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WO2013067300A1 - Méthode de traitement - Google Patents

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Publication number
WO2013067300A1
WO2013067300A1 PCT/US2012/063239 US2012063239W WO2013067300A1 WO 2013067300 A1 WO2013067300 A1 WO 2013067300A1 US 2012063239 W US2012063239 W US 2012063239W WO 2013067300 A1 WO2013067300 A1 WO 2013067300A1
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Prior art keywords
alkyl
methyl
mmol
indazole
cycloalkyl
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PCT/US2012/063239
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English (en)
Inventor
Anna K. BASSIL
Soren BEINKE
Rabinder Kumar Prinjha
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GlaxoSmithKline Intellectual Property No 2 Ltd
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GlaxoSmithKline Intellectual Property No 2 Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y201/00—Transferases transferring one-carbon groups (2.1)
    • C12Y201/01—Methyltransferases (2.1.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/1003—Transferases (2.) transferring one-carbon groups (2.1)
    • C12N9/1007—Methyltransferases (general) (2.1.1.)

Definitions

  • This invention relates to compounds which inhibit EZH2/EZH1 and their uses for treating T cell mediated inflammatory immune diseases.
  • Posttranslational modifications of proteins play a critical role in the regulation of signal transduction from receptors, chromatin remodelling and gene transcription. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, SUMOylation.
  • EZH (enhancer of zeste homolog) 1 and 2 are the catalytic subunits of the Polycomb Repressor Complex 2 (PRC2) and exhibit methyltransferase activity that can catalyse the methylation of lysine amino acids (Margueron R, Reinberg D:The Polycomb complex PRC2 and its mark in life. Nature. 201 1 Jan 20;469 (7330):343-9)
  • Histone H3 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Chromatin is the complex combination of DNA and protein that makes up chromosomes. It is found inside the nuclei of eukaryotic cells and is divided between heterochromatin (condensed) and euchromatin (extended).
  • the basic building blocks of chromatin are nucleosomes, each of which is composed of 146 base pairs of DNA wrapped around a histone octamer that consists of 2 copies of each H2A, H2B, H3 and H4.
  • the functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control gene expression and DNA replication.
  • the chromatin structure is controlled by a series of post translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the "histone tails" which extend beyond the core nucleosome structure.
  • H3K27me3 Binding of enzymes and adaptor proteins to posttranslational modification in histone tails regulates chromatin dynamics and gene expression.
  • H3K27me3 is thought to silence gene expression by recruiting histone deacetylases to the modified nucleosomes and stall transcriptional elongation by polymerase II.
  • inhibition of the enzymatic activity of EZH1 and EZH2 may result in a loss of H3K27me3 and up-regulation of target genes.
  • EZH2 has been implicated in the regulation of signal transduction that leads to actin polymerization in the cytoplasm of cells (Su IH, Dobenecker MW, Dickinson E, Oser M, Basavaraj A, Marqueron R, Viale A, Reinberg D, WQIfing C, Tarakhovsky A: Polycomb group protein ezh2 controls actin polymerization and cell signaling. Cell. 2005 May 6; 121 (3):425-36).
  • the reorganization of the actin cytoskeleton critically contributes to T cell responses by facilitating the interaction of T cells with antigen presenting cells or target cells.
  • actin remodelling plays an important role in T cell migration and motility during their recruitment to the sites of inflammation.
  • a fraction of EZH2 protein was found to localize to the cytoplasm of T cells and to interact with the small GTPase VAV1 , which is involved in actin remodelling.
  • Genetic elimination of EZH2 resulted in impaired polymerization of actin in TCR stimulated T cells or at the T cell - antigen presenting cell interphase.
  • actin polymerization induced by EZH2 over-expression was dependent on the methytransferase activity of EZH2. Proliferation of T cells in response to TCR was also impaired in the absence of EZH2.
  • inhibition of EZH1 and / or EZH2 may suppress the activation of T cells.
  • Mature T cell respond to foreign peptide antigens in the presence of appropriate co-stimulation by antigen presenting cells. They have the capability to discriminate between self and non self as a consequence of the selection of a TCR repertoire specific for foreign antigens in the thymus, tolerance induction of self reactive T cell clones in the periphery, and control of T cell activation by self antigen by regulatory T cells.
  • T cells provide protection against different classes of pathogens by mediating distinct types of adaptive immune responses as a consequence of the expression of distinct sets of cytokines and other soluble and cell-bound products. In addition, they act as principle amplifiers and inducers of the appropriate inflammatory and effector responses in cells of the innate immune system and nonimmune cells.
  • CD8 T cells can lyse cells bearing intracellular pathogens but may also contribute to tissue damage and secrete pro-inflammatory cytokines, e.g. TNF and IFNg.
  • CD4 T cells can have diverse functions in inflammation depending on their specific cytokine expression profiles.
  • CD4 + Th1 cells are important for the clearance of intracellular pathogens but also play a critical role in inflammation through the expression of TNF and IFNg.
  • IL-17 expressing CD4 + Th17 cells which mediate neutrophilia and tissue remodelling and repair, have also been shown to be involved in many inflammatory conditions.
  • CD4 + Th2 cells are involved in allergic responses by expressing IL-13, IL-5 and IL-4 which mediate airway hyper reactivity, eosinophil recruitment and IgE production.
  • T cell activation is considered central to many inflammatory immune diseases. Accordingly, compounds that inhibit EZH1 and / or EZH2 activity and suppress T cell activation would be useful for the treatment of T cell mediated inflammatory immune diseases.
  • Inhibitors of EZH1/EZH2 that are useful in treating cancer have been reported in PCT applications PCT/US201 1/035336, PCT/US201 1/035340, and PCT/US201 1/035344.
  • the present invention relates to a method of treating T cell mediated inflammatory immune diseases or T cell mediated hypersensitivity diseases, which comprises administering to a human in need thereof an effective amount of a compound which inhibits EZH2 and/or EZH1 , or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound or a pharmaceutically acceptable salt thereof which inhibits EZH2 and/or EZH1 for use in treating T cell mediated inflammatory immune diseases or T cell mediated hypersensitivity diseases.
  • the invention relates to the use of a compound or a pharmaceutically acceptable salt thereof which inhibits EZH2 and/or EZH1 in the manufacture of a medicament for treating T cell mediated inflammatory immune diseases or T cell mediated hypersensitivity diseases.
  • FIG. 3 EZHi/EZH 2 inhibitors impair T cell receptor-induced IL-2 production in CD4+ T cells.
  • the present invention relates to a method of treating T cell mediated inflammatory immune diseases as described above.
  • the present invention relates to a method of treating T cell mediated hypersensitivity diseases as described above.
