-1 , 1 -dioxide, quinoxalin
  • heteroaryl refers to a 5- to 1 0-membered aromatic monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from the group consisting of nitrogen, sulphur and an oxygen atom.
  • heteroaryls include, but are not limited to, pyrrole, pyrazole, imidazole, pyrazine, furan, thiophene, oxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrine) and tetrazole.
  • the oxidized form of the ring nitrogen and sulfur atom of the heteroaryl to provide N-oxide, S-oxide or S, S-dioxide is also encompassed.
  • a heterocyclyl or heteroaryl group can be unsubstituted or substituted.
  • a substituted heterocyclyl or heteroaryl refers to a heterocyclyl or heteroaryl substituted with 1 -5 identical or different groups independently selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (CrC8)-alkyl-(R c ) i -2, (Ci-C 8 )-alkoxy-(R c ) i-2, (C 3 -Ci 2 )-cycloalkyl-(R c ) 1 . 2 , (C 6 -Ci 4 )-aryl-(R c ) 1 .
  • isotopic forms or “isotopically labeled forms” is a general term used for isotopic forms of compounds of formula 1 , wherein one or more atoms of compounds of formula 1 are replaced by their respective isotopes. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention.
  • isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as 2 H (deuterium or D) and 3 H, carbon such as 11 C, 13 C and 14 C, nitrogen such as 13 N and 15 N, oxygen such as 15 0, 17 0 and 18 0, chlorine such as 36 CI, fluorine such as 18 F and sulphur such as 35 S.
  • isotopes of hydrogen such as 2 H (deuterium or D) and 3 H
  • carbon such as 11 C, 13 C and 14 C
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 0 and 18 0, chlorine such as 36 CI
  • fluorine such as 18 F
  • sulphur such as 35 S.
  • Substitution with heavier isotopes, for example, replacing one or more key carbon-hydrogen bonds with carbon-deuterium bond may show certain therapeutic advantages, resulting from longer metabolism cycles, (e.g., increased in vivo half life or reduced dosage requirements), improved safety or greater
  • isotopic forms of the compounds of formula 1 may include, without limitation, deuterated compounds of formula 1 .
  • deuterated as used herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom.
  • the compounds of formula 1 can include in the definitions of one or more of its various variables, wherever applicable, deuterium, deuterated-alkyl, deuterated-alkoxy, deuterated-cycloalkyl, deuterated-heterocyclyl, deuterated-aryl, deuterated-heteroaryl and the like.
  • deuterated-alkyl refers to an (d-CsJ-alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced with a deuterium, i.e., in a deuterated alkyl group, at least one carbon atom is bound to a deuterium.
  • a deuterated alkyl group it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium.
  • deuterated and the terms deuterated-heterocyclyl, deuterated-heteroaryl, deuterated-cycloalkyl, deuterated- aryl, deuterated-alkoxy each refer to the corresponding chemical moiety wherein at least one carbon is bound to a deuterium.
  • solvate refers to a compound formed by the interaction of a solute (in the present invention, a compound of formula 1 or a pharmaceutically acceptable salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • the solvent used is water and the solvates obtained are referred to as hydrates.
  • suitable solvates are the mono- or di-hydrates or alcoholates of the compounds according to the invention.
  • stereoisomer is a general term used for all isomers of individual compounds that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • tautomer refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.
  • the term “pharmaceutically acceptable” means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • pharmaceutically acceptable salts includes salts of the active compound (a compound of formula 1 ), which retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects; and are prepared with suitable acids or bases, depending on the particular substituents found on the compounds described herein.
  • polymorph or “polymorphic form” refers to crystals of the same compound (a compound of formula 1 ) that differs only in the arrangement and/or conformation of the molecule in the crystal lattice.
  • N-oxide refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N-oxide can be formed in the presence of an oxidizing agent such as m- chloro-perbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N- 0 bond.
  • S-oxide refers to the oxide of the sulfur atom (S-oxide) or dioxide of the sulfur atom (S,S-dioxide) of a sulfur-containing heteroaryl or heterocycle.
  • S-oxide and S,S-dioxides can be formed in the presence of an oxidizing agent for example peroxide such as m-chloro- perbenzoic acid or oxone.
  • a prodrug or “prodrugs” refers to any compound, which are derivatives of said compound, which following administration, release(s) the parent compound (a compound of formula 1 ) in vivo via a chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound.
  • the term "compound(s) of formula 1 " or “compounds of the present invention” are used interchangeably and includes all the isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, N- oxides and S-oxides thereof.
