WO2014155301A1 - Substituted bicyclic compounds as inhibitors of ezh2 - Google Patents

Substituted bicyclic compounds as inhibitors of 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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French (fr)
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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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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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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    • C07D213/02—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
    • 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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    • C07D401/14—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 three or more hetero rings

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

The present invention provides compounds of formula 1, isotopic forms, stereoisomers or tautomers thereof, or pharmaceutically acceptable salts, solvates, N-oxides, S-oxides and polymorphs thereof, and processes for their preparation. The invention further relates to pharmaceutical compositions containing said compounds and their use in the treatment of diseases or disorders mediated by EZH2 (enhancer of zeste homolog 2), particularly cancer.

Description

BICYCLIC COMPOUNDS AND USES THEREOF
Field of the Invention
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.
Background of the Invention
Histone methyl transferases (HMTs) 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. 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.
Thus, it is understood from the above discussion that the inhibition of EZH2 activity would effectively decrease cellular proliferation and invasion, and thereby provide therapeutic benefits in the treatment of diseases or disorders mediated by EZH2. The compounds of the present invention function as inhibitors of EZH2 and therefore, provide a therapeutic solution for the treatment of diseases or disorders mediated by EZH2 such as cancers. Summary of the Invention
According to one aspect of the present invention, there are provided 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.
According to another aspect of the present invention, there are provided processes for the preparation of the compounds of formula 1 , or pharmaceutically acceptable salts thereof.
According to a further aspect of the present invention, there are provided pharmaceutical 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.
According to a further aspect of the present invention, there is provided a compound of formula 1 for use as an EZH2 inhibitor. According to yet another aspect of the present invention, there is provided 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.
According to a further aspect of the present invention, there is provided 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.
In a further aspect 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.
According to yet another aspect of the present invention, there is provided use of a compound of formula 1 or a stereoisomer or tautomer; or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of diseases or disorders mediated by EZH2.
One or more further aspects of the present inventions are discussed in detail herein below. These and other aspects and objectives of the present invention will be apparent to those skilled in the art from the following description.
Detailed description of the invention
According to the first aspect, the present invention relates to a compound of formula 1 :
Figure imgf000004_0001
Formula 1
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;
wherein, Xi and X2 are independently selected from CRi and N, such that ring A is a phenyl, pyridyl or pyrimidinyl ring;
m and n are integers independently selected from 0 and 1 ; such that ring B is a 5-7 membered ring;
Yi , Y2, Y3, Y4 and Y5 are independently selected from the group consisting of CR1 R2, NR3, S(0)r, C(O) and C=N-(CN);
L is --C(0)NR5--, --NRsC(O)--, -NR5S(0)r-, --S(0)rNR5--, --CH(halo-(CrC8)- alkyl)NR5--, --NR5CH(halo-(CrC8)-alkyl)--, --C(halo-(Ci-C8)-alkyl)2NR5--, --
NR
Figure imgf000005_0001
5C(halo-(Ci-C8)-alkyl)2--, " " NK wherein the dotted line (-) indicates the points of attachment of L to ring A and the group
Figure imgf000005_0002
respectively;
p is an integer from 0 to 3;
r is an integer from 0 to 2;
Q is:
Figure imgf000005_0003
Ri and R2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (C C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C C8)- alkoxy, (C3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl, heterocyclyl, halo(CrC8)alkyl, NRaRb, COORa, CONRgRb, S(0)q(CrC6)-alkyl and S(0)qNRaRb; or Ri and R2 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,
(CrCs)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C5-C8)- cycloalkenyl, heterocyclyl, (C6-Ci4)-aryl, heteroaryl, CORa, C02Ra, CONRaRb and
CONRaNRaRb;
q is an integer 1 or 2; R4, R6, R7, Rs, R9 and R 0 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH)2, (CrC8)-alkyl, halo(CrC8)alkyl, (CrC8)-alkoxy, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, ar- (CrCs)-alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CONRaRb, CON(R)aNRaRb, OC(0)NRaRb, S(0)qRa, S(0)qNRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, NRaC(0)ORb, NRaS(0)qRb, NRaS(0)qNRaRb, NRaNRaRb, NRaNRaC(0)Rb, NRaNRaC(0)NRaRb, NRaNRaC(0)ORa, Ri2, (CrC8)-alkyl-(Ri2), (C C8)-alkoxy-(Ri2), (C3-Ci2)-cycloalkyl-(Ri2), (C6-Ci4)-aryl-(Ri2), 0-(C6-Ci4)-aryl-(Ri2), heterocyclyl-(Ri2) and heteroaryl-(R12);
wherein R12
Figure imgf000006_0001
Ra and Rb are independently selected from the group consisting of hydrogen, (Cr C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl, (C6-Ci4)-aryl, heterocyclyl and heteroaryl; or
Ra and Rb 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; wherein:
each of the (CrC8)-alkyl, (CrC8)alkoxy and halo(CrC8)alkyl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (CrC8)-alkoxy-(Rc)i-2, (C3- Ci2)-cycloalkyl-(Rc)i-2, (C6-Ci4)-aryl-(Rc)i-2, 0-(C6-Ci4)-aryl-(Rc)i.2, heterocyclyl-(Rc)i- 2, heteroaryl-(Rc)i-2, halo(CrC8)-alkyl, halo(CrC8)-alkoxy, C(0)Ra, OC(0)Ra, COORa, C(0)NRaRb, OC(0)NRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, SRa, S(0)qRa, S(0)qNRaRb, and NRaS(0)qRb; the 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-Ci4)-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, (CrC8)-alkyl-(Rc)1.2, (Ci -C8)-alkoxy-(Rc)i-2, (C3-C12)- cycloalkyl-( Rc)i -2, (C6-Ci4)-aryl-( Rc)i .2, 0-(C6-Ci4)-aryl-( Rc)i.2, heterocyclyl-(Rc)i-2, heteroaryl-( Rc)i-2, halo(C C8)-alkyl, halo(CrC8)-alkoxy, C(0) Ra, OC(0)Ra, COORa, C(0)N RaRb, OC(0)N RaRb, N RaRb, N RaC(0) Rb, N RaC(0)N RaRb, SRa, S(0)qRa, S(0)qN RaRb and N RaS(0)qRb; wherein Rc is hydrogen, halogen, hydroxy, cyano, nitro, (d-CsJ-alkyl, halo(d- Cs)alkyl, (C3-Ci2)-cycloalkyl, (C-6-Ci4)-aryl, ar-(Ci -C8)-alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CON RaRb, CON RaN RaRb, S(0)qRa, S(0)qN RaRb, N RaRb, N RaC(0) Rb, N RaC(0)N RaRb, N RaC(0)ORb, N RaS(0)qRb or N RaS(0)qN RaRb.
Definitions
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein and the appended claims. These definitions should not be interpreted in the literal sense as they are not general definitions and are relevant only for this application.
It will be understood that "substitution," "substituted" or "substituted with" 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.
The terms "a", "an" and "the" refers to "one or more" when used in the subject specification, including the claims. Thus, for example, reference to "a compound" may include a plurality of such compounds, or reference to "a disease" or "a disorder includes a plurality of diseases or disorders.
It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
The term "independently" when used in the context of selection of substituents for a variable, it means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
As used herein, the term "(CrC8)-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. As used herein, (CrC8)-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 C3-C8 for branched chain. Examples of alkyl 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.
Furthermore, unless stated otherwise, the alkyl groups can be unsubstituted or substituted with one or more substituents. A substituted alkyl refers to a (CrC8)- alkyl substituted with 1 -7 groups, preferably 1 -3 groups independently selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (CrC8)-alkoxy-(Rc)i- 2, (C3-Ci2)-cycloalkyl-(Rc)i-2, (C6-Ci4)-aryl-(Rc)1.2, 0-(C6-Ci4)-aryl-(Rc)1.2, heterocyclyl-(Rc)i-2, heteroaryl-(Rc)i-2, halo(CrC8)alkyl, halo(CrC8)alkoxy, C(0)Ra, OC(0)Ra, COORa, C(0)NRaRb, OC(0)NRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, SRa, S(0)qRa, S(0)qNRaRb and NRaS(0)qRb; wherein Rc is hydrogen, halogen, hydroxy, cyano, nitro, (CrC8)-alkyl, halo(CrC8)alkyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)- aryl, ar-(C C8)-alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CONRaRb, CONRaNRaRb, S(0)qRa, S(0)qNRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, NRaC(0)ORb, NRaS(0)qRb or NRaS(0)qNRaRb; q is 1 or 2; Ra and Rb are independently selected from the group consisting of hydrogen, (C C8)-alkyl, (C2-C8)- alkenyl, (C-2-C8)-alkynyl, (C-3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl, (C-6-Ci4)-aryl, heterocyclyl and heteroaryl, or Ra and Rb taken together with the nitrogen to which they are attached form a 5-8 membered saturated or unsaturated ring, optionally containing an additional heteroatom selected from the group consisting of oxygen, nitrogen, and sulphur. Examples of substituted alkyls include, but are not limited to, benzyl, hydroxymethyl, hydroxyethyl, N-morpholinomethyl, N-indolomethyl, piperidinylmethyl and aminoethyl.
The term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom. When the alkyl group is substituted with one or more halogens, it is specifically referred to as "halo(CrC8)alkyl" or haloalkyl. A monohalo(CrC8)alkyl radical, for example, can have a chlorine, bromine, iodine or fluorine atom. Dihalo and polyhalo(CrC8)alkyl radicals can have two or more of the same or different halogen atoms. Examples of halo(CrC8)alkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl or the like groups.
As used herein, the term "alkenyl" or "(C2-C8)-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 sp2 carbon atoms). For example, (C2-Cs)-alkenyl refers to an alkenyl group having 1 to 8 (both inclusive) carbon atoms. Depending on the placement of double bond and substituents if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis or trans. Examples of alkenyl include, but are not limited to, vinyl, allyl and 2-propenyl.
Unless stated otherwise, 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-C8)-alkyl-(Rc)1.2, (Ci-C8)-alkoxy-(Rc)i-2, (C3-Ci2)-cycloalkyl-(Rc)i-2, (C6-Ci4)-aryl-(Rc)i.2, 0-(C6-Ci4)- aryl-(Rc)i-2, heterocyclyl-(Rc)i-2, heteroaryl-(Rc)i-2, halo(Ci-C-8)alkyl, halo(d- C8)alkoxy, C(0)Ra, OC(0)Ra, COORa, C(0)NRaRb, OC(0)NRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, SRa, S(0)qRa, S(0)qNRaRb and NRaS(0)qRb; wherein Ra, Rb, Rc and q are as defined herein above.
As used herein, the term "alkynyl" or "(C2-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). For example, (C2-Cs)alkynyl refers to an alkynyl group having 1 to 8 (both inclusive) carbon atoms. Examples of (C2-C8)-alkynyl include, but are not limited to, ethynyl, 1 -propynyl, 3-propynyl and 3- butynyl. Unless stated otherwise, the "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-(Rc)i-2, (CrC8)- alkoxy-(Rc)i-2, (C3-Ci2)-cycloalkyl-(Rc)1.2, (C6-Ci4)-aryl-(Rc)1.2, 0-(C6-Ci4)-aryl-(Rc)1.2, heterocyclyl-(Rc)i-2, heteroaryl-(Rc)1 -2, halo(C C8)alkyl, halo(CrC8)alkoxy, C(0)Ra, OC(0)Ra, COORa, C(0)NRaRb, OC(0)NRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, SRa, S(0)qRa, S(0)qNRaRb and NRaS(0)qRb; wherein Ra, Rb, Rc and q are as defined herein above.
As used herein, the term "alkoxy" or "(d-C8)-alkoxy" refers to a (C C8)-alkyl having an oxygen radical attached thereto. The terms "(CrC8)-alkoxy" or 0-(d- C-6)alkyl wherever used in this specification have the same meaning. 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 (CrC8)-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 (CrC8)-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.
As used herein, the term "cycloalkyl" or " (C3-Ci2)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. For example, (C-3-Ci2)-cycloalkyl refers to a cycloalkyl group having 3 to 8 (both inclusive) carbon atoms. Representative examples of 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.
The term "(C5-C8)-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. Unless stated otherwise, the "cycloalkyl" and "(C5-C8)-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-C8)-alkyl-(Rc)i-2, (Ci-C8)-alkoxy-(Rc)i-2, (C3-Ci2)-cycloalkyl-(Rc)i-2, (C6-Ci4)- aryl-(Rc)i-2, 0-(C6-Ci4)-aryl-(Rc)i-2, heterocyclyl-(Rc)i-2, heteroaryl-(Rc)i-2, halo(C C8)alkyl, halo(C C8)alkoxy, C(0)Ra, OC(0)Ra, COORa, C(0)NRaRb, OC(0)NRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, SRa, S(0)qRa, S(0)qNRaRb, and NRaS(0)qRb; wherein Ra, Rb, Rc and q are as defined herein above.
The term "aryl" or "(C6-Ci4)-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-Ci4)-aryl residues are phenyl, naphthyl, fluorenyl or anthracenyl. Representative examples of (C6-Ci4)-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-(Rc)i-2, (d-Cs)- alkoxy-(Rc)i-2, (C3-Ci2)-cycloalkyl-(Rc)i-2, (C6-Ci4)-aryl-(Rc)i.2, 0-(C6-Ci4)-aryl-(Rc)i.2, heterocyclyl-(Rc)i-2, heteroaryl-(Rc)i-2, halo(Ci-C-8)alkyl, halo(Ci-C-8)alkoxy, C(0)Ra, OC(0)Ra, COORa, C(0)NRaRb, OC(0)NRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, SRa, S(0)qRa, S(0)qNRaRb and NRaS(0)qRb; wherein Ra, Rb, Rc and q are as defined herein above. In monosubstituted phenyl residues, 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. Examples of disubstituted phenyl groups include, but not limited to, 3, 5-difluorophenyl and 3, 4-dimethoxyphenyl.
As used herein, the term "aryloxy" refers to an "(C6-Ci4)-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-Ci4)-aryl herein above. Examples of aryloxy groups include, but not limited to, phenoxy, 4-chlorophenoxy, and 3, 4-dimethoxyphenoxy.
As used herein, the term "aralkyl" refers to an alkyl group substituted with an (C-6-Ci4)-aryl group, wherein the terms alkyl and aryl are as defined above. Exemplary aralkyl groups include (CH2)p-phenyl, wherein p is an integer from 1 to 6, such as benzyl wherein p is 1 . The aryl of the (C6-Ci4)-aralkyl group can be unsubstituted or substituted as explained in the definition of substituted aryl herein above.
The term "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.
As used herein, the terms "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. The term "heterocyclyl" primarily refers to a 3- to 1 0- membered ring system which can be a monocyclic or a bicyclic ring. Representative examples of 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, quinoxalinyl, quinolinyl and thiophenyl. The oxidized form of the ring nitrogen and sulfur atom of the heterocyclyl to provide N-oxide, S-oxide or S, S-dioxide is also encompassed.
Heterocyclyl having an aromatic ring containing heteroatom/s are herein referred to by the customary term "heteroaryl". Within the context of the present invention and as used herein, the term "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. Examples of 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-(Rc) i -2, (Ci-C8)-alkoxy-(Rc) i-2, (C3-Ci2)-cycloalkyl-(Rc)1.2, (C6-Ci4)-aryl-(Rc)1.2, 0-(C6-Ci4)- aryl-(Rc) 1 -2, heterocyclyl-(Rc)i -2, heteroaryl-(Rc) -2, halo(CrC8)alkyl, halo(C C8)alkoxy, C(0)Ra, OC(0)Ra, COORa, C(0)NRaRb, OC(0)NRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, SRa, S(0)qRa, S(0)qNRaRb and NRaS(0)qRb; wherein Ra, Rb. Rc and q are as defined herein above. The substituents can be present on either the ring carbon or the ring nitrogen atom(s). The substituents can be present at one or more positions provided that a stable molecule results.
As used herein, the term "carbonyl" or "oxo", whether used alone or as part of a substituent group, refers to a group of formula (C=0).
Within the context of this present application and as used herein the term "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. Representative examples of isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as 2H (deuterium or D) and 3H, carbon such as 11C, 13C and 14C, nitrogen such as 13N and 15N, oxygen such as 150, 170 and 180, chlorine such as 36CI, fluorine such as 18F and sulphur such as 35S. 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 effectiveness and hence, may be preferred in certain circumstances.
Representative examples of isotopic forms of the compounds of formula 1 may include, without limitation, deuterated compounds of formula 1 . The term "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. For example, 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.
The term "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. In 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. Analogously, the term "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.
The term "pharmaceutically acceptable solvate" or "solvates" as used herein 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. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Preferably, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably, the solvent used is water and the solvates obtained are referred to as hydrates. Examples for suitable solvates are the mono- or di-hydrates or alcoholates of the compounds according to the invention.
Within the context of the present invention and as used herein, the term "stereoisomer" is a general term used for all isomers of individual compounds that differ only in the orientation of their atoms in space. The term 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).
The term "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.
As used herein, 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. The term "pharmaceutically acceptable salts" as used herein 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.
Within the context of the present invention and as used herein, the term "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.
Within the context of the present invention and as used herein, "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.
Within the context of the present invention and as used herein "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.
Within the context of the present invention and as used herein, "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.
In the context of the present invention, 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. 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.
The term, "therapeutically effective amount" as used herein 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. An example of a disease or disorder mediated be EZH2 is cancer. Particularly, the term "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. In respect of the therapeutic amount of the compound, consideration is also given that 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.
As used herein, 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. The term "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human. The term "mammal" used herein 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. The term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human. The term "subject" may be used interchangeably with the term "patient". In the context of the present invention the phrase "a subject in need thereof" means a subject in need of the treatment for the disease or disorder that is mediated by EZH2.
As used herein, the terms "treatment" "treat" and "therapy" and the like refer 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.
Embodiments
The invention encompasses all the compounds described by the formula 1 without limitation, however, for the purpose of further illustrations, preferred aspects and elements of the invention are discussed herein in the form of the following embodiments.
In an embodiment, 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;
m and n are integers independently selected from 0 and 1 ; such that the ring B is a 5-7 membered ring;
Yi , Y2, Y3, Y4 and Y5 are independently selected from the group consisting of CR1 R2, NR3, S(0)r, C(O) and C=N-(CN);
L is --C(0)NR5— or --NR5C(0)--,
Q is:
Figure imgf000018_0001
R6, R7 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH)2, (CrC8)-alkyl, halo(CrC8)alkyl, (CrC8)- alkoxy, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, ar-(CrC8)- alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CONRaRb, CONRaNRaRb, OC(0)NRaRb, S(0)qRa, S(0)qNRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, NRaC(0)ORb, NRaS(0)qRb, NRaS(0)qN RaRb, NRaNRaRb, NRaNRaC(0)Rb, NRaNRaC(0)NRaRb and NRaNRaC(0)ORa; and
p, q, r, Ra, 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.
In an embodiment, the present invention relates to a compound of formula 1 : wherein,
Xi and X2 are CRi , such that ring A is a phenyl ring;
m and n are integers independently selected from 0 and 1 ; such that the ring B is a 5-7 membered ring;
Yi , Y2, Y3, Y4 and Y5 are independently selected from the group consisting of CRi R2, NR3, S(0)r, C(O) and C=N-(CN);
L is --C(0)NR5— or -NR5C(0)--;
Q is:
Figure imgf000018_0002
R6, R7 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH)2, (CrC8)-alkyl, halo(CrC8)alkyl, (CrC8)- alkoxy, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, ar-(CrC8)- alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CONRaRb, CONRaNRaRb, OC(0)NRaRb, S(0)qRa, S(0)qNRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, NRaC(0)ORb, NRaS(0)qRb, NRaS(0)qN RaRb, NRaNRaRb, NRaNRaC(0)Rb, NRaNRaC(0)NRaRb and NRaNRaC(0)ORa; and
p, q, r, Ra, 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.
In an embodiment, the present invention relates to a compound of formula 1 : wherein,
Xi and X2 are CRi , such that ring A is a phenyl ring;
m and n are 0, such that ring B is a 5-membered ring;
Y2, Y3 and Y4 are independently selected from the group consisting of CR1 R2, C=N(CN), C=0 and S(0)r; and
p, r, L, Q, R1 ; R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that ring A is a phenyl ring;
m and n are 0, such that ring B is a 5-membered ring;
Y2, Y3 and Y4 are CRi R2; and
p, L, Q, Ri , R2 and R4 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;
In another embodiment, the present invention provides a compound of formula 1 : wherein,
Xi and X2 are CRi , such that ring A is a phenyl ring;
m and n are 0, such that ring B is a 5-membered ring;
Y2 is C=0; Y3 and Y4 are CRi R2; or
Y4 is C=0; Y2 and Y3 are CRi R2; and
p, L, Q, R1 ; R2 and R4 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. In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that ring A is a phenyl ring;
m and n are 0, such that ring B is a 5-membered ring;
Y2 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r, and Y4 is C=N(CN) or CRi R2; or Y4 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r, and Y2 is C=N(CN) or CRi R2; and p, r, L, Q, Ri , R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that ring A is a phenyl ring;
m and n are 0, such that ring B is a 5-membered ring;
Y2 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r, and Y4 is C=N(CN) or CRi R2; or
Y4 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r, and Y2 is C=N(CN) or CRi R2;
Ri and R2 are independently selected from hydrogen and (Ci-C8)-alkyl; or
Ri and R2 may form a 3 to 7 membered ring optionally containing 1 -3 heteroatoms selected from the group consisting of O, N and S;
R3 is selected from hydrogen and (Ci-C8)-alkyl;
p, r, L, Q and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m and n are 0, such that the ring B is a 5-membered ring and the bicyclic heterocycle formed by fusion of rings A and B is indoline;
Y2 is NR3; Y3 and Y4 are CRi R2; or
Y4 is NR3; Y2 and Y3 are CRi R2; and
p, Q, L, Ri , R2, R3 and R4 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.
In another embodiment, the present invention relates to a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m and n are 0, such that the ring B is a 5-membered ring;
Y3 is NR3; Y2 and Y4 are independently selected from the group consisting of CR1 R2,
C=N(CN), C=0 and S(0)r; and
p, r, L, Q, R1 ; R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m and n are 0, such that the ring B is a 5-membered ring and the bicyclic heterocycle formed by fusion of rings A and B is isoindoline;
Y3 is NR3; Y2 and Y4 are CRi R2; and
p, Q, L, R1 ; R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m and n are 0, such that the ring B is a 5-membered ring;
Y2 and Y3 are NR3, Y4 is CRi R2, C=N(CN), C=0 or S(0)r; or
Y2 and Y4 are NR3, Y3 is CRi R2, C=N(CN), C=0 or S(0)r; or
Y3 and Y4 are NR3, Y2 is CRi R2, C=N(CN), C=0 or S(0)r; and
p, r, L, Q, R1 ; R2, R3 and R4 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. In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi , Y2, Y3 and Y4 are independently selected from the group consisting of CR1 R2, S(0)r, C(O) and C=N(CN); and
p, r, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi , Y2, Y3 and Y4 are CRi R2; and
p, r, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi is NR3; Y2 is CRi R2, C=N(CN), C=0 or S(0)r; Y3 and Y4 are independently selected from CRi R2 and C=N(CN); or
Y2 is NR3; Y and Y3 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; Y4 is CRi R2 or C=N(CN); or
Y3 is NR3; Y2 and Y4 are independently selected from CRi R2, C=N(CN), C=0 and S(0)r; Yi is CRi R2 or C=N(CN); or
Y4 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r; Yi and Y2 are independently selected from CRi R2 and C=N(CN); and
p, r, L, Q, Ri , R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi and Y2 are NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r; and Y4 is CRi R2 or
C=N(CN); or
Y and Y3 are NR3; Y2 and Y4 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Yi and Y4 are NR3; Y2 and Y3 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y2 and Y3 are NR3; Y^ and Y4 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y2 and Y4 are NR3; Yi and Y3 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y3 and Y4 are NR3; Yi is CRi R2 or C=N(CN); Y2 is CRi R2, C=N(CN), C=0 or S(0)r; and
p, r, L, Q, R1 ; R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m is 0, n is 1 , such that the ring B is a 6-membered ring;
Yi , Y2 and Y3 are NR3, Y4 is CRi R2, C=N(CN), C=0 or S(0)r; or
Yi , Y2 and Y4 are NR3, Y3 is CRi R2, C=N(CN), C=0 or S(0)r; or
Yi , Y3 and Y4 are NR3, Y2 is CRi R2, C=N(CN), C=0 or S(0)r; or
Y2, Y3 and Y4 are NR3, , is CRi R2, C=N(CN), C=0 or S(0)r; and
p, r, L, Q, R1 ; R2, R3 and R4 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. In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m is 1 and n is 1 , such that the ring B is a 7-membered ring;
Yi , Y2, Y3, Y4 and Y5 are independently selected from the group consisting of CR1 R2, S(0)r, C(O) and C=N(CN); and
p, r, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m is 1 and n is 1 , such that the ring B is a 7-membered ring;
Yi , Y2, Y3 and Y4 are CRi R2; and
p, r, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi is N and X2 is CRi or ΧΊ is CRi and X2 is N, such that the ring A is a pyridyl ring; L is --C(0)NR5— or --NR5C(0)--,
Q is:
Figure imgf000024_0001
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, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, ar-(CrC8)- alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CONRaRb, CONRaNRaRb, OC(0)NRaRb, S(0)qRa, S(0)qNRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, NRaC(0)ORb, NRaS(0)qRb, NRaS(0)qN RaRb, NRaNRaRb, NRaNRaC(0)Rb, NRaNRaC(0)NRaRb and NRaNRaC(0)ORa; and
p, q, m, n, Y1 ; Y2, Y3, Y4, Y5, Ra, Rb, Ri , R2, R4, R5 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
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;
Y2, Y3 and Y4 are independently selected from the group consisting of CR1 R2, C=N(CN) and C=0; and
p, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
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 is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi , Y2, Y3 and Y4 are independently selected from the group consisting of CRi R2, C=N(CN) and C=0; and
p, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi is N and X2 is CRi ; or ΧΊ is CRi and X2 is N, such that the ring A is a pyridyl ring; m is 1 and n is 1 , such that the ring B is a 7-membered ring; Yi , Y2, Υ3. Υ4 and Υ5 are independently selected from the group consisting of CRi R2, C=N(CN) and C=0; and
p, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi is N and X2 is CRi ; or ΧΊ 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;
Y2 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r; Y4 is CRi R2 or C=N(CN); or
Y3 is NR3; Y2 and Y4 are independently selected from the group consisting of CRi R2,
C=N(CN), C=0 and S(0)r; or
Y4 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r; Y2 is CRi R2 or C=N(CN); and p, r, L, Q, Ri , R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
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;
Y2 and Y3 are NR3, Y4 is CRi R2, C=N(CN), C=0 or S(0)r; or
Y2 and Y4 are NR3, Y3 is CRi R2, C=N(CN), C=0 or S(0)r; or
Y3 and Y4 are NR3, Y2 is CRi R2, C=N(CN), C=0 or S(0)r; and
L, p, r, Q, Ri , R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi is N and X2 is CRi ; or ΧΊ is CRi and X2 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; , is NR3; Y2 is CRi R2, C=N(CN), C=0 or S(0)r; Y3 and Y4 are independently selected from CRi R2 and C=N(CN); or
Y2 is NR3; Yi and Y3 are independently selected from the group consisting of CR1 R2, C=N(CN), C=0 and S(0)r; Y4 is CR1 R2 and C=N(CN); or
Y3 is NR3; Y2 and Y4 are independently selected from the group consisting of CR1 R2, C=N(CN), C=0 and S(0)r; Yi is CRi R2 or C=N(CN); or
Y4 is NR3; Yi and Y2 are independently selected from CRi R2 and C=N(CN); Y3 is CRi R2, C=N(CN), C=0 or S(0)r; and
p, r, L, Q, R1 ; R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
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 is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi and Y2 are NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r; Y4 is CRi R2 or C=N(CN); or
Yi and Y3 are NR3; Y2 and Y4 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Yi and Y4 are NR3; Y2 and Y3 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y2 and Y3 are NR3; Y^ and Y4 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y2 and Y4 are NR3; Yi and Y3 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y3 and Y4 are NR3; , is CRi R2 or C=N(CN); Y2 is CRi R2, C=N(CN), C=0 or S(0)r; and
p, r, L, Q, Ri , R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein, Xi is N and X2 is CRi ; or X- is CRi and X2 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;
Yi , Y2 and Y3 are NR3, Y4 is CRi R2, C=N(CN), C=0 or S(0)r; or
Yi , Y2 and Y4 are NR3, Y3 is CRi R2, C=N(CN), C=0 or S(0)r; or
Y1 ; Y3 and Y4 are NR3, Y2 is CRi R2, C=N(CN), C=0 or S(0)r; or
Y2, Y3 and Y4 are NR3, Y, is CRi R2, C=N(CN), C=0 or S(0)r; and
p, r, L, Q, Ri , R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
L is --C(0)NR5— or --NR5C(0)--,
Q is:
Figure imgf000028_0001
R6, R7 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH)2, (CrC8)-alkyl, halo(CrC8)alkyl, (CrC8)- alkoxy, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, ar-(CrC8)- alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CONRaRb, CONRaNRaRb, OC(0)NRaRb, S(0)qRa, S(0)qNRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, NRaC(0)ORb, NRaS(0)qRb, NRaS(0)qN RaRb, NRaNRaRb, NRaNRaC(0)Rb, NRaNRaC(0)NRaRb and NRaNRaC(0)ORa; and
p, q, m, n, Yi , Y2, Y3, Y4, Y5, Ra, Rb, Ri , R2, 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.
In another embodiment, the present invention provides a compound of formula 1 : wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m is 0 and n is 0, such that the ring B is a 5-membered ring;
Y2, Y3 and Y4 are independently selected from the group consisting of CR1 R2, C=N(CN) and C=0; and
p, Q, L, R1 ; R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi , Y2, Y3 and Y4 are independently selected from the group consisting of CR1 R2, C=N(CN) and C=0; and
p, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m is 1 , n is 1 , such that the ring B is a 7-membered ring;
Yi , Y2, Y3, Y4 and Y5 are independently selected from the group consisting of CRi R2, C=N(CN) and C=0; and
p, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m and n are 0, such that the ring B is a 5-membered ring;
Y2 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r; Y4 is CRi R2 or C=N(CN); or Y3 is NR3; Y2 and Y4 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y4 is NR3; Y3 is CR1 R2, C=N(CN), C=0 or S(0)r; Y2 is CR1 R2 or C=N(CN); and p, r, L, Q, Ri , R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
ΧΊ and X2 are N , such that the ring A is a pyrimidinyl ring;
m and n are 0, such that the ring B is a 5-membered ring;
Y2 and Y3 are NR3, Y4 is CRi R2, C=N(CN), C=0 or S(0)r; or
Y2 and Y4 are NR3, Y3 is CRi R2, C=N(CN), C=0 or S(0)r; or
Y3 and Y4 are NR3, Y2 is CRi R2, C=N(CN), C=0 or S(0)r; and
L, p, r, Q, Ri , R2, R3 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi is NR3; Y2 is CRi R2, C=N(CN), C=0 or S(0)r; Y3 and Y4 are independently selected from CRi R2 and C=N(CN); or
Y2 is NR3; Yi and Y3 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; Y4 is CRi R2 and C=N(CN); or
Y3 is NR3; Y2 and Y4 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; Yi is CRi R2 or C=N(CN); or
Y4 is NR3; Yi and Y2 are independently selected from CRi R2 and C=N(CN); Y3 is CRi R2, C=N(CN), C=0 or S(0)r; and
L, p, r, Q, R1 ; R2, R3 and R4 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.
In an embodiment, the present invention provides a compound of formula 1 : wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi and Y2 are NR3; Y3 is CRi R2, C=N(CN), C=0 and S(0)r; Y4 is CRi R2 or C=N(CN); or
Yi and Y3 are NR3; Y2 and Y4 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Yi and Y4 are NR3; Y2 and Y3 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y2 and Y3 are NR3; Y^ and Y4 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y2 and Y4 are NR3; Yi and Y3 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y3 and Y4 are NR3; Y, is CRi R2 or C=N(CN); Y2 is selected from CRi R2, C=N(CN), C=0 or S(0)r; and
L, p, r, Q, Ri , R2, R3 and R4 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.
In an embodiment, the present invention provides a compound of formula 1 : wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi , Y2 and Y3 are NR3, Y4 is CRi R2, C=N(CN), C=0 or S(0)r; or
Yi , Y2 and Y4 are NR3, Y3 is CRi R2, C=N(CN), C=0 or S(0)r; or
Yi , Y3 and Y4 are NR3, Y2 is CRi R2, C=N(CN), C=0 or S(0)r; or
Y2, Y3 and Y4 are NR3, Yi is CRi R2, C=N(CN), C=0 or S(0)r; and
L, p, r, Q, R1 ; R2, R3 and R4 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.