  • the present invention also relates to a method of treating T cell mediated inflammatory immune diseases or T cell mediated hypersensitivity diseases, which comprises administering to a human in need thereof an effective amount of a compound of formula (I)
  • X and Z are selected independently from the group consisting of hydrogen, (d- C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, unsubstituted or substituted (C 3 -C 8 )cycloalkyl, unsubstituted or substituted (C 3 -C 8 )cycloalkyl-(CrC 8 )alkyl or -(C 2 -C 8 )alkenyl,
  • R 1 is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, unsubstituted or substituted (C 3 - C 8 )cycloalkyl, unsubstituted or substituted (C 3 -C 8 )cycloalkyl-(C 1 -C 8 )alkyl or - (C 2 -C 8 )alkenyl, unsubstituted or substituted (C 5 -C 8 )cycloalkenyl, unsubstituted or substituted (C 5 -C 8 )cycloalkenyl-(Ci-C 8 )alkyl or -(C 2 -C 8 )alkenyl, unsubstituted or substituted (C 6 -Ci 0 )bicycloalkyl, unsubstituted or substituted heterocycloalkyi or - (
  • R 3 is hydrogen, (Ci-C 8 )alkyl, cyano, trifluoromethyl, -NR a R b , or halo;
  • R 6 is selected from the group consisting of hydrogen, halo, (Ci-C 8 )alkyl,
  • heterocycloalkyi unsubstituted or substituted heterocycloalkyl-(Ci-C 8 )alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-(C 1 -C 8 )alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-(C 1 -C 8 )alkyl, cyano, - COR a , -C0 2 R a , -CONR a R b , -CONR a NR a R b , -SR a , -SOR a , -S0 2 R a , -S0 2 NR a R b , nitro, - NR a R b , -NR a C(0)R b , -NR a C(0)NR a R b , -NR a C(0)OR a , -
  • any (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocycloalkyi, aryl, or heteroaryl group is optionally substituted by 1 , 2 or 3 groups independently selected from the group consisting of -0(Ci- C 6 )alkyl(R c ) 1-2 , -S(Ci-C 6 )alkyl(R c ) 1-2 , -(Ci-C 6 )alkyl(R c ) 1-2 , (Ci-C 8 )alkyl- heterocycloalkyl, (C 3 -C 8 )cycloalkyl-heterocycloalkyl, halo, (CrC 6 )alkyl,
  • any aryl or heteroaryl moiety of said aryl, heteroaryl, aryl(Ci-C 4 )alkyl, or heteroaryl(Ci-C 4 )alkyl is optionally substituted by 1 , 2 or 3 groups independently selected from the group consisting of halo, (d-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 8 )cycloalkenyl, (C C 6 )haloalkyl, cyano, -COR a , -C0 2 R a , -CONR a R b ,
  • R a and R b are each independently hydrogen, (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl,
  • heterocycloalkyi aryl, heteroaryl, wherein said (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 - C 8 )alkynyl, cycloalkyi, cycloalkenyl, bicycloalkyi, heterocycloalkyi ,aryl or heteroaryl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, hydroxyl, (Ci-C 4 )alkoxy, amino, (Ci-C 4 )alkylamino, ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, -C0 2 H, - C0 2 (CrC 4 )alkyl, -CONH 2 ,-CONH(C C 4 )alkyl, -CON((Ci-C 4 )alkyl)((C C 4 )alkyl), - S0 2 (C
  • R a and R b taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C 3 -C 8 )cycloalkyl, heterocycloalkyi, aryl, or heteroaryl ring;
  • each R c is independently (Ci-C 4 )alkylamino, -NR a S0 2 R b , -SOR a , -S0 2 R a , - NR a C(0)OR a , -NR a R b , or -C0 2 R a ;
  • the present invention also relates to the above method, wherein the compound of Formula (II) is further defined in one of the subgroups below:
  • X and Z are selected from the group consisting of (d-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyi, aryl, heteroaryl, -NR a R b , and -OR a ;
  • Y is H or F
  • R 1 is selected from the group consisting of (Ci-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyi, aryl, and heteroaryl;
  • R 3 is selected from the group consisting of hydrogen, (Ci-C 8 )alkyl, cyano, trifluoromethyl, -NR a R b , and halo;
  • R 6 is selected from the group consisting of hydrogen, halo, cyano, trifluoromethyl, amino, (Ci-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, acylamino; (C 2 -C 8 )alkynyl, arylalkynyl, heteroarylalkynyl, -S0 2 R a , -S0 2 NR a R b , and -NR a S0 2 R b ;
  • any (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )alkynyl, arylalkynyl, heteroarylalkynyl group is optionally substituted by 1 , 2 or 3 groups independently selected from -0(C 1 -C 6 )alkyl(R c ) 1-2 , -S(C 1 -C 6 )alkyl(R c ) 1-2 , -(C 1 -C 6 )alkyl(R c ) 1-2 , (C C 8 )alkyl-heterocycloalkyl, (C 3 -C 8 )cycloalkyl-heterocycloalkyl, halo, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 8 )cycloalkenyl, (C C 6 )haloalkyl
  • each R c is independently (C C 4 )alkylamino, -NR a S0 2 R b , -SOR a , -S0 2 R a , - NR a C(0)OR a , -NR a R b , or -C0 2 R a ;
  • R a and R b are each independently hydrogen, (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl,
  • heterocycloalkyi aryl, heteroaryl, wherein said (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 - C 8 )alkynyl, cycloalkyi, cycloalkenyl, bicycloalkyi, heterocycloalkyi ,aryl or heteroaryl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, hydroxyl, (Ci-C 4 )alkoxy, amino, (Ci-C 4 )alkylamino, ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, -C0 2 H, - C0 2 (CrC 4 )alkyl, -CONH 2 , -CONH(C C 4 )alkyl, -CON((C C 4 )alkyl)((Ci-C 4 )alkyl), - S0 2 (
  • R a and R b taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C 3 -C 8 )cycloalkyl, heterocycloalkyi, aryl, or heteroaryl ring.
  • An aryl or heteroaryl group in this particular subgroup A is selected independently from the group consisting of furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine, quinoline, cinnoline, quinazoline, quinoxaline, and naphthyridine or another aryl or heteroaryl group as follows:
  • A is 0 NH, or S; B is CH or N, and C is hydrogen or C1-C3 alkyl; or
  • D is N or C o tionally substituted by hydrogen or d-C 8 alkyl
  • E is NH or CH 2 ; F is 0 or CO; and
  • J is 0, S or CO;
  • Q is CH or N
  • M is CH or N
  • L7(5) is hydrogen, halo, amino, cyano, (Ci-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, -COR a , - C0 2 R a , -CONR a R b , -CONR a NR a R b , -S0 2 R a , -S0 2 NR a R b , -NR a R b , -NR a C(0)R b ,-NR a S0 2 R b , -NR a S0 2 NR b , -NR a S0 2 NR a R b , -NR a S0 2 NR a R b , -NR a NR a R b , -NR a NR a C(0)R b , -NR a NR a C(0)NR a R b , -OR a , wherein any (C
  • L/(6) is NH or CH 2 ;
  • M/(7) is hydrogen, halo, amino, cyano, (Ci-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl, -COR a , -C0 2 R a , -CONR a R b , -CONR a NR a R b , -S0 2 R a , - S0 2 NR a R b , -NR a R b , -NR a C(0)R b ,-NR a S0 2 R b , -NR a S0 2 R b , -NR a S0 2 NR a R b , -NR a S0 2 NR a R b , -NR a NR a R b , -NR a NR a C(0)R b , -NR a NR a C(0)NR b , -NR a NR a
  • any (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl group is optionally substituted by 1 , 2 or 3 groups independently selected from
  • P is CH 2 , NH, 0, or S
  • Q/(8) is CH or N
  • n is 0-2; or
  • S/(9) and T(9) is C, or S/(9) is C and T(9) is N, or S/(9) is N and T/(9) is C;
  • R is hydrogen, amino, methyl, trifluoromethyl, halo
  • U is hydrogen, halo, amino, cyano, nitro, trifluoromethyl, (d-C 8 )alkyl, (C 3 - C 8 )cycloalkyl, -COR a , -C0 2 R a , -CONR a R b , -S0 2 R a , -S0 2 NR a R b , -NR a R b , - NR a C(0)R b ,-NR a S0 2 R b , -NR a S0 2 NR b , -NR a S0 2 NR a R b , -NR a S0 2 NR a R b , -NR a NR a R b , -NR a NR a C(0)R b , , -OR a , 4-(1 H- pyrazol-4-yl),
  • any (Ci-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, group is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 8 )cycloalkenyl, (Ci-C 6 )haloalkyl, cyano, -COR a , -C0 2 R a ,-CONR a R b , -SR a , - SOR a , -S0 2 R a , -S0 2 NR a R b , nitro, -NR a R b , -NR a C(0)R b , -NR a C(0)NR a R b , - NR a C(0)OR a , -NR a S0 2 R b , -NR a S0 2 NR a R a
  • X and Z are selected independently from the group consisting of (d-C 8 )alkyl, (C 3 - C 8 )cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NR a R b , and -OR a ;
  • Y is H
  • R 1 is (Ci-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, or heterocycloalkyl;
  • R 3 is hydrogen, (Ci-C 8 )alkyl or halo
  • R 6 is hydrogen, halo, cyano, trifluoromethyl, amino, (Ci-C 8 )alkyl, (C 3 - C 8 )cycloalkyl;, aryl, heteroaryl, acylamino; (C 2 -C 8 )alkynyl, arylalkynyl, heteroarylalkynyl; - S0 2 R a ; -S0 2 NR a R b , or -NR a S0 2 R b ;
  • any (Ci-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )alkynyl, arylalkynyl, heteroarylalkynyl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, (Ci-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 8 )cycloalkenyl,
  • (Ci-C 6 )haloalkyl cyano, -COR a , -C0 2 R a , -CONR a R b , -SR a , -SOR a , -S0 2 R a , - S0 2 NR a R b , nitro, -NR a R b , -NR a C(0)R b , -NR a C(0)NR a R b , -NR a C(0)OR a , - NR a S0 2 R b , -NR a S0 2 NR b , -OR a , -OC(0)R a , -OC(0)NR a R b , heterocycloalkyi, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, and heteroaryl(C 1 -C 4 )alkyl;
  • R a and R b are each independently hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl,
  • heterocycloalkyi aryl, heteroaryl, wherein said (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 - C 8 )alkynyl, cycloalkyi, cycloalkenyl, bicycloalkyi, heterocycloalkyi ,aryl or heteroaryl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, hydroxyl, (Ci-C 4 )alkoxy, amino, (Ci-C 4 )alkylamino, ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, -C0 2 H, - C0 2 (CrC 4 )alkyl, -CONH 2 ,-CONH(C C 4 )alkyl, -CON((Ci-C 4 )alkyl)((C C 4 )alkyl), - S0 2 (C
  • R a and R b taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C 3 -C 8 )cycloalkyl, heterocycloalkyi, aryl, or heteroaryl ring.