  • An EZH2 inhibitor refers to an agent which is capable of inhibiting the increased expression of Histone-lysine N-methyltransferase EZH2 (enhancer of zeste homolog 2), which is a catalytic subunit of Polycomb repressive complex 2 (PRC2), responsible for methylation of Lys27 of a specific histone H3 (H3K27) and essential for the self-renewal of cancer stem cells.
  • Histone-lysine N-methyltransferase EZH2 encodehancer of zeste homolog 2
  • PRC2 Polycomb repressive complex 2
  • the diseases or disorders mediated by EZH2 include, but are not limited to, cancer, pulmonary arterial hypertension, myelofibrosis, human immunodeficiency virus (HIV) disease, graft versus host diseases, Weaver Syndrome, psoriasis vulgaris and liver fibrogenesis.
  • the cancers mediated by EZH2 include, but are not limited to, thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, endometrial cancer, head and neck cancer and oral cancer.
  • therapeutically effective amount means an amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof, effective in producing the desired therapeutic response in a particular patient suffering from a disease or disorder mediated by EZH2.
  • a disease or disorder mediated be EZH2 is cancer.
  • therapeutically effective amount includes the amount of a compound, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject.
  • the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment.
  • the therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized and other factors.
  • the term "pharmaceutically acceptable carrier” refers to a material that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent.
  • subject refers to an animal, preferably a mammal, and most preferably a human.
  • mammal refers to warmblooded vertebrate animals of the class 'mammalia', including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
  • subject may be used interchangeably with the term “patient”.
  • a subject in need thereof means a subject in need of the treatment for the disease or disorder that is mediated by EZH2.
  • treatment refers to alleviate, slow the progression, attenuation or cure of existing diseases or condition (e.g. cancer). Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the diseases or condition.
  • the present invention relates to a compound of formula 1 : wherein,
  • Xi and X2 are independently selected from CRi and N, such that ring A is a phenyl, pyridyl or pyrimidinyl ring;
  • n and n are integers independently selected from 0 and 1 ; such that the ring B is a 5-7 membered ring;
  • L is --C(0)NR 5 — or --NR 5 C(0)--
  • R 6 , R7 and R 8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH) 2 , (C r C 8 )-alkyl, halo(C r C 8 )alkyl, (C r C 8 )- alkoxy, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -Ci 4 )-aryl, ar-(C r C 8 )- alkyl, heteroaryl, heterocyclyl, COR a , C0 2 R a , CONR a R b , CONR a NR a Rb, OC(0)NR a R b , S(0) q R a , S(0) q NR a R b , NR a R b , NR a C(0)R b
  • p, q, r, R a , R b , Ri , R 2 , R 3 , R 4 , R 5 and Rn are as defined in the first aspect; or an isotopic form, stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula 1 : wherein,
  • Xi and X 2 are CRi , such that ring A is a phenyl ring;
  • n and n are integers independently selected from 0 and 1 ; such that the ring B is a 5-7 membered ring;
  • L is --C(0)NR 5 — or -NR 5 C(0)--;
  • R 6 , R7 and R 8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH) 2 , (C r C 8 )-alkyl, halo(C r C 8 )alkyl, (C r C 8 )- alkoxy, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -Ci 4 )-aryl, ar-(C r C 8 )- alkyl, heteroaryl, heterocyclyl, COR a , C0 2 R a , CONR a R b , CONR a NR a R b , OC(0)NR a R b , S(0) q R a , S(0) q NR a R b , NR a R b , NR a C(0)R
  • p, q, r, R a , Rb, Ri , R2, R3, R4, R5 and Rn are as defined in the first aspect; or an isotopic form, stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula 1 : wherein,
  • Xi and X 2 are CRi , such that ring A is a phenyl ring;
  • ring B is a 5-membered ring
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are CRi , such that ring A is a phenyl ring;
  • ring B is a 5-membered ring
  • Y 2 , Y 3 and Y 4 are CRi R 2 ;
  • the present invention provides a compound of formula 1 : wherein,
  • Xi and X 2 are CRi , such that ring A is a phenyl ring;