In an embodiment, the present invention provides a compound of formula 1 : wherein,
Q is:
Figure imgf000032_0001
R6, R7 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH)2, (CrC8)-alkyl, halo(CrC8)alkyl, (CrC8)- alkoxy, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, ar-(CrC8)- alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CONRaRb, CONRaNRaRb, OC(0)NRaRb, S(0)qRa, S(0)qNRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, NRaC(0)ORb, NRaS(0)qRb, NRaS(0)qNRaRb, NRaNRaRb, NRaNRaC(0)Rb, NRaNRaC(0)NRaRband NRaNRaC(0)ORa; and
p, q, m, n, Xi, X2, Yi, Y2, Y3, Y4, Y5, L, Ra, Rb, Ri, R2, R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
Q is selected from:
Figure imgf000032_0002
Rg and R10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH)2, (CrC8)-alkyl, halo(CrC8)alkyl, (C2-C8)- alkenyl, (C2-C8)-alkynyl, (C-3-Ci2)-cycloalkyl, (C-6-Ci4)-aryl, ar-(CrC8)-alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CONRaRb, CONRaNRaRb, OC(0)NRaRb, S(0)qRa, S(0)qNRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, NRaC(0)ORb, NRaS(0)qRb, NRaS(0)qNRaRb, NRaNRaRb, NRaNRaC(0)Rb, NRaNRaC(0)NRaRb and NRaNRaC(0)ORa; and
p, q, m, n, X2, Y1; Y2, Y3, Y4, Y5, L, Ra, Rb, R1; R2, R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
L is --C(0)NR5- or -NR5C(0)--; wherein the dotted line (--) indicates the points of
attachment of L to ring A and the group
Figure imgf000033_0001
respectively;
R5 is selected from hydrogen or (d-CsJalkyl; and
p, m, n, Xi, X2, Yi , Y2, Y3, Y4, Y5, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 ,
wherein,
L is -NR5S(0)r- or -S(0)rNR5--; wherein the dotted line (— ) indicates the points of
attachment of L to ring A and the group
Figure imgf000033_0002
respectively;
R5 is hydrogen or (CrC8)-alkyl; and
p, r, m, n, Xi, X2, Yi , Y2, Y3, Y4, Y5, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
L is --CH(halo-(Ci-C8)-alkyl)NR5--, --NR5CH(halo-(CrC8)-alkyl)--, -C(halo-(C C8)- alkyl)2NR5- or -NR5C(halo-(Ci-C8)-alkyl)2-,wherein the dotted line (--) indicates the
points of attachment of L to ring A and the group
Figure imgf000033_0003
respectively;
R5 is hydrogen or (d-CsJ-alkyl; and p, m, n, ΧΊ , X2, YI , Y2, Y3, Y4, Y5, L, Q, R1 ; R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
L is
Figure imgf000034_0001
wherein the dotted line
indicates the points of attachment of L to ring A and the group
Figure imgf000034_0002
respectively;
R5 is hydrogen or (CrC8)-alkyl; and
p, m, n, Xi, X2, Yi , Y2, Y3, Y4, Y5, L, Q, Ri , R2 and R4 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.
In another embodiment, the present invention provides a compound of formula 1 :
wherein,
R4 is hydrogen, (C3-Ci2)-cycloalkyl, (C3-C8)-cycloalkenyl, (C6-Ci4)-aryl, heteroaryl or heterocyclyl;
wherein (C-3-Ci2)-cycloalkyl, (C3-C8)-cycloalkenyl, (C-6-Ci4)-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 C8)-alkyl, (C C8)-alkoxy, halo-(CrC8)-alkyl, (C3-Ci2)-cycloalkyl, (C6- Ci4)-aryl, 0-(C-6-Ci4)-aryl, heterocyclyl and heteroaryl; and
p, m, n, Xi, X2, Yi , Y2, Y3, Y4, Y5, L, Q, Ri and R2 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:
tert-Butyl 4-(5-(1 -isopropyl-4-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methylcarbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide hydrochloride;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
tert-Butyl 4-(5-(4-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methylcarbamoyl)-1 - isopropylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6-(piperazin-1 - yl)pyridin-3-yl)indoline-4-carboxamide hydrochloride;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6-(piperazin-1 - yl)pyridin-3-yl)indoline-4-carboxamide;
tert-Butyl 4-(5-(4-(((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)carbamoyl) -1 -isopropylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
N-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6- (piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -Methyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- morpholinophenyl)indoline-4-carboxamide;
N-((4-lsopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -methyl-6-(4- morpholinophenyl)indoline-4-carboxamide;
N-((4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -methyl-6-(4- morpholinophenyl)indoline-4-carboxamide;
tert-Butyl 4-(5-(4-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methylcarbamoyl)-1 - methylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
tert-Butyl 4-(5-(4-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methylcarbamoyl)-
1 -methylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
tert-Butyl 4-(5-(4-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl carbamoyl)-1 -methylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -methyl-6-(6-(piperazin-1 -yl) pyridin-3-yl)indoline-4-carboxamide;
N-((4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -methyl-6-(6-(piperazin- 1 -yl)pyridin-3-yl)indoline-4-carboxamide; tert-Butyl 4-(5-(1 -ethyl-4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -Ethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)-6-(6-(piperazin-
1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -Ethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
te/t-Butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)carbamoyl)-1 - ethylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -ethyl-6-(6-(piperazin-1 - yl)pyridin-3-yl)indoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- morpholinophenyl)indoline-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(4- morpholinophenyl)indoline-4-carboxamide;
tert-Butyl 4-(5-(1 -sec-butyl-4-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methylcarbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
tert-Butyl 4-(5-(1 -isopropyl-4-(((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -lsopropyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-
(piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
tert-Butyl 4-(5-(1 -methyl-4-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methylcarbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -lsopropyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
N-((4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)indoline-4- carboxamide;
tert-Butyl 4-(5-(1 -isopropyl-4-(((1 ,4,6-trimethyl-2-oxo-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -lsopropyl-6-(6-(piperazin-1 -yl)pyridin-3-yl)-N-((1 ,4,6-trimethyl-2-oxo-1 ,2- dihydropyridin-3-yl)methyl)indoline-4-carboxamide; 1 -lsopropyl-6-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)-N-((1 ,4,6-trimethyl-2-oxo-1 ,2- dihydropyridin-3-yl)methyl)indoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(pyridin-3- yl)indoline-4-carboxamide;
tert-Butyl 4-(5-(1 -ethyl-4-(((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -Ethyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(2-(dimethylamino) pyrimidin-5-yl)-1 -isopropylindoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- (trifluoromethyl)phenyl)indoline-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6-(piperidin-1 - yl)pyridin-3-yl)indoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperidin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
6-(2-(Dimethylamino)pyrimidin-5-yl)-1 -isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)indoline-4-carboxamide;
1 -(Cyclobutylmethyl)-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6- (6-(trifluoromethyl)pyridin-3-yl)indoline-4-carboxamide;
1 -(Cyclobutylmethyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (trifluoromethyl)pyridin-3-yl)indoline-4-carboxamide;
1 -(Cyclobutylmethyl)-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-
(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
te/t-Butyl 4-(5-(1 -(cyclobutylmethyl)-4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-
3-yl)methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
ie/ -Butyl 4-(5-(1 -isobutyl-4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -lsobutyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)-6-(6-
(piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(3- (trifluoromethyl)phenyl)indoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6- phenylindoline-4-carboxamide; 6-(3,5-Difluorophenyl)-1 -isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3- yl)methyl)indoline-4-carboxamide;
tert-Butyl 4-(5-(1 -isopropyl-3,3-dimethyl-4-(((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)carbamoyl)-2-oxoindolin-6-yl)pyridin-2-yl)piperazine-1 - carboxylate;
1 - lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)
2- oxo-6-(6-(piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
te/t-Butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)carbamoyl)-1 - isopropyl-3,3-dimethyl-2-oxoindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-3,3-dimethyl-2- oxo-6-(6-(piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) 6-(4-morpholinophenyl)-2-oxoindoline-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-3,3-dimethyl-6-(4 morpholinophenyl)-2-oxoindoline-4-carboxamide;
1 -lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) 6-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)-2-oxoindoline-4-carboxamide;
tert-Butyl 4-(5-(1 '-isopropyl-4'-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)-2'-oxospiro[cyclopentane-1 ,3'-indolin]-6'-yl)pyridin-2-yl) piperazine-1 -carboxylate;
1 '-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2'-oxo-6'-(6- (piperazin-1 -yl)pyridin-3-yl)spiro[cyclopentane-1 ,3'-indoline]-4'-carboxamide;
1 '-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6'-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'- carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 '-isopropyl-6'-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'- carboxamide;
1 '-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6'-(4- morpholinophenyl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 '-isopropyl-6'-(4- morpholinophenyl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'-carboxamide;
1 -lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) 6-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide; N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropy
(4-methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
6-Bromo-1 -isopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3- yl)methyl)indoline-4-carboxamide;
6-Bromo-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-3,3- dimethylindoline-4-carboxamide;
tert-Butyl 4-(5-(4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl)-5,6,7,8-tetrahydroquinazolin-2-yl)pyridin-2-yl)piperazine-1 -carboxylate; N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(6-(piperazin-1 - yl)pyridin-3-yl)-5,6,7,8-tetrahydroquinazoline-4-carboxamide;
N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(methylsulfonyl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide;
N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(4-methylpiperazin-1 - yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide;
tert-Butyl 4-(5-(4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl)-6J-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyridin-2-yl)piperazine carboxylate;
N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(6-(piperazin-1 -yl) pyridin-3-yl)-6J-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -oxo-2,3-dihydro-1 H-indene 4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -hydroxy-2,3-dihydro-1 H- indene-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -morpholino-2,3-dihydro-1 H indene-4-carboxamide;
6-Bromo-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -oxo-2,3-dihydro- 1 H-indene-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4-methylpiperazin-1 -yl) pyridin-3-yl)-1 -oxo-2,3-dihydro-1 H-indene-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-morpholinopyridin-3-yl)- 1 -oxo-2, 3-dihydro-1 H-indene-4-carboxamide;
tert-Butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)carbamoyl)-1 - propylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate; tert-Butyl 4-(5-(4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl)-1 -propylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate; and
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(piperazin-1 -yl)pyridin-3- yl)-1 -propylindoline-4-carboxamide;
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 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.
According to another aspect of the present invention, there are provided processes for the preparation of the compound of formula 1 or a pharmaceutically acceptable salt thereof.
Thus, 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.
The reagents, reactants and intermediates used in the following processes are either commercially available or can be prepared according to standard procedures known in the art, for instance those reported in the literature references. In the following schemes and the description of the processes for the synthesis of the compounds of formula 1 , the starting compounds and the intermediates used for the synthesis of compounds of the present invention, are designated as compounds 2-8 for ease of reference. Throughout the process description, the corresponding substituent groups in the various formulae representing starting compounds and intermediates have the same meanings as that for the compound(s) of formula 1 unless stated otherwise. The processes used in the scheme of the present invention, are referred to by using general symbols namely a, b, c, d, e and f.
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)NR5-; wherein the dotted line (— ) indicates the points of attachment of L to ring
A and the group
Figure imgf000041_0001
respectively; Ri , R2, R3, R4, Q and p are as defined in the first aspect of the present invention.
Figure imgf000041_0002
Figure imgf000041_0003
Step 1 (Reaction a)
Preparation of compound of formula 3: The compound of formula 2:
Figure imgf000042_0001
is reacted with R3-X; where X is a halogen selected from Br or CI; R3 is (CrC8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl, heterocyclyl, (C6-Ci4)-aryl or heteroaryl; which can be unsubstituted or substituted as defined herein above; in presence of a base such as sodium hydride in a solvent such as DMF at a temperature range of 55-75 C for 4-6 h to obtain the compound of formula 3:
Figure imgf000042_0002
Step 2 (Reaction b)
Preparation of compound of formula 4:
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
(20-35 C) for 12-18 h, to obtain the compound of formula 4:
Figure imgf000042_0003
Step 3 (Reaction c)
Preparation of compound of formula 5:
The compound of formula 4 (as obtained in step 2) is coupled with the reagent A:
Figure imgf000042_0004
Reagent A
wherein R4 is (CrC8)-alkyl, halo(C C8)alkyl, (C C8)-alkoxy, (C2-C8)-alkenyl, (C2-C8)- alkynyl, (C-3-Ci2)-cycloalkyl, (C-6-Ci4)-aryl, ar-(CrC8)-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
0
at a temperature of 50-70 C for 0.5-3 h, to obtain the compound of formula 5:
Figure imgf000043_0001
Step 4 (Reaction d)
Preparation of compound of formula 6:
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
0
room temperature (20-35 C ) for 12-18 h, to obtain compound of formula 6:
Figure imgf000043_0002
Step 5 (Reaction e)
Preparation of compound of formula 7:
The compound of formula 6 (as obtained in step 4) is reacted with the reagent B:
Figure imgf000043_0003
. HCI
Reagent B
wherein p is an integer from 0 to 3;
Figure imgf000043_0004
wherein R6 to R are as defined in the first aspect;
Ri and R2 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, NRaRb, COORa, CONRaRb, S(0)q(C C6)-alkyl, and S(0)qNRaRb; or R! and R2 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, (C5-C8)-cycloalkenyl, heterocyclyl, (C6-Ci4)-aryl, heteroaryl, CORa, C02Ra, CONRaRb or CONRaNRaRb;
in the presence of 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
0
such as DMF at a temperature range of 55-75 C for 4-6 h to obtain the compound of formula 7 (a representative compound of formula 1 );
Figure imgf000044_0001
wherein L is --C(0)NR5--; where the dotted line (-) indicates the points of
attachment of L to indoline and the g
Figure imgf000044_0002
respectively; Ri, R2, R3, R4, p and Q are as defined herein above. Alternatively, the compound of formula 3 (as obtained in Step 1 above) may be reacted according to the procedures of Steps 3-5 followed by the procedure of Step 2 to obtain the compound of formula 7 (a representative compound of formula 1 ).
Step 6
Preparation of pharmaceutically acceptable salt of compound of formula : The compound of formula 1 (as obtained in step 5) can be converted into its pharmaceutically acceptable salt.
The present invention also includes within its scope pharmaceutically acceptable salts or solvates thereof.
The term "pharmaceutically acceptable salts" as used herein 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. When compounds of the present invention contain relatively acidic groups, 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. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, magnesium, ammonium or organic base salt. Examples of pharmaceutically acceptable organic base addition salts include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like.
When compounds of the present invention contain relatively basic groups, 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. Examples of 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 allow the compounds to be converted into either base or acid addition salts.
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.
Various 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.
Those skilled in the art will recognize that stereocentres exist in compounds of formula 1 . Accordingly, 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. 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).
Additionally, in situations wherein tautomers of the compounds of formula 1 are possible, the present invention is intended to include all tautomeric forms of the compounds.
The present invention also encompasses within its scope prodrugs of the compound of formula 1 . Preferably prodrugs are those compounds that are converted intracellular^, more preferably, where the cellular converting location is the site of therapeutic action. For instance, 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. Patrick, Second Edition, Oxford University Press, pg 239-248; Prodrugs: Challenges and Rewards, Part 1 and Part 2, AAPS Press, Edited by Valentino J. Stella, Renald T. Borchardt, Michael J. Hagemon, Reza Oliyai, Hans Maag, Jefferson W. Tilley).
In another further aspect, 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).
The 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.
For the production of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for example, lactose, corn starch or derivatives thereof, gum arabica, magnesia or glucose, etc. 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.
In addition to the compound of the formula 1 or its pharmaceutically acceptable salt and carrier substances, 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, methotrexate, cytarabine, mecaptopurine, thioguanine, gemcitabine); hormones and hormonal analogues (retinoids, histone deacetylase inhibitors); DNA methyltransferase inhibitors (azacitidine, decitabine); non-receptor tyrosine kinase angiogenesis inhibitors (endostatin, angiostatin); antibiotics (daunorubicin, doxorubicin, bleomycin); inhibitors of growth factor receptors (VEGFR inhibitors (pazopanib, ZD6474 (vandetanib, AstraZeneca), AZD2171 (cediranib, Astrazeneca), vatalanib, sunitinib and sorafenib), trastuzumab, cetuximab, bevacizumab, lapatinib, erlotinib, imatinib mesylate) or cell cycle signaling inhibitors (CDK inhibitors (ABT-751 (Eisai), veliparib)).
For instance, 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.
In one aspect, 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.
In another aspect, 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). In another aspect, 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.
In one aspect, 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.
In an embodiment, 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.
In an embodiment, 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.
In an embodiment of the present invention, the disease or disorder mediated by EZH2 is cancer. Cancers also include metastatic or malignant tumors.
In an embodiment, 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.
According to an embodiment of the present invention, the cancer is cardiac sarcoma selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, rhabdomyoma, fibroma, lipoma or teratoma.
According to another embodiment of the present invention, 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.
According to yet another embodiment of the present invention, 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).
According to another embodiment of the present invention, 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).
According to yet another embodiment of the present invention, the cancer is liver carcinoma selected from hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma or hepatocellular adenoma.
According to yet another embodiment of the present invention, 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.
According to another embodiment of the present invention, 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.
According to another embodiment of the present invention, 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.
According to yet another further embodiment of the present invention, 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.
According to another embodiment of the present invention, 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.
According to another embodiment of the present invention, the cancer is a skin cancer selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, angioma or dermatofibroma.
It is understood that modifications that do not substantially affect the activity of the various aspects of this invention are included. Accordingly, the following examples are intended to illustrate but not to limit the present invention.
The following abbreviations or terms are used herein:
BSA Bovine serum albumin
CDCI3 Deuteriated chloroform
CHCI3 Chloroform
CH2CI2 Dichloromethane
DIPEA N,N-Diisopropylethylamine
DMF N, N-dimethylformamide
DMSO Dimethylsulfoxide
Dppf : 1 ,1 '-Ferrocenediyl-bis(diphenylphosphine)
DTT : Dithiothreitol
EtOH : Ethano!
EiOAc : Ethyl acetate
Equiv : Equivalents
g : Gram
h Hour
HATU : 2-(7-Aza-1 H-benzotriazoie-1 -yi)-1 ,1 ,3,3- tetramethyiuroniurrt hexafluorophosphate)
HBr Hydrogen bromide HCI Hydrochloric acid
IPA Isopropyl alcohol
KotBu : Potassium tert-butoxide
mg Milligram
min : Minute(s)
ml_ Millilitre
μΙ_ Microlitre
μΜ Micromolar
M Molar
mM Millimolar
mmol Millimole
mol Mole
MeOH Methanol
N Normal
Na2C03 : Sodium carbonate
Na2S04 : Sodium sulphate
NaHC03 : Sodium bicarbonate
NaOH Sodium hydroxide
NaCI Sodium chloride
NBS N-Bromosuccinimide
°C : Degree Centigrade
POCI3 Phosphoryl chloride
PdCI2 Palladium(ll) chloride
psi Pounds per square inch
RT : Room temperature (20-35 °C)
THF Tetrahydrofuran
Tris-HCI 2-Amino-2-hydroxymethyl-1 ,3-propanediol hydrochloride w/w : Weight/weight
Examples
Example :
6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridine-3-carbonitrile
To a stirred solution of potassium te/t-butoxide (1 equiv) and 2- cyanoacetamide (1 .1 equiv) in DMSO was added (E)-hept-3-en-2-one (48.0 g, 428 mmol, 1 equiv) under argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 30 min and then additional potassium tert- butoxide (3 equiv) was added to the reaction mixture. The argon was then displaced by oxygen gas and stirred for 48 h at room temperature. The reaction mass was purged with argon, diluted with water and then 4.0 N aqueous HCI solution was added slowly with stirring. 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.
Yield: 31 g (37 %); 1 H NMR (DMSO-d6, 300 MHz): δ 12.39 (s, 1 H), 6.18 (s, 1 H), 2.54 (t, J = 7.2 Hz, 2H), 2.22 (s, 3H), 1 .53-1 .65 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 177.1 [M+H]+.
Example 2:
4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridine-3-carbonitrile
A stirred solution of potassium te/t-butoxide (1 equiv) and 2-cyanoacetamide (1 .1 equiv) in DMSO was treated with (E)-hex-3-en-2-one (5 g, 50.9 mmol, 1 equiv) according to the procedure described for the preparation of the compound of example 1 to obtain the title compound.
Yield: 14 %; 1 H NMR (DMSO-d6, 300 MHz): δ 12.33 (s, 1 H), 6.21 (s, 1 H), 2.57 (q, J = 7.5 Hz, 2H), 2.23 (s, 3H), 1 .16 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 163.2 [M+H]+.
Example 3:
4-lsopropyl-6-methyl-2-oxo-1 ,2-dihydropyridine-3-carbonitrile
A stirred solution of potassium te/t-butoxide (1 equiv) and 2-cyanoacetamide
(1 .1 equiv) in DMSO was treated with (E)-hex-3-en-2-one (10 g, 89 mmol, 1 .0 equiv) according to the procedure described for the preparation of the compound of example 1 to obtain the title compound.
Yield: 17 %; 1H NMR (DMSO-d6, 300 MHz): δ 12.34 (s, 1 H), 6.27 (s, 1 H), 2.97-3.06 (m, 1 H), 2.24 (s, 3H), 1 .18 (d, J = 6.9 Hz, 6H); MS (ESI+): m/z 177.2 [M+H]+.
Example 4:
3-(Aminomethyl)-6-methyl-4-propylpyridin-2(1 H)-one hydrochloride To a solution of the compound of example 1 (10 g, 56.7 mmol, 1 .0 equiv) in acetic acid (100 ml_), were added 10 % palladium (1 g, 9.40 mmol, 10 % w/w), platinum (IV) oxide (129 mg, 0.553 mmol, 0.01 equiv), and sodium acetate (13.6 g, 166 mmol, 3.0 equiv). The mixture was subjected to hydrogenation under an atmosphere of hydrogen at 80-90 psi for 24 h. This reaction mixture was filtered through celite. The resulting filtrate was concentrated and treated with concentrated HCI and the solid precipitated was filtered. The yellow filtrate obtained was concentrated and cone. HCI and EtOH were added to the crude compound. The reaction mass was stirred at 0 SC for 2 h and the solid obtained was filtered, washed with cold EtOH, diethyl ether and dried to obtain the title compound.
Yield: 8.0 g (67 %); 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .88 (s, 1 H), 8.13 (s, 3H), 5.98 (s, 1 H), 3.77 (d, J = 5.4 Hz, 2H), 3.47 (t, J = 6.9 Hz, 2H), 2.16 (s, 3H), 1 .45-1 .52 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 181 .1 [M+H]+. Example 5:
3-(Aminomethyl)-4-ethyl-6-methylpyridin-2(1 H)-one hydrochloride
A solution of the compound of example 2 (1 .25 g, 7.71 mmol, 1 .0 equiv) in acetic acid (100 ml_), was treated with 10 % palladium (1 g, 9.40 mmol, 10 % w/w), platinum (IV) oxide (129 mg, 0.553 mmol, 0.01 equiv), and sodium acetate (13.6 g, 166 mmol, 3.0 equiv) according to the procedure described for the preparation of the compound of example 4 to obtain the title compound.
Yield: 0.8 g (51 %); 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .85 (s, 1 H), 8.09 (s, 3H), 6.01 (s, 1 H), 3.78 (q, J = 5.4 Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H), 2.17 (s, 3H), 1 .09 (d, J = 7.5 Hz, 3H); MS (ESI+): m/z 167.2 [M+H]+.
Example 6:
3-(Aminomethyl)-4-isopropyl-6-methylpyridin-2(1 H)-one hydrochloride
A solution of the compound of example 3 (1 .25 g, 7.71 mmol, 1 .0 equiv) in acetic acid (100 ml_), was treated with 10 % palladium (1 g, 9.40 mmol, 10 % w/w), platinum (IV) oxide (129 mg, 0.553 mmol, 0.01 equiv), and sodium acetate (13.6 g, 166 mmol, 3.0 equiv) according to the procedure described for the preparation of the compound of example 4 to obtain the title compound. Yield: 1 .7 g (55 %);1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .88 (s, 1 H), 8.03 (s, 2H), 6.1 1 (s, 1 H), 3.81 (d, J = 5.4 Hz, 2H), 3.05-3.12 (m, 1 H), 2.18 (s, 3H), 1 .00 (d, J = 6.9 Hz, 6H); MS (ESI+): m/z 181 .2 [M+H]+. Example 7:
3-(Aminomethyl)-1 ,4,6-trimethylpyridin-2(1 H)-one hydrochloride
A solution of 1 ,4,6-trimethyl-2-oxo-1 ,2-dihydropyridine-3-carbonitrile (500 mg, 3.08 mmol, 1 equiv) in acetic acid (100 ml_), was treated with 10 % palladium (1 g, 9.40 mmol, 10 % w/w), platinum (IV) oxide (129 mg, 0.553 mmol, 0.01 equiv), and sodium acetate (13.6 g, 166 mmol, 3.0 equiv) according to the procedure described for the preparation of the compound of example 4 to obtain the title compound.
Yield: 345 mg (55 %); 1 H NMR (DMSO-d6, 300 MHz): δ 8.19 (s, 3H), 6.12 (s, 1 H), 3.77 (q, J = 5.4 Hz, 2H), 3.47 (s, 2H), 3.44 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H); MS (ESI+): m/z 167.2 [M+H]+.
Example 8:
(2-Methoxy-4,6-dimethylpyridin-3-yl)methanamine
To a slurry solution of aluminum (III) lithium hydride (234 mg, 6.17 mmol) in diethyl ether (2 ml_) was added a saturated solution of 2-methoxy-4,6- dimethylnicotinonitrile (500 mg, 3.08 mmol) in ether (5 ml_) and stirred at room temperature for 1 h. After completion of the reaction, minimum amount of water was carefully added and the crude product obtained was extracted with hot benzene / toluene and concentrated. Resulting oily compound was distilled at 0.5 mm vacuum at 95-100 SC to obtain the title compound.
Yield: 300 mg (58.66 %); 1H NMR (DMSO-d6, 300 MHz): δ 6.53 (s, 1 H), 3.92 (s, 3H), 3.76 (s, 2H), 2.36 (s, 3H), 2.27 (s, 3H); MS (ESI+): m/z 166.9 [M+H]+.
Example 9:
3-(Aminomethyl)-4,6-dimethylpyridin-2(1 H)-one hydrochloride
A solution of 4,6-dimethyl-2-oxo-1 ,2-dihydropyridine-3-carbonitrile (6.0 g, 40.5 mmol, 1 equiv) in acetic acid (90 ml_), was treated with 10 % palladium (0.46 g, 6.07 mmol, 10 % w/w), platinum (IV) oxide (46 mg, 0.202 mmol, 0.01 equiv), and sodium acetate (6.31 g, 77 mmol, 1 .9 equiv) according to the procedure described for the preparation of the compound of example 4 to obtain the title compound. Yield: 3 g (39.3 %); 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .83 (s, 1 H), 7.96 (s, 3H), 5.96 (s, 1 H), 3.77 (d, J = 5.1 , 2H), 2.19 (s, 3H), 2.14 (s, 3H); MS (ESI+): m/z 153 [M+H]+.
Example 10:
Methyl 6-bromo-1-isopropyl-1 H-indole-4-carboxylate
To a solution of methyl 6-bromo-1 H-indole-4-carboxylate (10 g, 39.4 mmol) in DMF (100 ml_) was added sodium hydride (1 .889 g, 47.2 mmol) and the reaction mixture was stirred at room temperature for 10 min. To this reaction mixture isopropyl bromide (5.54 ml_, 59.1 mmol) was added and the resulting mixture was stirred at 65 SC for 6 h. Following reaction completion, the mixture was quenched in ice water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, which was purified by column chromatography (silica gel, 2-5 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 5 g (43 %); 1H NMR (CDCI3, 300 MHz): δ 8.00 (s, 1 H), 7.73 (s, 1 H), 7.36 (d, J= 3Hz, 1 H), 7.13 (d, J= 3Hz, 1 H), 4.65 (m, 1 H), 3.99 (s, 3H), 1 .55 (d, J= 6.6 Hz, 6H); MS (ESI+): m/z 297.5 (M+H)+.
Example 11 :
Methyl 6-bromo-1 -isopropylindoline-4-carboxylate
To a solution of the compound of example 10 (3.08 g, 10.40 mmol) in acetic acid (30 ml_) was added sodium cyanoborohydride (1 .307 g, 20.80 mmol, 2.0 equiv) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, acetic acid was removed and a saturated solution of NaHC03 was added to neutralize the pH and the solution was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to yield crude product, which was purified by column chromatography (silica gel, 2 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 2.55 g (82 %); 1H NMR (CDCI3, 300 MHz): δ 7.30 (s, 1 H), 6.58 (s, 1 H), 3.87 (s, 3H), 3.76 (m, 1 H), 3.44 (t, J= 8.4 Hz & 8.1 Hz, 2H), 3.26 (t, J= 8.1 Hz & 8.4 Hz, 2H), 1 .17 (d, J= 6.6 Hz, 6H); MS (ESI+): m/z 298.9 (M+H)+. Example 12:
Methyl 6-(6-(4-(3,3-dimethylbutanoyl)piperazin-1 -yl)pyridin-3-yl)-1 -isopropyl indoline-4-carboxylate
To a solution of the compound of example 1 1 (2.0 g, 6.71 mmol) in dioxane (20 ml_) and water (20 ml_) were added te/t-butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl) pyridin-2-yl)piperazine-1 -carboxylate (2.376 g, 6.10 mmol) and 1 ,1 'Bis(diphenylphosphino) ferrocene palladium dichloromethane complex (3.39 g, 8.72 mmol) under nitrogen atmosphere and stirred at room temperature for 10 min. To this mixture, 2 M sodium carbonate (0.164 g, 0.201 mmol) solution was added and the resulting reaction mixture was stirred at 65 SC for 1 .5 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was washed with water and brine, dried over anhydrous sodium sulphate, and concentrated to yield crude product. Further purification of the crude product was carried out by column chromatography (silica gel, 5 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 2 g (62 %); 1H NMR (CDCI3, 300 MHz): δ 8.45 (s, 1 H), 7.75 (d, J=7.5 Hz, 1 H), 7.37 (s, 1 H), 6.72 (d, J= 8.7 Hz, 1 H), 6.65 (s, 1 H), 3.90 (s, 3H), 3.88 (m, 1 H), 3.58 (m, 8H), 3.46 (t, J= 7.8 Hz & 7.2 Hz, 2H), 3.33 (t, J= 7.2 Hz & 7.8 Hz, 2H), 1 .50 (s, 9H), 1 .20 (d, J=6.6 Hz, 6H); MS (ESI+): m/z 481 .4 (M+H)+.
Example 13:
6-(6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1-isopropylindoline-4- carboxylic acid
To a solution of the compound of example 12 (200 mg, 0.416 mmol) in THF (10 ml_) and water (10 ml_) was added 1 N NaOH (29.9 mg, 1 .248 mmol) and stirred at room temperature for 5 h. The reaction mixture was then heated at 75 SC with stirring for 3 h to ensure completion of the reaction. Following completion of the reaction, solvent was removed, water was added to the reaction mixture followed by acidification with dilute HCI and the mixture was extracted with ethyl acetate. Further purification of the crude product was carried out by column chromatography (silica gel, 5 % methanol in chloroform) to obtain the title compound.
Yield: 120 mg (61 %); 1 H NMR (DMSO-d6, 300 MHz): δ 12.73 (s, 1 H), 8.41 (s, 1 H), 7.82 (d, J= 7.2 Hz, 1 H), 7.22 (s, 1 H), 6.90 (d, J= 9 Hz, 1 H), 6.81 (s, 1 H), 3.98 (m, 1 H), 3.52 (s, 4H), 3.43 (s, 4H), 3.18 (t, J= 7.8 Hz , 2H), 1 .47 (t, J= 6.6 Hz, 2H), 1 .10 (d, J= 6.3 Hz, 6H); MS (ESI+): m/z 467.2 (M+H)+.
Example 14:
tert-Butyl 4-(5-(1 -isopropyl-4-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methylcarbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate
To a solution of the compound of example 12 (200 mg, 0.416 mmol) in MeOH (25 ml_) and THF (12.50 ml_) was added 1 N NaOH (16.64 mg, 0.416 mmol) solution and stirred at 65 SC for 5 h. After completion of the reaction, the solvent was removed. The resulting solid was dissolved in DMF (10.00 ml_) and to this mixture HATU (237 mg, 0.624 mmol) and the compound of example 4 (108 mg, 0.499 mmol) were added and the solution was stirred at 65 SC for 16 h. After completion of the reaction, water was added and the resulting mixture was extracted with ethyl acetate. The organic layers were washed with water and brine, dired over anhydrous sodium sulphate and concentrated to yield a crude residue, which was purified by column chromatography (silica gel, 2 % methanol in chloroform) to obtain the crude form of the title compound. The crude compound was stirred in a mixture of acetone and petroleum ether to obtain the title compound.
Yield: 90 mg (32 %); 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .51 (s, 1 H), 8.44 (s, 1 H), 8.04 (s, 1 H), 7.85 (d, J=8.1 Hz, 1 H), 6.96 (s, 1 H), 6.90 (d, J= 9.0 Hz, 1 H), 6.71 (s, 1 H), 5.88 (s, 1 H), 4.28 (s, 2H), 3.95 (m, 1 H), 3.50 (s, 4H), 3.42 (s, 4H), 3.21 (t, 2H), 3.08 (t, J= 7.8 Hz, 2H), 2.45 (m, 2H), 2.1 1 (s, 3H), 1 .52 (m, 2H), 1 .42 (s, 9H), 1 .09 (d, J=6.3 Hz, 6H), 0.88 (t, J=7.2 Hz, 3H); MS (ESI+): m/z 629.0 (M+H)+. Example 15:
1-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide hydrochloride
To a solution of the compound of example 14 (60 mg, 0.095 mmol) in MeOH (5 ml_) was added 10 % methanolic HCI (348 mg, 0.954 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was removed and the resulting oily compound was stirred in petroleum ether, the solvent was decanted, and dried to obtain the title compound.
Yield: 50 mg (93 %); 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .62 (s, 1 H), 9.33 (s, 2H), 8.45 (s, 1 H), 8.31 (s, 1 H), 8.14 (s, 1 H), 7.19 (t, J = 6 & 8.1 Hz, 2H), 6.97 (s, 1 H), 5.92 (s, 1 H), 4.30 (s, 2H), 4.03 (m, 1 H), 3.87 (s, 4H), 3.32 (s, 2H), 3.22 (s, 4H), 3.12 (d, J = 6.6 Hz, 4H), 2.12 (s, 2H), 1 .47-1 .54 (m, 2H), 1 .12 (d, J = 6.7 Hz, 6H), 0.88 (t, J = 7.8 Hz, 3H); MS (ESI+): m/z 529.3 (M+H)+. Example 16:
1-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
To a solution of the compound of example 15 (20 mg, 0.035 mmol) in water (5 ml_) was added aqueous 10 % sodium bicarbonate solution (9 mg, 0.100 mmol) to neutralize the pH and the reaction mixture was stirred at room temperature for 2 h and the precipitated solid was filtered, washed with water, and dried to obtain the title compound.
Yield: 15 mg (80 %); 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.42 (s, 1 H), 8.13 (s, 1 H), 7.80 (s, 1 H), 6.95 (s, 1 H), 6.84 (s, 1 H), 6.69 (s, 1 H), 5.88 (s, 1 H), 4.28 (s, 2H), 3.94 (m, 1 H), 3.42 (s, 8H), 3.32 (s, 2H), 3.06 (s, 2H), 2.79 (s, 3H), 2.1 1 (s, 2H), 1 .49 (s, 2H), 1 .08 (s, 6H), 0.88 (s, 3H); MS (ESI+): m/z 529.0 (M+H)+.