  • Aryl and heteroaryl in this definition are selected from the group consisting of furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine, quinoline, cinnoline, quinazoline, quinoxaline, and naphthyridine as or a
  • A is 0 NH, or S; B is CH or N, and C is hydrogen or C1-C3 alkyl; or
  • D is N or C optionally substituted by hydrogen or d-C 8 alkyl
  • E is NH or CH 2 ; F is 0 or CO; and
  • J is 0, S or CO;
  • Q is CH or N
  • M is CH or N
  • L7(5) is hydrogen, halo, amino, cyano, (d-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, -COR a , - C0 2 R a , -CONR a R b , -CONR a NR a R b , -S0 2 R a , -S0 2 NR a R b , -NR a R b , -NR a C(0)R b ,-NR a S0 2 R b , -NR a S0 2 NR b , -NR a S0 2 NR a R b , -NR a S0 2 NR a R b , -NR a NR a R b , -NR a NR a C(0)R b , -NR a NR a C(0)NR b , -NR a NR a C(0)NR a R
  • any (Ci-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, group is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 5 -Ce)cycloalkenyl, (Ci-C 6 )haloalkyl, cyano, -COR a , -C0 2 R a , -CONR a R b , -SR a , -SOR a , -S0 2 R a , -S0 2 NR a R , nitro, -NR a R , -NR a C(0)R , -NR a C(0)NR a R , - NR a C(0)OR a , -NR a S0 2 R , -NR a S0 2 NR a R , -OR a , -OC
  • L/(6) is NH or CH 2 ;
  • M/(7) is hydrogen, halo, amino, cyano, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl, -COR a , -C0 2 R a , -CONR a R b , -CONR a NR a R b , -S0 2 R a , - S0 2 NR a R b , -NR a R b , -NR a C(0)R b ,-NR a S0 2 R b , -NR a S0 2 R b , -NR a S0 2 NR a R b , -NR a S0 2 NR a R b , -NR a NR a R b , -NR a NR a C(0)R b , -NR a NR a C(0)NR b , -NR a NR
  • any (d-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl group is optionally substituted by 1 , 2 or 3 groups independently selected from
  • P is CH 2 , NH, 0, or S;
  • Q/(8) is CH or N; and
  • n is 0-2; or
  • S/(9) and T(9) is C, or S/(9) is C and T(9) is N, or S/(9) is N and T/(9) is C;
  • R is hydrogen, amino, methyl, trifluoromethyl, halo
  • U is hydrogen, halo, amino, cyano, nitro, trifluoromethyl, (Ci-C 8 )alkyl, (C 3 - C 8 )cycloalkyl, -COR a , -C0 2 R a , -CONR a R b , -S0 2 R a , -S0 2 NR a R b , -NR a R b , - NR a C(0)R b ,-NR a S0 2 R b , -NR a S0 2 NR b , -NR a S0 2 NR a R b , -NR a S0 2 NR a R b , -NR a NR a R b , -NR a NR a C(0)R b , , -OR a , 4- pyrazol-4-yl), wherein any (C 1 -C 8 )alkyl, (C 3
  • X is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, trifluoromethyl, tetrahydropyran, hydroxymethyl, methoxy methyl, or benzyl;
  • Y is H
  • Z is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or benzyl;
  • R 1 is isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, (1- methylethyl)cyclopropyl, l,l-dioxo-tetrahydrothiophene-3-yl, l-Me-piperidin-4-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, /V,/V-dimethyl-l-propanaminyl, benzyl, or 4- pyridyl;
  • R 3 is H, methyl, or Br
  • R 6 is methyl, bis(l,l-dimethylethyl), bis(l-methylethyl), cyclopropyl, propyl, dimethylamino, ethylamino, (2-hydroxyethyl)amino, 2-propen-l-ylamino, 1-piperazinyl, 1- piperidinyl, 4-morpholinyl, 4-piperidinylamino, tetrahydro-2H-pyran-4-ylamino, phenylamino, (phenylmethyl)amino, (4-pyridinylmethyl)amino, [2-(2- pyridinylamino)ethyl]amino, 2-(dimethylamino)ethyl]amino, 4-pyridinylamino , 4- (aminocarbonyl)phenyl]amino, 3-hydroxy-3-methyl-l-butyn-l-yl, 4-pyridinylethynyl, pheny
  • the present invention also relates to a method of treating T cell mediated inflammatory immune diseases or T cell mediated hypersensitivity diseases, which comprises administering to a human in need thereof an effective amount of a compound, which is selected from the group comprising:
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.
  • the phrase "optionally substituted” or variations thereof denote an optional substitution, including multiple degrees of substitution, with one or more substitutent group. The phrase should not be interpreted as duplicative of the substitutions herein described and depicted.
  • Exemplary optional substituent groups include acyl, d-C 6 alkyl, CrCsalkylsulfonyl, d-Csalkoxy, C
  • an “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • alkyl refers to a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms, so for example, as used herein, the terms “Ci.C 8 alkyr refers to an alkyl group having at least 1 and up to 8 carbon atoms respectively.
  • Examples of such branched or straight-chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyi, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, and n-octyl and branched analogs of the latter 5 normal alkanes.
  • alkoxy as used herein means -0(Ci.C 8 alkyl) including -OCH3, -
  • alkylthio as used herein is meant -S(Ci.C 8 alkyl) including -SCH3, -
  • acyloxy means -OC(0)Ci.C 8 alkyl and the like per the definition of alkyl above.
  • Acylamino means-N(H)C(0)C 1 .C 8 alkyl and the like per the definition of alkyl above.
  • Aryloxy means -O(aryl), -0(substituted aryl), -O(heteroaryl) or -0(substituted heteroaryl).
  • Arylamino means -NH(aryl), -NH(substituted aryl), -NH(heteroaryl) or - NH(substituted heteroaryl), and the like.
  • alkenyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 5 carbon-carbon double bonds. Examples include ethenyl (or ethenylene) and propenyl (or propenylene).
  • alkynyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 5 carbon-carbon triple bonds. Examples include ethynyl (or ethynylene) and propynyl (or propynylene).
  • Haloalkyl refers to an alkyl group group that is substituted with one or more halo substituents, suitably from 1 to 6 substituents. Haloalkyl includes trifluoromethyl.
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms.
  • C 3- C 8 cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having from three to eight carbon atoms.
  • Exemplary "C 3 -C 8 cycloalkyl” groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • 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.
  • Cycloalkenyl includes by way of example cyclopentenyl and cyclohexenyl.
  • C 3 -C 8 heterocycloalkyl means a non-aromatic heterocyclic ring containing the specified number of ring atoms being, saturated or having one or more degrees of unsaturation and containing one or more heteroatom substitutions independently selected from O, S and N. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s). Examples are given herein below.
  • aryl aromatic, hydrocarbon, ring system.
  • the ring system may be monocyclic or fused polycyclic (e.g., bicyclic, tricyclic, etc.), substituted or unsubstituted.
  • the monocyclic aryl ring is C5-C10, or C5-C7, or C5-C6, where these carbon numbers refer to the number of carbon atoms that form the ring system.
  • a C6 ring system i.e. a phenyl ring, is a suitable aryl group.
  • the polycyclic ring is a bicyclic aryl group, where suitable bicyclic aryl groups are C8-C12, or C9-C10.
  • a naphthyl ring, which has 10 carbon atoms, is a suitable polycyclic aryl group.
  • Suitable substituents for aryl, unless otherwise defined, are described below in the definition of "optionally substituted".
  • heteroaryl an aromatic ring system containing carbon(s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junctions, for example, bicyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms).
  • heteroaryl groups include benzofuran, benzothiophene, furan, imidazole, indole, isothiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, quinazoline, quinoxaline, thiazole, and thiophene.
  • Suitable substituents for heteroaryl, unless otherwise defined are described below in the definition of "optionally substituted"
  • a method may comprise administering to a human, e.g. a human in need thereof, a therapeutically effective amount of an agent described herein.
  • a compound or a pharmaceutically acceptable salt thereof which inhibits EZH2 and/or EZH 1 i.e. an EZH2 and/or EZH1 inhibitor
  • a method of treatment of T cell mediated inflammatory immune diseases or T cell mediated hypersensitivity diseases in a human comprising administering a therapeutically effective amount of an EZH1 and / EZH2 inhibitor.
  • Inflammation represents a group of vascular, cellular and neurological responses to trauma. Inflammation can be characterised as the movement of inflammatory cells such as monocytes, neutrophils and granulocytes into the tissues. This is usually associated with reduced endothelial barrier function and oedema into the tissues. Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical event propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterised by simultaneous destruction and healing of the tissue from the inflammatory process.
  • Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues.