  • ring B is a 5-membered ring
  • the present invention provides a compound of formula 1 :
  • Xi and X2 are CRi , such that ring A is a phenyl ring;
  • ring B is a 5-membered ring
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are CRi , such that ring A is a phenyl ring;
  • ring B is a 5-membered ring
  • Y 2 is NR 3 ;
  • Y 4 is NR 3 ;
  • Ri and R 2 are independently selected from hydrogen and (Ci-C8)-alkyl; or
  • Ri and R 2 may form a 3 to 7 membered ring optionally containing 1 -3 heteroatoms selected from the group consisting of O, N and S;
  • R 3 is selected from hydrogen and (Ci-C8)-alkyl
  • p, r, L, Q and R 4 are as defined in the first aspect
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are CRi , such that the ring A is a phenyl ring;
  • ring B is a 5-membered ring and the bicyclic heterocycle formed by fusion of rings A and B is indoline;
  • Y 2 is NR 3 ; Y 3 and Y 4 are CRi R 2 ; or
  • Y 4 is NR 3 ; Y 2 and Y 3 are CRi R 2 ; and
  • p, Q, L, Ri , R 2 , R 3 and R 4 are as defined in the first aspect; or an isotopic form, stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula 1 :
  • Xi and X 2 are CRi , such that the ring A is a phenyl ring;
  • n 0, such that the ring B is a 5-membered ring
  • Y3 is NR 3; Y 2 and Y 4 are independently selected from the group consisting of CR1 R2,
  • the present invention provides a compound of formula 1 :
  • Xi and X2 are CRi , such that the ring A is a phenyl ring;
  • ring B is a 5-membered ring and the bicyclic heterocycle formed by fusion of rings A and B is isoindoline;
  • Y 3 is NR 3; Y 2 and Y 4 are CRi R 2 ; and
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are CRi , such that the ring A is a phenyl ring;
  • n 0, such that the ring B is a 5-membered ring
  • the present invention provides a compound of formula 1 :
  • Xi and X2 are CRi , such that the ring A is a phenyl ring;
  • n is 1 , such that the ring B is a 6-membered ring;
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are CRi , such that the ring A is a phenyl ring;
  • n is 1 , such that the ring B is a 6-membered ring;
  • Yi , Y2, Y3 and Y 4 are CRi R 2 ;
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are CRi , such that the ring A is a phenyl ring;
  • n is 1 , such that the ring B is a 6-membered ring;
  • p, r, L, Q, Ri , R 2 , R 3 and R 4 are as defined in the first aspect; or an isotopic form, stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are CRi , such that the ring A is a phenyl ring;
  • n is 1 , such that the ring B is a 6-membered ring;
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are CRi , such that the ring A is a phenyl ring;
  • n is 1 , such that the ring B is a 6-membered ring;
  • the present invention provides a compound of formula 1 :
  • Xi and X2 are CRi , such that the ring A is a phenyl ring;
  • n 1 , such that the ring B is a 7-membered ring;
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are CRi , such that the ring A is a phenyl ring;
  • n 1 , such that the ring B is a 7-membered ring;
  • Yi , Y2, Y3 and Y 4 are CRi R 2 ;
  • the present invention provides a compound of formula 1 :
  • Xi is N and X 2 is CRi or ⁇ is CRi and X 2 is N, such that the ring A is a pyridyl ring; L is --C(0)NR 5 — or --NR 5 C(0)--,
  • R6, R7 and Rs are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH) 2 , (d-CsJ-alkyl, halo(Ci-C-8)alkyl, (d-Cs)- alkoxy, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -Ci 4 )-aryl, ar-(C r C 8 )- alkyl, heteroaryl, heterocyclyl, COR a , C0 2 R a , CONR a R b , CONR a NR a R b , OC(0)NR a R b , S(0) q R a , S(0) q NR a R b , NR a R b , NR a C(0)R b , NR a C
  • R a , R b , Ri , R2, R4, R5 and R are as defined in the first aspect;
  • the present invention provides a compound of formula 1 :
  • Xi is N and X2 is CRi or Xi is CRi and X2 is N, such that the ring A is a pyridyl ring; m and n are 0, such that the ring B is a 5-membered ring;
  • the present invention provides a compound of formula 1 :
  • Xi is N and X 2 is CRi ; or Xi is CRi and X 2 is N, such that the ring A is a pyridyl ring; m is 0 and n is 1 , such that the ring B is a 6-membered ring;
  • the present invention provides a compound of formula 1 :
  • the present invention provides a compound of formula 1 :