Example 17:
tert-Butyl 4-(5-(4-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl
carbamoyl)-1 -isopropylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate
To a solution of the compound of example 12 (0.9 g, 1 .873 mmol) in MeOH (25 ml_) and THF (12.50 ml_) was added 1 N NaOH (0.375 g, 9.36 mmol) solution and the resulting mixture was stirred for 16 h at room temperature and for 5 h at 65 SC. After completion of the reaction, the solvent was removed. The solid was subsequently dissolved in DMF (25 ml_) and to this were added 2-(3H- [1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-1 ,1 ,3,3-tetramethylisouronium hexafluorophosphate (V) (1 .068 g, 2.81 mmol) and the compound of example 9 (0.459 g, 2.434 mmol) and stirred at 65 SC for 16 h. After completion of the reaction, water was added to the reaction mixture and the compound was extracted with ethyl acetate. The crude residue was purified by column chromatography (2 % methanol in chloroform) to obtain the compound in crude form. The crude compound was stirred in a mixture of acetone and petroleum ether to obtain the title compound.
Yield: 400 mg (29 %); 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .51 (s, 1 H), 8.45 (s, 1 H), 8.15 (s, 1 H), 7.86 (d, J=7.2 Hz, 1 H), 6.97 (s, 1 H), 6.90 (d, J= 8.7 Hz, 1 H), 6.71 (s, 1 H), 5.86 (s, 1 H), 4.26 (d, J= 3.9 Hz, 2H), 3.96 (m, 1 H), 3.51 (s, 4H), 3.42 (s, 4H), 3.06 (t, J= 7.8 Hz & 7.5 Hz, 2H), 2.17 (s, 3H), 2.10 (s, 3H), 1 .47 (s, 2H), 1 .42 (s, 9H), 1 .08 (d, J=6 Hz, 6H); MS (ESI+): m/z 601 .6 (M+H)+, 623.0 (M+Na)+. Example 18:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(6- (piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide hydrochloride
To a solution of the compound of the example 17 (250 mg, 0.416 mmol) in MeOH (10 ml_) was added 12 % methanolic HCI (1200 mg, 4.16 mmol) and the reaction mixture was stirred at room temperature for 48 h. After completion of the reaction, solvent was removed and the resulting oily compound was stirred in petroleum ether, solvent was decanted, and the product obtained was dried to obtain the title compound.
Yield: 125 mg (50 %); 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .72 (s, 1 H), 9.56 (s, 2H), 8.50 (s, 1 H), 8.45 (s, 1 H), 8.30 (d, J = 8.4 Hz, 1 H), 7.31 (s, 2H), 7.16 (s, 1 H), 5.96 (s, 1 H), 4.30 (s, 2H), 3.47 (s, 2H), 3.24 (s, 4H), 3.17 (d, J = 5.1 Hz, 2H), 2.21 (s, 3H), 2.14 (s, 3H), 2.07 (s, 4H), 1 .13 (d, J = 6 Hz, 6H); MS (ESI+): m/z 501 .4 (M+H)+.
Example 19:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6- (piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
To a solution of the compound of example 18 (90 mg, 0.168 mmol) in water (10 ml_) was added 10 % sodium bicarbonate solution (42 mg, 0.504 mmol) and the reaction mixture was stirred at room temperature for 2 h, the solid precipitated was filtered, washed with water, and dried to obtain the title compound.
Yield: 50 mg (52 %); 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .56 (s, 1 H), 8.42 (s, 1 H), 8.13 (s, 1 H), 7.82 (d, 1 H), 6.96 (s, 1 H), 6.84 (d, 1 H), 6.69 (s, 1 H), 5.85 (s, 1 H), 4.27 (s, 2H), 3.95 (m, 1 H), 3.41 (s, 8H), 3.31 (s, 2H), 3.06 (s, 2H), 2.17 (s, 3H), 2.10 (s, 3H), 1 .08 (s, 6H); MS (ESI+): m/z 501 .3 (M+H)+.
Example 20:
tert-Butyl 4-(5-(4-(((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl)-1-isopropylindolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate The compound of the example 20 was prepared according to the procedure described for the preparation of the compound of example 14 using the compound of example 5 (1 .3 equiv) to obtain the title compound.
Yield: 19 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .51 (s, 1 H), 8.45 (d, J = 2.4 Hz, 1 H), 8.15 (s, 1 H), 7.87 (dd, J = 2.4 & 8.7 Hz, 1 H), 6.97 (s, 1 H), 6.90 (d, J = 9 Hz, 1 H), 6.71 (s, 1 H), 5.90 (s, 1 H), 4.30 (d, J = 4.8 Hz, 2H), 3.94-3.98 (m, 1 H), 3.51 (d, J = 5.7 Hz, 4H), 3.42 (s, 4H), 3.28 (t, 2H), 3.07 (t, J = 8.1 Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 2.12 (s, 3H), 1 .42 (s, 9H), 1 .09-1 .1 1 (m, 9H); MS (ESI+): m/z 615.4 [M+H]+. Example 21 :
N-((4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6- (piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide
A solution of compound of example 20 in MeOH was treated with 12 % methanolic HCI followed by treatment with 10 % sodium bicarbonate solution (10 equiv) according to the procedure described in examples 15 and 16 respectively, to obtain the title compound.
Yield: 43 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .47 (s, 1 H), 8.42 (s, 1 H), 8.15 (s, 1 H), 7.81 (s, 1 H), 6.95 (s, 1 H), 6.82 (s, 1 H), 6.69 (s, 1 H), 5.90 (s, 1 H), 4.28 (s, 2H), 3.95 (s, 1 H), 3.40 (s, 4H), 3.32 (s, 4H), 3.06 (s, 2H), 2.76 (s, 4H), 2.1 1 (s, 3H), 1 .08 (s, 9H); MS (ESI+): m/z 515.4 [M+H]+.
Example 22:
Methyl 6-bromo-1 -methyl-1 H-indole-4-carboxylate
A solution of 6-bromo-1 H-indole-4-carboxylate in DMF and sodium hydride was treated with methyl iodide (1 .2 equiv) according to the procedure described for the preparation of the compound of example 10 to obtain the title compound.
Yield: 50 %; 1H NMR (CDCI3, 300 MHz): δ 8.01 (d, J = 1 .5 Hz, 1 H), 7.66 (d, J = 0.6 Hz, 1 H), 7.17 (d, J = 3 Hz, 1 H), 7.07 (d, J = 3.3 Hz, 1 H), 3.99 (s, 3H), 3.80 (s, 3H); MS (ESI+): m/z 268.1 [M+H]+.
Example 23:
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.
Yield: 76 %; 1 H NMR (DMSO-d6, 300 MHz): δ 7.12 (s, 1 H), 6.79 (s, 1 H), 3.80 (s, 3H), 3.36 (t, J = 8.1 Hz, 2H), 3.13 (t, J = 8.1 Hz, 2H), 2.73 (s, 3H); MS (ESI+): m/z 271 .9 [M+H]+.
Example 24:
Methyl 6-(6-(4-(tert-butoxycarbonyl)piperazin-1 -yl)pyridin-3-yl)-1 -methyl indoline-4-carboxylate
A solution of the compound of example 23 in dioxane was treated with tert- butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylate (1 .15 equiv) according to the procedure described for the preparation of the compound of example 12 to obtain the title compound.
Yield: 62 %; 1 H NMR (DMSO-d6, 500 MHz): δ 8.84 (s, 1 H), 7.86 (d, J = 7 Hz, 1 H), 7.30 (s, 1 H), 6.92 (d, J = 10.5 Hz, 2H), 3.83(s, 3H), 3.53 (s, 4H), 3.44 (s, 4H), 3.35 (t, J = 8 Hz, 2H), 3.20 (t, J = 8.1 Hz, 2H), 2.80 (s, 3H), 1 .43 (s, 9H); MS (ESI+): m/z 453.5 [M+H]+. Example 25:
Methyl 1 -methyl-6-(4-morpholinophenyl)indoline-4-carboxylate
A solution of the compound of example 23 in dioxane was treated with 4-(4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine (1 .3 equiv) according to the procedure described for the preparation of the compound of example 12 to obtain the title compound.
Yield: 56 %; 1 H NMR (DMSO-d6, 300 MHz): δ 7.56 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 1 .5 Hz, 1 H), 7.00 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 1 Hz, 1 H), 4.33 (s, 2H), 3.41 (s, 3H), 3.33 (s, 4H), 3.07 (s, 2H), 2.77 (s, 4H), 2.13 (s, 3H); MS (ESI+): m/z 353.2 [M+H]+.
Example 26:
6-(6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1-methylindoline-4- carboxylic acid A solution of the compound of example 24 in THF was treated with 1 N NaOH (3.0 equiv) according to the procedure described for the preparation of the compound of example 13 to obtain the title compound.
Yield: 77 %; 1 H NMR (DMSO-d6, 500 MHz): δ 12.88 (s, 1 H), 8.30 (s, 1 H), 8.22 (s, 1 H), 7.34 (s, 1 H), 7.29 (s, 1 H), 6.98 (s, 1 H), 3.72 (s, 4H), 3.51 (s, 4H), 3.37 (t, J = 8 Hz, 2H), 3.22 (t, J = 8.1 Hz, 2H), 2.83 (s, 3H), 1 .44 (s, 9H); MS (ESI+): m/z 439.4 [M+H]+.
Example 27:
1-Methyl-6-(4-morpholinophenyl)indoline-4-carboxylic acid
A solution of the compound of example 25 in THF was treated with 1 N NaOH (5.0 equiv) according to the procedure described for the preparation of the compound of example 13 to obtain the title compound.
Yield: 89 %; 1H NMR (DMSO-d6, 300 MHz): δ 12.74 (s, 1 H), 7.52 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 1 .2 Hz, 1 H), 7.00 (d, J = 8.7 Hz, 2H), 6.87 (s, 1 H), 3.75 (t, J = 4.5 Hz, 4H), 3.32 (t, 2H), 3.18 (t, 2H), 3.14 (t, J = 4.2 Hz, 4H), 2.78 (s, 3H); MS (ESI+): m/z
339.2 [M+H]+.
Example 28:
1 -Methyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- morpholinophenyl)indoline-4-carboxamide
A solution of the compound of example 25 in MeOH and THF was treated with the compound of example 4 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 14 to obtain the title compound.
Yield: 1 1 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .50 (s, 1 H), 8.16 (s, 1 H), 7.53 (s, 2H), 7.03 (s, 1 H), 6.99 (s, 2H), 6.75 (s, 1 H), 5.87 (s, 1 H), 4.29 (s, 2H), 3.74 (s, 4H), 3.12 (bs, 10H), 2.74 (s, 3H), 2.1 1 (s, 3H), 1 .50 (s, 2H), 0.88 (s, 3H); MS (ESI+): m/z
501 .3 [M+H]+. Example 29:
N-((4-lsopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-methyl-6-(4- morpholinophenyl)indoline-4-carboxamide The solution of the compound of example 25 in MeOH and THF was treated with the compound of example 6 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 14 to obtain the title compound. Yield: 9 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.19 (s, 1 H), 7.53 (s, 2H), 7.03 (s, 1 H), 6.98 (s, 2H), 6.75 (s, 1 H), 5.99 (s, 1 H), 4.34 (s, 2H), 3.74 (s, 4H), 3.12 (bs, 9H), 2.74 (s, 3H), 2.13 (s, 3H), 1 .09 (s, 6H); MS (ESI+): m/z 501 .3 [M+H]+.
Example 30:
N-((4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-methyl-6-(4- morpholinophenyl)indoline-4-carboxamide
The solution of the compound of example 25 in MeOH and THF was treated with the compound of example 5 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 14 to obtain the title compound. Yield: 5 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .51 (s, 1 H), 8.17 (s, 1 H), 7.53 (s, 2H), 7.03 (s, 1 H), 6.98 (s, 2H), 6.75 (s, 1 H), 5.89 (s, 1 H), 4.29 (s, 2H), 3.73 (s, 4H), 3.33 (s, 6H), 3.12 (s, 4H), 2.74 (s, 3H), 2.13 (s, 3H), 1 .08 (s, 3H); MS (ESI+): m/z 487.3 [M+H]+.
Example 3 :
tert-Butyl 4-(5-(4-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl
carbamoyl)-1-methylindolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate
The solution of the compound of example 24 in MeOH and THF was treated with the compound of example 9 (1 .2 equiv) according to the procedure described for the preparation of the compound of example 14 to obtain the title compound. Yield: 45 %; 1 H NMR (DMSO-d6, 500 MHz): δ 1 1 .49 (s, 1 H), 8.48 (s, 1 H), 8.17 (s, 1 H), 7.89 (d, J = 9 Hz, 1 H), 7.06 (s, 1 H), 6.91 (d, J = 9 Hz, 1 H), 6.80 (s, 1 H), 5.87 (s, 1 H), 4.28 (d, J = 5 Hz, 2H), 3.52 (s, 4H), 3.43 (s, 4H), 3.27 (t, J = 8.5 Hz, 2H), 3.08 (t, J = 8 Hz, 2H), 2.76 (s, 3H), 2.18 (s, 3H), 2.1 1 (s, 3H), 1 .43 (s, 9H); MS (ESI+): m/z 573.5 [M+H]+.
Example 32:
tert-Butyl 4-(5-(4-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl carbamoyl)-! -methylindolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate The solution of the compound of 24 in MeOH and THF was treated with the compound of example 5 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 14 to obtain the title compound.
Yield: 40 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .51 (s, 1 H), 8.47 (d, J = 2.1 Hz, 1 H), 8.18 (s, 1 H), 7.87 (dd, J = 2.1 & 8.7 Hz, 1 H), 7.05 (s, 1 H), 6.90 (d, J = 8.7 Hz, 1 H), 6.79 (s, 1 H), 5.90 (s, 1 H), 4.30 (d, J = 4.8 Hz, 2H), 3.52 (d, J = 5.7 Hz, 4H), 3.43 (d, J = 5.1 Hz, 4H), 3.27 (t, J = 7.5 Hz, 2H), 3.08 (t, J = 7.8 Hz, 2H), 2.76 (s, 3H), 2.53 (q, J = 7.5 Hz, 2H), 2.12 (s, 3H), 1 .42 (s, 9H), 1 .09 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 587.4 [M+H]+.
Example 33:
tert-Butyl 4-(5-(4-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl carbamoyl)-1-methylindolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate
The solution of the compound of example 24 in MeOH and THF was treated with the compound of example 6 (1 .5 equiv) according to the procedure described for the preparation of the compound of example 14 to obtain the title compound. Yield: 19 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.47 (d, J = 2.4 Hz, 1 H), 8.19 (s, 1 H), 7.89 (dd, J = 2.4 & 9 Hz, 1 H), 7.05 (s, 1 H), 6.90 (d, J = 9 Hz, 1 H), 6.79 (s, 1 H), 6.00 (s, 1 H), 4.35 (d, J = 4.5 Hz, 2H), 3.51 (d, J = 5.4 Hz, 4H), 3.43 (d, J = 5.1 Hz, 4H), 3.27 (t, J = 7.8 Hz, 2H), 3.18 (t, J = 6.9 Hz, 1 H), 3.08 (t, J = 7.8 Hz, 2H), 2.76 (s, 3H), 2.14 (s, 3H),1 .42 (s, 9H), 1 .09 (t, J = 6.9 Hz, 6H); MS (ESI+): m/z 601 .4 [M+H]+.
Example 34:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -methyl-6-(6- (piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
A solution of compound of example 31 in MeOH was treated with 12 % methanolic HCI followed by treatment with 10 % sodium bicarbonate solution according to the procedure described in examples 15 and 16 respectively, to obtain the title compound.
Yield: 79 %; 1 H NMR (DMSO-d6, 500 MHz): δ 1 1 .49 (s, 1 H), 8.48 (s, 1 H), 8.17 (s, 1 H), 7.89 (d, J = 8 Hz, 1 H), 7.06 (s, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 6.80 (s, 1 H), 5.87 (s, 1 H), 4.29 (d, J = 4 Hz, 2H), 3.60 (s, 4H), 3.28 (t, J = 8 Hz, 2H), 3.08 (t, J = 8 Hz, 2H), 3.00 (s, 4H), 2.76 (s, 3H), 2.18 (s, 3H), 2.1 1 (s, 3H); MS (ESI+): m/z 473.4 [M+H]+.
Example 35:
N-((4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -methyl-6-(6- (piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
A solution of compound of example 33 in MeOH was treated with 12 % methanolic HCI followed by treatment with 10 % sodium bicarbonate solution according to the procedure described in examples 15 and 16 respectively, to obtain the title compound.
Yield: 85 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .51 (s, 1 H), 8.44 (s, 1 H), 8.15 (s, 1 H), 7.82 (s, 1 H), 7.04 (s, 1 H), 6.77 (s, 2H), 5.90 (s, 1 H), 4.30 (s, 2H), 3.42 (s, 4H), 3.07 (s, 4H), 2.76 (s, 8H), 2.53 (s, 2H), 2.10 (d, J = 12 Hz, 3H), 1 .08 (s, 3H); MS (ESI+): m/z 487.3 [M+H]+.
Example 36:
Methyl 6-bromo-1 -ethyl-1 H-indole-4-carboxylate
The solution of 6-bromo-1 H-indole-4-carboxylate in DMF and sodium hydride was treated with ethyl iodide (2 equiv) according to the procedure described for the preparation of the compound of example 10 to obtain the title compound.
Yield: 81 %; 1 H NMR (DMSO-d6, 300 MHz): δ 8.09 (s, 1 H), 7.79 (s, 1 H), 7.63 (s, 1 H), 6.94 (s, 1 H), 4.36 (m, 2H), 3.90 (s, 3H), 1 .38 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 252 (M-30)+. Example 37:
Methyl 6-bromo-1 -ethylindoline-4-carboxylate
The solution of the compound of example 36 in acetic acid was treated with sodium cyanoborohydride (1 .5 equiv) according to the procedure described for the preparation of the compound of example 1 1 to obtain the title compound.
Yield: 51 .4 %; 1 H NMR (DMSO-d6, 300 MHz): δ 7.10 (s, 1 H), 6.80 (s, 1 H), 3.90 (s, 3H), 3.44 (m, 2H), 3.18 (m, 4H), 1 .09 (t, J = 6.9 Hz, 3H); MS (ESI+): m/z 285 (M+H)+. Example 38:
Methyl 6-(6-(4-(tert-butoxycarbonyl)piperazin-1 -yl)pyridin-3-yl)-1 -ethylindoline- 4-carboxylate
The solution of the compound of example 37 in dioxane was treated with tert- butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylate (1 .5 equiv) according to the procedure described for the preparation of the compound of example 12 to obtain the title compound.
Yield: 34 %; 1 H NMR (DMSO-d6, 300 MHz): δ 8.43 (s, 1 H), 7.85 (d, J = 6.6 Hz, 1 H), 7.26 (s, 1 H), 6.92 (m, 2H), 3.82 (s, 3H), 3.53 (s, 4H), 3.42 (s, 4H), 3.39 (m, 2H), 3.24 (m, 2H), 3.20 (m, 2H), 1 .42 (s, 9H), 1 .13 (t, J = 6.9 Hz, 3H); MS (ESI+): m/z 467 (M+H)+.
Example 39:
6-(6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1-ethylindoline-4- carboxylic acid
The solution of the compound of example 38 in THF was treated with NaOH (5.0 equiv) according to the procedure described for the preparation of the compound of example 13 to obtain the title compound.
Yield: 66 %; 1 H NMR (DMSO-d6, 300 MHz): δ 12.77 (bs, 1 H), 8.41 (s, 1 H), 7.86 (d, J = 7.2 Hz, 1 H), 7.26 (s, 1 H), 6.93 (m, 2H), 3.53 (s, 4H), 3.51 (s, 4H), 3.26 (m, 2H), 3.21 (s, 4H), 1 .42 (s, 9H), 1 .13 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 453.1 (M+H)+.
Example 40:
tert-Butyl 4-(5-(1 -ethyl-4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate
To the solution of the compound of example 38 (200 mg, 0.429 mmol) in DMF, was added N-methylmorpholine (0.071 ml_, 0.643 mmol) and the reaction mixture was stirred at room temperature for 5 minutes, followed by the addition of isobutyl chloroformate (0.062 ml_, 0.472 mmol) at -30 °C. The reaction mass was stirred at the same temperature for 20 minutes and the compound of example 4 (139 mg, 0.643 mmol) and DIPEA (0.187 ml_, 1 .072 mmol) were added and the reaction mixture was warmed to room temperature and stirred for 12-16 h. After completion of the reaction, water was added and extracted with ethyl acetate and purified by column chromatography (silica gel, 2 % methanol in chloroform) to obtain the title compound.
Yield: 40 mg (15 %); 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .50 (bs, 1 H), 8.45 (s, 1 H), 8.16 (d, J = 7.2 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 1 H), 7.01 (s, 1 H), 6.91 (m, 1 H), 6.77 (s, 1 H), 5.88 (s, 1 H), 4.30 (s, 2H), 3.51 (s, 4H), 3.44 (s, 4H), 3.21 (m, 2H), 3.1 1 (m, 2H),
2.1 1 (s, 3H), 1 .52 (m, 2H), 1 .42 (s, 9H), 1 .33 (m, 2H), 1 .13 (t, J = 7.2 Hz, 3H), 0.9 (t, J = 7.2 Hz, 3H); MS (ESI+) m/z 615 (M+H)+.
Example 4 :
1 -Ethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)-6-(6- (piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
The solution of the compound of example 38 in MeOH was treated with 10 % methanolic HCI according to the procedure described for the preparation of the compound of example 15 to obtain the title compound.
Yield: 53 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .51 (s, 1 H), 8.44 (s, 1 H), 8.15 (s, 1 H), 7.83 (m, 1 H), 7.01 (s, 1 H), 6.85 (m, 1 H), 6.77 (s, 1 H), 5.89 (s, 1 H), 4.30 (s, 2H), 3.43 (s, 4H), 3.21 (m, 2H), 3.19 (m, 2H), 3.09 (m, 2H), 2.78 (s, 4H), 2.50 (m, 2H),
2.12 (s, 3H), 1 .56 (m, 2H), 1 .24 (t, 3H), 0.9 (t, 3H); MS (ESI+): m/z 515 (M+H)+.
Example 42:
Methyl 1 -ethyl-6-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxylate
The solution of the compound of example 37 in dioxane was treated with 1 - methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1 .5 equiv) according to the procedure for the preparation of the compound of example 12 to obtain the title compound.
Yield: 24 %; 1H NMR (DMSO-d6, 300 MHz): δ 8.41 (d, J = 1 .5. Hz, 1 H), 7.83 (d, J = 2.1 Hz, 1 H), 7.26 (s, 1 H), 6.90 (m, 2H), 3.82 (s, 3H), 3.51 (s, 4H), 3.33 (m, 2H), 3.24 (m, 4H), 2.40 (s, 4H), 2.22 (s, 3H), 1 .13 (t, J = 6.9 Hz, 3H); MS (ESI+): m/z 381 (M+H)+.
Example 43:
1-Ethyl-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)indoline-4-carboxylic acid The solution of the compound of example 42 in THF was treated with NaOH (5.0 equiv) according to the procedure described for the preparation of the compound of example 13 to obtain the title compound.
Yield: 50 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .31 (bs, 1 H), 8.42 (s, 1 H), 8.07 (d, J = 9.3 Hz, 1 H), 7.33 (s, 1 H), 7.17 (d, J = 9 Hz, 1 H), 6.98 (s, 1 H), 4.50 (m, 2H), 3.83 (m, 4H), 3.46 (m, 2H), 3.27 (m, 4H), 3.81 (m, 2H), 2.77 (s, 3H), 1 .39 (t, 3H); MS (ESI+): m/z 367 (M+H)+.
Example 44:
1 -Ethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
The compound of example 42 in MeOH and THF was treated with the compound of example 4 (1 .5 equiv) according to the procedure described for the preparation of the compound of example 14 to obtain the title compound.
Yield: 33 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 .50 (s, 1 H), 8.43 (s, 1 H), 7.49 (d, J = 6.6 Hz, 1 H), 7.01 (s, 1 H), 6.89 (m, 1 H), 6.91 (m, 1 H), 6.76 (s, 1 H), 5.88 (s, 1 H), 4.30 (s, 2H), 3.50 (s, 4H), 3.23 (m, 2H), 3.16 (m, 2H), 3.08 (m, 2H), 2.60 (m, 2H), 2.50 (s, 4H), 2.22 (s, 3H), 2.1 1 (s, 3H), 1 .33 (m, 2H), 1 .13 (t, J = 7.2 Hz, 3H), 0.9 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 529 (M+H)+.
Example 45:
ieri-Butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)
carbamoyl)-1-ethylindolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate
The compound of example 38 in MeOH and THF was treated with the compound of example 9 (1 .2 equiv) according to the procedure described for the preparation of the compound of example 14 to obtain the title compound.
Yield: 35 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.46 (s, 1 H), 8.17 (s, 1 H), 7.89 (d, J = 8.7 Hz, 1 H), 7.02 (s, 1 H), 6.91 (d, J = 9 Hz, 1 H), 6.77 (s, 1 H), 5.86 (s, 1 H), 4.28 (s, 2H), 3.50 (s, 4H), 3.32 (s, 4H), 3.20 (s, 2H), 3.16 (m, 2H), 3.08 (m, 2H), 2.26 (s, 3H), 2.17 (s, 3H), 1 .42 (s, 9H), 1 .22 (t, 3H); MS (ESI+): m/z 587 (M+H)+.
Example 46:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-ethyl-6-(6-(piperazin- 1-yl)pyridin-3-yl)indoline-4-carboxamide A solution of compound of example 45 in MeOH was treated with 12 % methanolic HCI followed by treatment with 10 % sodium bicarbonate solution according to the procedure described in examples 15 and 16 respectively, to obtain the title compound.
Yield: 71 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .51 (s, 1 H), 8.44 (s, 1 H), 8.16 (s, 1 H), 7.82(s, 1 H), 7.01 (s, 1 H), 6.85 (d, J = 8.7 Hz, 1 H), 6.76 (s, 1 H), 5.86 (s, 1 H), 4.27 (s, 2H), 3.43 (s, 4H), 3.20 (m, 2H), 3.18 (m, 2H), 3.08 (m, 2H), 2.78 (s, 4H), 2.17 (s, 3H), 2.10 (m, 3H), 1 .09 (t, 3H); MS (ESI+): m/z 487 (M+H)+. Example 47:
Methyl 1 -isopropyl-6-(4-morpholinophenyl)-1 H-indole-4-carboxylate
To a solution of the compound of example 10 (1 .5 g, 5.06 mmol, 1 .0 equiv) in 1 ,4-dioxane (10 ml_) were added 4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)morpholine (1 .61 1 g, 5.57 mmol, 1 .1 equiv), PdCI2(dppf)-CH2Cl2 adduct (0.124 g, 0.152 mmol, 0.030 equiv) and 2 M aqueous solution of Na2C03 (7.60 ml_, 15.19 mmol, 3.0 equiv) and stirred reaction mass at 65 SC for 3 h. After the reaction is complete, the 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.
Yield: 1 .2 g (63 %); 1 H NMR (CDCI3, 500 MHz): δ 8.16 (s, 1 H), 7.74 (s, 1 H), 7.65 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 2.5 Hz, 1 H), 7.14 (d, J = 2.5 Hz, 1 H), 7.04 (d, J = 8 Hz, 2H), 4.76 (m, 1 H), 4.02 (s, 3H), 3.92 (d, J = 4 Hz, 4H), 3.24 (d, J = 4.5 Hz, 4H), 1 .58 (d, J = 5.5 Hz, 6H); MS (ESI+): m/z 379.3 [M+H]+.
Example 48:
1 -lsopropyl-6-(4-morpholinophenyl)-1 H-indole-4-carboxylic acid
To a solution of the compound of example 47 (1 .3 g, 3.43 mmol. 1 .0 equiv) in MeOH (10 ml_) and THF (5 ml_) was added 1 N NaOH (0.687 g, 17.17 mmol, 5.0 equiv) and the reaction mixture was stirred at 65 SC for 16 h. After completion of the reaction, solvent was removed and 1 .0M aqueous HCI solution was added to bring the pH to 2 and the solid precipitated was filtered, washed with water and dried to obtain the title compound. Yield 1 .09 g (86 %); 1H NMR (DMSO-d6, 300 MHz): δ 12.69 (s, 1 H), 7.97 (d, J = 5.4 Hz, 2H), 7.63-7.66 (m, 3H), 7.04 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 3 Hz, 1 H), 4.91 -5.00 (m, 1 H), 3.76 (t, J = 4.2 & 4.8 Hz, 4H), 3.16 (t, J = 4.2 & 4.8 Hz, 4H), 1 .48 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 364.2 [M+H]+.
Example 49:
1-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- morpholinophenyl)-1 H-indole-4-carboxamide
To a solution of the compound of example 48 (150 mg, 0.412 mmol, 1 .0 equiv) in DMF (2 mL) were added the compound of example 4 (134 mg, 0.617 mmol, 1 .5 equiv), HATU (235 mg, 0.617 mmol, 1 .5 equiv) and DIPEA (0.108 mL, 0.617 mmol, 1 .5 equiv) stirred at room temperature for 16 h. After completion of the reaction, residue obtained was quenched in water and the solid precipitated was filtered, dried to yield the solid compound which was purified by column chromatography (silica gel, 3:7 methanohchloroform) to obtain the title compound. Yield: 40 mg (18 %); 1H NMR (DMSO-d6, 500 MHz): δ 1 1 .56 (s, 1 H), 8.26 (s, 1 H), 7.83 (s, 1 H), 7.68 (d, J = 9 Hz, 2H), 7.66 (s, 1 H), 7.58 (s, 1 H), 7.04 (d, J = 8 Hz, 2H), 6.64 (s, 1 H), 5.91 (s, 1 H), 4.93 (d, J = 7 Hz, 1 H), 4.40 (d, J = 4.5 Hz, 2H), 3.77 (s, 4H), 3.15 (s, 4H), 2.54 (t, J = 7.5 Hz, 2H), 2.13 (s, 3H), 1 .52-1 .56 (m, 2H), 1 .47 (d, J = 6.5 Hz, 6H), 0.912 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 527.6 [M+H]+.
Example 50:
1-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- morpholinophenyl)indoline-4-carboxamide
To a solution of the compound of example 49 (35 mg, 0.066 mmol, 1 .0 equiv) in acetic acid (5 mL) was added sodium cyanoborohydride (42 mg, 0.66 mmol, 10 equiv) and the reaction mass was stirred at room temperature for 16 h. After the reaction was complete, solvent was removed and aqueous saturated NaHC03 solution was added and extracted with ethyl acetate and concentrated. The residue obtained was further purified by column chromatography (silica gel, 3:7 methanohchloroform) to yield solid compound, which was stirred in 2 mL MeOH, filtered and dried to obtain the title compound.
Yield 13 mg (32 %); 1H NMR (DMSO-d6, 500 MHz): δ 1 1 .51 (s, 1 H), 8.14 (s, 1 H), 7.53 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8 Hz, 2H), 6.96 (s, 1 H), 6.69 (s, 1 H), 5.89 (s, 1 H), 4.30 (s, 2H), 3.95 (m 1 H), 3.75 (s, 4H), 3.33 (m, 2H), 3.13 (s, 4H), 3.08 (t, J = 8 Hz, 2H), 2.12 (s, 3H), 1 .46-1 .52 (m, 4H), 1 .10 (d, J = 6.5 Hz, 6H), 0.90 (t, J = 7 Hz, 3H); MS (ESI+): m/z 529.4 [M+H]+. Example 5 :
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(4- morpholinophenyl)-1 H-indole-4-carboxamide
The solution of the compound of example 47 in DMF was treated with the compound of example 9 (1 .5 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 46 %; 1 H NMR (DMSO-d6, 500 MHz): δ 1 1 .54 (s, 1 H), 8.27 (s, 1 H), 7.83 (s, 1 H), 7.83 (s, 2H), 7.68 (d, J = 9.5 Hz, 1 H), 7.66 (s, 1 H), 7.04 (d, J = 8 Hz, 2H), 6.85 (s, 1 H), 5.89 (s, 1 H), 4.91 -4.93 (m, 1 H), 4.38 (d, J = 4 Hz, 2H), 3.77 (s, 4H), 3.15 (s, 4H), 2.23 (s, 3H), 2.12 (s, 3H), 1 .47 (d, J = 6.5 Hz, 6H); MS (ESI+): m/z 499.6 [M+H]+.
Example 52:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(4- morpholinophenyl)indoline-4-carboxamide
The solution of the compound of example 51 in acetic acid was treated with sodium cyanoborohydride (10.0 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 54 %; 1 H NMR (DMSO-d6, 500 MHz): δ 1 .50 (s, 1 H), 8.15 (s, 1 H), 7.54 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 9 Hz, 2H), 6.97 (s, 1 H), 6.69 (s, 1 H), 5.86 (s, 1 H), 3.94-3.97 (m, 1 H), 3.75 (s, 4H), 3.31 (t, J = 8 Hz, 2H), 3.13 (s, 4H), 3.06 (t, J = 8 Hz, 2H), 2.18 (s, 3H), 2.1 1 (s, 3H), 1 .10 (d, J = 6.5 Hz, 6H); MS (ESI+): m/z 501 .5 [M+H]+.
Example 53:
Methyl 6-bromo-1 -sec-butyl-1 H-indole-4-carboxylate
A solution of methyl 6-bromo-1 H-indole-4-carboxylate in DMF was treated with 2-bromobutane (1 .1 equiv) according to the procedure described for the preparation of the compound of example 10 to obtain the title compound.
Yield: 14 %; 1 H NMR (CDCI3, 300 MHz): δ 8.00 (d, J = 1 .5 Hz, 1 H), 7.72 (s, 1 H), 7.32 (d, J = 3.3 Hz, 1 H), 7.15 (d, J = 3.3 Hz, 1 H), 4.37 (q, J = 6.9 Hz, 1 H), 3.99 (s, 3H), 1 .85-1 .95 (m, 2H), 1 .53 (d, J = 6.6 Hz, 3H), 0.84 (t, J = 6.6 Hz, 3H); MS (ESI+): m/z 310 and 312 [M+H]+.