  • a cascade of biochemical event propag
  • inflammation When occurring as part of an immune response to infection or as an acute response to trauma, inflammation can be beneficial and is normally self-limiting. However, inflammation can be detrimental under various conditions. This includes the production of excessive inflammation in response to infectious agents, which can lead to significant organ damage and death (for example, in the setting of sepsis). Moreover, chronic inflammation is generally deleterious and is at the root of numerous chronic diseases, causing severe and irreversible damage to tissues. In such settings, the immune response is often directed against self-tissues (autoimmunity), although chronic responses to foreign entities can also lead to bystander damage to self tissues.
  • autoimmunity autoimmunity
  • the aim of anti-inflammatory therapy is therefore to reduce this inflammation, to inhibit autoimmunity when present and to allow for the physiological process or healing and tissue repair to progress.
  • the agents may be used to treat inflammation of any tissue and organs of the body, including musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation, as exemplified below.
  • Musculoskeletal inflammation refers to any inflammatory condition of the musculoskeletal system, particularly those conditions affecting skeletal joints, including joints of the hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knew, ankle, and foot, and conditions affecting tissues connecting muscles to bones such as tendons.
  • musculoskeletal inflammation examples include arthritis (including, for example, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis fibrosa cystic).
  • arthritis including, for example, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis
  • tendonitis synovitis
  • tenosynovitis bursitis
  • fibrositis fibromyalgia
  • epicondylitis myos
  • Ocular inflammation refers to inflammation of any structure of the eye, including the eye lids.
  • ocular inflammation which may be treated in this invention include blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis.
  • inflammation of the nervous system examples include encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis and schizophrenia.
  • inflammation of the vasculature or lymphatic system examples include arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.
  • Examples of inflammatory conditions of the digestive system which may be treated in this invention include cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, ileitis, and proctitis.
  • Examples of inflammatory conditions of the reproductive system which may be treated in this invention include cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo-ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.
  • the agents may be used to treat autoimmune conditions having an inflammatory component.
  • Such conditions include acute disseminated alopecia universalise, Behcet's disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, diabetes mellitus type 1 , giant cell arteritis, goodpasture's syndrome, Grave's disease, Guillain-Barre syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, ord's thyroiditis, pemphigus, polyarteritis nodos
  • the agents may be used to treat T-cell mediated hypersensitivity diseases having an inflammatory component.
  • T-cell mediated hypersensitivity diseases having an inflammatory component.
  • Such conditions include contact hypersensitivity, contact dermatitis (including that due to poison ivy), uticaria, skin allergies, respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitive enteropathy (Celliac disease).
  • inflammatory conditions which may be treated in this invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, ulceris, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, percarditis, peritonoitis, pharyngitis, pleuritis, pneumonitis, prostatistis, pyelonephritis, and stomatisi, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xengrafts, sewrum sickness, and graft vs host disease), acute pan
  • Preferred treatments include any one of treatment of transplant rejection, psoriatic arthritis, multiple sclerosis, Type 1 diabetes, asthma, systemic lupus erythematosis, chronic pulmonary disease, and inflammation accompanying infectious conditions (e.g., sepsis).
  • salts of the compounds for use in the inevntion are pharmaceutically acceptable salts. Salts encompassed within the term
  • salts of the compounds of the present invention may comprise acid addition salts.
  • the salts are formed from pharmaceutically acceptable inorganic and organic acids. More specific examples of suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic, and the like.
  • salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, a
  • salts which are not pharmaceutically acceptable, may be useful in the preparation of compounds for use in this invention.
  • These salts such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association a compound of formal (I) with the carrier(s) or excipient(s).
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds for use in this invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of formula (I).
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit pharmaceutical compositions for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the pharmaceutical compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a therapeutically effective amount of a compound for use in this invention will depend upon a number of factors including, for example, the age and weight of the intended recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant prescribing the medication.
  • an effective amount of a compound of formula (I) for the treatment of anemia will generally be in the range of 0.001 to 100 mg/kg body weight of recipient per day, suitably in the range of .01 to 10 mg/kg body weight per day.
  • the actual amount per day would suitably be from 7 to 700 mg and this amount may be given in a single dose per day or in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt or solvate, etc. may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • the title compound was prepared in a similar manner as described for example 8 from 6- bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-methyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 H- indazole-4-carboxamide (90 mg, 0.216 mmol) and 1 -[5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2-pyridinyl]piperazine (94 mg, 0.324 mmol).
  • the product obtained from HPLC purification was treated with a saturated solution of NaHC0 3 , and solids that crashed out were filtered .
  • the title compound was prepared in a similar manner as described for example 8 from 6- bromo-1-(1-methylethyl)-N- ⁇ [6-methyl-4-(1 -methylethyl)-2-oxo-1 ,2-dihydro-3- pyridinyl]methyl ⁇ -1 H-indazole-4-carboxamide (90 mg, 0.202 mmol) and dimethyl ⁇ [4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl ⁇ amine (90 mg, 0.303 mmol). The product was collected as a white solid (54 mg, 49%).
  • PdCl2(dppf)-CH 2 Cl2 adduct (4.95 mg, 0.006 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min.
  • Sodium bicarbonate (50.9 mg, 0.61 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 100 °C for 20 min. Upon cooling down, any solids that crashed out were filtered.
  • DCM/MeOH (1 :1 ) was added, the contents pre-absorbed on silica gel, and purified by Si0 2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH 4 OH).
  • the collected product was then further purified by reverse-phase HPLC (15% to 80% CH3CN in water with 0.1 % TFA), which afforded the product as a TFA salt.
  • CH3CN was evaporated and a saturated solution of sodium bicarbonate was added to the water layer followed by DCM/isopropanol (70:30).
  • the organic layer was separated, and the aqueous layer was further extracted with DCM/isopropanol (70:30).
  • the combined organic layers were washed with brine, dried over MgS0 4 , filtered, and concentrated. DMF was added along with some water, and after sitting overnight, the solids that precipitated were filtered.
  • PdCI 2 (dppf)-CH 2 CI 2 adduct (10.8 mg, 0.013 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min.
  • Sodium bicarbonate (66.4 mg, 0.79 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 100 °C for 20 min. The mixture was evaporated, DCM/MeOH (1 :1 ) was added, and the contents pre-absorbed on silica gel and purified by Si0 2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH 4 OH).
  • the title compound was prepared in a similar manner as described for example 8 from 6- bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 H- indazole-4-carboxamide (90 mg, 0.202 mmol) and 1 -[5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2-pyridinyl]piperazine (88 mg, 0.303 mmol). The final product was collected as a white solid (91 mg, 83%). 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ ppm 1 1 .54 (br.
  • PdCI 2 (dppf)-CH 2 CI 2 adduct (9.2 mg, 0.01 1 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min.
  • Sodium bicarbonate (56.6 mg, 0.67 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 1 10 °C for 20 min.
  • the mixture was evaporated, DCM/MeOH (1 :1 ) was added, and the contents pre-absorbed on silica gel and purified by Si0 2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH 4 OH).
  • the title compound was prepared in a similar manner as described for example 13 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide (100 mg, 0.225 mmol) and [6-(dimethylamino)-3- pyridinyl]boronic acid (49 mg, 0.292 mmol). The final product was collected as a white solid (49 mg, 44%).
  • the title compound was prepared in the same manner as described for example 75 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide (100 mg, 0.225 mmol) and 5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2-pyrimidinamine (75 mg, 0.337 mmol). The final product was collected as a white solid (87 mg, 82%).
  • the title compound was prepared in the same manner as described for example 75 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide (100 mg, 0.225 mmol) and 5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2-pyridinamine (75 mg, 0.337 mmol). The final product was collected as a white solid (60 mg, 57%).
  • the title compound was prepared in the same manner as described for example 75 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide (100 mg, 0.225 mmol) and 5-pyrimidinylboronic acid (42 mg, 0.337 mmol). The final product was collected as a white solid (77 mg, 75%).
  • the title compound was prepared in a similar manner as described for example 8 from 6- bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 H- indazole-4-carboxamide (90 mg, 0.202 mmol) and 1-methyl [5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2-pyridinyl]piperazine (92 mg, 0.303 mmol). The final product was collected as a light brown solid (54 mg, 49%).
  • the title compound was prepared in a similar manner as described for example 8 from 6- bromo-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1 H- indazole-4-carboxamide (1 10 mg, 0.264 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid (66 mg, 0.395 mmol). The product was collected as a white solid (33 mg, 27%).
  • the title compound was prepared in a similar manner as described for example 8 from 6- bromo-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1 H- indazole-4-carboxamide (1 10 mg, 0.264 mmol) and [6-(trifluoromethyl)-3-pyridinyl]boronic acid (75 mg, 0.395 mmol). The product was collected as a solid (75 mg, 57%).
  • the title compound was prepared in a similar manner as described for example 12 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-methyl-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide (100 mg, 0.240 mmol) and dimethyl ⁇ [3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]methyl ⁇ amine (93 mg, 0.312 mmol).