  • Xi is N and X 2 is CRi ; or ⁇ is CRi and X 2 is N, such that the ring A is a pyridyl ring; m and n are 0, such that the ring B is a 5-membered ring;
  • Y3 is NR 3 ; Y 2 and Y 4 are independently selected from the group consisting of CRi R 2 ,
  • the present invention provides a compound of formula 1 :
  • Xi is N and X 2 is CRi ; or Xi is CRi and X 2 is N, such that the ring A is a pyridyl ring; m and n are 0, such that the ring B is a 5-membered ring;
  • L, p, r, Q, Ri , R 2 , R 3 and R 4 are as defined in the first aspect
  • the present invention provides a compound of formula 1 :
  • the present invention provides a compound of formula 1 :
  • Xi is N and X 2 is CRi ; or Xi is CRi and X 2 is N, such that the ring A is a pyridyl ring; m is 0 and n is 1 , such that the ring B is a 6-membered ring;
  • the present invention provides a compound of formula 1 :
  • Xi is N and X 2 is CRi ; or X- is CRi and X 2 is N, such that the ring A is a pyridyl ring; m is 0 and n is 1 , such that the ring B is a 6-membered ring;
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are N, such that the ring A is a pyrimidinyl ring;
  • L is --C(0)NR 5 — or --NR 5 C(0)--
  • R 6 , R7 and R 8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH) 2 , (C r C 8 )-alkyl, halo(C r C 8 )alkyl, (C r C 8 )- alkoxy, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -Ci 4 )-aryl, ar-(C r C 8 )- alkyl, heteroaryl, heterocyclyl, COR a , C0 2 R a , CONR a R b , CONR a NR a Rb, OC(0)NR a R b , S(0) q R a , S(0) q NR a R b , NR a R b , NR a C(0)R b
  • the present invention provides a compound of formula 1 : wherein,
  • Xi and X 2 are N, such that the ring A is a pyrimidinyl ring;
  • n is 0, such that the ring B is a 5-membered ring
  • the present invention provides a compound of formula 1 :
  • Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
  • n is 1 , such that the ring B is a 6-membered ring;
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are N, such that the ring A is a pyrimidinyl ring;
  • n 1 , such that the ring B is a 7-membered ring;
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are N, such that the ring A is a pyrimidinyl ring;
  • n 0, such that the ring B is a 5-membered ring
  • the present invention provides a compound of formula 1 :
  • ⁇ and X 2 are N , such that the ring A is a pyrimidinyl ring;
  • n 0, such that the ring B is a 5-membered ring
  • L, p, r, Q, Ri , R 2 , R 3 and R 4 are as defined in the first aspect
  • the present invention provides a compound of formula 1 :
  • Xi and X 2 are N, such that the ring A is a pyrimidinyl ring;
  • n is 1 , such that the ring B is a 6-membered ring;
  • L, p, r, Q, R 1 ; R 2 , R 3 and R 4 are as defined in the first aspect
  • the present invention provides a compound of formula 1 : wherein,
  • Xi and X 2 are N, such that the ring A is a pyrimidinyl ring;
  • n is 1 , such that the ring B is a 6-membered ring;
  • Y 3 and Y 4 are NR 3 ;
  • L, p, r, Q, Ri , R 2 , R 3 and R 4 are as defined in the first aspect
  • the present invention provides a compound of formula 1 : wherein,
  • Xi and X 2 are N, such that the ring A is a pyrimidinyl ring;
  • n is 1 , such that the ring B is a 6-membered ring;
  • L, p, r, Q, R 1 ; R 2 , R 3 and R 4 are as defined in the first aspect
  • the present invention provides a compound of formula 1 : wherein,
  • R 6 , R7 and R 8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH) 2 , (C r C 8 )-alkyl, halo(C r C 8 )alkyl, (C r C 8 )- alkoxy, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -Ci 4 )-aryl, ar-(C r C 8 )- alkyl, heteroaryl, heterocyclyl, COR a , C0 2 R a , CONR a R b , CONR a NR a Rb, OC(0)NR a R b , S(0) q R a , S(0) q NR a R b , NR a R b , NR a C(0)R b
  • the present invention provides a compound of formula 1 :
  • Q is selected from:
  • Rg and R10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH) 2 , (CrC 8 )-alkyl, halo(CrC 8 )alkyl, (C 2 -C 8 )- alkenyl, (C 2 -C 8 )-alkynyl, (C-3-Ci 2 )-cycloalkyl, (C-6-Ci 4 )-aryl, ar-(CrC 8 )-alkyl, heteroaryl, heterocyclyl, COR a , C0 2 R a , CONR a R b , CONR a NR a R b , OC(0)NR a R b , S(0) q R a , S(0) q NR a R b , NR a R b , NR a C(0)R b , NR a C(0)NR a R b , NR a C
  • R a , R b , R 1; R 2 , R 4 and R are as defined in the first aspect; or an isotopic form, stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.