Example 54:
Methyl 6-(6-(4-(tert-butoxycarbonyl)piperazin-1 -yl)pyridin-3-yl)-1 -sec-butyl-1 H- indole-4-carboxylate
A solution of the compound of example 53 in 1 ,4-dioxane was treated with tert-butyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylate (1 .1 equiv) according to the procedure described for the preparation of the compound of example 47 to obtain the title compound.
Yield: 71 %; 1 H NMR (DMSO-d6, 300 MHz): δ 8.54 (d, J = 2.4 Hz, 1 H), 8.08 (s, 1 H), 7.86 (dd, J = 2.4 & 8.7 Hz, 1 H), 7.69 (s, 1 H), 7.36 (d, J = 3 Hz, 1 H), 7.16 (d, J = 3 Hz, 1 H), 6.77 (d, J = 8.78 Hz, 1 H), 4.50 (q, J = 6.9 Hz, 1 H), 4.01 (s, 3H), 3.60 (s, 8H), 1 .87-1 .94 (m, 2H), 1 .56 (d, J = 6.9 Hz, 3H), 1 .27 (s, 9H), 0.96 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 493.4 [M+H]+.
Example 55:
6-(6-(4-(tert-Butoxycarbonyl)piperazin-1 -yl)pyridin-3-yl)-1 -sec-butyl-1 H-indole- 4-carboxylic acid
A solution of the compound of example 54 in MeOH and THF was treated with
1 M NaOH (4.0 equiv) according to the procedure described for the preparation of the compound of example 48 to obtain the title compound.
Yield: 69 %; 1 H NMR (DMSO-d6, 300 MHz): δ 12.80 (bs, 1 H), 8.39 (s, 1 H), 8.35 (d, J = 9 Hz, 1 H), 8.16 (s, 1 H), 7.94 (s, 1 H), 7.70 (d, J = 3 Hz, 1 H), 7.34 (d, J = 9 Hz, 1 H), 7.01 (d, J = 3 Hz, 1 H), 4.78 (q, J = 6 Hz, 1 H), 3.74 (s, 4H), 3.51 (s, 4H), 1 .83-1 .88 (m, 2H), 1 .47 (d, J = 6.6 Hz, 3H), 1 .43 (s, 9H), 0.72 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 479.4 [M+H]+.
Example 56:
tert-Butyl 4-(5-(1 -sec-butyl-4-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methylcarbamoyl)-1 H-indol-6-yl)pyridin-2-yl)piperazine-1 -carboxylate
A solution of the compound of example 55 in DMF was treated with the compound of example 4 (1 .5 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound. Yield: 41 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .54 (bs, 1 H), 8.57 (s, 1 H), 8.25 (s, 1 H), 8.00 (d, J = 8.1 Hz, 1 H), 7.89 (s, 1 H), 7.64 (s, 1 H), 7.55 (s, 1 H), 6.94 (d, J = 8.7 Hz, 1 H), 6.88 (s, 1 H), 5.90 (s, 1 H), 4.70 (q, J = 6.9 Hz, 1 H), 4.39 (s, 2H), 3.53 (s, 4H), 3.44 (s, 4H), 2.50-2.55 (m, 2H), 2.13 (s, 3H), 1 .84 (t, 2H), 1 .52 (t, J = 7.5 Hz, 2H), 1 .43 (bs, 12H), 0.90 (t, J = 7.2 Hz, 3H), 0.72 (t, J = 6.9 Hz, 3H); MS (ESI+): m/z 641 .5 [M+H]+.
Example 57:
tert-Butyl 4-(5-(1 -sec-butyl-4-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methylcarbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate
A solution of the compound of example 56 in acetic acid was treated with sodium cyanoborohydride (5.0 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 47 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .50 (bs, 1 H), 8.42 (s, 1 H), 8.13 (s, 1 H), 7.94 (d, J = 1 1 .4 Hz, 1 H), 6.94 (s, 2H), 6.69 (s, 1 H), 5.88 (s, 1 H), 4.28 (s, 2H), 3.67 (s, 1 H), 3.55 (s, 4H), 3.43 (s, 4H), 3.36 (s, 6H), 3.09 (s, 2H), 2.1 1 (s, 3H), 1 .47- 1 .50 (m, 2H), 1 .42 (s, 9H), 1 .23 (s, 3H), 1 .02 (d, J = 9.6 Hz, 3H), 0.90 (d, J = 5.7 Hz, 3H); MS (ESI+): m/z 643.4 [M+H]+. Example 58A:
6-(6-(4-(tert-butoxycarbonyl)piperazin-1 -yl)pyridin-3-yl)-1 -isopropyl-1 H-indole- 4-carboxylic acid
To a solution of methyl 6-(6-(4-(tert-butoxycarbonyl)piperazin-1 -yl)pyridin-3- yl)-1 -isopropyl-1 H-indole-4-carboxylate (2.8 g, 5.85 mmol) in MeOH (10 mL) was added 1 N NaOH (0.936 g, 23.40 mmol) solution and stirred at 65 °C for 8 h. After completion of the reaction, solvent was removed and dilute HCI was added to make the pH acidic and the resulting mixture was extracted with ethyl acetate. The organic layer obtained was washed with water, concentrated, and further purified by column chromatography (20 % ethyl acetate in chloroform) to obtain the title compound. Yield: 2.0 g (74 %); 1 H NMR (DMSO-d6, 300 MHz): δ 12.73 (s, 1 H),8.55 (s, 1 H), 8.03 (s, 1 H), 7.98 (d, J = 9 Hz, 1 H), 7.93 (s, 1 H), 7.67 (s, 1 H), 6.97 (s, 2H), 4.95-4.98 (m, 1 H), 3.55 (s, 4H), 3.46 (s, 4H), 1 .49 (d, J = 6.5 Hz, 6H), 1 .44 (s, 9H); MS (ESI+): m/z 465.4 [M+H]+. Example 58B:
tert-Butyl 4-(5-(1 -isopropyl-4-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3- yl)methylcarbamoyl)-1 H-indol-6-yl)pyridin-2-yl)piperazine-1-carboxylate
A solution of the compound of example 58A in DMF was treated with the compound of example 6 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 34 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .55 (s, 1 H), 8.58 (d, J = 2.4 Hz, 1 H), 8.31 (d, J = 5.7 Hz, 1 H), 8.01 (dd, J = 2.7 & 8.7 Hz, 1 H), 7.87 (s, 1 H), 7.65 (s, 1 H), 7.58 (d, J = 3 Hz, 1 H), 6.94 (d, J = 9 Hz, 1 H), 6.87 (d, J = 3 Hz, 1 H), 6.02 (s, 1 H), 4.90 (q, J = 9.6 Hz, 1 H), 4.43 (d, J = 4.8 Hz, 2H), 3.53 (d, J = 5.7 Hz, 4H), 3.44 (s, 4H), 3.27-3.28 (m, 1 H), 2.15 (s, 3H), 1 .46 (d, J = 6.6 Hz, 6H), 1 .42 (s, 9H), 1 .10 (d, J = 6.9 Hz, 6H); MS (ESI+): m/z 627.5 [M+H]+.
Example 59:
tert-Butyl 4-(5-(1 -isopropyl-4-(((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin- 3-yl)methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate
A solution of the compound of example 58B in acetic acid was treated with sodium cyanoborohydride (10.0 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 60 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.45 (d, J = 2.1 Hz, 1 H), 8.16 (s, 1 H), 7.85 (dd, J = 2.4 & 6.6 Hz, 1 H), 6.96 (s, 1 H), 6.90 (d, J = 9 Hz, 1 H), 6.71 (s, 1 H), 6.00 (s, 1 H), 4.34 (d, J = 4.5 Hz, 2H), 3.93-3.98 (m, 1 H), 3.51 (d, J = 5.7 Hz, 4H), 3.44 (d, J = 5.4 Hz, 4H), 3.28 (t, 2H), 3.13-3.28 (m, 1 H), 3.07 (t, J = 8.1 Hz, 2H), 2.14 (s, 3H), 1 .42 (s, 9H), 1 .10 (d, J = 6.6 Hz, 12H); MS (ESI+): m/z 629.5 [M+H]+.
Example 60:
1-lsopropyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6- (6-(piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
A solution of compound of example 59 in MeOH was treated with 12 % methanolic HCI followed by treatment with 10 % sodium bicarbonate solution (10 equiv) according to the procedure described in examples 15 and 16 respectively, to obtain the title compound. Yield: 44 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.42 (s, 1 H), 8.16 (s, 1 H), 7.86 (s, 1 H), 6.96 (s, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 6.70 (s, 1 H), 5.99 (s, 1 H), 4.33 (s, 2H), 3.95 (s, 1 H), 3.41 (s, 4H), 3.33 (s, 3H), 3.07 (s, 2H), 2.77 (s, 4H), 2.13 (s, 3H), 1 .09 (d, J = 5.7 Hz, 12H); MS (ESI+): m/z 529.4 [M+H]+.
Example 6 :
tert-Butyl 4-(5-(1 -methyl-4-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methylcarbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate
A solution of the compound of example 26 in MeOH and THF was treated with the compound of example 4 according to the procedure described for the preparation of the compound of example 14 to obtain the title compound.
Yield: 15 mg (38.5 %); 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .51 (s, 1 H), 8.47 (s, 1 H), 8.17 (s, 1 H), 7.90 (d, J = 9 Hz, 1 H), 7.06 (s, 1 H), 6.90 (d, J = 9 Hz, 1 H), 6.80 (s, 1 H), 5.89 (s, 1 H), 4.31 (d, J = 4.5 Hz, 2H), 3.52 (d, J = 5.5 Hz, 4H), 3.43 (s, 4H), 3.27 (t, J = 8 Hz, 2H), 3.10 (t, J = 8 Hz, 2H), 2.76 (s, 3H), 2.47 (t, 2H), 2.12 (s, 3H), 1 .50-1 .55 (m, 2H), 1 .43 (s, 9H), 0.89 (t, J = 7 Hz, 3H); MS (ESI+): m/z 601 .3 [M+H]+.
Example 62:
Methyl 1 -isopropyl-6-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)-1 H-indole-4- carboxylate
A solution of the compound of example 10 in 1 ,4-dioxane was treated with 1 - methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1 .3 equiv) according to the procedure described for the preparation of the compound of example 47 to obtain the title compound.
Yield: 92 %; 1 H NMR (CDCI3, 500 MHz): δ 8.54 (s, 1 H), 8.09 (s, 1 H), 7.84 (d, J = 8.5 Hz, 1 H), 7.70 (d, J = 7.5 Hz 1 H), 7.39 (d, J = 2.5 Hz, 1 H), 7.14 (s, 1 H), 6.78 (d, J = 8.5 Hz 1 H), 4.74-4.79 (m, 1 H), 4.01 (s, 3H), 3.64 (s, 4H), 2.59 (d, J = 4.5 Hz, 4H), 3.38 (s, 3H), 1 .58 (d, J = 6.5 Hz, 6H); MS (ESI+): m/z 393.4 [M+H]+.
Example 63:
1-lsopropyl-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1 H-indole-4-carboxylic acid A solution of the compound of example 62 in MeOH and THF was treated with 1 N NaOH (4.0 equiv) according to the procedure described for the preparation of the compound of example 48 to obtain the title compound.
Yield: 72 %; 1 H NMR (DMSO-d6, 300 MHz): δ 8.53 (d, J = 2.1 Hz, 1 H), 8.01 (s, 1 H), 7.96 (d, J = 2.1 Hz, 1 H), 7.92 (s, 1 H), 7.66 (d, J = 3 Hz 1 H), 6.96 (d, J = 3 Hz, 1 H), 6.92 (s, 1 H), 4.91 -5.00 (m, 1 H), 3.54 (s, 4H), 2.43 (s, 4H), 2.24 (s, 3H), 1 .48 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 379.2 [M+H]+.
Example 64:
1-lsopropyl-N-((6-methyl-2-oxo-4^ropyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)-1 H-indole-4-carboxamide
A solution of the compound of example 63 in DMF was treated with the compound of example 4 according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 42 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .56 (s, 1 H), 8.61 (d, J = 1 .8 Hz, 1 H), 8.27 (s, 1 H), 8.05 (d, J = 6.9 Hz, 1 H), 7.89 (s, 1 H), 7.66 (s, 1 H), 7.60 (d, J = 3 Hz, 1 H), 7.03 (d, J = 9 Hz 1 H), 6.86 (d, J = 1 .8 Hz, 1 H), 5.91 (s, 1 H), 4.90-4.95 (m, 1 H), 3.39 (d, J = 4.8 Hz 2H), 3.73 (s, 4H), 3.07 (s, 4H), 2.69 (s, 3H), 2.54 (d, J = 7.2 Hz, 2H), 2.12 (s, 3H), 1 .54 (t, J = 7.5 Hz, 2H), 1 .46 (d, J = 6.3 Hz, 6H), 0.89 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 541 .3 [M+H]+.
Example 65:
1-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
A solution of the compound of example 64 in acetic acid was treated with sodium cyanoborohydride (10 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 20 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .51 (s, 1 H), 8.43 (d, J = 1 .8 Hz, 1 H), 8.15 (s, 1 H), 7.84 (d, J = 8.7 Hz, 1 H), 6.96 (s, 1 H), 6.88 (d, J = 9 Hz, 1 H), 6.71 (s, 1 H), 5.88 (s, 1 H), 4.29 (d, J = 4.5 Hz, 2H), 4.94-4.98 (m, 1 H), 3.50 (s, 4H), 3.10 (t, J = 8.1 Hz 2H), 3.07 (t, J = 8.1 Hz, 2H), 2.45 (t, 2H), 2.41 (s, 4H), 2.22 (s, 3H), 2.1 1 (s, 3H), 1 .47-1 .54 (m, 2H), 1 .08 (d, J = 6.6 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 543.3 [M+H]+. Example 66:
1-lsopropyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6- (6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1 H-indole-4-carboxamide
A solution of the compound of example 63 in DMF was treated with the compound of example 6 according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 28 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .55 (s, 1 H), 8.61 (s, 1 H), 8.31 (s, 1 H), 8.06 (d, J = 6.9 Hz, 1 H), 7.89 (s, 1 H), 7.65 (s, 1 H), 7.60 (d, J = 3 Hz, 1 H), 7.04 (d, J = 8.7 Hz 1 H), 6.86 (d, J = 3 Hz, 1 H), 6.02 (s, 1 H), 4.90-4.95 (m, 1 H), 4.43 (d, J = 4.5 Hz 2H), 3.27 (s, 3H), 3.03-3.06 (m, 8H), 2.70 (s, 1 H), 2.14 (s, 3H), 1 .46 (d, J = 6.3 Hz, 6H), 1 .10 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 541 .3 [M+H]+.
Example 67:
N-((4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)-1 H-indole-4-carboxamide
A solution of the compound of example 63 in DMF was treated with the compound of example 5 according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 21 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .55 (s, 1 H), 8.56 (d, J = 2.1 Hz, 1 H), 8.28 (s, 1 H), 7.98 (dd, J = 2.1 & 7.8 Hz, 1 H), 7.87 (s, 1 H), 7.65 (s, 1 H), 7.58 (d, J = 3 Hz, 1 H), 6.93 (d, J = 8.7 Hz 1 H), 6.87 (d, J = 3 Hz, 1 H), 5.92 (s, 1 H), 4.89-4.94 (m, 1 H), 4.39 (d, J = 4.8 Hz, 2H), 3.52 (d, J = 4.5 Hz, 4H), 2.58 (q, J = 7.8 Hz, 2H), 2.40 (d, J = 4.8 Hz, 4H), 2.22 (s, 3H), 2.13 (s, 3H), 1 .46 (d, J = 6.6 Hz, 6H), 1 .1 1 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 527.4 [M+H]+.
Example 68:
1-lsopropyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6- (6-(4-methylpiperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
A solution of the compound of example 66 in acetic acid was treated with sodium cyanoborohydride (10 equiv) according to the procedure described for the preparation of example 50 to obtain the title compound.
Yield: 20 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.42 (s, 1 H), 8.16 (s, 1 H), 7.82 (dd, J = 2.1 & 8.7 Hz, 1 H), 6.96 (s, 1 H), 6.87 (d, J = 9 Hz, 1 H), 6.70 (s, 1 H), 5.99 (s, 1 H), 4.34 (d, J = 4.5 Hz, 2H), 4.93-4.98 (m, 1 H), 3.50 (s, 4H), 3.18 (t, J = 7.2 Hz, 2H), 3.10 (t, J = 8.1 Hz, 2H), 2.75 (d, J = 8.1 Hz, 1 H), 2.40 (s, 4H), 2.21 (s, 3H), 2.14 (s, 3H), 1 .10 (d, J = 6.6 Hz, 12H); MS (ESI+): m/z 543.3 [M+H]+.
Example 69:
N-((4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
A solution of the compound of example 67 in acetic acid was treated with sodium cyanoborohydride (10 equiv) according to the procedure described for the preparation of example 50 to obtain the title compound.
Yield: 53 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .51 (s, 1 H), 8.48 (s, 1 H), 8.16 (s, 1 H), 7.93 (d, J = 8.7 Hz, 1 H), 7.01 (s, 1 H), 6.98 (s, 1 H), 6.72 (s, 1 H), 5.90 (s, 1 H), 4.29 (d, J = 4.2 Hz, 2H), 3.92-4.01 (m, 1 H), 3.42 (t, 2H), 3.28 (s, 2H), 3.03-3.10 (m, 8H), 2.74 (s, 3H), 2.56 (s, 2H), 2.12 (s, 3H), 1 .18 (t, J = 7.2 Hz, 3H), 1 .08 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 529.3 [M+H]+.
Example 70:
Methyl 1 -isopropyl-1 H-indole-4-carboxylate
To a solution of methyl 1 H-indole-4-carboxylate (5 g, 28.5 mmol, 1 .0 equiv) in DMF (50 ml_) was added NaH (1 .256 g, 31 .4 mmol) slowly for 10 min at room temperature. To this mixture was added 2-bromopropane (3.22 ml_, 34.2 mmol, 1 .1 equiv) and the reaction mass was stirred at 65 SC for 1 h. After completion of the reaction, water was added and extracted with ethyl acetate. Organic layer was washed with water, concentrated and purified by column chromatography (silica gel, 0.5:9.5 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 5 g (81 %): 1H NMR (CDCI3, 300 MHz): δ 7.92 (d, J = 7.5 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 7.40 (d, J = 3.3 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.17 (d, J = 3 Hz, 1 H), 4.69- 4.78 (m, 1 H), 4.00 (s, 3H), 1 .56 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 218.2 [M+H]+.
Example 71 :
1 -lsopropyl-1 H-indole-4-carboxylic acid
To a solution of the compound of example 70 (1 g, 4.60 mmol, 1 .0 equiv) in MeOH (100 ml_) was added 1 N NaOH (23.01 ml_, 23.01 mmol, 5.0 equiv) solution and the reaction mixture was stirred at 75 SC for 6 h. After completion of the reaction, 1 N HCI was added to adjust pH to 2.0 and solvent was removed, the precipitated solid was filtered, and washed with water and dried to obtain the title compound. Yield: 680 mg (73 %); 1 H NMR (DMSO-d6, 300 MHz): δ 12.57 (s, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 7.5 Hz, 1 H), 7.64 (d, J = 3 Hz, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 6.99 (d, J = 3 Hz, 1 H), 4.77-4.86 (m, 1 H), 1 .46 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 204.2 [M+H]+.
Example 72:
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-1 H- indole-4-carboxamide
To a solution of the compound of example 71 (300 mg, 1 .476 mmol, 1 .0 equiv) in DMF (2 ml_) were added the compound of example 4 (416 mg, 1 .919 mmol, 1 .3 equiv), 2-(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-1 ,1 ,3,3-tetramethylisouronium hexafluorophosphate (V) (842 mg, 2.214 mmol, 1 .5 equiv) and triethylamine (0.309 ml_, 2.214 mmol, 1 .5 equiv) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, water was added and the solid precipitated was filtered, washed with water and dried to yield the solid compound. The crude product obtained was further purified by column chromatography (silica gel, 0.3:9.7 MeOH:CHCI3) to obtain the title compound.
Yield: 200 mg (37 %); 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .56 (s, 1 H), 8.05 (t, J = 5.1 Hz, 1 H), 7.64 (d, J = 8.1 Hz, 1 H), 7.58 (d, J = 3.3 Hz, 1 H), 7.38 (d, J = 7.2 Hz, 1 H), 7.14 (t, J = 7.8 Hz, 1 H), 6.83 (d, J = 3 Hz, 1 H), 5.90 (s, 1 H), 4.77-4.81 (m, 1 H), 4.37 (d, J = 5.1 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.13 (s, 3H), 1 .49-1 .57 (m, 2H), 1 .45 (d, J = 6.6 Hz, 6H), 0.91 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 366.2 [M+H]+.
Example 73:
1-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) indoline-4-carboxamide
To a solution of the compound of example 72 (125 mg, 0.342 mmol, 1 .0 equiv) in acetic acid (10 ml_) was added sodium cyanoborohydride (215 mg, 3.42 mmol, 10 equiv) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, solvent was removed and saturated NaHC03 was added, the mixture obtained was extracted with ethyl acetate and purified by column chromatography (silica gel, 0.6:9.4 methanohchloroform) to obtain the title compound.
Yield: 90 mg (71 %); 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 7.92 (s, 1 H), 6.98 (t, J = 7.5 Hz, 1 H), 6.71 (d, J = 7.8 Hz, 1 H), 6.50 (d, J = 7.5 Hz, 1 H), 5.88 (s, 1 H), 4.26 (d, J = 4.8 Hz, 2H), 3.80 (s, 1 H), 3.26 (t, J = 8.1 Hz, 2H), 3.03 (t, J = 8.1 Hz, 2H), 2.94 (s, 3H), 2.49 (t, 2H), 1 .47-1 .51 (m, 2H), 1 .06 (d, J = 6.6 Hz, 6H), 0.89 (t, J = 6.9 Hz, 3H); MS (ESI+): m/z 368.2 [M+H]+.
Example 74:
tert-Butyl 4-(5-(1 -isopropyl-4-(((1 ,4,6-trimethyl-2-oxo-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)-1 H-indol-6-yl)pyridin-2-yl)piperazine-1-carboxylate
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.
1 H NMR (DMSO-de, 300 MHz): δ 8.59 (d, J = 2.1 Hz, 1 H), 8.24 (s, 1 H), 8.00 (dd, J =
2.4 & 6.6 Hz, 1 H), 7.87 (s, 1 H), 7.65 (s, 1 H), 7.60 (d, J = 3.3 Hz, 1 H), 6.95 (d, J = 9 Hz 1 H), 6.86 (d, J = 2.7 Hz, 1 H), 6.04 (s, 1 H), 4.90-4.94 (m, 1 H), 4.40 (d, J = 5.1 Hz, 2H), 3.52 (d, J = 5.4 Hz, 4H), 3.42 (s, 7H), 2.30 (s, 3H), 2.24 (s, 3H), 1 .45 (d, J = 6.3 Hz, 6H), 1 .43 (s, 9H); MS (ESI+): m/z 613.4 [M+H]+.
Example 75:
1-lsopropyl-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-N-((1 ,4,6-trimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)-1 H-indole-4-carboxamide
A solution of the compound of example 63 in DMF was treated with the compound of example 7 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 65 %; 1H NMR (DMSO-d6, 300 MHz): δ 8.62 (s, 1 H), 8.25 (s, 1 H), 8.06 (d, J =
7.5 Hz, 1 H), 7.89 (s, 1 H), 7.66 (s, 1 H), 7.61 (d, J = 2.7 Hz, 1 H), 7.04 (d, J = 8.7 Hz 1 H), 6.58 (s, 1 H), 6.05 (s, 1 H), 4.90-4.94 (m, 1 H), 4.40 (d, J = 4.5 Hz, 2H), 3.73 (s, 4H), 3.42 (s, 3H), 3.15 (s, 4H), 2.74 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H), 1 .46(d, J = 6.3 Hz, 6H); MS (ESI+): m/z 527.3 [M+H]+.
Example 76:
tert-Butyl 4-(5-(1 -isopropyl-4-(((1 ,4,6-trimethyl-2-oxo-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate
A solution of the compound of example 74 in acetic acid was treated with sodium cyanoborohydride (25 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 55 %; 1H NMR (DMSO-d6, 300 MHz) δ 8.46 (d, J = 2.1 Hz, 1 H), 8.13 (s, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 6.98 (s, 1 H), 6.90 (d, J = 9 Hz, 1 H), 6.71 (s, 1 H), 6.02 (s, 1 H), 4.31 (d, J = 4.8 Hz, 2H), 3.93-3.98 (m, 1 H), 3.52 (d, J = 4.5 Hz, 4H), 3.43 (s, 3H), 3.41 (s, 4H), 3.30 (t, J = 7.8 Hz, 2H), 3.06 (t, J = 7.8 Hz, 2H), 2.29 (s, 3H), 2.18 (s, 3H), 1 .42 (s, 9H), 1 .06 (d, J = 6.6 Hz, 6H); MS (ESI+) m/z 615.4 [M+H]+.
Example 77:
1 -lsopropyl-6-(6-(piperazin-1 -yl)pyridin-3-yl)-N-((1 ,4,6-trimethyl-2-oxo-1 ,2- dihydropyridin-3-yl)methyl)indoline-4-carboxamide
A solution of compound of example 76 in MeOH was treated with 12 % methanolic HCI followed by treatment with 10 % sodium bicarbonate solution (10 equiv) according to the procedure described in examples 15 and 16 respectively, to obtain the title compound.
Yield: 50 %; 1 H NMR (DMSO-d6, 300 MHz): δ 8.43 (s, 1 H), 8.1 1 (s, 1 H), 7.83 (s, 1 H), 6.96 (s, 1 H), 6.84 (s, 1 H), 6.69 (s, 1 H), 6.01 (s, 1 H), 4.30 (s, 2H), 3.94 (s, 1 H), 3.40 (s, 4H), 3.32 (s, 2H), 3.03 (s, 2H), 2.79 (s, 4H), 2.28 (s, 3H), 2.18 (s, 3H), 1 .42 (s, 3H), 1 .07 (s, 6H); MS (ESI+): m/z 515.3 [M+H]+.
Example 78:
1-lsopropyl-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-N-((1 ,4,6-trimethyl-2-oxo- ,2-dihydropyridin-3-yl)methyl)indoline-4-carboxamide
A solution of the compound of example 75 in acetic acid was treated with sodium cyanoborohydride (20 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound. Yield: 63 %; 1H NMR (DMSO-d6, 300 MHz): δ 8.43 (s, 1 H), 8.12 (s, 1 H), 7.84 (d, J = 9 Hz, 1 H), 6.97 (s, 1 H), 6.88 (d, J = 9 Hz, 1 H), 6.70 (s, 1 H), 6.02 (s, 1 H), 4.31 (d, J = 4.8 Hz, 2H), 3.90-3.99 (m, 1 H), 3.50 (s, 4H), 3.41 (s, 3H), 3.30 (t, 2H), 3.09 (t, J = 7.8 Hz, 2H), 2.41 (s, 4H), 2.30 (s, 3H), 2.22 (s, 3H), 2.19 (s, 3H), 1 .09 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 529.3 [M+H]+.
Example 79:
1-lsopropyl-N-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-(6-(4-methyl piperazin-1 -yl)pyridin-3-yl)-1 H-indole-4-carboxamide
A solution of the compound of example 63 in DMF was treated with (2- methoxy-4,6-dimethylpyridin-3-yl)methanamine (1 .3 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 56 %; 1H NMR (DMSO-d6, 300 MHz): δ 8.55 (s, 1 H), 8.30 (s, 1 H), 7.95 (d, J = 8.4 Hz, 1 H), 7.84 (s, 1 H), 7.60 (s, 1 H), 7.55 (s, 1 H), 6.91 (d, J = 8.7 Hz, 1 H), 6.80 (s, 1 H), 6.69 (s, 1 H), 4.90 (s, 1 H), 4.46 (s, 2H), 3.86 (s, 3H), 3.51 (s, 4H), 2.40 (s, 4H), 2.32 (s, 6H), 2.21 (s, 3H), 1 .44 (d, J = 6.3 Hz, 6H); MS (ESI+): m/z 527.3 [M+H]+.
Example 80:
1-lsopropyl-N-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-(6-(4-methyl piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide
A solution of the compound of example 79 in acetic acid was treated with sodium cyanoborohydride (20 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 26 %; 1H NMR (DMSO-d6, 300 MHz): δ 8.41 (s, 1 H), 8.18 (s, 1 H), 7.82 (d, J = 8.7 Hz, 1 H), 6.93 (s, 1 H), 6.86 (d, J = 8.7 Hz, 1 H), 6.69 (s, 1 H), 6.67 (s, 1 H), 4.37 (d, J = 8.7 Hz, 2H), 3.92-3.97 (m, 1 H), 3.49 (s, 4H), 3.27 (t, 2H), 3.03 (t, J = 8.1 Hz, 2H), 2.41 (s, 4H), 2.31 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 1 .22 (s, 3H), 1 .07 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 529.3 [M+H]+.
Example 8 :
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.
Yield: 56 %; 1H NMR (CDCI3, 300 MHz): δ 8.94 (s, 1 H), 8.59 (s, 1 H), 8.13 (s, 1 H), 8.00 (d, J = 7.5 Hz, 1 H), 7.76 (s, 1 H), 7.46 (s, 1 H), 7.39 (s, 1 H), 7.16 (s, 1 H), 4.77- 4.81 (m, 1 H), 4.01 (s, 3H), 1 .59 (d, J = 6.3 Hz, 6H); MS (ESI+): m/z 295.1 [M+H]+.
Example 82:
1 -lsopropyl-6-(pyridin-3-yl)-1 H-indole-4-carboxylic acid
A solution of the compound of example 81 in MeOH and THF was treated with
1 N NaOH (4.0 equiv) according to the procedure described for the preparation of the compound of example 48 to obtain the title compound.
Yield: 49 %; 1H NMR (DMSO-d6, 300 MHz): δ 12.83 (bs, 1 H), 8.98 (s, 1 H), 8.54 (s, 1 H), 8.17 (s, 2H), 8.00 (s, 1 H), 7.72 (s, 1 H), 7.48 (s, 1 H), 7.00 (s, 1 H), 4.49 (s, 1 H), 1 .48 (d, J = 5.4 Hz, 6H); MS (ESI+): m/z 281 .1 [M+H]+.
Example 83:
1-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6- (pyridin-3-yl)-1 H-indole-4-carboxamide
A solution of the compound of example 82 in DMF was treated with the compound of example 4 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 28 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .54 (s, 1 H), 9.02 (s, 1 H), 8.51 (s, 1 H), 8.32 (s, 1 H), 8.18 (d, J = 7.8 Hz, 1 H), 8.02 (s, 1 H), 7.73 (s, 1 H), 7.64 (s, 1 H), 7.47 (s, 1 H), 6.90 (s, 1 H), 5.89 (s, 1 H), 4.95 (s, 1 H), 4.38 (s, 2H), 2.52 (t, 2H), 2.1 1 (s, 3H), 1 .47-1 .50 (m, 2H), 1 .46 (d, J = 6.3 Hz, 6H), 0.88 (t, J = 6.9 Hz, 3H); MS (ESI+): m/z 443.2 [M+H]+.
Example 84:
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6- (pyridin-3-yl)indoline-4-carboxamide
A solution of the compound of example 83 in acetic acid was treated with sodium cyanoborohydride (10 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound. Yield: 90 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.92 (s, 1 H), 8.62 (s, 2H), 8.24 (s, 1 H), 7.91 -7.95 (m, 1 H), 7.1 1 (s, 1 H), 6.94 (s, 1 H), 5.87 (s, 1 H), 4.30 (d, J = 4.8 Hz, 2H), 4.00-4.05 (m, 1 H), 3.31 -2.39 (m, 4H), 3.12 (t, J = 7.8 Hz, 2H), 2.10 (s, 3H), 1 .46-1 .53 (m, 2H), 1 .08 (d, J = 6.6 Hz, 6H), 0.87 (t, 7.2 Hz, 3H); MS (ESI+): m/z 445.2 [M+H]+.
Example 85:
tert-Butyl 4-(5-(1 -ethyl-4-(((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate
A solution of the compound of example 39 in DMF was treated with the compound of example 6 according to the procedure described for the preparation of the compound of example 40 to obtain the title compound.
Yield: 33 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.46 (s, 1 H), 8.20 (s, 1 H), 7.90 (m, 1 H), 7.01 (s, 1 H), 6.91 (d, J = 9 Hz, 1 H), 6.77 (s, 1 H), 6.00 (s, 1 H), 4.35 (s, 2H), 3.51 (s, 4H), 3.42 (s, 4H), 3.23 (m, 2H), 3.20 (m, 4H), 3.1 1 (m, 1 H), 2.50 (s, 3H), 1 .42 (s, 9H), 1 .20 (t, 3H), 1 .12 (d, J = 6.9 Hz, 6H); MS (ESI+): m/z 615 (M+H)+.
Example 86:
1 -Ethyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
To a solution of compound of example 85 (50 mg, 0.081 mmol) in MeOH (5 ml_) was added 10 % methanolic HCI and stirred reaction mixture at room temperature for 16 h. After completion of the reaction, solvent was removed and resulting oily compound was stirred in petroleum ether, the solvent was decanted and the residue obtained was dried to obtain the title compound.
Yield: 30 mg (71 %); 1H NMR (CD3OD, 300 MHz): δ 8.37 (s, 1 H), 7.87 (d, J = 9.6 Hz, 1 H), 7.00 (s, 1 H), 6.92 (d, J = 6.3 Hz, 1 H), 6.75 (s, 1 H), 6.26 (s, 1 H), 4.65 (s, 2H), 4.55 (s, 1 H), 3.60 (s, 4H), 3.55 (m, 2H), 3.13 (m, 2H), 3.08 (m, 2H) 3.03 (s, 4H), 2.49 (s, 3H), 1 .63 (t, 3H), 1 .30 (d, J = 6.9 Hz, 6H); MS (ESI+): m/z 514.7 (M+H)+.