  • the product obtained from HPLC purification was treated with a saturated solution of NaHC0 3 , solids that crashed out were filtered, and air-dried for 15 min.
  • the title compound was prepared in a similar manner as described for example 12 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-methyl-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide (100 mg, 0.240 mmol) and dimethyl ⁇ [3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-3-yl)phenyl]methyl ⁇ amine (93 mg, 0.312 mmol).
  • the product obtained from HPLC purification was treated with a saturated solution of NaHC0 3 , solids that crashed out were filtered, and air-dried for 15 min.
  • the title compound was prepared from 6-bromo-N-((1 ,2-dihydro-6-methyl-2-oxo-4- propylpyridin-3-yl)methyl)-1-isopropyl-1 H-indazole-4-carboxamide (0.2 g, 0.44 mmol) and 2-(furan-3-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (0.1 g, 0.51 mmol) in the same manner as described for example 31.
  • the product was collected as an off-white solid (55 mg, 25.7 %).
  • the solid was taken up in CH 2 CI 2 and treated with Silicycle Si-Thiol (2 g, 1 .46 mMol/g). After stirring for 30 minutes on a rotary evaporator (no vacuum) the mixture was filtered through a pad of Celite, washed with CH 2 CI 2 , and evaporated to dryness. The light yellow colored solid was taken up in a small volume of MeOH and treated with 6 N HCI (200 uL) and re-evaporated to dryness. The residue was dissolved in a small volume of MeOH, ppt.
  • the title compound was prepared in the same manner as described for example 33 using from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-1 H-indazole-4-carboxamide (200 mg, 0.449 mmol), 3-(N,N dimethylaminomethyl)phenylboronic acid pinacol ester hydrochloride (170 mg, 0.571 mmol), potassium phosphate (300 mg, 1.413 mmol), dioxane (12 ml_), water (3 ml_), and PdCl 2 (dppf)-CH 2 CI 2 adduct (50 mg, 0.061 mmol).
  • step a from methyl 6-bromo-1-isopropyl-3-methyl-1 H-indazole-4-carboxylate (1 g, 3.36 mmol) and 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine (0.98 g, 4.04 mmol) wherein the reaction mixture was stirred at 100 °C for 5 h. The product was collected as an off white solid (600 mg, 53%). LCMS (ES-) m/z: 333.08. b) 1 -isopropyl-6-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-indazole-4-carboxylic acid
  • step b The title compound was prepared in the same manner as described for example 35 (step b) from methyl 1-isopropyl-6-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-indazole-4-carboxylate 1 (0.6 g, 1 .79 mmol) and LiOH H 2 0 (0.22 g, 5.37 mmol) wherein the mixture was heated at 80 °C for 5 h. The product was collected as an off-white solid (0.5 g, 87.7%).
  • step c The title compound was prepared in the same manner as described for example 35 (step c) from 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1 H-indazole-4-carboxylic acid and 3- (aminomethyl)-6-methyl-4-propylpyridin-2(1 H)-one (0.28 g, 1.56 mmol).
  • the crude product was purified by silica gel chromatography (eluent: 5% MeOH ⁇ EtOAc) to afford the product as an off-white solid (200 mg, 26 %).
  • step c The title compound was prepared using the procedure described for example 37 (step c) from 6 (4-((dimethylamino)methyl)piperidin-1-yl)-1 -isopropyl-1 H-indazole-4-carboxylic acid and 3 (aminomethyl)-6-methyl-4-propyl-2(1 H)-pyridinone.
  • PdCI 2 (dppf)-CH 2 CI 2 adduct (8.24 mg, 0.01 1 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min.
  • Sodium bicarbonate (50.9 mg, 0.61 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 1 10 °C for 20 min, then at 120 °C for 15 min and then at 130 °C for 15 min. Upon cooling down, water was added, and solids that crashed out were filtered.
  • the crude product was purified by silica gel chromatography (eluent: 0 to 30% EtOAc in petroleum ether) to afford the title compound 6-bromo-1-ethyl-1 H-indazole-4-carboxylic acid methyl ester (700 mg, 25%) and the undesired isomer 6-bromo-2-ethyl-2H-indazole-4-carboxylic acid methyl ester (500 mg, 18%) as white solids.
  • Step 1 To a stirred solution of 6-bromo-1-ethyl-1 H-indazole-4-carboxylic acid methyl ester (700 mg, 2.47 mmol) in THF (35 mL) was added a solution of LiOH H 2 0 (312 mg, 7.42 mmol) in water (15 mL) and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL) and washed with EtOAc (2x25 mL). The aqueous layer was acidified (pH ⁇ 5) with 1 N HCI. The precipitated solid was collected by filtration and dried to furnish 6-bromo-1-ethyl-1 H- indazole-4-carboxylic acid as a white solid (450 mg, 68 %).
  • Step 2 To a stirred suspension of 6-bromo-1 -ethyl-1 H-indazole-4-carboxylic acid, 4 (450 mg, 1 .67 mmol) in DCM (50 mL) were added EDC.HCI (384 mg, 2.00 mmol), HOBt.H 2 0 (306 mg, 2.00 mmol) and then stirred for 15 min at RT. To the resulting mixture, DIPEA (1 .2 mL, 5.59 mmol) followed by 3-aminomethyl-6-methyl-4-propyl-1 H-pyridin-2-one (301 mg, 1 .67 mmol) were added and the contents stirred for 18 h at RT.
  • EDC.HCI 384 mg, 2.00 mmol
  • HOBt.H 2 0 306 mg, 2.00 mmol
  • the reaction mixture was diluted with DCM (50 mL) and washed with water (2x50 mL), 10% aq citric acid solution (2x50 mL), saturated aq NaHC0 3 solution (2x30 mL) and brine (2x50 mL).
  • the organic layer was dried over Na 2 S0 4, filtered, and concentrated under reduced pressure.
  • the obtained solid was washed with diethyl ether (2 x 50 mL) to afford the title compound as a white solid (230 mg, 32 %).
  • step a The title compounds were prepared in the same manner as described for example 42 (step a) from 6-bromo-1 H-indazole-4-carboxylic acid methyl ester (3.0 g, 1 1.66 mmol) and 1-propyl bromide (1.59 g, 12.94 mmol) wherein the contents were heated at at 40 °C for 30 min.
  • step b, part 1 The title compound was prepared in the same manner as described for example 42 (step b, part 1 ) from 6-bromo-1-propyl-1 H-indazole-4-carboxylic acid, 7 (700 mg, 2.35 mmol ) and LiOH.H 2 0 (290 mg, 7.07 mmol). The product was collected as an off-white solid (600 mg, 90 %).
  • step b, part 2 The title compound was prepared in the same manner as described for example 42 (step b, part 2) from 6-bromo-1 -propyl-1 H-indazole-4-carboxylic acid (300 mg, 1 .06 mmol) and 3-aminomethyl-6-methyl-4-propyl-1 H-pyridin-2-one (190 mg, 1.06 mmol).
  • the crude product was triturated with diethyl ether (10 ml.) and n-pentane (10 ml.) to afford the title compound as a white solid ( 200 mg, 42.5 %).
  • Hexanes was added to the brown oil and it was purified using silica gel chromatography (eluent: Hex/EtOAc , gradient 0 to 25%). The less polar product was evaporated to give an orange oil, and was dried on hivac overnight. The product was confirmed to be the alkylated 1-isomer as suggested by 2D HNMR, and was collected as 807 mg (32%).
  • Step 1 Methyl 6-bromo-1-cyclopentyl-1 H-indazole-4-carboxylate (1 .5 g, 4.64 mmol) was suspended in Methanol (8 mL) and Tetrahydrofuran (THF) (16 mL) followed by addition of 3N Sodium Hydroxide (3.09 mL, 9.28 mmol). The solution was heated to 55 °C with stirring overnight (16h). The organic solvents were removed in vacuo and the residue was diluted with water (20 mL) and stirred in an ice bath. To the chilled aqueous solution was added 1 N HCI, dropwise, until precipitation stopped. The suspension was stirred in the ice bath for 20 min and then filtered. The solid cake was washed with water, dried, and used directly in step 2.
  • Step 2 6-bromo-1-cyclopentyl-1 H-indazole-4-carboxylic acid (1 .44 g, 4.61 mmol), 3- (aminomethyl)-4,6-dimethyl-2(1 H)-pyridinone hydrochloride (1 .138 g, 6.03 mmol), N-[3- (dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (1.335 g, 6.96 mmol), and 3H- [1 ,2,3]triazolo[4,5-b]pyridin-3-ol hydrate (1 .073 g, 6.96 mmol) were suspended in DMSO (8.00 mL), followed by N-methylmorpholine (2.82 g, 27.8 mmol).
  • the contents were irradiated in a microwave reactor at 150 °C for 30 min.