  • the present invention provides a compound of formula 1 :
  • L is --C(0)NR 5 - or -NR 5 C(0)--; wherein the dotted line (--) indicates the points of
  • R5 is selected from hydrogen or (d-CsJalkyl
  • the present invention provides a compound of formula 1 ,
  • L is -NR 5 S(0)r- or -S(0) r NR 5 --; wherein the dotted line (— ) indicates the points of
  • R 5 is hydrogen or (C r C 8 )-alkyl
  • the present invention provides a compound of formula 1 :
  • L is --CH(halo-(Ci-C 8 )-alkyl)NR 5 --, --NR 5 CH(halo-(CrC 8 )-alkyl)--, -C(halo-(C C 8 )- alkyl) 2 NR 5 - or -NR 5 C(halo-(Ci-C 8 )-alkyl)2-,wherein the dotted line (--) indicates the
  • R5 is hydrogen or (d-CsJ-alkyl; and p, m, n, ⁇ , X 2 , YI , Y 2 , Y3, Y4, Y5, L, Q, R 1 ; R 2 and R 4 are as defined in the first aspect;
  • the present invention provides a compound of formula 1 :
  • R5 is hydrogen or (CrC8)-alkyl
  • the present invention provides a compound of formula 1 :
  • R 4 is hydrogen, (C 3 -Ci 2 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, (C 6 -Ci 4 )-aryl, heteroaryl or heterocyclyl;
  • (C-3-Ci 2 )-cycloalkyl, (C3-C 8 )-cycloalkenyl, (C-6-Ci 4 )-aryl, heteroaryl and heterocyclyl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (C C 8 )-alkyl, (C C 8 )-alkoxy, halo-(C r C 8 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 - Ci 4 )-aryl, 0-(C-6-Ci 4 )-aryl, heterocyclyl and heteroaryl; and
  • p, m, n, Xi, X 2 , Yi , Y 2 , Y3, Y4, Y5, L, Q, Ri and R 2 are as defined in the first aspect; or an isotopic form, stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.
  • Representative compounds of formula 1 encompassed in accordance with the present invention include:
  • the compounds of the present invention include all isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios and their pharmaceutically acceptable salts, solvates, prodrugs, N-oxides, S-oxides and polymorphs.
  • the compound of formula 1 can be prepared by various methods including using methods well known to the person skilled in the art. Examples of processes for the preparation of the compounds of formula 1 are described below and illustrated in the scheme but are not limited thereto. It will be appreciated by persons skilled in the art that within certain of the processes described herein, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent such as bases, solvents, coupling agents to be used in the reaction steps.
  • Scheme 1 depicts a process for the preparation of the compounds of formula 1 , wherein ring A is a phenyl ring; m and n are 0, such that ring B is a 5-membered ring, such that the bicyclic ring formed by fusion of rings A and B is indoline; L is -- C(0)NR 5 -; wherein the dotted line (— ) indicates the points of attachment of L to ring
  • Ri , R 2 , R3, R 4 , Q and p are as defined in the first aspect of the present invention.
  • the compound of formula 3 (as obtained in step 1 ) is reacted with a reducing agent such as sodium cyanoborohydride in a solvent such as DMF at room temperature
  • R 4 is (C r C 8 )-alkyl, halo(C C 8 )alkyl, (C C 8 )-alkoxy, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )- alkynyl, (C-3-Ci 2 )-cycloalkyl, (C-6-Ci 4 )-aryl, ar-(CrC 8 )-alkyl, heteroaryl, or heterocyclyl; which can be unsubstituted or substituted as defined herein above, in presence of 1 ,1 '-Bis(diphenylphosphino)ferrocene palladium-dichloromethane complex and a base such as sodium carbonate in a solvent such as a mixture of dioxane and water
  • the compound of formula 5 (as obtained in step 3) is reacted with a alkaline base such as LiOH, NaOH or KOH in a solvent such as a mixture of methanol and THF at
  • p is an integer from 0 to 3;
  • R 6 to R are as defined in the first aspect
  • Ri and R 2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (Ci-C8)-alkyl, (C2-Cs)-alkenyl, (C2-Cs)-alkynyl, (d-Cs)- alkoxy, (C-3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl, heterocyclyl, halo(CrC8)alkyl, NR a R b , COOR a , CONR a R b , S(0) q (C C 6 )-alkyl, and S(0) q NR a R b ; or R ! and R 2 can form a 3 to 7 membered ring optionally containing 1 -3 heteroatoms selected from the group consisting of O, N and S;
  • R5 is hydrogen, (Ci-C8)-alkyl, (C2-Cs)-alkenyl, (C2-Cs)-alkynyl, (C-3-Ci2)-cycloalkyl, (C 5 -C 8 )-cycloalkenyl, heterocyclyl, (C 6 -Ci 4 )-aryl, heteroaryl, COR a , C0 2 R a , CONR a R b or CONR a NR a R b ;
  • a base such as NaOH or KOH and HATU (2-(7-Aza-1 H- benzotriazole-1 -yl)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate) in a solvent
  • L is --C(0)NR 5 --; where the dotted line (-) indicates the points of
  • the present invention also includes within its scope pharmaceutically acceptable salts or solvates thereof.