Example 87:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(2-(dimethylamino) pyrimidin-5-yl)-1-isopropylindoline-4-carboxamide A solution of the compound of example 1 1 in THF was treated with N,N- dimethylpyrimidin-2-amine according to the procedure of example 12, followed by treatment with the compound of example 9 according to the procedure described for the preparation of the compound of example 13 and example 14 respectively to obtain the title compound.
Yield: 43 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .46 (bs, 1 H), 9.69 (bs, 1 H), 8.23 (s, 1 H), 6.70 (s, 1 H), 6.64 (s, 1 H), 6.52 (s, 1 H), 5.83 (s, 1 H), 4.21 (s, 4H), 3.93 (m, 1 H), 3.31 (m, 2H), 3.01 (s, 6H), 2.14 (s, 3H), 2.08 (s, 3H), 1 .10 (d, J = 6.3 Hz, 6H); MS (ESI+): m/z 461 (M+H)+.
Example 88:
1-lsopropyl-N-((6-methyl-2-oxo-4^ropyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- (trifluoromethyl)phenyl)indoline-4-carboxamide
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.
Yield: 46 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (bs, 1 H), 8.20 (s, 1 H), 7.85 (s, 2H), 7.76 (s, 2H), 7.06 (s, 1 H), 6.79 (s, 1 H), 5.87 (s, 1 H), 4.28 (s, 2H), 3.97 (s, 1 H), 3.31 (s, 2H), 3.09 (s, 2H), 2.48(s, 2H), 2.10 (s, 3H), 1 .48 (m, 2H), 1 .10 (d, J = 6.3 Hz, 6H), 0.87 (s, 3H); MS (ESI+): m/z 512 (M+H)+.
Example 89:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6- (piperidin-1-yl)pyridin-3-yl)indoline-4-carboxamide
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.
Yield: 46 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (bs, 1 H), 8.40(s, 1 H), 8.13 (s, 1 H), 7.81 (m, 1 H), 6.95 (s, 1 H), 6.85 (m, 1 H), 6.68 (s, 1 H), 5.84 (s, 1 H), 4.26 (s, 2H), 3.94 (s, 1 H), 3.52 (s, 4H), 3.31 (s, 2H), 3.08 (m, 2H), 2.22 (s, 3H), 2.16 (s, 3H), 1 .54 (bs, 6H), 1 .07 (d, J = 6.3 Hz, 6H); MS (ESI+): m/z 500 (M+H)+. Example 90:
1-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperidin-1-yl)pyridin-3-yl)indoline-4-carboxamide
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.
Yield: 49 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .54 (bs, 1 H), 8.39 (s, 1 H), 8.12 (s, 1 H), 7.76 (m, 1 H), 6.94 (s, 1 H), 6.84 (m, 1 H), 6.68 (s, 1 H), 5.87 (s, 1 H), 4.27 (s, 2H), 3.94 (s, 1 H), 3.52 (s, 4H), 3.05 (m, 2H), 2.10 (s, 3H), 1 .79 (m, 4H), 1 .53 (bs, 8H), 1 .09 (d, J = 6.3 Hz, 6H), 0.87 (t, 3H); MS (ESI+): m/z 528 (M+H)+.
Example 9 :
6-(2-(Dimethylamino)pyrimidin-5-yl)-1-isopropyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)indoline-4-carboxamide
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.
Yield: 38.4 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .52 (s, 1 H), 7.98 (s, 1 H), 6.84 (s, 1 H), 6.50 (s, 1 H), 6.39 (s, 1 H), 6.87 (s, 1 H), 4.24 (s, 1 H), 4.10 (s, 2H), 3.85 (m, 1 H), 3.31 (m, 2H), 2.85 (m, 4H), 2.10 (s, 3H), 1 .79 (s, 3H), 1 .74 (s, 3H), 1 .48 (m, 2H), 1 .10 (d, J = 6.6 Hz, 6H), 0.90 (t, 3H); MS (ESI+): m/z 489 (M+H)+.
Example 92:
Methyl 6-bromo-1 -(cyclobutylmethyl)-l H-indole-4-carboxylate
A solution of methyl 6-bromo-1 H-indole-4-carboxylate in DMF was treated with bromomethylcyclobutane (1 .5 equiv) according to the procedure described for the preparation of the compound of example 10 to obtain the title compound.
Yield: 55 %; 1 H NMR (CDCI3, 300 MHz): δ 8.00 (s, 1 H), 7.69 (s, 1 H), 7.22 (d, J = 3.0 Hz, 1 H), 7.09 (d, J = 3.0 Hz, 1 H), 4.12 (d, J = 7.2 Hz, 2H), 3.99 (s, 3H), 2.87 - 2.78 (m, 1 H), 2.08 - 2.06 (m, 2H), 1 .98 - 1 .95 (m, 1 H), 1 .92 - 1 .90 (m, 1 H), 1 .88 - 1 .87 (m, 1 H), 1 .85 - 1 .82 (m, 1 H); MS (ESI+): m/z 323.2 (M+H)+.
Example 93:
Methyl 1 -(cyclobutylmethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1 H-indole-4- carboxylate
A solution of the compound of example 92 in dioxane was treated with 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (1 .4 equiv) according to the procedure described for the preparation of the compound of example 47 to obtain the title compound.
Yield: 44 %; 1 H NMR (CDCI3, 500 MHz): δ 9.05 (s, 1 H), 8.13 (s, 2H), 7.80 (d, J = 8.0 Hz, 1 H), 7.76 (s, 1 H), 7.35 (d, J = 2.5 Hz, 1 H), 7.16 (d, J = 2.5 Hz, 1 H), 4.25 (d, J = 7.0 Hz, 2H), 4.05 (s, 3H), 2.91 - 2.85 (m, 1 H), 2.12 - 2.10 (m, 2H), 1 .98 - 1 .91 (m, 2H), 1 .88 - 1 .83 (m, 2H); MS (ESI+): m/z 389.3 (M+H)+.
Example 94:
1-(Cyclobutylmethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1 H-indole-4-carboxylic acid
A solution of the compound of example 93 in MeOH and THF was treated with 1 M aqueous NaOH solution (4.0 equiv) according to the procedure described for the preparation of the compound of example 48 to obtain the title compound.
Yield: 57 %; 1 H NMR (DMSO-d6, 500 MHz): δ 12.92 (bs, 1 H), 9.21 (s, 1 H), 8.48 (d, J = 8.0 Hz, 1 H), 8.32 (s, 1 H), 8.09 (s, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.66 (d, J = 2.5 Hz, 1 H), 6.98 (d, J = 2.5 Hz, 1 H), 4.37 (d, J = 7.5 Hz, 2H), 2.87 - 2.82 (m, 1 H), 1 .99 - 1 .94 (m, 2H), 1 .88 - 1 .79 (m, 4H); MS (ESI+): m/z 375.4 (M+H)+.
Example 95:
1-(Cyclobutylmethyl)-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3- yl)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1 H-indole-4-carboxamide
A solution of the compound of example 94 in DMF was treated with the compound of example 4 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 38 %; 1 H NMR (DMSO-d6, 500 MHz): δ 1 .56 (s, 1 H), 9.23 (s, 1 H), 8.50 (d, J = 8 Hz, 1 H), 8.36 (s, 1 H), 8.17 (s, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.83 (s, 1 H), 7.58 (s, 1 H), 6.90 (s, 1 H), 5.91 (s, 1 H), 4.41 (d, J = 4.5 Hz, 2H), 4.34 (d, J =7.0 Hz, 2H), 2.56
- 2.534 (m, 2H), 2.13 (s, 3H), 1 .94 - 1 .91 (m, 2H), 1 .85 - 1 .79 (s, 5H), 1 .56 - 1 .51 (q, J = 7.5 Hz, 2H), 0.90 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 537.6 (M+H)+. Example 96:
1-(Cyclobutylmethyl)-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3- yl)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)indoline-4-carboxamide
A solution of the compound of example 95 in acetic acid was treated with sodium cyanoborohydride (7.0 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 62 %; 1 H NMR (DMSO-d6, 500 MHz): δ 1 1 .50 (s, 1 H), 9.10 (s, 1 H), 8.37 (d, J = 8.0 Hz, 1 H), 8.23 (s, 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 7.18 (s, 1 H), 6.91 (s, 1 H), 5.89 (s, 1 H), 4.31 (d, J = 4.5 Hz, 2H), 3.36 (m, 2H), 3.20 (d, J = 7.0 Hz, 2H), 3.16 - 3.12 (m, 2H), 2.64 (m, 1 H), 2.12 (s, 3H), 2.06 (m, 2H), 1 .90 - 1 .86 (q, J = 8.5 Hz, 2H), 1 .78 - 1 .66 (q, J = 8.50 Hz, 2H), 1 .52 - 1 .50 (m, 2H), 1 .23 (s, 2H), 0.89 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 539.3 (M+H)+.
Example 97:
1-(Cyclobutylmethyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6- (6-(trifluoromethyl)pyridin-3-yl)-1 H-indole-4-carboxamide
A solution of the compound of example 94 in DMF was treated with the compound of example 9 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 76 %; 1 H NMR (DMSO-d6, 500 MHz): δ 1 .54 (s, 1 H), 9.24 (s, 1 H), 8.50 (d, J = 8.0 Hz, 1 H), 8.36 (s, 1 H), 8.17 (s, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.83 (s, 1 H), 7.57 (s, 1 H), 6.90 (s, 1 H), 5.89 (s, 1 H), 4.39 (d, J = 6.0 Hz, 2H), 4.33 (d, J =7.0 Hz, 2H), 2.84
- 2.73 (m, 1 H), 2.23 (s, 3H), 2.12 (s, 3H), 1 .94 - 1 .93 (m, 2H), 1 .85 - 1 .79 (s, 4H); MS (ESI+): m/z 509.4 (M+H)+. Example 98:
1-(Cyclobutylmethyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6- (6-(trifluoromethyl)pyridin-3-yl)indoline-4-carboxamide A solution of the compound of example 97 in acetic acid was treated with sodium cyanoborohydride (7.0 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 52 %; 1 H NMR (DMSO-d6, 500 MHz): δ 1 1 .49 (s, 1 H), 9.24 (s, 1 H), 8.38 (d, J = 8.0 Hz, 1 H), 8.23 (s, 1 H), 8.17 (s, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.19 (s, 1 H), 5.87 (s, 1 H), 4.29 (d, J = 4.0 Hz, 2H), 3.37 (m, 2H), 3.20 (d, J = 7.0 Hz, 2H), 3.14 (t, J = 8.0 Hz, 2H), 2.66 - 2.63 (m, 1 H), 2.18 (s, 3H), 2.1 1 (s, 3H), 2.06 (m, 2H), 1 .90 - 1 .86 (m, 2H), 1 .78 - 1 .74 (m, 2H); MS (ESI+): m/z 51 1 .3 (M+H)+.
Example 99:
Methyl 1-(cyclobutylmethyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1 H- indole-4-carboxylate
A solution of the compound of example 92 in dioxane was treated with 1 - methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1 .4 equiv) according to the procedure described for the preparation of the compound of example 47 to obtain the title compound.
Yield: 77 %; 1 H NMR (CDCI3, 300 MHz): δ 8.54 (d, J = 2.1 Hz, 1 H), 8.09 (s, 1 H), 7.85 - 7.82 (dd, J = 2.4 Hz, 1 H), 7.66 (s, 1 H), 7.25 (d, J = 3.0 Hz, 1 H), 7.09 (d, J = 3.0 Hz, 1 H), 6.79 (d, J = 8.7 Hz, 1 H), 4.20 (d, J = 7.2 Hz, 2H), 4.01 (s, 3H), 3.64 (t, J = 5.1 Hz, 4H), 2.88 - 2.83 (m, 1 H), 2.58 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H), 2.09 - 2.03 (m, 2H), 1 .88 - 1 .85 (m, 2H), 1 .82 - 1 .79 (m, 2H); MS (ESI+): m/z 419.4 (M+H)+.
Example 100:
1 -(Cyclobutylmethyl)-6-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)-1 H-indole-4- carboxylic acid
A solution of the compound of example 99 in MeOH and THF was treated with 1 M aqueous NaOH solution (4.0 equiv) according to the procedure described for the preparation of the compound of example 48 to obtain the title compound.
Yield: 29 %; 1 H NMR (DMSO-d6, 300 MHz): δ 8.35 (d, J = 2.4 Hz, 1 H), 8.02 (s, 1 H), 7.95 (d, J = 2.4 Hz, 1 H), 7.92 (s, 1 H), 7.52 (d, J = 3.0 Hz, 1 H), 6.96 (d, J = 8.7 Hz, 1 H), 6.91 (d, J = 2.7 Hz, 1 H), 4.31 (d, J = 7.2 Hz, 2H), 3.54 (m, 4H), 2.85 - 2.77 (m, 1 H), 2.45 (m, 4H), 2.24 (s, 3H), 1 .95 - 1 .93 (m, 2H), 1 .90 - 1 .75 (m, 4H); MS (ESI+): m/z 405.3 (M+H)+. Example 10 :
1-(Cyclobutylmethyl)-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl )-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1 H-indole-4-carboxamide
A solution of the compound of example 100 in DMF was treated with the compound of example 4 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 43 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .56 (s, 1 H), 8.60 (s, 1 H), 8.27 (bs, 1 H), 8.05 (d, J = 6.6 Hz, 1 H), 7.89 (s, 1 H), 7.65 (s, 1 H), 7.47 (d, J = 3.0 Hz, 1 H), 7.04 (d, J = 8.7 Hz, 1 H), 6.81 (d, J = 2.7 Hz, 1 H), 5.91 (s, 1 H), 4.39 (d, J = 4.5 Hz, 2H), 4.29 (d, J = 7.2 Hz, 2H), 4.09 - 3.99 (m, 1 H), 3.17 (d, J = 4.2 Hz, 1 H), 3.05 (bs, 4H), 2.68 (s, 3H), 2.12 (s, 3H), 1 .92 (m, 2H), 1 .87 (m, 4H), 1 .54 - 1 .22 (m, 2H), 1 .23 (s, 3H), 1 .17 (t, J = 7.2 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 567.3 (M+H)+.
Example 102:
1-(Cyclobutylmethyl)-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl )-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
A solution of the compound of example 101 in acetic acid was treated with sodium cyanoborohydride (7.0 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 33 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.43 (s, 1 H), 8.14 (bs, 1 H), 7.85 (d, J = 6.6 Hz, 1 H), 6.99 (s, 1 H), 6.89 (d, J = 9.0 Hz, 1 H), 6.77 (s, 1 H), 5.88 (s, 1 H), 4.30 (d, J = 4.5 Hz, 2H), 3.50 (m, 4H), 3.15 (d, J = 7.2 Hz, 2H), 3.07 (m, 2H), 2.62 - 2.59 (m, 1 H), 2.45 (m, 2H), 2.39 (m, 4H), 2.21 (s, 3H), 2.1 1 (s, 3H), 2.04 (m, 2H), 1 .86 - 1 .80 (m, 3H), 1 .78 - 1 .72 (m, 3H), 1 .54 - 1 .47 (q, J = 7.5 Hz, 2H), 0.88 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 569.5 (M+H)+.
Example 103:
Methyl 6-(6-(4-(tert-butoxycarbonyl)piperazin-1 -yl)pyridin-3-yl)-1 -(cyclobutyl methyl )-1 H-indole-4-carboxylate
A solution of the compound of example 92 in dioxane was treated with tert- butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylate (1 .4 equiv) according to the procedure described for the preparation of the compound of example 47 to obtain the title compound. Yield: 53 %; 1 H NMR (CDCI3, 500 MHz): δ 8.55 (s, 1 H), 8.09 (s, 1 H), 7.86 (d, J = 4.5 Hz, 1 H), 7.66 (s, 1 H), 7.25 (d, J = 2.5 Hz, 1 H), 7.10 (d, J = 2.5 Hz, 1 H), 6.78 (d, J = 8.5 Hz, 1 H), 4.20 (d, J = 7.0 Hz, 2H), 4.02 (s, 3H), 3.61 (s, 8H), 2.88 - 2.85 (m, 1 H), 2.09 - 2.08 (m, 2H), 1 .94 - 1 .90 (m, 2H), 1 .87 - 1 .82 (m, 2H), 1 .52 (s, 9H); MS (ESI+): m/z 505.3 (M+H)+.
Example 104:
6-(6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1-(cyclobutylmethyl)- 1 H-indole-4-carboxylic acid
A solution of the compound of example 103 in MeOH and THF was treated with 1 M aqueous NaOH solution (4.0 equiv) according to the procedure described for the preparation of the compound of example 48 to obtain the title compound. Yield: 86 %; 1 H NMR (CDCI3, 500 MHz): δ 8.54 (s, 1 H), 7.96 (d, J = 8.5 Hz, 1 H), 7.91 - 7.89 (m, 2H), 7.44 (s, 1 H), 6.97 - 6.95 (m, 2H), 4.28 (d, J = 7.0 Hz, 2H), 3.54 (s, 4H), 3.46 (s, 4H), 2.82 - 2.80 (m, 1 H), 1 .95 (m, 2H), 1 .85 - 1 .79 (m, 4H), 1 .44 (s, 9H); MS (ESI+): m/z 491 .4 (M+H)+.
Example 105:
ieri-Butyl 4-(5-(1 -(cyclobutylmethyl)-4-(((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)carbamoyl)-1 H-indol-6-yl)pyridin-2-yl)piperazine-1 - carboxylate
A solution of the compound of example 104 in DMF was treated with the compound of example 4 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 28 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .56 (s, 1 H), 8.57 (s, 1 H), 8.27 (m, 1 H), 8.00 (d, J = 7.8 Hz, 1 H), 7.87 (m, 1 H), 7.64 (s, 1 H), 7.44 (d, J = 3.0 Hz, 1 H), 6.96 (d, J = 8.7 Hz, 1 H), 6.81 (d, J = 3.0 Hz, 1 H), 5.90 (s, 1 H), 4.39 (d, J = 4.5 Hz, 2H), 4.08 (d, J = 7.2 Hz, 2H), 3.52 (s, 4H), 3.44 (s, 4H), 2.79 (m, 1 H), 2.56 (m, 2H), 2.12 (s, 3H), 1 .98 - 1 .92 (m, 2H), 1 .81 (m, 4H), 1 .54 - 1 .49 (q, J = 7.5 Hz, 2H), 1 .43 (s, 9H), 0.89 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 653.4 (M+H)+. Example 106:
ieri-Butyl 4-(5-(1 -(cyclobutylmethyl)-4-(((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1- carboxylate
A solution of the compound of example 105 in acetic acid was treated with sodium cyanoborohydride (7.0 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 65 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.45 (s, 1 H), 8.14 (m, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 6.99 (m, 1 H), 6.99 (d, J = 8.7 Hz, 1 H), 6.77 (s, 1 H), 5.88 (s, 1 H), 4.28 (d, J = 4.5 Hz, 2H), 3.51 (s, 4H), 3.43 (s, 4H), 2.27 (m, 2H), 3.15 - 3.13 (m, 2H), 3.10 -3.07 (m, 2H), 2.69 - 2.59 (m, 1 H), 2.1 1 (s, 3H), 2.04 (bs, 2H), 1 .86 - 1 .84 (m, 3H), 1 .80 - 1 .74 (m, 2H), 1 .51 - 1 .49 (m, 3H), 1 .42 (s, 9H), 0.88 (t, J = 6.9 Hz, 3H); MS (ESI+): m/z 655.4 (M+H)+.
Example 107:
ieri-Butyl 4-(5-(1 -(cyclobutylmethyl)-4-(((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin- 3-yl)methyl)carbamoyl)-1 H-indol-6-yl)pyridin-2-yl)piperazine-1-carboxylate
A solution of the compound of example 104 in DMF was treated with the compound of example 9 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 38 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .55 (s, 1 H), 8.58 (s, 1 H), 8.29 - 8.26 (m, 1 H), 8.01 (d, J = 7.8 Hz, 1 H), 7.87 (m, 1 H), 7.65 (s, 1 H), 7.53 - 7.49 (dd, J = 4.5 Hz, 1 H), 6.96 (d, J = 8.7 Hz, 1 H), 6.82 (s, 1 H), 5.88 (s, 1 H), 4.37 (d, J = 4.5 Hz, 2H), 4.28 (d, J = 6.9 Hz, 2H), 3.52 (s, 4H), 3.44 (s, 4H), 2.78 (m, 1 H), 2.56 (m, 2H), 2.22 (s, 1 H), 2.1 1 (s, 3H), 1 .90 (m, 2H), 1 .81 (m, 4H), 1 .43 (s, 9H); MS (ESI+): m/z 625.5 (M+H)+.
Example 108:
Methyl 6-bromo-1 -isobutyl-1 H-indole-4-carboxylate
A solution of methyl 6-bromo-1 H-indole-4-carboxylate in DMF was treated with 1 -bromo-2-methylpropane (1 .5 equiv) according to the procedure described for the preparation of the compound of example 10 to obtain the title compound. Yield: 55 %; 1 H NMR (CDCI3, 300 MHz): δ 8.00 (s, 1 H), 7.67 (s, 1 H), 7.21 (d, J = 3.0 Hz, 1 H), 7.10 (d, J = 3.0 Hz, 1 H), 3.99 (s, 3H), 3.92 (d, J = 7.5 Hz, 2H), 2.23 - 2.14 (m, 1 H), 0.94 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 310.9 (M+H)+. Example 109:
Methyl 6-(6-(4-(tert-butoxycarbonyl)piperazin-1 -yl)pyridin-3-yl)-1 -isobutyl-1 H- indole-4-carboxylate
A solution of the compound of example 108 in dioxane was treated with tert- butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylate (1 .4 equiv) according to the procedure described for the preparation of the compound of example 47 to obtain the title compound.
Yield: 84 %; 1 H NMR (DMSO-d6, 300 MHz): δ 8.55 (d, J = 2.4 Hz, 1 H), 8.06 (s, 1 H), 7.94 (m, 2H), 7.56 (d, J = 3.0 Hz, 1 H), 6.98 (d, J = 9.0 Hz, 1 H), 6.92 (d, J = 3.0 Hz, 1 H), 4.12 (d, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.55 - 3.53 (m, 4H), 3.46 - 3.45 (m, 4H), 2.20 - 2.10 (m, 1 H), 1 .43 (s, 9H), 0.86 (d, J = 6.3 Hz, 6H); MS (ESI+): m/z 514.6 (M+Na)+.
Example 110:
6-(6-(4-(tert-Butoxycarbonyl)piperazin-1 -yl)pyridin-3-yl)-1 -isobutyl-1 H-indole-4- carboxylic acid
A solution of the compound of example 109 in MeOH and THF was treated with 1 M aqueous NaOH solution (4.0 equiv) according to the procedure described for the preparation of the compound of example 48 to obtain the title compound. Yield: 79 %; 1H NMR (DMSO-d6, 300 MHz): δ 12.74 (bs, 1 H), 8.55 (d, J = 2.4 Hz, 1 H), 8.01 (s, 1 H), 7.98 - 7.94 (dd, J = 2.4 Hz, 1 H), 7.92 (s, 1 H), 7.51 (d, J = 3.0 Hz, 1 H), 6.97 (d, J = 8.7 Hz, 1 H), 6.93 (d, J = 3.0 Hz, 1 H), 4.1 1 (d, J = 7.2 Hz, 2H), 3.55 - 3.53 (m, 4H), 3.45 (m, 4H), 2.15 (m, 1 H), 1 .43 (s, 9H), 0.86 (d, J = 6.3 Hz, 6H); MS (ESI+): m/z 479.3 (M+H)+. Example 111 :
ieri-Butyl 4-(5-(1 -isobutyl-4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)-1 H-indol-6-yl)pyridin-2-yl)piperazine-1 -carboxylate A solution of the compound of example 1 10 in DMF was treated with the compound of example 4 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 22 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .57 (s, 1 H), 8.53 (s, 1 H), 8.29 (bs, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 7.87 (s, 1 H), 7.64 (s, 1 H), 7.44 (d, J = 2.7 Hz, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 6.84 (d, J = 2.7 Hz, 1 H), 5.91 (s, 1 H), 4.39 (d, J = 4.5 Hz, 2H), 4.07 (d, J =7.2 Hz, 2H), 3.53 (m, 4H), 3.44 (m, 4H), 2.56 (m, 1 H), 2.12 (s, 4H), 1 .54-
1 .49 (m, 2H), 1 .42 (s, 9H), 0.92 (m, 10H); MS (ESI+): m/z 641 .5 (M+H)+.
Example 112:
ieri-Butyl 4-(5-(1 -isobutyl-4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate
A solution of the compound of example 1 1 1 in acetic acid was treated with sodium cyanoborohydride (7.0 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 87 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .50 (s, 1 H), 8.45 (s, 1 H), 8.14 (bs, 1 H), 7.86 (d, J = 6.9 Hz, 1 H), 6.97 (s, 1 H), 6.90 (d, J = 9.0 Hz, 1 H), 6.72 (s, 1 H), 5.89 (s, 1 H), 4.30 (d, J = 4.5 Hz, 2H), 4.03 - 4.01 (m, 1 H), 3.51 (m, 4H), 3.44 (m, 4H), 3.1 1 (m, 2H), 2.92 - 2.89 (d, J = 7.2 Hz, 2H), 2.45 (m, 1 H), 2.12 (s, 3H), 1 .74 - 1 .72 (m, 3H), 1 .52- 1 .50 (m, 2H), 1 .42 (s, 9H), 0.94 (d, J = 6.6 Hz, 6H), 0.89 - 0.86 (m, 3H); MS (ESI+): m/z 643.4 (M+H)+.
Example 113:
1 -lsobutyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl )-6-(6- (piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
A solution of the compound of example 1 12 in MeOH was treated with 12 % methanolic HCI followed by treatment with 10 % sodium bicarbonate solution (10 equiv) according to the procedure described in examples 15 and 16 respectively, to obtain the title compound.
Yield: 29 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .46 (s, 1 H), 8.41 (s, 1 H), 8.13 (s, 1 H), 7.79 (s, 1 H), 6.96 (s, 1 H), 6.82 (s, 1 H), 6.70 (s, 1 H), 5.87 (s, 1 H), 4.29 (bs, 2H), 3.41 (m, 5H), 3.10 (m, 3H), 2.90 (m, 2H), 2.77 (m, 5H), 2.1 1 (s, 3H), 1 .91 (s, 2H),
1 .50 (bs, 2H), 0.92 (bs, 10H); MS (ESI+): m/z 543.4 (M+H)+. Example 114:
Methyl 1 -isopropyl-6-(3-(trif luoromethyl)phenyl)-1 H-indole-4-carboxylate
A solution of the compound of example 10 in dioxane was treated with (3- (trifluoromethyl)phenyl)boronic acid (1 .4 equiv) according to the procedure described for the preparation of the compound of example 47 to obtain the title compound.
Yield: 95 %; 1 H NMR (CDCI3, 300 MHz): δ 8.15 (d, J = 1 .5 Hz, 1 H), 7.91 (s, 1 H), 7.87 (d, J = 6.9 Hz, 1 H), 7.75 (s, 1 H), 7.61 - 7.54 (m, 2H), 7.43 (d, J = 3.0 Hz, 1 H), 7.16 (d, J = 3.0 Hz, 1 H), 4.85 - 4.78 (m, 1 H), 4.01 (s, 3H), 1 .59 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 362.2 (M+H)+.
Example 115:
1-lsopropyl-6-(3-(trifluoromethyl)phenyl)-1 H-indole-4-carboxylic acid
A solution of the compound of example 1 14 in MeOH and THF was treated with 1 M NaOH (4.0 equiv) according to the procedure described for the preparation of the compound of example 48 to obtain the title compound.
Yield: 98 %; 1H NMR (DMSO-d6, 300 MHz): δ 12.84 (bs, 1 H), 8.21 (s, 1 H), 8.09 (s, 2H), 8.04 (s, 1 H), 7.75 - 7.70 (m, 3H), 7.02 (d, J = 3.3 Hz, 1 H), 5.09 - 5.01 (m, 1 H), 1 .44 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 348.1 (M+H)+. Example 116:
1-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(3- (trifluoromethyl)phenyl)-1 H-indole-4-carboxamide
A solution of the compound of example 1 15 in DMF was treated with the compound of example 4 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 70 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 .54 (s, 1 H), 8.34 (s, 1 H), 8.1 1 - 8.04 (m, 3H), 7.72 - 7.67 (m, 4H), 6.88 (s, 1 H), 5.89 (s, 1 H), 4.99 (m, 1 H), 4.39 (s, 2H), 2.53 (m, 2H), 2.1 1 (s, 3H), 1 .47 (d, J = 6.0 Hz, 6H), 1 .21 (m, 2H), 0.88 (t, J = 6.9 Hz, 3H); MS (ESI+): m/z 510.2 (M+H)+.
Example 117:
1-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(3- (trifluoromethyl)phenyl)indoline-4-carboxamide A solution of the compound of example 1 16 in acetic acid was treated with sodium cyanoborohydride (7.0 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 80 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.21 (s, 1 H), 7.95 (s, 2H), 7.66 (s, 2H), 7.03 (s, 1 H), 6.81 (s, 1 H), 5.87 (s, 1 H), 4.28 (m, 2H), 4.019 (s, 1 H), 3.09 (m, 2H), 2.10 (s, 3H), 1 .49 (m, 4H), 1 .21 (m, 2H), 1 .09 (d, J = 6.0 Hz, 6H), 0.87 (t, J = 6.9 Hz, 3H); MS (ESI+): m/z 512.2 (M+H)+.
Example 118:
Methyl 1-isopropyl-6-phenyl-1 H-indole-4-carboxylate
A solution of the compound of example 10 in dioxane was treated with phenylboronic acid (1 .4 equiv) according to the procedure described for the preparation of the compound of example 47 to obtain the title compound.
Yield: 93 %; 1 H NMR (CDCI3, 300 MHz): δ 8.17 (d, J = 1 .8 Hz, 1 H), 7.76 (s, 1 H), 7.70 (d, J = 7.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.40 (d, J = 3.0 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.14 (d, J = 3.0 Hz, 1 H), 4.82 - 4.76 (m, 1 H), 4.00 (s, 3H), 1 .56 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 294.2 (M+H)+.
Example 119:
1-lsopropyl-6-phenyl-1 H-indole-4-carboxylic acid
A solution of the compound of example 1 18 in MeOH and THF was treated with 1 M NaOH (4.0 equiv) according to the procedure described for the preparation of the compound of example 48 to obtain the title compound.
Yield: 93 %; 1 H NMR (DMSO-d6, 300 MHz): δ 12.76 (bs, 1 H), 8.08 (s, 1 H), 8.01 (d, J = 1 .5 Hz, 1 H), 7.78 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 3.0 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.5 Hz, 1 H), 7.14 (d, J = 3.0 Hz, 1 H), 5.03 - 4.94 (m, 1 H), 1 .49 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 280.1 (M+H)+.
Example 120:
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6- phenyl-1 H-indole-4-carboxamide
A solution of the compound of example 1 19 in DMF was treated with the compound of example 4 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound. Yield: 39 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .55 (s, 1 H), 8.30 (s, 1 H), 7.90 (s, 1 H), 7.78 (d, J = 1 .5 Hz, 2H), 7.69 (s, 1 H), 7.61 (d, J = 3.0 Hz, 1 H), 7.45 (d, J = 7.5 Hz, 2H), 7.32 (d, J = 7.5 Hz, 1 H), 6.86 (d, J = 3.0 Hz, 1 H), 5.89 (s, 1 H), 4.93 (m, 1 H), 4.39 (d, J = 5.1 Hz, 2H), 2.53 (m, 2H), 2.1 1 (s, 3H), 1 .56 - 1 .51 (m, 2H), 1 .47 (d, J = 6.0 Hz, 6H), 0.89 (t, J = 6.9 Hz, 3H); MS (ESI+): m/z 442.2 (M+H)+.
Example 12 :
1-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6- phenylindoline-4-carboxamide
A solution of the compound of example 120 in acetic acid was treated with sodium cyanoborohydride (7.0 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 50 mg (62 %); 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.16 (s, 1 H), 7.64 (d, J = 7.5 Hz, 2H), 7.40 (m, 2H), 7.33 (m, 1 H), 6.99 (s, 1 H), 6.72 (s, 1 H), 5.87 (s, 1 H), 4.38 (d, J = 5.1 Hz, 2H), 3.95 (m, 1 H), 3.07 (m, 2H), 2.10 (s, 3H), 1 .51 - 1 .49 (m, 2H), 1 .21 (m, 4H), 1 .10 (d, J = 6.3 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 444.2 (M+H)+.
Example 122:
Methyl 6-(3,5-difluorophenyl)-1-isopropyl-1 H-indole-4-carboxylate
A solution of the compound of example 10 in dioxane was treated with (3,5- difluorophenyl)boronic acid (1 .4 equiv) according to the procedure described for the preparation of the compound of example 47 to obtain the title compound.
Yield: 95 %; 1 H NMR (CDCI3, 300 MHz): δ 8.10 (d, J = 1 .2 Hz, 1 H), 7.72 (s, 1 H), 7.43 (d, J = 3.3 Hz, 1 H), 7.22 - 7.18 (dd, J = 2.1 Hz, 2H), 7.58 (d, J = 3.3 Hz, 1 H), 7.34 (t, J = 2.1 Hz, 1 H), 4.82 - 4.73 (m, 1 H), 4.00 (s, 3H), 1 .58 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 330.2 (M+H)+.
Example 123:
6-(3,5-Dif luorophenyl)-1 -isopropyl-1 H-indole-4-carboxylic acid
A solution of the compound of example 122 in MeOH and THF was treated with 1 M NaOH (4.0 equiv) according to the procedure described for the preparation of the compound of example 48 to obtain the title compound. Yield: 450 mg (97 %); 1H NMR (DMSO-d6, 300 MHz): δ 12.85 (bs, 1 H), 8.22 (s, 1 H), 8.02 (d, J = 1 .2 Hz, 1 H), 7.76 (d, J = 3.3 Hz, 1 H), 7.57 - 7.46 (dd, J = 2.1 Hz, 2H), 7.23 - 7.17 (t, J = 2.1 Hz, 1 H), 7.00 (d, J = 3.3 Hz, 1 H), 5.08 - 4.99 (m, 1 H), 1 .50 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 316.1 (M+H)+.