  • the reaction solution was filtered through a Whatman 0.45 I Teflon syringless filter device and diluted with DMSO (6 mL).
  • the DMSO solution was purified by HPLC reverse phase chromatography (phenomenex Gemini-NX, 30x100 5 column, 5-30% acetonitrile/water 0.01 % formic acid, 8 min gradient).
  • the fractions containing the desired product were concentrated to dryness using a Genovac HT-4 instrument at 40 °C.
  • the title compound was obtained as a pale cream colored foam (28 mg, 14.83 % yield).
  • Examples 47-52 were prepared in a similar manner as described above using 6-bromo-1- cyclopentyl-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4- carboxamide and the appropriate boronic acid reagent.
  • Example 47
  • the title compound was prepared in a similar manner as described for example 8 from 6- bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole- 4-carboxamide (100 mg, 0.226 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (70 mg, 0.338 mmol). The product was collected as a white solid (82 mg, 81 %).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ ppm 1 1.53 (br.
  • the title compound was prepared in a similar manner as described for example 8 from 6- bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole- 4-carboxamide (200 mg, 0.451 mmol) and 1 -[5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-2-pyridinyl]piperazine (196 mg, 0.677 mmol). The product was collected as a white solid (92 mg, 37%).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ ppm 1 1.54 (br.
  • 6-bromo-1 -cyclopentyl-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro- 3-pyridinyl)methyl]-1 H-indazole-4-carboxamide (.10g, 0.226 mmol)
  • N,N-dimethyl-1 -[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methanamine 0.081 g, 0.271 mmol
  • potassium phosphate tribasic
  • the suspension was stirred with degassing under N 2 for 10 min, followed by addition of PdCI 2 (dppf)-CH 2 CI 2 adduct (0.018 g, 0.023 mmol).
  • the reaction vessel was sealed and stirred with heating at 100 °C (heat block) for 2h. The contents were allowed to stir with cooling to RT overnight.
  • the mixture was diluted with EtOAc followed by addition of silica gel.
  • the mixture was concentrated in vacuo and the obtained solid purified by silica gel chromatography (dry loaded, eluent: 8-95% gradient of chloroform (containing 10% 2M Ammonia in Methanol) and DCM.
  • the collected product was concentrated from DCM/MTBE and then dried in vacuum oven for 16h.
  • Methyl 6-chloro-1 -cyclopentyl-1 H-indazole-4-carboxylate (2.1 g, 9.97 mmol) was suspended in DMF (40 mL), placed into an ice bath, and stirred for 15 min. Next added sodium hydride (0.997 g, 24.93 mmol) slowly over 5 min (gas evolution) and stirred for 15 min. Bromocyclopentane (3.21 mL, 29.9 mmol) was added at once via syringe, and the mixture allowed to stir with warming to RT. After 15 min stirring at RT, the contents were stirred with heating at 45 °C for 16h.
  • the contents were cooled to RT, and then 0.5g sodium carbonate and 1 mL of iodomethane were added.
  • the contents were stirred at RT for 3h, after which time the mixture was poured onto 400 mL of ice/water with stirring. After 5 min stirring, the contents were extracted with ether (2x100mL). The combined organic layers were concentrated in vacuo.
  • the crude product was purified by silica gel chromatography (eluent : gradient 3-25% EtOAc in hexanes) The first product off the column was determined to be the desired N1 -substituted isomer, and was collected after drying (vacuum pump, 1 h) as an orange solid (1.1 1 g, 39%).
  • step 2 The title compound was prepared in the same manner as described for example 1 (step 2) from methyl 6-chloro-1 -cyclopentyl-1 H-indazole-4-carboxylate (1 .1 1 g, 3.98 mmol), wherein the reaction stir time was 12h. The product was collected as 0.99g (85%).
  • step c The title compound was prepared in the same manner as described for example 3 (step c) from 6-chloro-1 -cyclopentyl-1 H-indazole-4-carboxylic acid (.12g, 0.453 mmol) and 3- (aminomethyl)-4,6-dimethyl-2(1 H)-pyridinone (0.128 g, 0.680 mmol), wherein the stir time was 12h.
  • the crude product was purified by silica gel chromatography (eluent: 5-85% gradient chloroform (containing 10% 2M Ammonia in methanol) and dichloromethane). The isolated product was concentrated from MTBE to afford an off-white solid that was dried in hi-vac oven for 6h.
  • step c The title compound was prepared in the same manner as described for example 3 (step c) from 6-chloro-1 -cyclopentyl-1 H-indazole-4-carboxylic acid (.12g, 0.453 mmol) and 3- (aminomethyl)-6-methyl-4-propyl-2(1 H)-pyridinone (0.128 g, 0.680 mmol).
  • the contents were purified by silica gel chromatograrphy (dry loaded; eluent: 2-65% gradient of 10% methanol in dichloromethane and dichloromethane).
  • the product was concentrated from MTBE and dried in hi-vac oven for 6 h at 45 °C to afford the title compound as 0.190 g (85 %) .
  • 6-cyano-1 -cyclopentyl-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H- indazole-4-carboxamide (.1 Og, 0.257 mmol) was suspended in acetic acid (8 mL). The contents were placed heated at 40 °C under an atmosphere of hydrogen (50 psi; H-cube reactor) at a flow rate of 1 ml_/min with recirculation 2 h. Then contents were diluted with MeOH, concentrated in vacuo, and dried under hi vacuum for 18 h.
  • the crude product was dissolved in DCM and purified by silica gel chromatography (eluent: 10-100% gradient of chloroform (containing 10% 2M ammonia in methanol) and dichloromethane.
  • the product was concentrated from MTBE and dried in a vacuum oven at 45 °C for 4 h.
  • the residue was dried under hi-vacuum, and then dissolved in MeOH/DCM followed by addition of silica gel.
  • the contents were concentrated to dryness and dried under hi-vacuum for 1 h.
  • the contents were purified by silica gel chromatography (dry loaded, eluent: 3-95% gradient chloroform (containing 10% 2M ammonia in methanol) and DCM).
  • the collected solid was triturated from hot acetontrile, and then placed in freezer for 15 min. The contents were filtered cold and washed with additional acetonitrile.
  • 6-amino-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H indazole-4-carboxamide (30 mg, 0.079 mmol) was suspended in DCM (3 mL) followed by pyridine (0.032 mL, 0.395 mmol). The contents were vigorously stirred and then benzenesulfonyl chloride (0.01 1 mL, 0.087 mmol) was added and the contents stirred at RT for 1 h. The volatiles were removed in vacuo and dried on hi-vac for 1 h. The crude product was purified by reverse phase HPLC (Gradient B: 15-70%.
  • A Water + .1 % TFA.
  • B CH3CN + .1 % TFA).
  • the product was neutralized with water and sat. NaHC03, and extracted with 10% THF/EtOAC (hot) in duplicate.
  • the combined organic layers were dried over MgS0 4 , filtered, and concentrated in vacuo.
  • the solid was concentrated from DCM and dried in vacuum oven for 4 h at 45 °C.
  • the crude product was purified by silica gel chromatography (eluent: 5-80% gradient chloroform (containing 10% 2M ammonia in methanol) in DCM).
  • the collected product was purified by reverse phase HPLC ( Gradient B: 15-75 %; A: Water + .1 % TFA. B: CH3CN + .1 % TFA).
  • the product was suspended in 10% MeOH/CHCI 3 .
  • Methyl 6-bromo-1 H-indazole-4-carboxylate (1.0 g, 3.92 mmol) was dissolved in 1 ,2- Dichloroethane (DCE) (14 mL) and stirred for 15 min. Next added cyclopropylboronic acid (0.674 g, 7.84 mmol) and sodium carbonate (0.831 g, 7.84 mmol). The reaction was stirred at RT (suspension). Copper (II) acetate (0.712 g, 3.92 mmol) and 2,2'-bipyridine (0.612 g, 3.92 mmol) were suspended in DCE (24 mL) with heating and the hot suspension was added to the reaction mixture.
  • DCE 1 ,2- Dichloroethane
  • Methyl 6-bromo-1 -cyclopropyl-1 H-indazole-4-carboxylate (0.54g, 1 .830 mmol) was dissolved in methanol (16 mL) and THF (4 mL) with stirring at RT. A solution of 3N NaOH (1 .830 mL, 5.49 mmol) was added the contents were stirred at RT for 2 days. The volatiles were removed in vacuo. The residue was diluted with water and slowly acidifed to pH 3-4 with 1 M HCI wherein solids were observed to precipitate. The contents were extracted with EtOAc (2x).
  • step c The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-1 -cyclopropyl-1 H-indazole-4-carboxylic acid (.22 g, 0.783 mmol) and 3- (aminomethyl)-4,6-dimethyl-2(1 H)-pyridinone (0.221 g, 1.174 mmol), wherein the reaction stir time was 12h.