  • pharmaceutically acceptable salts refers to organic and inorganic salts of a compound of the invention, depending on the particular group (acidic or basic group) present in the compounds of formula 1 described herein.
  • base addition salts can be obtained by contacting the compounds of formula 1 with a sufficient amount of an appropriate base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, magnesium, ammonium or organic base salt.
  • pharmaceutically acceptable organic base addition salts include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like.
  • acid addition salts can be obtained by contacting the compounds of formula 1 with a sufficient amount of an appropriate acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, mono-hydrogensulfuric or hydriodic acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, glucuronic or galacturonic acids and the like.
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that
  • the compounds of formula 1 can be regenerated from their corresponding salts by contacting the salt with an appropriate base or acid depending on the type of salt and isolating the parent compound in the conventional manner.
  • the compound differs from the various salt forms in certain physical properties.
  • An example of physical properties that may differ is solubility in polar solvents.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • polymorphs of compounds of formula 1 can be prepared by crystallization of the compounds under different conditions.
  • the different conditions are, for example, using different solvents or their mixtures for crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
  • Polymorphs can also be obtained by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs can be determined by IR (infra-red) spectroscopy, solid probe NMR (nuclear magnetic resonance) spectroscopy, differential scanning calorimetry, powder x-ray diffraction or such other techniques.
  • the present invention includes all possible stereoisomers and geometric isomers of formula 1 and includes not only racemic compounds but also the optically active isomers as well.
  • a compound of formula 1 When a compound of formula 1 is desired as a single enantiomer, it may be obtained either by resolution of the final product (the compound of formula 1 ) or by stereospecific synthesis from either isomerically pure starting material or an appropriate intermediate. Resolution of the final product, an intermediate or a starting material can be effected by any suitable method known in the art, for example, Chiral reagents for asymmetric synthesis by Leo A. Paquette; John Wiley & Sons Ltd (2003).
  • the present invention is intended to include all tautomeric forms of the compounds.
  • prodrugs of the compound of formula 1 are those compounds that are converted intracellular ⁇ , more preferably, where the cellular converting location is the site of therapeutic action.
  • preferred produgs are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters such as the pivaloyloxymethyl ester and the like conventionally used in the art (An introduction to Medicinal Chemistry, Graham. L.
  • the present invention furthermore relates to pharmaceutical compositions that contain a therapeutically effective amount of at least one compound of formula 1 or its pharmaceutically acceptable salt in addition to a customary pharmaceutically acceptable carrier or excipient.
  • the present invention also relates to a process for production of the pharmaceutical composition, which includes bringing at least one compound of formula 1 , into a suitable administration form using a pharmaceutically acceptable excipient and, if appropriate, further suitable therapeutically active compounds, additives or auxiliaries.
  • the pharmaceutical preparations according to the invention are prepared in a manner known to one skilled in the art.
  • Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compound(s) of formula 1 , and/or its (their) pharmaceutically acceptable salt(s).
  • compositions can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
  • Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc.
  • Suitable carriers for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents which have been mentioned.
  • the pharmaceutical compositions normally contain from about 1 % to 99 %, for example, from about 5 % to 70 %, or from about 10 % to about 30 % by weight of the compound of formula 1 or its pharmaceutically acceptable salt.
  • the amount of the compound of formula 1 or its pharmaceutically acceptable salt in the pharmaceutical compositions normally can be from about 5 mg to 500 mg.
  • the dose of the compounds of formula 1 of the present invention, which is to be administered, can cover a wide range depending on the type of disease or disorder to be treated. The dose to be administered daily can be selected to suit the desired effect.
  • a suitable dosage can be from about 0.01 mg/kg to 100 mg/kg of the compound of formula 1 or its pharmaceutically acceptable salt depending on the body weight of the recipient (subject) per day, for example, about 0.1 mg/kg/day to 50 mg/kg/day of a compound of formula 1 or a pharmaceutically acceptable salt of the compound. If required, higher or lower daily doses can also be administered.
  • the selected dosage level will depend upon a variety of factors including the activity of a compound of the present invention employed, or the salt thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compounds employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • the pharmaceutical compositions can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain two or more compounds of formula 1 or their pharmaceutically acceptable salts. Furthermore, in addition to at least one compound of formula 1 or its pharmaceutically acceptable salt, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active agents.
  • the present invention also encompasses within its scope; use of a compound of formula 1 or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof; in combination with at least one other therapeutically active agent in the treatment of a disease or disorder mediated by EZH2.
  • the compound of fomrula 1 or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof can be administered with at least one other therapeutically active agent, either simultaneously or sequentially.