Example 124:
6-(3,5-Difluorophenyl)-1-isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)-1 H-indole-4-carboxamide
A solution of the compound of example 123 in DMF was treated with the compound of example 4 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 49 to obtain the title compound.
Yield: 62 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .56 (s, 1 H), 8.35 (s, 1 H), 8.06 (s, 1 H), 7.72 (s, 1 H), 7.66 (d, J = 3.0 Hz, 1 H), 7.62 (dd, J = 2.1 Hz, 2H), 7.19 - 7.13 (t, J = 2.1 Hz, 1 H), 6.91 (d, J = 3.0 Hz, 1 H), 5.89 (s, 1 H), 5.00 - 4.93 (m, 1 H), 4.39 (d, J = 4.8 Hz, 2H), 2.53 (m, 2H), 2.10 (s, 3H), 1 .55 - 1 .50 (m, 2H), 1 .47 (d, J = 6.0 Hz, 6H), 0.90 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 478.2 (M+H)+.
Example 125:
6-(3,5-Difluorophenyl)-1-isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)indoline-4-carboxamide
A solution of the compound of example 124 in acetic acid was treated with sodium cyanoborohydride (7.0 equiv) according to the procedure described for the preparation of the compound of example 50 to obtain the title compound.
Yield: 85 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.21 (s, 1 H), 8.46 (d, J = 8.1 Hz, 2H), 7.16 (m, 1 H), 7.05 (s, 1 H), 7.82 (s, 1 H), 5.87 (s, 1 H), 4.28 (d, J = 4.8 Hz, 2H), 4.00 (m, 1 H), 3.09 (m, 2H), 2.10 (s, 3H), 1 .48 (m, 2H), 1 .21 (m, 4H), 1 .08 (d, J = 6.0 Hz, 6H), 0.90 (t, J = 6.9 Hz, 3H); MS (ESI+): m/z 480.2 (M+H)+.
Example 126:
Methyl 3,6-dibromo-1-isopropyl-2-oxoindoline-4-carboxylate (126 A) and
Methyl 6-bromo-1-isopropyl-2-oxoindoline-4-carboxylate (126 B)
To a solution of the compound of example 10 (15 g, 50.6 mmol, 1 .0 equiv) in t-butyl alcohol (300 mL) was added NBS (9.92 g, 55.7 mmol, 1 .1 equiv) in small portions over 20 minutes and the reaction mixture was heated to 85 °C for 24 h. The reaction mass was concentrated to obtain dark brown residue which was dissolved in dichloromethane followed by washing with sodium bicarbonate solution and brine. The organic layer obtained was dried over sodium sulfate and concentrated to obtain a crude product. The crude product was purified by column chromatography (silica gel, 1 :9 EtOAc: petroleum ether) to obtain the title compounds.
Example 126 A:
Yield: 4.5 g (23 %); 1H NMR (DMSO-d6, 300 MHz): δ 7.72 (d, J = 1 .2 Hz, 1 H), 7.65 (d, J = 1 .2 Hz, 1 H), 5.71 (s, 1 H), 4.52 - 4.43 (m, 1 H), 3.89 (s, 3H), 1 .41 - 1 .39 (d, J = 6.90 Hz, 6H); MS (ESI+): m/z 391 .9 (M+H)+.
Example 126 B:
Yield: 7 g (44 %); 1H NMR (DMSO-d6, 300 MHz) δ 7.61 (s, 1 H), 7.59 (s, 1 H), 4.51 - 4.43 (m, 1 H), 3.85 (s, 3H), 3.71 (s, 2H), 1 .40 - 1 .38 (d, J = 6.90 Hz, 6H); MS (ESI+): m/z 313 (M+H)+.
Example 127:
Methyl 6-bromo-1-isopropyl-3,3-dimethyl-2-oxoindoline-4-carboxylate
To a cooled solution of potassium tert-butoxide (3.59 g, 32.0 mmol, 2.5 equiv) in THF (80 ml_) at -30 °C was added a mixture of the compound of example 126 B (4 g, 12.81 mmol, 1 .0 equiv) in THF (40 ml_) and methyl iodide (4.01 ml_, 64.1 mmol, 5.0 equiv) dropwise over 30 minutes. The reaction mass was gradually allowed to attain room temperature and stirred for 2 h. To this reaction mass, water was added and the resultant mass was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous sodium sulfate and concentrated to obtain a crude product which was purified by column chromatography (silica gel, 2:8, EtOAc : petroleum ether) to obtain the title compound.
Yield: 3.025 g (75 %); 1 H NMR (DMSO-d6, 300 MHz): δ 7.76 (d, J = 1 .8 Hz, 1 H), 7.30 (d, J = 1 .8 Hz, 1 H), 4.63 - 4.58 (m, 1 H), 3.93 (s, 3H), 1 .50 (s, 9H), 1 .48 (s, 3H); MS (ESI+): m/z 341 .1 (M+H)+. Example 128:
Methyl 6-(6-(4-(tert-butoxycarbonyl)piperazin-1 -yl)pyridin-3-yl)-1 -isopropyl-3,3- dimethyl-2-oxoindoline-4-carboxylate
To a solution of the compound of example 127 (525 mg, 1 .543 mmol, 1 .0 equiv) in dioxane (26 ml_) was added te/t-butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (781 mg, 2.006 mmol, 1 .3 equiv) and PdCI2(dppf)-CH2CI2 adduct (37.8 mg, 0.046 mmol, 0.03 equiv) and stirred at room temperature for 10 min. To this reaction mixture was added 2 M aqueous sodium carbonate solution (2.3 ml_, 4.63 mmol, 3.0 equiv) and the reaction mixture was stirred and heated to 85 °C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated to obtain a residue. To this residue water was added and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with brine, dried over sodium sulfate, and concentrated to yield a crude product which was purified by column chromatography (silica gel, 4:6, EtOAc:CHCI3) to obtain the title compound.
Yield: 625 mg (77 %); 1 H NMR (DMSO-d6, 300 MHz): δ 8.52 (d, J = 2.4 Hz, 1 H), 7.96 - 7.92 (dd, J = 2.4 Hz, 1 H), 7.67 (s, 1 H), 7.58 (s, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 4.63 - 4.58 (m, 1 H), 3.89 (s, 3H), 3.56 (s, 4H), 3.44 (s, 4H), 1 .46 (s, 6H), 1 .43 (s, 9H), 1 .40 (s, 6H); MS (ESI+): m/z 523.4 (M+H)+.
Example 129:
6-(6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1-isopropyl-3,3- dimethyl-2-oxoindoline-4-carboxylic acid
To a solution of the compound of example 128 (600 mg, 1 .148 mmol, 1 .0 equiv) in MeOH (12.00 ml_) and THF (12 ml_) was added 1 M aqueous NaOH solution (4.59 ml_, 4.59 mmol, 4.0 equiv) and heated to 65 °C for 2 h. The reaction mass was cooled and the solvent was removed to obtain a residue. The residue obtained was dissolved in water, acidified with aqueous sodium hydrogen sulfate to bring the pH between 3 and 4, and extracted with ethyl acetate. The organic layer was washed with brine and evaporated to obtain the title compound.
Yield: 400 mg (68 %); 1 H NMR (DMSO-d6, 300 MHz): δ 13.21 (bs, 1 H), 8.51 (d, J = 2.1 Hz, 1 H), 7.95 - 7.91 (dd, J = 2.4 Hz, 1 H), 7.66 (s, 1 H), 7.53 (s, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 4.60 (m, 1 H), 3.56 (m, 4H), 3.44 (m, 4H), 1 .45 - 1 .36 (s, 21 ); MS (ESI+): m/z 509.3 (M+H)+.
Example 130:
tert-Butyl 4-(5-(1 -isopropyl-3,3-dimethyl-4-(((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)carbamoyl)-2-oxoindolin-6-yl)pyridin-2-yl) piperazine-1 -carboxylate
To a solution of the compound of example 129 (200 mg, 0.393 mmol, 1 .0 equiv) in DMF (10 ml_) was added HATU (224 mg, 0.590 mmol, 1 .5 equiv) and the reaction mixture was stirred for 5 min at room temperature. To this reaction mixture, the compound of example 4 (1 1 1 mg, 0.51 1 mmol, 1 .3 equiv) was added followed by DIPEA (0.103 ml_, 0.590 mmol, 1 .5 equiv) and heated to 70 °C for 16 h. Following the completion of the reaction, the solvent was removed to obtain a residue. To this residue water was added and extracted with ethyl acetate. Organic layer obtained was washed with brine, dried over sodium sulfate, concentrated to obtain a crude product which was purified by column chromatography (silica gel, 6:4, EtOAc:CHCl3) to obtain the title compound.
Yield: 100 mg (38 %); 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.50 (d, J = 2.1 Hz, 1 H), 8.29 (bs, 1 H), 7.95 - 7.91 (dd, J = 2.4 Hz, 1 H), 7.37 (s, 1 H), 7.16 (s, 1 H), 6.95 (d, J = 9.0 Hz, 1 H), 5.89 (s, 1 H), 4.57 (m, 1 H), 4.31 (d, J = 4.5 Hz, 2H ), 3.55 (m, 4H), 3.43 (m, 4H), 2.1 1 (s, 3H), 1 .55 - 1 .50 (m, 2H), 1 .42 (s, 1 1 H), 1 .33 (s, 12H), 0.91 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 671 .5 (M+H)+.
Example 13 :
1 -lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl )-2-oxo-6-(6-(piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
To a solution of the compound of example 130 (80 mg, 0.1 19 mmol, 1 .0 equiv) in isopropyl alcohol (4 ml_) was added IPA.HCI (1 .988 ml_, 5.96 mmol, 50 equiv) and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, solvent was removed and pH was adjusted between 8 and 9 with saturated solution of NaHCO3 and the mixture was stirred for 30 minutes at room temperature. The resulting solid was filtered and dried to obtain the title compound.
Yield: 40 mg (59 %); 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (bs, 1 H), 8.47 (s, 1 H), 8.29 (bs, 1 H), 7.89 (s, 1 H), 7.36 (s, 1 H), 7.15 (s, 1 H), 6.86 (s, 1 H), 5.88 (s, 1 H), 4.56 (s, 1 H), 4.30 (s, 2H), 3.44 (m, 4H), 2.77 (m, 4H), 2.10 (s, 3H), 1 .55 (s, 2H), 1 .41 (s, 6H), 1 .32 (s, 6H), 1 .22 (s, 3H), 0.90 (s, 3H); MS (ESI+): m/z 571 .4 (M+H)+. Example 132:
ieri-Butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)
carbamoyl )-1-isopropyl-3,3-dimethyl-2-oxoindolin-6-yl)pyridin-2-yl)piperazine- 1-carboxylate
A solution of the compound of example 129 in DMF was treated with the compound of example 9 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 74 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.72 (s, 1 H), 8.51 (s, 1 H), 7.96 - 7.93 (dd, J = 2.4 Hz, 1 H), 7.37 (s, 1 H), 7.17 (s, 1 H), 6.95 (d, J = 6.0 Hz, 1 H), 5.85 (s, 1 H), 4.59 - 4.55 (m, 1 H), 4.30 (d, J = 4.8 Hz, 2H ), 3.55 (m, 4H), 3.43 (m, 4H), 2.20 (s, 3H), 2.1 1 (s, 3H), 1 .42 (s, 9H), 1 .32 (s, 6H), 1 .23 (s, 6H); MS (ESI+): m/z 643.4 (M+H)+.
Example 133:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-3,3-dimethyl -2-oxo-6-(6-(piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
A solution of the compound of example 132 in isopropyl alcohol was treated with I PA HCI (50 equiv) according to the procedure described for the preparation of the compound of example 131 to obtain the title compound.
Yield: 63 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.49 (d, J = 2.1 Hz, 1 H), 8.23 (bs, 1 H), 7.91 (d, J = 6.6 Hz, 1 H), 7.36 (s, 1 H), 7.16 (s, 1 H), 6.89 (d, J = 9.0 Hz, 1 H), 5.85 (s, 1 H), 4.59 - 4.55 (m, 1 H), 4.30 (d, J = 4.5 Hz, 2H), 3.45 (m, 4H), 2.78 (m, 4H), 2.20 (s, 3H), 2.10 (s, 3H), 1 .43 (d, J = 6.6 Hz, 6H), 1 .32 (s, 6H), 1 .17 (m, 1 H); MS (ESI+): m/z 543.3 (M+H)+.
Example 134:
Methyl 1-isopropyl-3,3-dimethyl-6-(4-morpholinophenyl)-2-oxoindoline-4- carboxylate
A solution of the compound of example 127 in dioxane was treated with 4-(4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine (1 .4 equiv) according to the procedure described for the preparation of the compound of example 128 to obtain the title compound.
Yield: 98 %; 1 H NMR (DMSO-d6, 300 MHz): δ 7.68 (s, 1 H), 7.63 (d, J = 8.7 Hz, 2H), 7.54 (s, 1 H), 7.06 (d, J = 8.7 Hz, 2H), 4.66 - 4.56 (m, 1 H), 3.89 (s, 3H), 3.77 - 3.74 (m, 4H), 3.18 - 3.15 (m, 4H), 1 .45 - 1 .43 (d, J = 6.9 Hz, 6H), 1 .39 (s, 6H); MS (ESI+): m/z 423.3 (M+H)+.
Example 135:
1-lsopropyl-3,3-dimethyl-6-(4-morpholinophenyl)-2-oxoindoline-4-carboxylic acid
A solution of the compound of example 134 in MeOH and THF was treated with 1 M NaOH (1 .4 equiv) according to the procedure described for the preparation of the compound of example 129 to obtain the title compound.
Yield: 80 %; 1 H NMR (DMSO-d6, 300 MHz): δ 12.23 (bs, 1 H), 7.68 (s, 1 H), 7.62 (d, J = 8.7 Hz, 2H), 7.50 (s, 1 H), 7.06 (d, J = 8.7 Hz, 2H), 4.63 - 4.58 (m, 1 H), 3.77 - 3.74 (m, 4H), 3.18 - 3.15 (m, 4H), 1 .46 - 1 .42 (m, 12H); MS (ESI+): m/z 409.3 (M+H)+.
Example 136:
1 -lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl )-6-(4-morpholinophenyl)-2-oxoindoline-4-carboxamide
A solution of the compound of example 135 in DMF was treated with the compound of example 4 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 61 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.32 (bs, 1 H), 7.61 (d, J = 8.4 Hz, 2H), 7.33 (s, 1 H), 7.15 (s, 1 H), 7.04 (d, J = 8.4 Hz, 2H), 5.89 (s, 1 H), 4.59 - 4.55 (m, 1 H), 4.31 (d, J = 4.2 Hz, 2H ), 3.75 (m, 4H), 3.15 (m, 4H), 2.1 1 (s, 3H), 1 .58 - 1 .50 (m, 2H), 1 .43 (d, J = 6.9 Hz, 6H), 1 .33 (s, 6H), 1 .23 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 571 .4 (M+H)+.
Example 137:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3,3- dimethyl-6-(4-morpholinophenyl)-2-oxoindoline-4-carboxamide
A solution of the compound of example 135 in DMF was treated with the compound of example 9 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 45 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.34 (bs, 1 H), 7.61 (d, J = 8.4 Hz, 2H), 7.33 (s, 1 H), 7.15 (s, 1 H), 7.04 (d, J = 8.4 Hz, 2H), 5.85 (s, 1 H), 4.57 (m, 1 H), 4.28 (d, J = 4.2 Hz, 2H ), 3.75 (m, 4H), 3.15 (m, 4H), 2.19 (s, 3H), 2.09 (s, 3H), 1 .43 (d, J = 6.3 Hz, 6H), 7.32 (s, 6H); MS (ESI+): m/z 543.3 (M+H)+.
Example 138:
Methyl 1 -isopropyl-3,3-dimethyl-6-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)-2- oxoindoline-4-carboxylate
A solution of the compound of example 127 in dioxane was treated with 1 - methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1 .4 equiv) according to the procedure described for the preparation of the compound of example 128 to obtain the title compound.
Yield: 62 %; 1H NMR (DMSO-d6, 300 MHz): δ 8.50 (d, J = 2.4 Hz, 1 H), 7.93 - 7.89 (dd, J = 2.4 Hz, 1 H), 7.66 (s, 1 H), 7.58 (s, 1 H), 6.94 (d, J = 9.0 Hz, 1 H), 4.63 - 4.58 (m, 1 H), 3.89 (s, 3H), 3.56 - 3.53 (m, 4H), 2.42 - 2.39 (m, 4H), 2.22 (s, 3H), 1 .45 - 1 .43 (d, J = 6.6 Hz, 6H), 1 .39 (s, 6H); MS (ESI+): m/z 437.3 (M+H)+.
Example 139:
1-lsopropyl-3,3-dimethyl-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2- oxoindoline-4-carboxylic acid
A solution of compound of example 138 in MeOH and THF was treated with 1 M NaOH (4.0 equiv) according to the procedure described for the preparation of the compound of example 129 to obtain the title compound.
Yield: 40 %; 1H NMR (DMSO-d6, 300 MHz): δ 8.51 (s, 1 H), 7.93 - 7.96 (d, J = 7.5 Hz, 1 H), 7.66 (s, 1 H), 7.53 (m, 1 H), 7.01 (d, J = 8.7 Hz, 1 H), 4.63 - 4.58 (m, 1 H), 3.68 (s, 4H), 2.85 (s, 4H), 2.50 (s, 3H), 1 .45 - 1 .32 (m, 12H); MS (ESI+): m/z 423.3 (M+H)+.
Example 140:
1-lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl )-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxoindoline-4-carboxamide A solution of the compound of example 139 in DMF was treated with the compound of example 4 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 48 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.50 (bs, 1 H), 8.30 (s, 1 H), 7.95 (d, J = 8.1 Hz, 1 H), 7.37 (s, 1 H), 7.16 (s, 1 H), 6.98 (d, J = 8.7 Hz, 1 H), 5.89 (s, 1 H), 4.57 (m, 1 H), 4.29 (d, J = 4.2 Hz, 2H), 3.64 (m, 4H), 2.76 (m, 4H), 2.56 (s, 3H), 2.1 1 (s, 3H), 1 .55 - 1 .53 (m, 2H), 1 .43 (d, J = 6.3 Hz, 6H), 1 .32 (s, 6H), 1 .24 - 1 .19 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 585.4 (M+H)+. Example 141 :
Methyl 6'-bromo-1 '-isopropyl-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'- carboxylate
A solution of the compound of example 126 B in THF was treated with 1 ,4- diiodobutane (1 .2 equiv) according to the procedure described for the preparation of the compound of example 127 to obtain the title compound.
Yield: 55 %; 1H NMR (DMSO-d6, 300 MHz): δ 7.60 (s, 1 H), 7.57 (s, 1 H), 4.49 - 4.44 (m, 1 H), 3.85 (s, 3H), 2.18 - 2.14 (m, 2H), 1 .96 (bs, 4H), 1 .82 - 1 .77 (m, 2H), 1 .39 (d, J = 7.2 Hz, 6H); MS (ESI+): m/z 367.1 (M+H)+.
Example 142:
Methyl 6'-(6-(4-(tert-butoxycarbonyl)piperazin-1 -yl)pyridin-3-yl)-1 '-isopropyl-2'- oxospiro[cyclopentane-1 ,3'-indoline]-4'-carboxylate
A solution of the compound of example 141 in dioxane was treated with tert- butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylate (1 .4 equiv) according to the procedure described for the preparation of the compound of example 128 to obtain the title compound.
Yield: 80 %; 1H NMR (DMSO-d6, 300 MHz): δ 8.51 (d, J = 2.4 Hz, 1 H), 7.94 - 7.90 (dd, J = 2.4 Hz, 1 H ), 7.66 (s, 1 H), 7.52 (s, 1 H), 6.95 (d, J = 8.7 Hz, 1 H), 4.57 (m, 1 H), 3.86 (s, 3H), 3.56 - 3.54 (m, 4H), 3.45 - 3.43 (m, 4H), 2.21 - 2.17 (m, 2H), 1 .98 (bs, 4H), 1 .83 - 1 .79 (m, 2H), 1 .43 (s, 9H), 1 .06 (s, 6H); MS (ESI+): m/z 549.4 (M+H)+.
Example 143:
6'-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1 '-isopropyl-2'- oxospiro[cyclopentane-1 ,3'-indoline]-4'-carboxylic acid
A solution of the compound of example 142 in MeOH and THF was treated with 1 M NaOH (4.0 equiv) according to the procedure described for the preparation of the compound of example 129 to obtain the title compound. Yield: 90 %; 1 H NMR (DMSO-d6, 300 MHz): δ 13.28 (bs, 1 H), 8.50 (d, J = 2.4 Hz, 1 H), 7.94 - 7.91 (dd, J = 2.4 Hz, 1 H ), 7.63 (s, 1 H), 7.48 (s, 1 H), 6.95 (d, J = 9.0 Hz, 1 H), 4.59 - 4.55 (m, 1 H), 3.55 (m, 4H), 3.43 (m, 4H), 2.27 - 2.23 (m, 2H), 1 .96 (bs, 4H), 1 .82 - 1 .78 (m, 2H), 1 .43 (s, 15H); MS (ESI+): m/z 535.3 (M+H)+.
Example 144:
tert-Butyl 4-(5-(1 '-isopropyl-4'-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3- yl)methyl)carbamoyl)-2'-oxospiro[cyclopentane-1 ,3'-indolin]-6'-yl)pyridin-2-yl) piperazine-1 -carboxylate
A solution of the compound of example 143 in DMF was treated with the compound of example 4 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 49 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.49 (d, J = 2.1 Hz, 1 H), 8.32 (bs, 1 H), 7.91 - 7.90 (dd, J = 2.4 Hz, 1 H), 7.31 (s, 1 H), 7.12 (s, 1 H), 6.95 (d, J = 9.0 Hz, 1 H), 5.88 (s, 1 H), 4.58 (m, 1 H), 4.27 (d, J = 4.8 Hz, 2H ), 3.54 (m, 4H), 3.43 (m, 4H), 2.55 (m, 2H), 2.19 (bs, 2H), 2.1 1 (s, 3H), 1 .80 - 1 .75 (m, 6H), 1 .55 - 1 .50 (m, 2H), 1 .42 (s, 15H), 0.92 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 697.5 (M+H)+.
Example 145:
1 '-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2'- oxo-6 6-(piperazin-1-yl)pyridin-3-yl)spiro[cyclopentane-1 ,3'-indoline]-4'- carboxamide
A solution of the compound of example 144 in isopropyl alcohol was treated with I PA HCI (50 equiv) according to the procedure described for the preparation of the compound of example 131 to obtain the title compound.
Yield: 77 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .50 (s, 1 H), 8.46 (s, 1 H), 8.33 (bs, 1 H), 7.88 - 7.65(dd, J = 2.4 Hz, 1 H), 7.30 (s, 1 H), 7.1 1 (s, 1 H), 6.89 (d, J = 8.7 Hz, 1 H), 5.88 (s, 1 H), 4.56 - 4.51 (m, 1 H), 4.26 (d, J = 4.2 Hz, 2H ), 3.45 (m, 4H), 2.77 (m, 4H), 2.55 (m, 2H), 2.20 (bs, 2H), 2.10 (s, 3H), 1 .80 - 1 .75 (m, 6H), 1 .57 - 1 .50 (m, 2H), 1 .41 - 1 .39 (d, J = 6.9 Hz, 6H), 0.92 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 597.5 (M+H)+.
Example 146:
Methyl 1 '-isopropyl-6'-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)-2'-oxospiro [cyclopentane-1 ,3'-indoline]-4'-carboxylate
A solution of the compound of example 141 in dioxane was treated with 1 - methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1 .4 equiv) according to the procedure described for the preparation of the compound of example 128 to obtain the title compound.
Yield: 82 %; 1 H NMR (DMSO-d6, 300 MHz): δ 8.49 (d, J = 2.4 Hz, 1 H), 8.31 (s, 1 H), 7.92 - 7.88 (dd, J = 2.4 Hz, 1 H ), 7.65 (s, 1 H), 7.55 - 7.51 (m, 2H), 6.94 (d, J = 9.0 Hz, 1 H), 4.57 (m, 1 H), 3.86 (s, 3H), 2.40 (m, 4H), 2.22 (m, 4H), 1 .98 (m, 3H), 1 .83 - 1 .79 (m, 2H), 1 .44 (d, J = 6.9 Hz, 4H), 1 .06 (s, 6H); MS (ESI+): m/z 463.3 (M+H)+.
Example 147:
1 '-lsopropyl-6'-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2'-oxospiro
[cyclopentane-1 ,3'-indoline]-4'-carboxylic acid
A solution of the compound of example 146 in MeOH and THF was treated with 1 M NaoH (4.0 equiv) according to the procedure described for the preparation of the compound of example 129 to obtain the title compound.
Yield: 44 %; 1H NMR (DMSO-d6, 300 MHz): δ 8.49 (s, 1 H), 7.92 - 7.88 (d, J = 2.4 Hz, 1 H), 8.32 (s, 1 H), 7.63 (s, 1 H), 7.55 - 7.50 (m, 2H), 6.98 (d, J = 8.7 Hz, 1 H), 4.60 (m, 1 H), 3.63 (m, 4H), 2.66 (m, 4H), 2.39 (s, 3H), 2.22 (m, 2H), 1 .98 (m, 3H), 1 .82 - 1 .75 (m, 2H), 1 .44 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 449.3 (M+H)+.
Exampe 148:
1 '-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6'-(6- (4-methylpiperazin-1 -yl)pyridin-3-yl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'- carboxamide
A solution of the compound of example 147 in DMF was treated with the compound of example 4 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 60 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.46 (d, J = 8.4 Hz, 1 H), 8.31 (bs, 1 H), 7.94 - 7.91 (dd, J = 2.4 Hz, 1 H), 7.31 (s, 1 H), 7.12 (s, 1 H), 6.98 (d, J = 9.0 Hz, 1 H), 5.88 (s, 1 H), 4.56 - 4.51 (m, 1 H), 4.27 (d, J = 4.8 Hz, 2H), 3.64 (m, 4H), 2.55 (m, 2H), 2.46 (m, 3H), 2.55 (m, 2H), 2.19 (bs, 2H), 2.1 1 (s, 3H), 1 .80 - 1 .75 (m, 6H), 1 .57 - 1 .50 (m, 2H), 1 .42 (d, J = 6.6 Hz, 6H), 1 .23 - 1 .14 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 61 1 .4 (M+H)+.
Example 149:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 '-isopropyl-6'-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'- carboxamide
A solution of the compound of example 147 in DMF was treated with the compound of example 9 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 18.5 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .47 (s, 1 H), 8.49 (d, J = 9.0 Hz, 1 H), 8.31 (bs, 1 H), 7.94 - 7.91 (dd, J = 2.4 Hz, 1 H), 7.30 (s, 1 H), 7.12 (s, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 5.85 (s, 1 H), 4.56 - 4.51 (m, 1 H), 4.25 (d, J = 4.8 Hz, 2H), 3.61 (s, 4H), 2.65 (s, 4H), 2.39 (s, 3H), 2.22 (s, 3H), 2.13 (m, 2H), 2.10 (s, 3H), 1 .74 - 1 .71 (m, 6H), 1 .41 (d, J = 6.9 Hz, 6H); MS (ESI+): m/z 583.3 (M+H)+.
Example 150:
Methyl 1 '-isopropyl-6'-(4-morpholinophenyl)-2'-oxospiro[cyclopentane-1 ,3'- indoline]-4'-carboxylate
A solution of the compound of example 141 in dioxane was treated with 4-(4-
(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine (1 .4 equiv) according to the procedure described for the preparation of the compound of example 128 to obtain the title compound.
Yield: 85 %; 1 H NMR (DMSO-d6, 300 MHz): δ 7.67 (s, 1 H), 7.62 (d, J = 8.4 Hz, 2H), 7.48 (s, 1 H), 7.06 (d, J = 8.4 Hz, 2H), 4.60 - 4.55 (m, 1 H), 3.87 (s, 3H), 3.76 (m, 4H), 3.17 (m, 4H), 2.22 - 2.18 (m, 2H), 1 .98 (m, 4H), 1 .83 - 1 .79 (m, 2H), 1 .45 (d, J = 6.9 Hz, 6H); MS (ESI+): m/z 449.4 (M+H)+.
Example 151 :
1 '-lsopropyl-6'-(4-morpholinophenyl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]- 4'-carboxylic acid
A solution of the compound of example 150 in MeOH and THF was treated with 1 M NaoH (4.0 equiv) according to the procedure described for the preparation of the compound of example 129 to obtain the title compound. Yield: 83 %; 1 H NMR (DMSO-d6, 300 MHz): δ 13.21 (bs, 1 H), 7.65 (s, 1 H), 7.61 (d, J = 8.7 Hz, 2H), 7.44 (s, 1 H), 7.05 (d, J = 8.4 Hz, 2H), 4.60 - 4.55 (m, 1 H), 3.77 - 3.44 (m, 4H), 3.18 - 3.15 (m, 4H), 2.27 - 2.23 (m, 2H), 1 .97 (m, 4H), 1 .87 - 1 .77 (m, 2H), 1 .44 (d, J = 6.9 Hz, 6H); MS (ESI+): m/z 435.3 (M+H)+.
Example 152:
1 sopropyl-N-((6-methyl-2-oxo-4^ropyl-1 ,2-dihydropyridin-3-yl)methyl)-6'-(4- morpholinophenyl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'-carboxamide
A solution of the compound of example 151 in DMF was treated with the compound of example 4 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 36 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (s, 1 H), 8.52 (d, J = 8.1 Hz, 1 H), 8.31 (bs, 1 H), 7.59 (d, J = 8.4 Hz, 2H), 7.27 (s, 1 H), 7.03 (d, J = 8.4 Hz, 2H), 5.88 (s, 1 H), 4.56 - 4.51 (m, 1 H), 4.25 (d, J = 4.8 Hz, 2H), 3.75 (m, 4H), 3.15 (m, 4H), 2.56 (m, 2H), 2.21 (m, 2H), 2.1 1 (s, 3H), 1 .80 - 1 .75 (m, 6H), 1 .55 - 1 .52 (m, 2H), 1 .42 (d, J = 6.6 Hz, 6H), 0.92 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 597.4 (M+H)+.
Example 153:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 '-isopropyl-6'-(4- morpholinophenyl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'-carboxamide
A solution of the compound of example 151 in DMF was treated with the compound of example 9 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 59 %; 1 H NMR (DMSO-afe, 300 MHz): δ 1 1 .47 (s, 1 H), 8.35 (bs, 1 H), 7.60 (d, J = 8.4 Hz, 2H), 7.27 (s, 1 H), 7.1 1 (s, 1 H), 7.04 (d, J = 8.4 Hz, 2H), 5.85 (s, 1 H), 4.56 - 4.51 (m, 1 H), 4.25 (d, J = 4.5 Hz, 2H), 3.75 (m, 4H), 3.15 (m, 4H), 2.22 (m, 5H), 2.10 (s, 3H), 1 .80 - 1 .75 (m, 6H), 1 .42 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 569.4 (M+H)+.
Example 154:
Methyl 6-bromo-1-isopropyl-3,3-dimethylindoline-4-carboxylate (154 A) and (6-Bromo-1-isopropyl-3,3-dimethylindolin-4-yl)methanol (154 B)
To a solution of the compound of example 127 (2.5 g, 7.35 mmol, 1 .0 equiv) in THF (125 ml_) was added borane-THF complex 1 M solution in THF (36.7 ml_, 36.7 mmol, 5.0 equiv) and heated to 60 °C for 18 h. The reaction mass was cooled to room temperature, methanol (10 ml_) was added and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and quenched with water. The reaction mass was extracted with ethyl acetate, dried over sodium sulfate and concentrated to obtain pale yellow oil. The oil was purified by column chromatography (silica gel, 1 :9, EtOAc - petroleum ether) to obtain the title compounds.
Example 54 A:
Yield: 1 .47 g (61 %); 1 H NMR (CDCI3, 300 MHz): δ 7.10 (d, J = 1 .8 Hz, 1 H), 7.61 (d, J = 1 .8 Hz, 1 H), 3.88 (s, 3H), 3.81 - 3.72 (m, 1 H), 3.10 (s, 2H), 1 .39 (s, 6H), 1 .17 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 327.1 (M+H)+.
Example 154 B:
Yield: 723 mg (33 %); 1 H NMR (DMSO-d6, 300 MHz): δ 6.77 (d, J = 1 .8 Hz, 1 H), 6.49 (d, J = 1 .8 Hz, 1 H), 5.13 (t, J = 5.7 Hz, 1 H), 4.49 (d, J = 5.7 Hz, 2H), 3.82 - 3.77 (m, 1 H), 3.00 (s, 2H), 1 .25 (s, 6H), 1 .06 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 299.1 (M+H)+.
Example 155:
Methyl 1 -isopropyl-3,3-dimethyl-6-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl) indoline-4-carboxylate
A solution of the compound of example 154 A in dioxane was treated with 4-
(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine (1 .4 equiv) according to the procedure described for the preparation of the compound of example 128 to obtain the title compound.
Yield: 71 %; 1H NMR (DMSO-d6, 300 MHz): δ 8.39 (d, J = 2.4 Hz, 1 H), 7.81 - 7.77 (d, J = 2.4 Hz, 1 H), 7.01 (d, J = 1 .5 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 1 H), 6.83 (d, J = 1 .5 Hz, 1 H), 4.02 - 3.97 (m, 1 H), 3.82 (s, 3H), 3.53 - 3.50 (m, 4H), 3.08 (s, 2H), 3.42 - 3.39 (m, 4H), 2.22 (s, 3H), 1 .33 (s, 6H), 1 .10 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 423.3 (M+H)+. Example 156:
1-lsopropyl-3,3-dimethyl-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)indoline-4- carboxylic acid A solution of the compound of example 155 in MeOH and THF was treated with 1 M NaOH (4.0 equiv) according to the procedure described for the preparation of the compound of example 129 to obtain the title compound.