  • step c The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-1 -cyclopropyl-1 H-indazole-4-carboxylic acid (.22 g, 0.783 mmol) and 3- (aminomethyl)-6-methyl-4-propyl-2(1 H)-pyridinone (0.236 g, 1.089 mmol), wherein the reaction stir time was 12 h.
  • the title compound was prepared in the same manner as described for example 67 from 6-bromo-1-cyclopropyl-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 H- indazole-4-carboxamide (.075g, 0.169 mmol) and N,N-dimethyl-1 -[4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]methanamine (0.060 g, 0.203 mmol).
  • the reaction mixture was then filtered through a celite pad.
  • the filtrate was poured onto ice water (1 L) and extracted with diethyl ether (3 X 700 ml).
  • the combined organic layers were washed with sat NaHC0 3 , brine, and dried over anhydrous Na 2 S0 4 , filtered, and evaporated under vaccum.
  • the crude product was purified by silica gel chromatography (eluent: 10 % ethyl acetate in pet ether) and afforded the title compound as a solid (80g, 59%).
  • the resulting reaction mixture was stirred at 100 °C for 2 h and then at RT for 6 h.
  • the reaction mixture was diluted with water and extracted with ethyl acetate (4x300 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na 2 S0 4 , filtered, and concentrated.
  • the crude residue (4.4 g) was purified by silica gel chromatography (eluent: 0-5% ethyl acetate: pet ether) to afford the title compound as an off white solid (2.95 g, 68 % ).
  • step c The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-3-methyl-1 -(1 -methylethyl)-1 H-indazole-4-carboxylic acid (0.24g, 0.808 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-2(1 H)-pyridinone (0.219 g, 1.010 mmol).
  • the collected product was suspended in EtOAc along with some hexanes. The contents were sonicated and solids that precipitated were filtered. Acetonitrile was added, the solids were triturated, and again filtered. The collected solid was then suspended in DMF along with some water and then allowed to sit at room temperature overnight. Solids that precipitated were filtered, washed with DCM, and dried to afford the title compound as a light grey solid (34 mg, 32%).
  • the title compound was prepared in a similar manner as described for example 8 from 6- bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-1 H-indazole-4-carboxamide (65 mg, 0.141 mmol) and 1-[5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (61 mg, 0.212 mmol). The product was collected as a white solid (54 mg, 49%).
  • the title compound was prepared from 6-bromo-N-((1 ,2-dihydro-4,6-dimethyl-2- oxopyridin-3-yl)methyl)-1 -isopropyl-1 H-indazole-4-carboxamide (500 mg, 1 .14 mmol) and N,N-dimethyl(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methanamine (300 mg, 1 .14 mmol) in the same manner as described for example 73 wherein the contents were heated at 120 °C for 2 h. The product was collected as a pale red solid (120 mg, 21 %).
  • the title compound was prepared from 6-bromo-N-((1 ,2-dihydro-4,6-dimethyl-2- oxopyridin-3-yl)methyl)-1-isopropyl-1 H-indazole-4-carboxamide (300 mg, 0.696 mmol) and dimethyl-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzyl]-amine (199 mg, 0.765 mmol) in the same manner as described for example 73. The final product was collected as a grey colored solid (80 mg, 26%).
  • the reaction mixture was stirred for 5 min, then sodium bicarbonate (0.4 g, 4.80 mmol) dissolved in water (8 mL) was added and the reaction mixture was stirred at 100 °C for 6 h.
  • the reaction mixture was diluted with water and extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with cold water (2x25 mL), brine solution (25 mL), dried over anhydrous Na 2 S0 4, filtered, and concentrated to afford the crude product.
  • the crude compound was purified by silica gel chromatography (eluent: 100 % ethyl acetate) to afford the title compound as an off-white solid (470 mg, 94%).
  • the reaction mixture was filtered and the precipitate was washed with water followed by ether and dried.
  • the solid compound was further purified by silica gel chromatography (eluent: 10 % MeOH in ethyl acetate) to afford the title compound as an off-white solid (225 mg, 31 %).
  • the title compound was prepared from methyl 6-bromo-1-isopropyl-3-methyl-1 H- indazole-4-carboxylate, (0.7 g, 2.25 mmol) and 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 H-pyrrolo[2,3-b]pyridine (0.65 g, 2.70 mmol) in the same manner as described for example 80 (step a). The product was collected as an off-white solid (600 mg, 82.5%).
  • the title compound was prepared from methyl 1-isopropyl-3-methyl-6-(1 H-pyrrolo[2,3- b]pyridin-5-yl)-1 H-indazole-4-carboxylate, 1 (50 mg, 0.14 mmol) and LiOH H 2 0 (20 mg, 0.43 mmol) in the same manner as described for example 80 (step b).
  • the product was collected as an off-white solid (60 mg) and used in the next step without any further purification.
  • step c The title compound was prepared in the same manner as described for example 80 (step c) from 1 -isopropyl-3-methyl-6-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-indazole-4-carboxylic acid (50 mg, 0.149 mmol) and 3-(aminomethyl)-6-methyl-4-propylpyridin-2(1 H)-one (26 mg, 0.149 mmol) wherein the contents were stirred at RT for 5h. The crude product was washed with DCM, filtered, and dried to afford the title compound as an off-white solid. (48 mg, 64 %).
  • the title compound was prepared in the same manner as described for example 80 (step a) from methyl 6-bromo-1-isopropyl-3-methyl-1 H-indazole-4-carboxylate (0.5 g, 1.60 mmol) and 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.37 g, 1.92 mmol) wherein the reaction mixture was heated at 1 15 °C for 3 h.
  • the crude compound was purified silica gel chromatography (eluent: 50 % ethyl acetate ⁇ pet ether) to afford the title compound as an off-white solid.
  • the title compound was prepared from methyl 1-isopropyl-3-methyl-6-(1 H-pyrazol-4-yl)- 1 H-indazole-4-carboxylate (0.2 g, 0.67 mmol) and LiOH.H 2 0 (0.084 g, 2.01 mmol) in the same manner as described for example 80 (step b). The product was collected as a white solid (0.2 g).
  • the title compound was prepared from 1 -isopropyl-3-methyl-6-(1 H-pyrazol-4-yl)-1 H- indazole-4-carboxylic acid and 3-(aminomethyl)-4,6-dimethylpyridin-2(1 H)-one (0.059 g, 0.387 mmol) in the same manner as described for example 80 (step c) wherein the contents were stirred at RT for 5h.
  • the product was collected as a pale yellow solid (30 mg, 20%).
  • the title compound was prepared in the same manner as described for example 80 (step c) from 1 -isopropyl-3-methyl-6-(1 H-pyrazol-4-yl)-1 H-indazole-4-carboxylic acid (0.15 g, 0.52 mmol) and 3-(aminomethyl)-6-methyl-4-propylpyridin-2(1 H)-one (0.09 g, 0.52 mmol) wherein the contents were stirred at RT for 5h.
  • the crude compound was purified by silica gel chromatography (eluent: 2 % MeOH ⁇ DCM) to afford the title compound as an off-white solid (60 mg, 25%).
  • the title compound was prepared in the same manner as described for example 76 from 6-bromo-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1 H- indazole-4-carboxamide (300 mg, 0.696 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridine (183 mg, 0.835 mmol).
  • the title compound was prepared in the same manner as described for example 67 from 6 bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide (.079 g, 0.172 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acic (0.034 g, 0.206 mmol).
  • the product was triturated from EtOAc spiked with DCM, and dried in ; hi-vacuum oven for 4h.
  • the title compound was prepared in the same manner as described for example 67 from 6 bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide (.090 g, 0.196 mmol).
  • the crude product was purified by revers ⁇ phase HPLC (Gradient B: 10-60%. 8min A: Water + .1 % TFA. B: CH3CN + .1 % TFA). Th ⁇ isolated product was then treated with 1.0 g of Silicycle Carbonate resin, and filtered througl celite washing with 10% MeOH/DCM.
  • the title compound was prepared in the same manner as described for example 67 from 6 bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide (.090 g, 0.196 mmol) and N,N-dimethyl-1-[4-(4,4,5,5-tetramethyl 1 ,3,2-dioxaborolan-2-yl)phenyl]methanamine (0.070 g, 0.235 mmol).
  • the title compound was prepared in the same manner as described for example 67 from 6- bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide (.1 Og, 0.218 mmol).
  • the title compound was prepared in the same manner as described for example 67 from 6-bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-1 H-indazole-4-carboxamide (0.1 Og, 0.218 mmol) and 1 -methyl-4-[5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (0.086 g, 0.283 mmol).