  • the therapeutically active agents used in combination with a compound of Formula 1 or its pharmaceutically acceptable salt can be selected from antineoplastic agents or chemotherapeutic compounds such as anti-microtubule agents (diterpenoids (paclitaxel, docetaxel) and vinca alkaloids (vinblastine, vincristine, vinorelbine)); platinum coordination complexes (cisplatin, carboplatin), alkylating agents (nitrogen mustards (oxazaphosphorines, cyclophosphamide, melphalan, chlorambucil)); alkyl sulfonates (busulfan); nitrosoureas (carmustine); triazenes (dacarbazine); topoisomerase I inhibitors (camptothecins (irinotecan, topotecan)); topoisomerase II inhibitors (epipodophyllotoxins (etoposide, teniposide)); antimetabolite neoplastic agents (fluorouracil
  • a pharmaceutical composition comprising a compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof; can be administered to a subject, in particular a human, with any other therapeutically active compounds, in combination with one another or in the form of pharmaceutical preparations.
  • the present invention relates to a method for the treatment of a disease or a disorder mediated by EZH2, comprising administering to a subject in need thereof; a therapeutically effective amount of a compound of formula 1 or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a compound of formula 1 , or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof; for use in the treatment of a disease or a disorder mediated by EZH2 (enhancer of zeste homolog 2).
  • the present invention provides use of a compound of formula 1 or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof; for the treatment of a disease or a disorder mediated by EZH2.
  • the present invention provides use of a compound of formula 1 or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of a disease or a disorder mediated by EZH2.
  • the present invention encompasses within its scope all the diseases or disorders wherein EZH2 is implicated for the treatment of which one or more compounds of formula 1 or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof can be provided.
  • the disease or disorder mediated by EZH2 is cancer, pulmonary arterial hypertension, myelofibrosis, human immunodeficiency virus (HIV) disease, graft versus host diseases (GVHD), Weaver Syndrome, psoriasis vulgaris or liver fibrogenesis.
  • HIV human immunodeficiency virus
  • GVHD graft versus host diseases
  • Weaver Syndrome psoriasis vulgaris or liver fibrogenesis.
  • the disease or disorder mediated by EZH2 is cancer.
  • Cancers also include metastatic or malignant tumors.
  • cancer that can be treated by the compound of formula 1 of the invention or pharmaceutical compositions containing the said compounds is thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, endometrial cancer, head and neck cancer or oral cancer.
  • the cancer is cardiac sarcoma selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, rhabdomyoma, fibroma, lipoma or teratoma.
  • the cancer is lung carcinoma selected from squamous cell carcinoma, undifferentiated small or large cell carcinoma, adenocarcinoma, bronchiolar carcinoma, bronchial adenoma, bronchial sarcoma or bronchial lymphoma.
  • the cancer is gastrointestinal carcinoma selected from stomach carcinoma, stomach lymphoma, pancreatic carcinoma (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma), small bowel carcinoma (adenocarcinoma, lymphoma, Kaposi's sarcoma, hemangioma, lipoma, neurofibroma, fibroma) or large bowel carcinoma (adenocarcinoma, tubular adenoma).
  • pancreatic carcinoma ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma
  • small bowel carcinoma adenocarcinoma, lymphoma, Kaposi's sarcoma, hemangioma, lipoma, neurofibroma, fibroma
  • large bowel carcinoma adenocarcinoma, tubular adenoma
  • the cancer is genitourinary tract carcinoma selected from carcinoma of kidney (adenocarcinoma, nephroblastoma, lymphoma, leukemia), malignant rhabdoid tumor of kidney, carcinoma of bladder and urethra (squamous cell carcinoma, adenocarcinoma), carcinoma of prostate (adenocarcinoma, sarcoma), or carcinoma of testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, lipoma).
  • the cancer is liver carcinoma selected from hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma or hepatocellular adenoma.
  • the cancer is bone sarcoma selected from osteogenic sarcoma (osteosarcoma), fibrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma or giant cell tumors.
  • osteogenic sarcoma osteosarcoma
  • fibrosarcoma fibrosarcoma
  • Ewing's sarcoma malignant lymphoma (reticulum cell sarcoma)
  • multiple myeloma benign chondroma
  • chondroblastoma chondromyxofibroma
  • osteoid osteoma giant cell tumors.
  • the cancer is an oral cancer selected from tongue cancer, squamous cell carcinoma, Kaposi's sarcoma, teratoma, adenocarcinoma derived from a major or minor salivary gland, lymphoma from tonsillar or other lymphoid tissue, or melanoma from the pigment- producing cells of the oral mucosa.