Yield: 85 %; 1 H NMR (DMSO-d6, 300 MHz): δ 12.60 (bs, 1 H), 8.39 (s, 1 H), 7.81 - 7.77 (d, J = 2.4 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.01 (s, 1 H), 6.90 (d, J = 8.4 Hz, 1 H), 3.99 (m, 1 H), 3.54 (m, 4H), 3.08 (s, 2H), 2.29 (m, 4H), 1 .36 (s, 6H), 1 .23 (s, 3H), 1 .10 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 409.2 (M+H)+.
Example 157:
1 -lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl )-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
A solution of the compound of example 156 in DMF was treated with the compound of example 4 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 54 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (bs, 1 H), 8.45 (d, J = 8.1 Hz, 1 H), 8.38 (s, 1 H), 8.06 (bs, 1 H), 7.81 (d, J = 8.7 Hz, 1 H), 6.93 (d, J = 8.7 Hz, 1 H), 6.68 (s, 1 H), 5.88 (s, 1 H), 4.95 (m, 1 H), 4.27 (d, J = 4.5 Hz, 2H), 3.59 (m, 4H), 2.99 (s, 2H), 2.66 (m, 4H), 2.40 (s, 3H), 2.1 1 (s, 3H), 1 .55 - 1 .50 (m, 2H), 1 .35 (m, 2H), 1 .27 (s, 6H), 1 .23 (s, 6H), 0.91 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 571 .4 (M+H)+.
Example 158:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3,3- dimethyl-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide
A solution of the compound of example 156 in DMF was treated with the compound of example 9 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 85 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .47 (bs, 1 H), 8.48 (d, J = 7.5 Hz, 1 H), 8.41 (d, J = 2.4 Hz, 1 H), 8.08 (bs, 1 H), 7.85 (dd, J = 2.4 Hz, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 6.68 (s, 1 H), 5.85 (s, 1 H), 4.94 (m, 1 H), 4.26 (d, J = 4.8 Hz, 2H), 3.65 (m, 4H), 3.16 (s, 2H), 2.86 (m, 4H), 2.55 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1 .27 (s, 6H), 1 .08 (d, J = 6.6 Hz, 6H); MS (ESI+): m/z 543.4 (M+H)+.
Example 159:
6-Bromo-1-isopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)indoline-4-carboxamide
A solution of the compound of example 154 A in DMF was treated with the compound of example 4 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 44 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (bs, 1 H), 8.1 1 (bs, 1 H), 6.62 (s, 1 H), 6.48 (d, J = 1 .2 Hz, 1 H), 5.87 (s, 1 H), 4.22 (d, J = 4.5 Hz, 2H), 3.85 - 3.81 (m, 1 H), 3.00 (s, 2H), 2.48 (m, 2H), 2.1 1 (s, 3H), 1 .56 - 1 .48 (m, 2H), 1 .23 (s, 6H), 1 .05 (d, J = 6.6 Hz, 6H), 0.91 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 475.3 (M+H)+. Example 160:
6-Bromo-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl- 3,3-dimethylindoline-4-carboxamide
A solution of the compound of example 154 A in DMF was treated with the compound of example 9 (1 .4 equiv) according to the procedure described for the preparation of the compound of example 130 to obtain the title compound.
Yield: 81 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .48 (bs, 1 H), 8.15 (bs, 1 H), 6.62 (s, 1 H), 6.49 (d, J = 1 .5 Hz, 1 H), 5.84 (s, 1 H), 4.21 (d, J = 4.8 Hz, 2H), 3.85 - 3.81 (m, 1 H), 2.99 (s, 2H), 2.17 (s, 3H), 2.10 (s, 3H), 1 .23 (s, 6H), 1 .05 (d, J = 6.3 Hz, 6H); MS (ESI+): m/z 447.3 (M+H)+.
Example 161 :
Ethyl 2-oxo-2-(2-oxocyclohexyl)acetate
A solution of sodium ethoxide was prepared by the addition of 2.55 g (1 10 mmol) of sodium to 40 ml_ of anhydrous ethyl alcohol. The flask was then immersed in an ice bath and the reaction mass was stirred for 10 minutes. A cold solution of 10.5 ml_ (100 mmol) of cyclohexanone in 13.5 ml_ (100 mmol) of diethyl oxalate was added from the dropping funnel to the reaction mixture over a period of about 15 min. On completion of the dropwise addition of the cold solution, the ice bath was retained for 1 h, and then the mixture was stirred at room temperature for another 6 h. The reaction mixture was added to ice cooled water and acidified using 2 N HCI. The aqueous solution was extracted with DCM, washed with brine, dried over anhydrous MgSO4, and evaporated to give the residue, which was purified by column chromatography (silica gel, EtOAc and Petroleum ether) to obtain the title compound. Yield: 14.15 g (52 %); 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .92(s, 1 H), 4.22(t, J = 7.2Hz, 2H), 2.4(s, 2H), 2.3(s, 2H), 1 .63(d, J = 4.8Hz, 2H), 1 .54(d, J = 4.5Hz, 2H), 1 .23 (t, J = 7.2Hz, 3H); MS (ESI+): m/z 199.3 (M+H)+. Example 162:
Ethyl 2-methoxy-5,6,7,8-tetrahydroquinazoline-4-carboxylate
To a solution of 100 ml_ of DMF were added the compound of example 161 (20 g, 101 mmol) and methyl carbamimidate (4.47, 101 mmol). The reaction mass was heated to 95 °C for 12-16 h. The reaction mass obtained was cooled, and the DMF was removed. To this reaction mass, water was added and the product was extracted using ethyl acetate. Purification was done by column chromatography (silica gel, 20 % ethyl acetate in pet ether) to obtain the title compound.
Yield: 10 g (41 .9 %); 1 H NMR (DMSO-d6, 500 MHz): δ 4.36 (t, J =7 Hz, 2H), 3.80 (s, 3H), 2.79 (m, 2H), 2.70 (m, 2H), 1 .80 (d, J = 5Hz, 2H), 1 .74 (d, J = 5Hz, 2H), 1 .23 (t, J = 7.2Hz, 3H); MS (ESI+): m/z 237.2 (M+H)+.
Example 163A:
Ethyl 2-hydroxy-5,6,7,8-tetrahydroquinazoline-4-carboxylate
The compound of example 162 (10 g, 42.3 mmol) was dissolved in HBr in acetic acid (32 g, 423 mmol). The reaction mass was heated at 50 °C for 30 min. and then cooled to room temperature. The pH of reaction mass was adjusted between 6 and 7 using sodium bicarbonate. The product was then extracted with ethyl acetate and the crude product obtained was used in the next step without purification.
Yield: 6 g (63.8 %); 1 H NMR (DMSO-d6, 500 MHz): δ 4.40 (t, J =7 Hz, 2H), 2.89 (t, J = 5.5Hz, 2H), 2.83 (t, J = 6Hz 2H), 1 .82 (d, J = 5.5Hz, 2H), 1 .76 (d, J = 5Hz, 2H), 1 .32 (t, J =7.2Hz, 3H); MS (ESI+): m/z 222.8 (M+H)+.
Example 163B:
Ethyl 2-chloro-5,6,7,8-tetrahydroquinazoline-4-carboxylate
To a solution of compound of example 163A (200 mg, 0.900 mmol) was added thionyl chloride (10 ml_, 137 mmol). The reaction mass was heated at 90 °C for 4h. Following the completion of the reaction, the reaction mass was concentrated with the addition of ice water. The product was extracted with ethyl acetate. Purification was done using column chromatography (silica gel; ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 100 mg (46.2 %); 1 H NMR (DMSO-dfe, 500 MHz): δ 4.40(t, J =7 Hz, 2H), 2.89(t, J = 5.5Hz, 2H), 2.83(t, J = 6Hz 2H), 1 .82(d, J = 5.5Hz, 2H), 1 .76(d, J = 5Hz, 2H), 1 .32(t, J =7.2Hz, 3H); MS (ESI+): m/z 241 .2 (M+H)+.
Example 164:
Ethyl 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-5,6,7,8- tetrahyd roqu i nazol i ne-4-car boxylate
To a solution of the compound of example 163 B (250mg, 0.53 mmol) in 10 ml_ of 1 -4 dioxane, were added tert-butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (566 mg, 1 .454 mmol) and sodium bicarbonate (262 mg, 3.12 mmol) in 2 ml_ of water. Argon gas was purged for 10 minutes. To this reaction mixture PdCI2(dppf) (22 mg, 0.031 mmol) was added. Argon was purged for 10 minutes and the reaction mass was heated for 12- 16 h at 90 °C. The reaction mass was concentrated and quenched by addition of water and the product obtained was extracted with ethyl acetate. The crude product obtained was purified by column chromatography (silica gel, DCM and methanol) to obtain the title compound.
Yield: 90 mg (18.53 %); 1H NMR (DMSO-d6, 500 MHz): δ 9.03 (s, 1 H), 8.36 (t, J = 8.5Hz, 1 H), 6.94 (d, J = 9Hz, 1 H), 4.40 (q, J = 7.0 Hz, 14.0 Hz, 2H), 3.63 (s 4H), 3.45 (s, 4H), 2.9(s, 2H), 2.78 (s, 2H), 1 .82 (d, J = 5Hz, 2H), 1 .74 (d, J = 4Hz, 2H), 1 .43 (s, 9H), 1 .33 (t, J = 7.0Hz, 3H); MS (ESI+): m/z 468.3 (M+H)+. Example 165:
2-(6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-5,6,7,8- tetrahydroquinazoline-4-carboxylic acid
To a solution of the compound of example 164 (95 mg, 0.203 mmol) in 5 ml_ of methanol and 5 ml_ of THF was added sodium hydroxide (26mg, 0.650 mmol) taken in 1 ml_ of water. The reaction mass was heated for 60 °C for 1 h. Subsequently the reaction mass was concentrated and the pH of reaction mass was adjusted between 4 and 5 using citric acid solution at 0 °C. The solid obtained was filtered to obtain the title compound. Yield: 73 mg (82 %); 1H NMR (DMSO-d6, 500 MHz): δ 9.06 (s, 1 H), 8.40 (d, J = 8.5Hz, 1 H), 6.94 (d, J =9 Hz, 1 H), 3.63 (s, 4H), 3.56 (s, 4H), 2.89 (s, 2H), 2.81 (s, 2H), 1 .84 (s, 2H), 1 .79 (s, 2H), 1 .43 (s, 9H); MS (ESI+): m/z 440.3 (M+H)+. Example 166:
tert-Butyl 4-(5-(4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl )-5,6,7,8-tetrahydroquinazolin-2-yl)pyridin-2-yl)piperazine-1- carboxylate
To a solution of the compound of example 165 (73 mg, 0.166 mmol), in 1 .5 mL of DMF were added the compound of example 4 (38.9 mg, 0.216 mmol), HATU (82 mg, 0.216 mmol), and DIPEA (0.102 mL, 0.581 mmol) and the reaction mass was stirred for 12-16 h at room temperature. After 12-16 h, the reaction mass obtained was concentrated. To this reaction mass, 2 mL of water was added and the product was extracted with chloroform. The crude product obtained was purified with column chromatography (silica gel, DCM and methanol) to obtain the title compound. Yield: 30 mg (30 %); 1H NMR (DMSO-d6, 500 MHz): δ 1 1 .66 (s, 1 H), 9.14 (s, 1 H), 9.0 (s, 1 H), 8.41 (d, J = 9 Hz, 1 H), 6.93 (d, J = 10 Hz, 1 H), 5.92 (s, 1 H), 4.36 (d, J = 5 Hz, 2H), 3.63 (s 4H), 3.45 (s, 4H), 3.02 (s, 2H), 2.89 (s, 2H), 2.13 (s, 3H), 1 .82 (m, 2H), 1 .74 (m, 2H), 1 .59 (m, 2H), 1 .43 (s, 9H), 1 .23 (s, 2H), 0.93 (t, J = 7 Hz, 3H); MS (ESI+): m/z 602.4 (M+H)+.
Example 167:
N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(6-(piperazin-1- yl)pyridin-3-yl)-5,6,7,8-tetrahydroquinazoline-4-carboxamide
To a solution of the compound of example 166 (30 mg, 0.050 mmol) in 1 mL of methanol was added 2 mL of methanolic HCI and the reaction mass was stirred for 12-16 h. The reaction mass obtained was concentrated and 2 mL sodium bicarbonate solution was added to make the pH basic. The precipitated solid was filtered and the product was dried to obtain the title compound.
Yield: 1 1 mg (44 %); 1H NMR (DMSO-d6, 500 MHz): δ 1 1 .67 (s, 1 H), 9.14 (s, 1 H), 9.0 (s, 1 H), 8.37 (d, J = 9Hz, 1 H), 6.87 (d, J = 10 Hz, 1 H), 5.92 (s, 1 H), 4.36 (s, 2H), 3.53 (s, 5H), 3.02 (s, 2H), 2.88 (s, 2H), 2.7 (s, 3H), 2.13 (s, 3H), 1 .82 (m, 2H), 1 .74 (m, 2H), 1 .55 (m, 2H), 1 .23 (s, 2H), 0.92 (t, J = 7.0 Hz, 3H); MS (ESI+): m/z 502.3 (M+H)+. Example 168:
Ethyl 2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate
A mixture of ethyl 2-oxo-2-(2-oxocyclopentyl)acetate (1 .0 g, 5.43 mmol) and S-methylisothiourea hemisulfate salt (0.979 g, 10.86 mmol) in methanol (15 mL) was refluxed for 12-16 h. The reaction mixture was concentrated, residue obtained was diluted with ethyl acetate (50 mL) and washed with water (10 mL), and brine (5 mL). The combined organic layers obtained were dried over anhydrous Na2S04, filtered, concentrated, and the residue obtained was purified by column chromatography (silica gel, 10 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 0.0565 mg (5 %); 1 H NMR (300 MHz, DMSO-d6): δ 4.48 (q, J = 7.5 Hz, 2H), 3.25 (t, J = 7.5 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 2.65 (s, 3H), 2.20 (m, 2H), 1 .46 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 239 (M+H)+.
Example 169:
2-(Methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylic acid
A mixture of the compound of example 168 (0.238 mg, 1 mmol) and 1 M NaOH (2 mL, 2 mmol) in MeOH: THF (1 :1 ) (6.0 mL) was heated at 60 °C for 3 h. The mixture was concentrated to obtain a residue. The residue obtained was acidified with 1 M HCI solution and the solid obtained was filtered to obtain the title compound. Yield: 90 %; 1 H NMR (300 MHz, DMSO-d6): δ 10.63 (br. s, 1 H), 3.37 (t, J = 7.5 Hz, 2H), 3.08 (t, J = 7.5 Hz, 2H), 2.62 (s, 3H), 2.26 (m, 2H); MS (ESI+): (m/z) 21 1 (M+H)+.
Example 170:
N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(methylthio)-6,7- dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide
A mixture of the compound of the example 169 (0.210 g, 1 mmol), Hunig's base (0.870 mL, 5 mmol), the compound of the example 4 (0.283 g, 1 .5 mmol) and DMF (15 mL) was stirred at ambient temperature in argon atmosphere and HATU (0.760 g, 2 mmol) was added. The mixture was stirred for 48 h. The mixture was concentrated and residue obtained was mixed with ice-cooled water, solid obtained was filtered to obtain the title compound.
Yield: 0.210 g (61 %);1 H NMR (300 MHz, CDCI3): δ 1 1 .75 (br. s, 1 H), 8.99 (br. s, 1 H), 5.95 (s, 1 H), 5.32 (d, J = 3.6 Hz, 2H), 3.37 (t, J = 7.5 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.57 (s, 3H), 2.32 (s, 3H), 2.14-2.1 1 (m, 2H), 1 .66-1 .57 (m, 3H), 1 .01 (t, J = 7.2 Hz, 2H); MS (ESI+): m/z 373 (M+H)+.
Example 171 :
N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(methylsulfonyl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide
A mixture of the compound of the example 170 (0.125 g, 0.336 mmol), 3- chlorobenzoperoxoic acid (0.1 16 g, 0.671 mmol) and dichloromethane (15 mL) was stirred at ambient temperature for 12-16 h. Saturated solution of sodium bicarbonate (20 mL) was added and stirred for 30 minutes, the layers obtained were separated. The organic layer was washed with water (10 mL), and brine (5 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, concentrated, and the residue obtained was purified by column chromatography (silica gel, 5 % methanol in dichloromethane) to obtain the title compound.
Yield: 0.045 g (33 %); 1H NMR (300 MHz, CDCI3): δ 1 1 .77 (br. s, 1 H), 9.1 1 (br. s, 1 H), 5.96 (s, 1 H), 4.59 (d, J = 5.7 Hz, 2H), 3.56 (t, J = 7.5 Hz, 2H), 3.35 (s, 3H), 3.19 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.35 (s, 3H), 2.30-2.20 (m, 2H), 1 .66-1 .57 (m, 3H), 1 .02 (t, J = 7.2 Hz, 2H); MS (ESI+): m/z 405 (M+H)+. Example 172:
N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(4- methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide
A mixture of the compound of example 171 (0.040 g, 0.099 mmol), 1 - methylpiperazine (55 mL, 0.494 mmol), Hunig's base (173 mL, 0.989 mmol) and N- methyl pyrrolidone (2 mL) were sealed in a seal-tube, and kept in pre-heated oil bath of 160 °C for 12-16 h. The mixture was concentrated and the residue obtained was purified by column chromatography (silica gel, 5 % methanol in dichloromethane) to obtain the title compound.
Yield: 0.028 g (66 %); 1H NMR (300 MHz, CDCI3): δ 1 1 .78 (br. s, 1 H), 8.98 (br. s, 1 H), 5.94 (s, 1 H), 4.55 (d, J = 6.0 Hz, 2H), 3.80 (m, 4H), 3.24 (t, J = 7.5 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.35 (m, 4H), 2.29 (s, 3H), 2.21 (s, 3H), 2.1 1 -2.03 (m, 2H), 1 .62-1 .57 (m, 2H), 0.89 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 425 (M+H)+. Example 173:
Ethyl 2-methoxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate
A mixture of ethyl 2-oxo-2-(2-oxocyclopentyl)acetate (1 .0 g, 5.43 mmol) and O-methylisourea hemisulfate (0.483 g, 6.52 mmol) in methanol (15 ml_) was refluxed for 12-16 h. The reaction mixture was concentrated, the residue obtained was diluted with ethyl acetate (50 ml_) and washed with water (10 ml_), and brine (5 ml_). The combined organic layers were dried over anhydrous Na2S04, filtered, concentrated, and the residue obtained was purified by column chromatography to obtain the title compound.
Yield: 0.140 mg (1 1 %);1H NMR (300 MHz, DMSO-d6): δ 4.47 (q, J = 4.2 Hz, 2H), 4.06 (s, 3H), 3.23 (t, J = 4.5 Hz, 2H), 3.02 (t, J = 4.5 Hz, 2H), 2.20 (m, 2H), 1 .45 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 223 (M+H)+.
Example 174A:
Ethyl 2-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate
A mixture of the compound of example 173 (0.550 g, 2.475 mmol) and HBr (30-33 %) in acetic acid (6.0 ml_) was stirred at 50 °C for 30 minutes. On completion of the reaction, the mixture was concentrated and the crude material obtained was used without purification. The crude material was mixed with POCI3 (5.0 ml_) and heated at 90 °C for 12-16 h. The mixture was concentrated and the crude material obtained was purified by column chromatography (silica gel, 5 % methanol in chloroform) to obtain the title compound.
Yield: 20 %; MS (ESI+): m/z 209.4 (M+H)+. Example 174B:
Ethyl 2-bromo-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate
To a mixture of compound of example 174A (0.050 g, 0.238 mmol) in dichloromethane was added tribromoborane (0.310 g, 1 .237 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. To this was added aqueous sodium bicarbonate and extracted with ethyl acetate, dried over sodium sulphate. The solvent was evaporated and the mixture was further treated with phosphorous tribromide (w/w) and heated to 1 10 °C. Following the completion of the reaction, water was added and the mixture was extracted with ethyl acetate and purified using column chromatography (5 % methanol in chloroform). Yield: 25 %; MS (ESI+): m/z 272 (M+H)+. Example 175:
Ethyl 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine-4-carboxylate
A mixture of the compound of example 174 B (0.230 g, 0.844 mmol) and tert- butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylate (0.553 g, 1 .421 mmol) along with sodium carbonate (2 M, 1 .55 mL) in 1 ,4-dioxane (10 mL) were sonicated for two minutes and stirred under argon atmosphere at an ambient temperature. The PdCI2(dppf).CH2Cl2 adduct (0.166 g, 0.2 mmol) was added to the reaction mixture and stirred at 1 10 °C until the reaction was complete. The reaction mass was diluted with EtOAc (50 mL) and filtered through a celite bed. The filtrate was washed with water (20 mL), brine (5 mL). The organic layer was dried over anhydrous Na2S04, filtered, concentrated and the residue obtained was purified by column chromatography (silica gel, 5 % methanol in dichloromethane) to obtain the title compound
Yield: 0.220 g (49 %); MS (ESI+): m/z 454 (M+H)+.
Example 176:
2-(6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine-4-carboxylic acid
A mixture of the compound of example 175 (0.220 g, 0.485 mmol) and 1 M NaOH (0.970 mL, 0.970 mmol) in MeOH: THF (1 :1 ) (6.0 mL) was heated at 60 °C for 3 h. The reaction mixture was concentrated, residue obtained was neutralised to pH of about 7 with 1 M HCI solution and the crude product obtained was filtered to obtain the title compound.
Yield: 155 mg (75 %); MS (ESI+): m/z 426 (M+H)+. Example 177:
tert-Butyl 4-(5-(4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl )-6 ,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyridin-2-yl)piperazine- 1 -carboxylate
A mixture of the compound of example 176 (0.152 g, 0.357 mmol), Hunig's base (0.218 mL, 1 .25 mmol), the compound of example 4 (0.093 g, 0.429 mmol) and DMF (5 mL) was stirred at ambient temperature in argon atmosphere and HATU (0.177 g, 0.464 mmol) was added. The mixture was stirred for 48 h. The resulting mixture was concentrated and the residue obtained was mixed with ice-cool water and the solid obtained was filtered to obtain the title compound.
Yield: 0.075 g (35 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 1 .70 (br. s, 1 H), 9.34 (t, J = 1 .8 Hz, 1 H), 9.25 (d, J = 1 .8 Hz, 1 H), 8.49 (dd, J = 9.0 and 2.1 Hz, 1 H), 6.55 (J = 9.0 Hz, 1 H), 5.93 (s, 1 H), 4.62 (J = 6.0 Hz, 2H), 3.57-3.54 (m, 6H), 3.45 (t, J = 7.5 Hz, 2H), 3.06 (t, J = 7.8 Hz, 2H), 2.71 (t, J = 7.8 Hz, 2H), 2.29 (s, 3H), 2.19-2.14 (m, 2H), 1 .63-1 .58 (m, 2H), 1 .51 (s, 9H), 1 .27 (m, 2H), 1 .03 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 588 (M+H)+.
Example 178:
N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(6-(piperazin-1- yl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide
A mixture of the compound of example 177 and methanolic HCI (2 mL) was stirred at ambient temperature for 12-16 h. The resulting mixture was concentrated, residue obtained was neutralised with saturated sodium bicarbonate solutionand was extracted with chloroform (25 mL), washed with water (10 mL), and brine (5 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, concentrated, and the residue obtained was purified by column chromatography (silica gel, 5 % methanol in dichloromethane) to obtain the title compound.
Yield: 0.040 g (64 %); 1 H NMR (300 MHz, DMSO-d6): δ 9.36 (br. s, 1 H), 9.24 (d, J = 1 .8 Hz, 1 H), 8.47 (dd, J = 9.0 and 2.1 Hz, 1 H), 6.51 (J = 9.0 Hz, 1 H), 5.91 (s, 1 H), 4.62 (J = 6.0 Hz, 2H), 3.53-3.51 (m, 4H), 3.45 (t, J = 7.5 Hz, 2H), 3.06 (t, J = 7.8 Hz, 2H), 2.91 (m, 4H), 2.70 (d, J = 7.5 Hz, 2H), 2.28 (s, 3H), 2.21 -2.06 (m, 2H), 1 .68-1 .58 (m, 1 H), 1 .43-1 .27 (m, 3H), 1 .03 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 488 (M+H)+.
Example 179:
4-(Furan-2-yl)-2,3-dihydro-1 H-inden-1 -one
A mixture of 4-bromo-2,3-dihydro-1 H-inden-1 -one (0.5 g, 2.37 mmol), furan-2- ylboronic acid (0.318 g, 2.84 mmol) and potassium carbonate (0.458 g, 3.32 mmol) in DMF:H20 (2:1 ) (12 mL) were sonicated for two minutes and stirred under argon atmosphere at an ambient temperature. Dichlorobis(triphenylphosphine)Palladium(ll) (0.083 g, 0.237 mmol) was added to the reaction mixture and stirred at 120 °C till the reaction was complete. The reaction mass obtained was diluted with EtOAc (50 ml_) and filtered through a celite bed. The filtrate was washed with water (20 ml_) and brine (5 ml_). The organic layer obtained was dried over anhydrous Na2S04, filtered, concentrated and the residue obtained was purified by column chromatography (silica gel, 5 % methanol in dichloromethane) to obtain the title compound.
Yield: 0.3 g (64 %); 1H NMR (300 MHz, CDCI3): δ 8.01 (d, J = 7.8 Hz, 1 H), 7.71 (d, J = 7.5 Hz, 1 H), 7.56 (d, J = 1 .5 Hz, 1 H), 7.48 (t, J = 7.8 Hz, 1 H), 6.71 (d, J = 3.3 Hz, 1 H), 6.57-6.55 (m, 1 H), 3.35-3.31 (m, 2H), 2.79-2.75 (m, 2H); MS (ESI+): m/z 199 (M+H)+.
Example 180:
1 -Oxo-2,3-dihydro-1 H-indene-4-carboxylic acid
A mixture of sodium periodate (4.86 g, 22.70 mmol), CH2CI2 (17 ml_), acetonitrile (0.680 ml) and water (23.80 ml_) was stirred at ambient temperature in argon atmosphere to form homogenous solution. Ruthenium(lll) chloride hydrate (0.017 g, 0.076 mmol) was added and stirred for 1 h. The compound of example 179 (0.3 g, 1 .513 mmol) was dissolved in CH2CI2 (17 ml_) and added to reaction mixture and stirred for another h. The reaction mixture was diluted with EtOAc (50 ml_) and filtered through a celite bed. The filtrate obtained was washed with water (20 ml_) and brine (5 ml_). The organic layer was dried over anhydrous Na2S04, filtered, concentrated and the residue obtained was purified by column chromatography (silica gel, 5 % methanol in dichloromethane) to obtain the title compound.
Yield: 0.23 g (86 %); 1H NMR (300 MHz, CDCI3): δ 13.26 (br.s, 1 H), 8.21 (d, J = 7.5 Hz, 1 H), 7.71 (d, J = 7.5 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 1 H), 3.40-3.36 (m, 2H), 2.65- 2.62 (m, 2H); MS (ESI+): m/z 175 (M-H)\
Example 18 :
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -oxo-2,3-dihydro-1 H- indene-4-carboxamide
A mixture of the compound of example 180 (0.200 g, 1 .135 mmol), Hunig's base (0.9 ml_, 5.68 mmol), compound of example 9 (0.300 g, 1 .589 mmol) and DMF (25 ml_) was stirred at ambient temperature in argon atmosphere and HATU (0.691 g, 1 .816 mmol) was added. The mixture was stirred for 48 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was mixed with ice-cool water, solid obtained was filtered to obtain the title compound.
Yield: 0.255 g (72 %); 1H NMR (300 MHz, DMSO-d6): δ 1 1 .52 (br. s, 1 H), 8.41 (br. s, 1 H), 7.85 (d, J = 4.5 Hz, 1 H), 7.27 (d, J = 4.5 Hz, 1 H), 7.48 (t, J = 4.5 Hz, 1 H), 5.88 (s, 1 H), 4.32 (d, J = 3.0 Hz, 2H), 3.27 (m, 2H), 2.63 (m, 2H), 2.20 (s, 3H), 2.1 1 (s, 3H); MS (ESI+): m/z 31 1 (M+H)+.
Example 182:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-hydroxy-2,3-dihydro- 1 H-indene-4-carboxamide
A mixture of the compound of example 181 (0.050 g, 0.161 mmol), MeOH (2 mL) and THF (5.0 mL) was stirred at 0 °C for 30 minutes. Sodium borohydride (0.006 g, 0.161 mmol) was added to the reaction mixture, and the reaction mixture was stirred for 12-16 h. The resulting mixture was concentrated, cooled in ice bath and 1 M HCI was added till pH was acidic. Solid obtained was filtered out and dried to obtain the title compound.
Yield: 70 %; 1H NMR (300 MHz, DMSO-d6): δ 1 1 .50 (br. s, 1 H), 8.07 (br. s, 1 H), 7.41 (s, 1 H), 7.39 (d, 1 H), 7.24 (t, J = 4.5 Hz, 1 H), 5.86 (s, 1 H), 5.27 (d, J = 3.6 Hz, 1 H), 5.03 (q, J = 3.9 Hz, 1 H), 4.27 (m, 2H), 3.1 1 -3.05 (m, 1 H), 2.87-2.80 (m, 1 H), 2.30- 2.28 (m, 1 H), 2.18 (s, 3H), 2.1 1 (s, 3H), 1 .74-1 .70 (m, 1 H); MS (ESI+): m/z 313 (M+H)+.
Example 183:
Methyl 1 -oxo-2,3-dihydro-1 H-indene-4-carboxylate
A mixture of the compound of example 180 (0.700 g, 3.97 mmol), MeOH (10 mL) and 1 drop of concentrated sulfuric acid was refluxed for 12-16 h. The reaction mixture was concentrated, neutralised with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue obtained was purified by column chromatography (silica gel, 5 % methanol in dichloromethane) to obtain the title compound.
Yield: 81 %; 1H NMR (300 MHz, CDCI3): δ 8.31 (d, J = 4.2 Hz, 1 H), 7.98 (d, J = 4.5 Hz, 1 H), 7.52 (t, J = 4.5 Hz, 1 H), 4.01 (s, 3H), 3.52-3.50 (m, 2H), 2.76-2.69 (m, 2H); MS (ESI+): m/z 191 (M+H)+. Example 184:
Methyl 1 -hydroxy-2,3-dihydro-1 H-indene-4-carboxylate
A mixture of the compound of example 183 (0.4 g, 2.103 mmol) and EtOH (20 mL) was stirred at 0 °C for 15 min. Sodium borohydride was added to the mixture and stirred at 0 °C for 30 minutes. The reaction mixture was stirred for 12-16 h at ambient temperature. The resulting mixture was concentrated, acidified with 1 M HCI solution and extracted with ethyl acetate (30 mL), dried over anhydrous Na2S04, filtered, concentrated, and the residue obtained was further used without purification. Yield: 70 %; 1H NMR (300 MHz, CDCI3): δ 7.98 (d, J = 4.5 Hz, 1 H), 7.63 (d, J = 4.2 Hz, 1 H), 7.36 (t, J = 4.5 Hz, 1 H), 5.28 (br. s, 1 H), 3.09 (s, 3H), 3.50-3.44 (m, 1 H), 3.20-3.08 (m, 1 H), 2.57-2.50 (m, 1 H), 2.06-1 .86 (m, 1 H) 1 .86 (br. s, 1 H); MS (ESI+): m/z 193 (M+H)+.
Example 185:
Methyl 1-chloro-2,3-dihydro-1 H-indene-4-carboxylate
A mixture of the compound of example 184 (0.4 g, 2.081 mmol) and CHCI3 (5 mL) was stirred at 0 °C. Thionyl chloride (1 mL) was added dropwise and the reaction mixture stirred for 3 h. Mixture was concentrated and purified by column chromatography (silica gel, chloroform) to obtain the title compound.
Yield: 73 %; 1H NMR (300 MHz, CDCI3): δ 8.00 (d, J = 4.5 Hz, 1 H), 7.83 (d, J = 4.2 Hz, 1 H), 7.56 (t, J = 4.5 Hz, 1 H), 5.45 (br. s, 1 H), 3.78 (s, 3H), 3.54-3.44 (m, 1 H), 3.40-3.35 (m, 1 H), 2.66-2.63 (m, 1 H), 2.44-1 .42 (m, 1 H); MS (ESI+): m/z 21 1 (M+H)+. Example 186:
Methyl 1 -morpholino-2,3-dihydro-1 H-indene-4-carboxylate
A mixture of the compound of example 185 (0.080 g, 0.380 mmol), morpholine ( 0.4 mL) and Hunig's base (0.5 mL) was heated in seal-tube at 90 °C for 3 h. The reaction mixture was concentrated the residue obtained was purified using column chromatography (silica gel, 5 % methanol in chloroform) to obtain the title compound.
Yield: 30 %; 1H NMR (300 MHz, CDCI3): δ 7.93 (d, J = 4.5 Hz, 1 H), 7.57 (d, J = 4.2 Hz, 1 H), 7.32 (t, J = 4.5 Hz, 1 H), 4.38 (t, J = 3.9 Hz, 1 H), 3.91 (s, 3H), 3.73-3.72 (m, 2H), 3.62 (t, J = 3.9 Hz, 2H), 3.37-3.30 (m, 1 H), 3.21 -3.14 (m, 1 H), 2.75 (t, J = 4.2 Hz, 2H), 2.45 (m, 2H) 2.17-2.09 (m, 2H); MS (ESI+): m/z 262 (M+H)+.
Example 187:
1-Morpholino-2,3-dihydro-1 H-indene-4-carboxylic acid
A mixture of the compound of the example 186 (0.010 g) and 1 M NaOH (0.1 mL) in MeOH: THF (1 :1 ) (1 mL) was heated at 60 °C for 3 h. The reaction mixture was concentrated, residue obtained was neutralised to pH of about 7 with 1 M HCI solution and extracted with MeOH:CH2CI2 (1 :9) (10 mL), concentrated and used further without purification.
MS (ESI+): m/z 248 (M+H)+.
Example 188:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-morpholino-2,3- dihydro-1 H-indene-4-carboxamide
A mixture of the compound of example 187 (0.010 g, 0.040 mmol), Hunig's base (0.035 mL, 0.202 mmol), compound of example 9 (0.015 g, 0.081 mmol) and DMF (2.0 mL) was stirred at ambient temperature in argon atmosphere and HATU (0.034 g, 0.089 mmol) was added. The reaction mixture was stirred for 48 h. The mixture was concentrated and the residue obtained was mixed with ice-cool water, solid obtained was filtered to obtain the title compound.
Yield: 20 %; 1H NMR (300 MHz, DMSO-d6): δ 12.30 (br. s, 1 H), 7.75 (d, J = 7.5 Hz, 1 H), 7.73 (d, J = 7.5 Hz, 1 H), 7.36 (m, 1 H), 6.22 (s, 1 H), 4.96 (m, 1 H), 4.54 (m, 1 H), 3.98 (s, 3H), 3.50-3.15 (m, 2H), 3.15-2.80 (m, 3H), 2.49-1 .60 (m, 4H), 2.49 (s, 3H), 2.35 (s, 3H), 1 .47-1 .39 (m, 2H); MS (ESI+): m/z 382 (M+H)+.
Example 189:
6-Bromo-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-oxo-2,3- dihydro-1 H-indene-4-carboxamide
A mixture of 6-bromo-1 -oxo-2,3-dihydro-1 H-indene-4-carboxylic acid
(prepared according to the procedure disclosed in WO2005095387A1 ) (0.200 g, 0.141 mmol), Hunig's base (1 .369 mL, 7.84 mmol), compound of example 9 (0.296 g, 1 .568 mmol) and DMF (25 mL) was stirred at ambient temperature in argon atmosphere and HATU (0.691 g, 1 .725 mmol) was added. The reaction mixture was stirred for 48 h. The mixture was concentrated and the residue obtained was mixed with ice-cool water, solid obtained was filtered to obtain the title compound.
Yield: 0.178 g (57 %); 1H NMR (300 MHz, DMSO-d6): δ 1 1 .52 (br. s, 1 H), 8.56 (br. s, 1 H), 8.00 (d, J = 1 .8 Hz, 1 H), 7.82 (d, J = 1 .8 Hz, 1 H), 5.87 (s, 1 H), 4.29 (d, J = 4.8 Hz, 2H), 3.23-3.19 (m, 2H), 2.66-2.62 (m, 2H), 2.18 (s, 3H), 2.1 1 (s, 3H); MS (ESI+): m/z 389 (M+H)+ and 391 (M+H)+.
Example 190:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)-1 -oxo-2,3-dihydro-1 H-indene-4-carboxamide
A mixture of the compound of example 189 (0.055 g, 0.141 mmol), 1 -methyl- 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.064 g, 0.212 mmol), and potassium carbonate (0.039 g, 0.283 mmol) in DMF:H20 (2:1 ) (12 ml_) were sonicated for two minutes and the reaction mixture was stirred under argon atmosphere at an ambient temperature. The dichlorobis(triphenylphosphine) Palladium(ll) (4.96 mg, 0.014 mmol) was added to the reaction mixture and stirred at 120 °C till the reaction was complete. The reaction mixture was diluted with EtOAc (50 ml_) and filtered through a celite bed. The filtrate was washed with water (20 ml_), brine (5 ml_). The organic layer was dried over anhydrous Na2S04, filtered, concentrated and the residue obtained was purified by column chromatography (silica gel, 5 % methanol in chloroform) to obtain the title compound.
Yield: 0.069 g (97 %); 1H NMR (300 MHz, DMSO-d6): δ 1 1 .52 (br. s, 1 H), 8.54-8.52 (m, 2H), 8.09 (m, 1 H), 7.99 (dd, J = 8.7 and 2.4 Hz, 1 H), 7.86 (m, 1 H), 6.94 (d, J = 8.7 Hz, 1 H), 5.87 (s, 1 H), 4.34 (d, J = 1 .8 Hz, 2H), 3.54 (m, 4H), 3.30-3.20 (m, 2H), 2.60-2.50 (m, 2H), 2.45-2.35 (m, 4H), 2.21 -2.20 (m, 6H), 2.1 1 (s, 3H); MS (ESI+): m/z 486 (M+H)+.
Example 191 :
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-morpholinopyridin- 3-yl)-1 -oxo-2,3-dihydro-1 H-indene-4-carboxamide
A mixture of the compound of example 189 (0.055 g, 0.141 mmol), 4-(5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (0.062 g, 0.212 mmol) and potassium carbonate (0.039 g, 0.283 mmol) in DMF:H20 (2:1 ) (12 ml_) were sonicated for two minutes and the reaction mixture was stirred under argon atmosphere at an ambient temperature. The dichlorobis(triphenylphosphine) Palladium(ll) (4.96 mg, 0.014 mmol) was added to the reaction mixture and stirred at 120 °C till the reaction was complete. The reaction mixture was diluted with EtOAc (50 ml_) and filtered through a celite bed. The filtrate was washed with water (20 ml_), brine (5 ml_). The organic layer was dried over anhydrous Na2S04, filtered, concentrated and the residue obtained was purified by column chromatography (silica gel, 5 % methanol in chloroform) to obtain the title compound.
Yield: 0.067 g (95 %); 1H NMR (300 MHz, DMSO-d6): δ 1 1 .52 (br. s, 1 H), 8.57-8.56 (m, 2H), 8.10 (m, 1 H), 8.03 (dd, J = 8.7 and 2.4 Hz, 1 H), 7.88 (m, 1 H), 6.95 (d, J = 8.7 Hz, 1 H), 5.87 (s, 1 H), 4.34 (d, J = 1 .8 Hz, 2H), 3.72-3.69 (m, 4H), 3.51 -3.48 (m, 4H), 3.22-3.20 (m, 2H), 2.65-2.64 (m, 1 H), 2.20 (s, 3H), 2.1 1 (s, 3H), 1 .33-1 .18 (m, 1 H); MS (ESI+): m/z 473 (M+H)+.
Example 192:
Methyl 6-bromo-1-propyl-1 H-indole-4-carboxylate
A solution of methyl 6-bromo-1 H-indole-4-carboxylate in DMF was reacted with n-propyl bromide according to the procedure described for the preparation of the compound of example 10 to obtain the title compound.
Yield: 51 %; 1 H NMR (DMSO-d6, 300 MHz): δ 8.73 (s, 1 H), 8.05 (s, 1 H), 7.33 (s, 1 H), 6.41 (s, 1 H), 4.16 (m, 2H), 3.89 (s, 3H), 1 .70 (m, 2H), 0.90 (t, J = 4.2 Hz, 3H); MS (ESI+): m/z 297 (M+H)+.
Example 193:
Methyl 6-bromo-1 -propylindoline-4-carboxylate
A solution of the compound of example 192 in acetic acid was treated with sodium cyanoborohydride according to the procedure described for the preparation of the compound of example 1 1 to obtain the title compound.
Yield: 76 %; 1 H NMR (DMSO-d6, 300 MHz): δ 7.09 (s, 1 H), 6.78 (s, 1 H), 3.79 (s, 3H), 3.40 (m, 2H), 3.16 (m, 2H), 3.06 (m, 2H), 1 .56 (m, 2H), 0.93 (t, J = 4.5 Hz, 3H); MS (ESI+): m/z 300 (M+H)+.
Example 194:
Methyl 6-(6-(4-(3,3-dimethylbutanoyl)piperazin-1 -yl)pyridin-3-yl)-1 -propyl indoline-4-carboxylate A solution of the compound of example 193 in dioxane was treated with tert- butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylate according to the procedure described for the preparation of the compound of example 12 to obtain the title compound.
Yield: 89 %; 1 H NMR (DMSO-d6, 300 MHz): δ 8.42 (s, 1 H), 7.15 (s, 1 H), 7.23 (s, 1 H), 6.92 (d, J = 5.4 Hz, 1 H), 6.85 (s, 1 H), 3.82 (s, 3H), 3.53 (m, 4H), 3.44 (m, 6H), 3.39 (m, 4H), 3.18 (m, 2H), 1 .43 (s, 9H), 1 .13 (s, 3H); MS (ESI+): m/z 481 (M+H)+.
Example 195:
6-(6-(4-(3,3-Dimethylbutanoyl)piperazin-1 -yl)pyridin-3-yl)-1 -propylindoline-4- carboxylic acid
A solution of the compound of example 194 in MeOH and THF was treated with NaOH according to the procedure described for the preparation of the compound of example 13 to obtain the title compound.
Yield: 76 %; 1 H NMR (DMSO-dfe, 300 MHz): δ 1 1 .23 (s, 1 H), 8.42 (s, 1 H), 7.15 (s, 1 H), 7.23 (s, 1 H), 6.92 (d, J = 5.4 Hz, 1 H), 6.85 (s, 1 H), 3.53 (m, 4H), 3.44 (m, 6H), 3.39 (m, 4H), 3.18 (m, 2H), 1 .43 (s, 9H), 1 .13 (s, 3H); MS (ESI+): m/z 467.3 (M+H)+. Example 196:
tert-Butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)
carbamoyl )-1-propylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate
A solution of the compound of example 195 in DMF was treated with the compound of example 9 according to the procedure described for the preparation of the compound of example 14 to obtain the title compound.
Yield: 51 %; 1 H NMR (DMSO-d6, 300 MHz): δ 1 1 .49 (s, 1 H), 8.47 (s, 1 H), 8.15 (s, 1 H), 7.88 (m, 1 H), 7.01 (s, 1 H), 6.91 (m, 1 H), 6.76 (s, 1 H), 5.87(s, 1 H), 4.28 (s, 2H), 3.52 (s, 4H), 3.44 (s, 4H), 3.33 (s, 2H), 3.10 (m, 4H), 2.18 (s, 3H), 2.1 1 (s, 3H), 1 .58 (m, 2H), 1 .43 (s, 9H), 0.95 (t, J = 4.2 Hz, 3H); MS (ESI+): m/z 601 (M+H)+.
Example 197:
tert-Butyl 4-(5-(4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl )-1-propylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate A solution of the compound of example 195 in DMF was treated with the compound of example 4 according to the procedure described for the preparation of the compound of example 14 to obtain the title compound
Yield: 46 %; 1H NMR (DMSO-d6, 300 MHz): δ 1 1 .50 (bs, 1 H), 8.45 (s, 1 H), 8.14 (s, 1 H), 7.87 (d, J = 7.8 Hz, 1 H), 6.99 (s, 1 H), 6.91 (m, 1 H), 6.75 (s, 1 H), 5.88 (s, 1 H), 4.30 (s, 2H), 3.50 (s, 4H), 3.49 (s, 4H), 3.09 (s, 4H), 2.50 (m, 4H), 2.1 1 (s, 3H), 1 .57 (m, 4H), 1 .47 (s, 9H), 0.9 (m, 6H); MS (ESI+): m/z 629 (M+H)+.
Example 198:
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(piperazin-1 - yl)pyridin-3-yl)-1-propylindoline-4-carboxamide
A solution of the compound of example 196 in MeOH was treated with 12 % methanolic HCI followed by treatment with 10 % sodium bicarbonate solution (10 equiv) according to the procedure described in examples 15 and 16 respectively, to obtain the title compound.
Yield: 41 %; 1 H NMR (CDCI3, 300 MHz): δ 8.39 (s, 1 H), 7.67 (m, 1 H), 7.47 (m, 1 H), 7.27 (s, 1 H), 6.95 (m, 1 H), 6.64 (d, J = 8.7 Hz, 1 H), 6.58 (s, 1 H), 5.92 (s, 1 H), 4.55 (s, 2H), 3.53 (s, 4H), 3.43 (m, 2H), 3.29 (m, 2H), 3.10 (m, 2H), 3.07 (s, 4H), 2.46 (s, 3H), 2.21 (s, 3H), 1 .65 (m, 2H), 1 .01 (t, 3H); MS (ESI+): m/z 500.6 [M+H]+.
Biological Assays
Example 199:
In vitro EZH2 Assay
Representative compounds of formula 1 of the present invention (referred to as test compounds) were tested for their EZH2 inhibitory activity using the assay and method described below:
EZH2 biochemical activity assay was performed to measure the rate of trimethylation of Histone 3 at lysine 27. Serial dilutions of the compounds of formula 1 (representative compounds), ranging from 0.1 nM to 10 μΜ were pre-incubated for 10 min with 50 ng EZH2 protein complex and enzymatic reactions were initiated by the addition of 100 nM Histone H3 peptide (ATKAARKSAPATGGVKKPHRYRP-GG- K) substrate and 10 μΜ of S-(5'-Adenosyl)-L-methionine chloride. The assay buffer used in every reaction contained 0.5 % DMSO in assay buffer containing 50 mM Tris-HCI pH 9.0, 50 mM NaCI, 1 mM DTT, 0.01 % Tween-20 and 0.01 % BSA. Detection mixture containing 500 ng of anti tri methyl Histone H3 Lysine 27 Acceptor Bead conjugate (Perkin Elmer) and 500 ng of Straptavidin donor beads(Perkin Elmer) were added to each reaction mixture and plate was incubated for one hour at room temperature. Alpha counts were detected using Multilable Plate Reader. The IC50 values for the compounds of formula 1 (the representative compounds) were determined by a four-parameter sigmoidal curve fit (Sigma plot or Graph pad).
(Reference: Dillon SC, et al.; Genome Biology, 2005, 6, 227).
Table 1 : Symbols used to indicate IC50 range class
Sr. No. Symbol IC50 range class
1 + 0.001 μΜ to 1 μΜ
2 ++ 1 .1 μΜ to 10 μΜ
3 +++ 10.1 μΜ to 50 μΜ Table 2: IC50 values for the representative compounds of the present invention for their EZH2 inhibiting activity
Example No. IC5o range (μΜ) Example No. IC50 range (μΜ)
14 + 87 +
16 + 89 +
19 + 90 +
17 + 91 +
20 + 98 +++
21 + 102 +
28 + 106 ++
29 ++ 1 12 ++
30 + 1 13 +
32 ++ 130 ++
33 ++ 131 ++
35 + 132 +++
41 + 133 ++
45 ++ 136 +++
46 + 137 +++
50 + 144 +++
52 + 145 ++
57 + 148 ++
59 + 149 ++
60 + 152 +++
65 + 153 +++
68 + 172 ++
69 + 177 +++
73 ++ 178 ++
76 +++ 181 +
78 ++ 196 ++
84 + 197 ++
85 ++ 198 +
86 + All publications and patent applications in this specification are indicative of the level of ordinary skill in the art to which this invention pertains.
The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

We claim:
1 . A compound of formula 1
Figure imgf000134_0001
Formula 1
wherein,
Xi and X2 are independently selected from CRi and N, such that ring A is a phenyl, pyridyl or pyrimidinyl ring;
m and n are integers independently selected from 0 and 1 ; such that ring B is a 5-7 membered ring;
Yi , Y2, Y3, Y4 and Y5 are independently selected from the group consisting of CR1 R2, NR3, S(0)r, C(O) and C=N-(CN);
L is ~C(0)NR5- --NR5C(0)--, -NR5S(0)r-, --S(0)rNR5--, --CH(halo-(CrC8)- alkyl)NR5--, --NR5CH(halo-(CrC8)-alkyl)--, --C(halo-(Ci-C8)-alkyl)2NR5--, --
NR5C(halo-(Ci-C8)-alkyl)2-,
Figure imgf000134_0002
; wherein the dotted line (-) indicates the points of attachment of L to ring A and the group
Figure imgf000134_0003
respectively;
p is an integer from 0 to 3;
r is an integer from 0 to 2;
Q is:
Figure imgf000134_0004
Ri and R2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (CrC8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (CrC8)- alkoxy, (C3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl, heterocyclyl, halo(CrC8)alkyl, NRaRb, COORa, CONRgRb, S(0)q(CrC6)-alkyl and S(0)qNRaRb; or Ri and R2 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, (CrCs)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C5-C8)- cycloalkenyl, heterocyclyl, (C6-Ci4)-aryl, heteroaryl, CORa, C02Ra, CONRaRb and CONRaNRaRb;
q is an integer 1 or 2;
R4, R6, R7, Re, R9 and R10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH)2, (C C8)-alkyl, halo(CrC8)alkyl, (Ci-C8)-alkoxy, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, ar- (CrCs)-alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CONRaRb, CON(R)aNRaRb, OC(0)NRaRb, S(0)qRa, S(0)qNRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, NRaC(0)ORb, NRaS(0)qRb, NRaS(0)qNRaRb, NRaNRaRb, NRaNRaC(0)Rb, NRaNRaC(0)NRaRb, NRaNRaC(0)ORa, Ri , (CrC8)-alkyl-(Ri2), (C C8)-alkoxy-(Ri2), (C3-Ci2)-cycloalkyl-(R12), (C6-Ci4)-aryl-(R12), 0-(C6-Ci4)-aryl-(R12), heterocyclyl-(Ri2) and heteroaryl-(R12);
Figure imgf000135_0001
Ra and Rb are independently selected from the group consisting of hydrogen, (d- C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl, (C6-Ci4)-aryl, heterocyclyl and heteroaryl; or
Ra and Rb 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; wherein: each of the (CrC8)-alkyl, (CrC8)alkoxy and halo(CrC8)alkyl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carbonyl, cyano, nitro, (CrC8)-alkoxy-(Rc)i-2, (C3- Ci2)-cycloalkyl-(Rc)i-2, (C6-Ci4)-aryl-(Rc)i .2, 0-(C6-Ci4)-aryl-(Rc)i .2, heterocyclyl-(Rc)i- 2,
Figure imgf000136_0001
halo(CrC8)-alkyl, halo(CrC8)-alkoxy, C(0)Ra, OC(0)Ra, COORa, C(0)NRaRb, OC(0)NRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, SRa, S(0)qRa, S(0)qNRaRb, and NRaS(0)qRb; the 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-C8)-alkenyl, (C-2-C8)-alkynyl, (C-3-Ci2)-cycloalkyl, (C3-C8)-cycloalkenyl, (C-6-Ci4)-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, (CrC8)-alkyl-(Rc)1.2, (CrC8)-alkoxy-(Rc)i-2, (C3-C12)- cycloalkyl-(Rc)i -2, (C6-Ci4)-aryl-(Rc)i .2, 0-(C6-Ci4)-aryl-(Rc)i.2, heterocyclyl-(Rc)i-2, heteroaryl-(Rc)i-2, halo(C C8)-alkyl, halo(CrC8)-alkoxy, C(0)Ra, OC(0)Ra, COORa, C(0)NRaRb, OC(0)NRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, SRa, S(0)qRa, S(0)qNRaRb and NRaS(0)qRb; wherein Rc is hydrogen, halogen, hydroxy, cyano, nitro, (CrC8)-alkyl, halo(d- C8)alkyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, ar-(C C8)-alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CONRaRb, CONRaNRaRb, S(0)qRa, S(0)qNRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, NRaC(0)ORb, NRaS(0)qRb or NRaS(0)qNRaRb;
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.
2. The compound according to claim 1 :
wherein, Xi and X2 are CRi , such that ring A is a phenyl ring;
m and n are 0, such that ring B is a 5-membered ring; and
Y2, Y3 and Y4 are independently selected from the group consisting of CR1 R2, C=N(CN), C=0 and S(0)r;
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.
3. The compound according to claim 1 or claim 2:
wherein,
Xi and X2 are CRi , such that ring A is a phenyl ring;
m and n are 0, such that ring B is a 5-membered ring; and
Figure imgf000137_0001
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.
4. The compound according to claim 1 or claim 2:
wherein,
Xi and X2 are CRi , such that ring A is a phenyl ring;
m and n are 0, such that ring B is a 5-membered ring; and
Y2 is C=0; Y3 and Y4 are CRi R2; or
Y4 is C=0; Y2 and Y3 are CRi R2;
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.
5. The compound according to claim 1 :
wherein,
Xi and X2 are CRi , such that ring A is a phenyl ring;
m and n are 0, such that ring B is a 5-membered ring; and
Y2 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r, and Y4 is C=N(CN) or CRi R2; or Y4 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r, and Y2 is C=N(CN) or CRi R2;
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.
6. The compound according to claim 1 or claim 5: wherein,
Xi and X2 are CRi , such that ring A is a phenyl ring;
m and n are 0, such that ring B is a 5-membered ring;
Y2 is N R3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r, and Y4 is C=N(CN) or CRi R2; or Y4 is N R3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r, and Y2 is C=N(CN) or CRi R2;
Ri and R2 are independently selected from hydrogen and (CrC8)-alkyl; or
Ri and R2 may form a 3 to 7 membered ring optionally containing 1 -3 heteroatoms selected from the group consisting of O, N and S; and
R3 is selected from hydrogen and (CrC8)-alkyl;
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.
7. The compound according to claim 1 or claim 5:
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m and n are 0, such that the ring B is a 5-membered ring and the bicyclic heterocycle formed by fusion of rings A and B is indoline;
Y2 is N R3; Y3 and Y4 are CRi R2; or
Y4 is N R3; Y2 and Y3 are CRi R2;
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.
8. The compound according to claim 1 :
wherein,
Xi and X2 are CRi , such that the ring A is a phenyl ring;
m is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi , Y2, Y3 and Y4 are independently selected from the group consisting of CRi R2, S(0)r, C(O) and C=N(CN);
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.
9. The compound according to claim 1 :
wherein,
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;
Y2, Y3 and Y4 are independently selected from the group consisting of CR1 R2,
C=N(CN) and C=0;
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.
10. The compound according to claim 1 :
wherein,
Xi is N and X2 is CRi ; or ΧΊ is CRi and X2 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; and
Yi , Y2, Y3 and Y4 are independently selected from the group consisting of CRi R2, C=N(CN) and C=0;
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.
1 1 . The compound according to claim 1 :
wherein,
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;
Y2 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r; Y4 is CRi R2 or C=N(CN); or Y3 is NR3; Y2 and Y4 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y4 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r; Y2 is CRi R2 or C=N(CN);
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.
12. The compound according to claim 1 :
wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m and n are 0, such that the ring B is a 5-membered ring;
Y2, Y3 and Y4 are independently selected from the group consisting of CRi R2, C=N(CN) and C=0;
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.
13. The compound according to claim 1 :
wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m is 0 and n is 1 , such that the ring B is a 6-membered ring;
Yi , Y2, Y3 and Y4 are independently selected from the group consisting of CR1 R2, C=N(CN) and C=0;
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.
14. The compound according to claim 1 :
wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m and n are 1 , such that the ring B is a 7-membered ring;
Yi , Y2, Y3, Y4 and Y5 are independently selected from the group consisting of CR1 R2, C=N(CN) and C=0;
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.
15. The compound according to claim 1 :
wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m and n are 0, such that the ring B is a 5-membered ring;
Y2 is NR3; Y3 is CRi R2, C=N(CN), C=0 or S(0)r; Y4 is CRi R2 or C=N(CN); or
Y3 is NR3; Y2 and Y4 are independently selected from the group consisting of CRi R2, C=N(CN), C=0 and S(0)r; or
Y4 is NR3; Y3 is selected from CRi R2, C=N(CN), C=0 or S(0)r; Y2 is selected from
Figure imgf000140_0001
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.
16. The compound according to claim 1 :
wherein,
Xi and X2 are N, such that the ring A is a pyrimidinyl ring;
m is 0 and n is 1 , such that the ring B is a 6-membered ring; Υ is NR3; Y2 is CRi R2, C=N(CN), C=0 or S(0)r; Y3 and Y4 are independently selected from CRi R2 and C=N(CN); or
Y2 is NR3; Yi and Y3 are independently selected from the group consisting of CR1 R2, C=N(CN), C=0 and S(0)r; Y4 is CR1 R2 or C=N(CN); or
Y3 is NR3; Y2 and Y4 are independently selected from the group consisting of CR1 R2, C=N(CN), C=0 and S(0)r; Yi is CRi R2 or C=N(CN); or
Y4 is NR3; Yi and Y2 are independently selected from CRi R2 and C=N(CN); Y3 is CRi R2, C=N(CN), C=0 or S(0)r;
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.
17. The compound according to claim 1 :
wherein,
Q is:
Figure imgf000141_0001
R6, R7 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, B(OH)2, (CrC8)-alkyl, halo(CrC8)alkyl, (CrC8)- alkoxy, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, ar-(CrC8)- alkyl, heteroaryl, heterocyclyl, CORa, C02Ra, CONRaRb, CONRaNRaRb, OC(0)NRaRb, S(0)qRa, S(0)qNRaRb, NRaRb, NRaC(0)Rb, NRaC(0)NRaRb, NRaC(0)ORb, NRaS(0)qRb, NRaS(0)qN RaRb, NRaNRaRb, NRaNRaC(0)Rb, NRaNRaC(0)NRaRb and NRaNRaC(0)ORa;
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.
18. The compound according to claim 1 :
wherein, L is --C(0)NR5- or -NR5C(0)--; wherein the dotted line (--) indicates the points of
attachment of L to ring A and the group
Figure imgf000142_0001
respectively;
R5 is hydrogen or (CrC8)alkyl;
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.
19. The compound according to claim 1 :
wherein,
R4 is hydrogen, (C-3-Ci2)-cycloalkyl, (C-3-C-8)-cycloalkenyl, (C-6-Ci4)-aryl, heteroaryl or heterocyclyl;
wherein (C3-Ci2)-cycloalkyl, (C3-C8)-cycloalkenyl, (C6-Ci4)-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, (CrC8)-alkyl, (d-C8)-alkoxy, halo-(CrC8)-alkyl, (C3-Ci2)-cycloalkyl, (C6- Ci4)-aryl, 0-(C6-Ci4)-aryl, heterocyclyl and heteroaryl;
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.
20. The compound according to claim 1 selected from:
tert-Butyl 4-(5-(1 -isopropyl-4-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3- yl)methylcarbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-
(piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide hydrochloride;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-
(piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
tert-Butyl 4-(5-(4-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methylcarbamoyl)-1 - isopropylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6-(piperazin-1 - yl)pyridin-3-yl)indoline-4-carboxamide hydrochloride;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6-(piperazin-1 - yl)pyridin-3-yl)indoline-4-carboxamide; tert-Butyl 4-(5-(4-(((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3- yl)methyl)carbamoyl)-1 -isopropylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylat^ N-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6- (piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -Methyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- morpholinophenyl)indoline-4-carboxamide;
N-((4-lsopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -methyl-6-(4- morpholinophenyl)indoline-4-carboxamide;
N-((4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -methyl-6-(4- morpholinophenyl)indoline-4-carboxamide;
tert-Butyl 4-(5-(4-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methylcarbamoyl)-1 - methylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
tert-Butyl 4-(5-(4-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methylcarbamoyl)-
1 -methylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
tert-Butyl 4-(5-(4-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl carbamoyl)-1 -methylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -methyl-6-(6-(piperazin-1 -yl) pyridin-3-yl)indoline-4-carboxamide;
N-((4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -methyl-6-(6-(piperazin- 1 -yl)pyridin-3-yl)indoline-4-carboxamide;
tert-Butyl 4-(5-(1 -ethyl-4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -Ethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)-6-(6-(piperazin-
1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -Ethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
te/t-Butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)carbamoyl)-1 - ethylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -ethyl-6-(6-(piperazin-1 - yl)pyridin-3-yl)indoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- morpholinophenyl)indoline-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(4- morpholinophenyl)indoline-4-carboxamide; tert-Butyl 4-(5-(1 -sec-butyl-4-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methylcarbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
tert-Butyl 4-(5-(1 -isopropyl-4-(((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -lsopropyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-
(piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
tert-Butyl 4-(5-(1 -methyl-4-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methylcarbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -lsopropyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
N-((4-Ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)indoline-4- carboxamide;
tert-Butyl 4-(5-(1 -isopropyl-4-(((1 ,4,6-trimethyl-2-oxo-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -lsopropyl-6-(6-(piperazin-1 -yl)pyridin-3-yl)-N-((1 ,4,6-trimethyl-2-oxo-1 ,2- dihydropyridin-3-yl)methyl)indoline-4-carboxamide;
1 -lsopropyl-6-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)-N-((1 ,4,6-trimethyl-2-oxo-1 ,2- dihydropyridin-3-yl)methyl)indoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(pyridin-3- yl)indoline-4-carboxamide;
tert-Butyl 4-(5-(1 -ethyl-4-(((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -Ethyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(2-(dimethylamino) pyrimidin-5-yl)-1 -isopropylindoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- (trifluoromethyl)phenyl)indoline-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(6-(piperidin-1 - yl)pyridin-3-yl)indoline-4-carboxamide; 1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperidin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
6-(2-(Dimethylamino)pyrimidin-5-yl)-1 -isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)indoline-4-carboxamide;
1 -(Cyclobutylmethyl)-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6- (6-(trifluoromethyl)pyridin-3-yl)indoline-4-carboxamide;
1 -(Cyclobutylmethyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (trifluoromethyl)pyridin-3-yl)indoline-4-carboxamide;
1 -(Cyclobutylmethyl)-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-
(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
te/t-Butyl 4-(5-(1 -(cyclobutylmethyl)-4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-
3-yl)methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
te/t-Butyl 4-(5-(1 -isobutyl-4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)indolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
1 -lsobutyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)-6-(6-
(piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(3- (trifluoromethyl)phenyl)indoline-4-carboxamide;
1 -lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6- phenylindoline-4-carboxamide;
6-(3,5-Difluorophenyl)-1 -isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3- yl)methyl)indoline-4-carboxamide;
tert-Butyl 4-(5-(1 -isopropyl-3,3-dimethyl-4-(((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)carbamoyl)-2-oxoindolin-6-yl)pyridin-2-yl)piperazine-1 - carboxylate;
1 - lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)
2- oxo-6-(6-(piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
ie/ -Butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)carbamoyl)-1 - isopropyl-3,3-dimethyl-2-oxoindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-3,3-dimethyl-2- oxo-6-(6-(piperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
1 -lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) 6-(4-morpholinophenyl)-2-oxoindoline-4-carboxamide; N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-3,3-dimethyl-6-(4 morpholinophenyl)-2-oxoindoline-4-carboxamide;
1 -lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) 6-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)-2-oxoindoline-4-carboxamide;
tert-Butyl 4-(5-(1 '-isopropyl-4'-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)-2'-oxospiro[cyclopentane-1 ,3'-indolin]-6'-yl)pyridin-2-yl) piperazine-1 -carboxylate;
1 '-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2'-oxo-6'-(6- (piperazin-1 -yl)pyridin-3-yl)spiro[cyclopentane-1 ,3'-indoline]-4'-carboxamide;
1 '-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6'-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'- carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 '-isopropyl-6'-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'- carboxamide;
1 '-lsopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6'-(4- morpholinophenyl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 '-isopropyl-6'-(4- morpholinophenyl)-2'-oxospiro[cyclopentane-1 ,3'-indoline]-4'-carboxamide;
1 -lsopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) 6-(6-(4-methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-3,3-dimethyl-6-(6 (4-methylpiperazin-1 -yl)pyridin-3-yl)indoline-4-carboxamide;
6-Bromo-1 -isopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3- yl)methyl)indoline-4-carboxamide;
6-Bromo-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-3,3- dimethylindoline-4-carboxamide;
tert-Butyl 4-(5-(4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl)-5, 6 ,7, 8-tetrahydroquinazolin-2-yl)pyridin-2-yl)piperazine-1 -carboxylate; N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(6-(piperazin-1 - yl)pyridin-3-yl)-5,6,7,8-tetrahydroquinazoline-4-carboxamide;
N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(methylsulfonyl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide; N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(4-methylpiperazin-1 - yl)-6J-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide;
tert-Butyl 4-(5-(4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl)-6J-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyridin-2-yl)piperazin carboxylate;
N-((6-Methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-2-(6-(piperazin-1 -yl) pyridin-3-yl)-6J-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -oxo-2,3-dihydro-1 H-indene- 4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -hydroxy-2,3-dihydro-1 H- indene-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -morpholino-2,3-dihydro-1 H- indene-4-carboxamide;
6-Bromo-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -oxo-2,3-dihydro- 1 H-indene-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4-methylpiperazin-1 -yl) pyridin-3-yl)-1 -oxo-2,3-dihydro-1 H-indene-4-carboxamide;
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-morpholinopyridin-3-yl)- 1 -oxo-2, 3-dihydro-1 H-indene-4-carboxamide;
tert-Butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)carbamoyl)-1 - propylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate;
tert-Butyl 4-(5-(4-(((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl) carbamoyl)-1 -propylindolin-6-yl)pyridin-2-yl)piperazine-1 -carboxylate; and
N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(piperazin-1 -yl)pyridin-3- yl)-1 -propylindoline-4-carboxamide;
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.
21 . A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of the claims 1 -20, 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; and at least one pharmaceutically acceptable carrier or excipient.
22. A method for the treatment of a disease or a disorder mediated by EZH2 (enhancer of zeste homolog 2), comprising administering to a subject in need thereof; a therapeutically effective amount of a compound as defined in any of the claims 1 -20, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof.
23. The method according to claim 22, wherein the disease or disorder is cancer, pulmonary arterial hypertension, myelofibrosis, human immunodeficiency virus (HIV) disease, graft versus host diseases (GVHD), Weaver Syndrome, psoriasis vulgaris or liver fibrogenesis.
24. The method according to claim 22 or claim 23, wherein the disease or disorder is cancer.
25. The method according to claim 24, wherein the cancer 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.
26. A compound as defined in any one of the claims 1 -20, 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).
27. A compound for the use according to claim 26, wherein the disease or disorder is cancer, pulmonary arterial hypertension, myelofibrosis, human immunodeficiency virus (HIV) disease, graft versus host diseases (GVHD), Weaver Syndrome, psoriasis vulgaris or liver fibrogenesis.
28. A compound for the use according to claim 26 or claim 27; wherein the disease or disorder is cancer.
29. A compound for the use according to claim 28; wherein the cancer 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.
30. Use of a compound of formula 1 as defined in any one of the claims 1 -20 or a stereoisomer or tautomer; or a pharmaceutically acceptable salt thereof; in combination with one further therapeutically active agent; for the treatment of a disease or a disorder mediated by EZH2 (enhancer of zeste homolog 2).
PCT/IB2014/060157 2013-03-26 2014-03-26 Substituted bicyclic compounds as inhibitors of ezh2 WO2014155301A1 (en)

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