  • the cancer is sarcoma of the nervous system selected from sarcoma of skull (osteoma, granuloma, xanthoma), meninges (meningioma, meningiosarcoma, gliomatosis), sarcoma of brain (astrocytoma, medulloblastoma, glioma, glioblastoma multiform, oligodendroglioma, retinoblastoma, congenital tumors), sarcoma of spinal cord (neurofibroma, meningioma, glioma, sarcoma) or malignant rhabdoid tumor of brain.
  • skull ovaloma, granuloma, xanthoma
  • meninges meningioma, meningiosarcoma, gliomatosis
  • sarcoma of brain astrocytoma, medulloblastoma, glio
  • the cancer is carcinoma of gynaecological organs selected from carcinoma of uterus (endometrial carcinoma), carcinoma of cervix (cervical carcinoma, ovary carcinoma), carcinoma of vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), carcinoma of vagina (clear cell carcinoma, squamous cell carcinoma, embryonal rhabdomyosarcoma) or carcinoma of fallopian tubes.
  • carcinoma of gynaecological organs selected from carcinoma of uterus (endometrial carcinoma), carcinoma of cervix (cervical carcinoma, ovary carcinoma), carcinoma of vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), carcinoma of vagina (clear cell carcinoma, squamous cell carcinoma, embryonal rhabdomyosarcoma) or carcinoma of fallopian tubes
  • the cancer is haematological cancer selected from blood cancer (acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (Hodgkin's disease), non-Hodgkin's lymphoma (malignant lymphoma) or mantle cell lymphoma.
  • blood cancer acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Ho
  • the cancer is a skin cancer selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, angioma or dermatofibroma.
  • HATU 2-(7-Aza-1 H-benzotriazoie-1 -yi)-1 ,1 ,3,3- tetramethyiuroniurrt hexafluorophosphate)
  • the precipitated solid was filtered, washed with water, and dried to yield the desired solid product.
  • the product was further purified by dissolving in DCM and the undissolved solid was filtered out. The filtrate was dried over sodium sulfate and concentrated to obtain the title compound.
  • Methyl 6-bromo-1 -methylindoline-4-carboxylate A solution of the compound of example 22 in acetic acid was treated with sodium cyanoborohydride (1 .8 equiv) according to the procedure described for the preparation of the compound of example 1 1 to obtain the title compound.
  • reaction mass is cooled to room temperature and passed through celite.
  • the filtrate was washed with water, brine and concentrated.
  • the residue obtained was further purified by column (silica gel, (2.5:7.5) ethyl acetate: petroleum ether) to obtain the title compound.
  • Step a A solution of the compound of example 10 in dioxane and water was treated with te/t-butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2- yl)piperazine-1 -carboxylate and 1 ,1 '-bis(diphenylphosphino) ferrocene palladium dichloromethane complex according to the procedure described for the preparation of the compound of example 12 to obtain an intermediate compound.
  • Step b The compound obtained in the above step a was treated with compound of example 7 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 14 to obtain the title compound.
  • Methyl 1 -isopropyl-6-(pyridin-3-yl)-1 H-indole-4-carboxylate A solution of the compound of example 10 in 1 ,4-dioxane was treated with pyridin-3-yl boronic acid (1 .0 equiv) according to the procedure described for the preparation of the compound of example 47 to obtain the title compound.
  • a solution of the compound of example 1 1 in THF was treated with 4- tnfluoromethylbenzene according to the procedure described for the preparation of the compound of example 12, followed by treatment with the compound of example 4 according to the procedure described for the preparation of the compound of example 13 and example 14 respectively to obtain the title compound.
  • the compound of example 89 was prepared according to the procedure described for the preparation of the compound of example 52 by replacing 4-(4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine with 2-(piperidin-1 - yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine.
  • the compound of example 90 was prepared according to the procedure described for the preparation of the compound of example 14 by replacing te/t-butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylate with 2-(piperidin-1 -yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridine.
  • the compound of example 91 was prepared according to the procedure described for the preparation of the compound of example 14 by replacing te/t-butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylate with N,N-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyrimidin-2-amine.

Abstract

La présente invention concerne des composés de formule 1, des formes isotopes, des stéréoisomères et des tautomères de ceux-ci, ou des sels pharmaceutiquement acceptables de ceux-ci, des solvates, des N-oxides, des S-oxides et des polymorphes de ceux-ci, ainsi que des procédés permettant de les préparer. La présente invention concerne des compositions pharmaceutiques contenant ces composés et leur utilisation pour traiter des maladies ou des troubles induits par EZH2 (séquence activatrice de l'homologue 2 zeste), en particulier le cancer. par
PCT/IB2014/060157 2013-03-26 2014-03-26 Composés bicycliques substitués utilisés comme inhibiteurs d'ezh2 WO2014155301A1 (fr)

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