  • the vessel was sealed, and the insoluble mixture was heated to 120 °C for 6 hours. Upon cooling down, the mixture was quenched with water, and dark grey solids that crashed out and were filtered. DCM/MeOH (1 :1 ) was added, the contents pre-absorbed on silica gel and purified by Si0 2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH 4 OH). The collected product was futher purified by reverse-phase HPLC (20% to 80% CH3CN in water with 0.1 % TFA) which afforded the TFA salt. CH3CN was evaporated, and a saturated solution of sodium bicarbonate was added to the water layer.
  • the title compound was prepared from 6-bromo-N-[(4-ethyl-6-methyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide (70 mg, 0.162 mmol) and the sodium salt of cyclopropanesulfinic acid (41 .9 mg, 0.325 mmol) in the same manner as described for example 91. The product was collected an off-white solid (52 mg).
  • the title compound was prepared from 6-bromo-N-[(4-ethyl-6-methyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide (70 mg, 0.162 mmol) and the sodium salt of methanesulfinic acid (33.5 mg, 0.325 mmol), in the same manner as described for example 91.
  • Methyl 1 -(1 -methylethyl)-6-nitro-1 H-indazole-4-carboxylate (1.39 g, 5.28 mmol) was dissolved in ethanol (70 mL) and hydrogenated using an H-Cube instrument (full H 2 mode and 10% Pd/C). The solvent was removed in vacuo and the residue was purified via silica gel chromatography (eluent: 0% to 40% gradient; EtOAc:Hex). The product was obtained as 1 .05 g (85%).
  • Methyl 6-amino-1-(1-methylethyl)-1 H-indazole-4-carboxylate 500 mg, 2.143 mmol was dissolved in cone, hydrochloric acid (5 mL) and cooled in an ice water bath. A solution of sodium nitrite (155 mg, 2.251 mmol) in 2 mL of water was then added dropwise, and the contents were stirred for 90 min. The contents were added portion-wise to a solution of ca. 5 mL of S0 2 , copper(ll) chloride (303 mg, 2.251 mmol) and acetic acid (20 mL). The contents were stirred at room temperature for 15 h, and then concentrated in vacuo.
  • Examples 96-99 were prepared using the general procedures outlined for the above compound.
  • step c The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-1 -(1 -methylethyl)-1 H-indazole-4-carboxylic acid (0.50 g, 1 .77 mmol) and 3-(aminomethyl)-4-(sec-butyl)-6-methylpyridin-2(1 H)-one (0.446 g, 2.296 mmol). The product was collected as 0.81 g (98%).
  • 6-Bromo-1-(1-methylethyl)-1 H-indazole-4-carboxylic acid 80 mg, 0.28 mmol
  • 3- (aminomethyl)-6-methyl-4-propyl-2(1 H)-pyridinone (1 12 mg, 0.38 mmol)
  • 1 -hydroxy-7- azabenzotriazole 57.7 mg, 0.42 mmol
  • N-Methylmorpholine (0.12 ml, 1 .13 mmol) was added along with EDC (81 mg, 0.42 mmol) and the mixture was stirred at room temperature overnight under nitrogen. Ice-water was added and solids crashed out.
  • the title compound was prepared in the same manner as example 101 from 6-Bromo-1 - (1 -methylethyl)-1 H-indazole-4-carboxylic acid and 3-(aminomethyl)-6-methyl-4-(1- methylethyl)2(1 H)-pyridinone.
  • PdCI 2 (dppf)-CH 2 CI 2 (10.76 mg, 0.013 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min.
  • Sodium bicarbonate (66.4 mg, 0.79 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 120 °C for 20 min. Water was added and the solids that precipitated were filtered off. DCM was added to the solids and it was purified by Si0 2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH 4 OH). Fractions were evaporated.

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Abstract

La présente invention concerne une méthode de traitement de maladies immunes inflammatoires médiées par les lymphocytes T ou de maladies d'hypersensibilité médiées par les lymphocytes T, la méthode consistant à administrer à un être humain nécessitant ce traitement une quantité efficace d'un composé qui inhibe EZH2 et/ou EZH1, ou un sel pharmaceutiquement acceptable de ce composé.
PCT/US2012/063239 2011-11-04 2012-11-02 Méthode de traitement Ceased WO2013067300A1 (fr)

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JP2015506985A (ja) * 2012-02-10 2015-03-05 コンステレーション・ファーマシューティカルズ・インコーポレイテッドＣｏｎｓｔｅｌｌａｔｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． メチル基変更酵素の調節物質、組成物及びその使用
WO2015077194A1 (fr) * 2013-11-22 2015-05-28 Bristol-Myers Squibb Company Inhibiteurs de la lysine méthyltransférase
US9051269B2 (en) 2011-11-18 2015-06-09 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US20150344459A1 (en) * 2012-12-21 2015-12-03 Epizyme, Inc. 1,4-pyridone bicyclic heteroaryl compounds
US9527837B2 (en) 2014-12-05 2016-12-27 Eli Lilly And Company Inhibitors of EZH2
US9718838B2 (en) 2015-08-27 2017-08-01 Eli Lilly And Company Inhibitors of EZH2
US9745305B2 (en) 2013-03-15 2017-08-29 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9969716B2 (en) 2013-08-15 2018-05-15 Constellation Pharmaceuticals, Inc. Indole derivatives as modulators of methyl modifying enzymes, compositions and uses thereof
WO2018210296A1 (fr) * 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 Utilisation d'un inhibiteur d'ezh2 combiné à un inhibiteur de btk dans la préparation d'un médicament pour le traitement d'une tumeur
WO2018210302A1 (fr) 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 Formes cristallines du chlore libre dérivé du benzofurane et son procédé de préparation
US10239843B2 (en) 2014-12-12 2019-03-26 Cancer Research Technology Limited 2,4-dioxo-quinazoline-6-sulfonamide derivatives as inhibitors of PARG
US10457640B2 (en) 2016-10-19 2019-10-29 Constellation Pharmaceuticals, Inc. Synthesis of inhibitors of EZH2
US10508086B2 (en) 2014-12-19 2019-12-17 Cancer Research Technology Limited PARG inhibitory compounds
US10577350B2 (en) 2015-08-28 2020-03-03 Constellation Pharmaceuticals, Inc. Crystalline forms of (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide
US10633371B2 (en) 2016-04-22 2020-04-28 Dana-Farber Cancer Institute, Inc. EZH2 inhibitors and uses thereof
US10759787B2 (en) 2015-11-19 2020-09-01 Jiangsu Hengrui Medicine Co., Ltd. Benzofuran derivative, preparation method thereof and use thereof in medicine
EP3885343A1 (fr) 2014-11-06 2021-09-29 Dana-Farber Cancer Institute, Inc. Composés d'indole comme inhibiteurs de ezh2 et utilisations associées
WO2023244917A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents dégradant bcl6 hétérobifonctionnels 1,8-naphthyridin-2-one
WO2023244918A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents de dégradation bifonctionnels de quinolone bcl6
CN117362277A (zh) * 2023-10-13 2024-01-09 沈阳药科大学 含咪唑啉酮结构的苯甲酰胺类化合物及其制备方法和应用
WO2024108691A1 (fr) * 2022-11-25 2024-05-30 深圳先进技术研究院 Lymphocyte t régulateur et son procédé de préparation
US12269820B2 (en) 2022-03-23 2025-04-08 Ideaya Biosciences, Inc. Piperazine substituted indazole compounds as inhibitors of PARG

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US9051269B2 (en) 2011-11-18 2015-06-09 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9409865B2 (en) 2011-11-18 2016-08-09 Constellation_Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
JP2015506985A (ja) * 2012-02-10 2015-03-05 コンステレーション・ファーマシューティカルズ・インコーポレイテッドＣｏｎｓｔｅｌｌａｔｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． メチル基変更酵素の調節物質、組成物及びその使用
US9085583B2 (en) 2012-02-10 2015-07-21 Constellation—Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9371331B2 (en) 2012-02-10 2016-06-21 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
USRE47428E1 (en) 2012-02-10 2019-06-11 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9469646B2 (en) 2012-02-10 2016-10-18 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US10016405B2 (en) 2012-02-10 2018-07-10 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9980952B2 (en) 2012-02-10 2018-05-29 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US20150344459A1 (en) * 2012-12-21 2015-12-03 Epizyme, Inc. 1,4-pyridone bicyclic heteroaryl compounds
US10150759B2 (en) 2012-12-21 2018-12-11 Epizyme, Inc. 1,4-pyridone bicycic heteroaryl compounds
US9701666B2 (en) * 2012-12-21 2017-07-11 Epizyme, Inc. 1,4-pyridone bicyclic heteroaryl compounds
US9745305B2 (en) 2013-03-15 2017-08-29 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9969716B2 (en) 2013-08-15 2018-05-15 Constellation Pharmaceuticals, Inc. Indole derivatives as modulators of methyl modifying enzymes, compositions and uses thereof
US9822103B2 (en) 2013-11-22 2017-11-21 Bristol-Myers Squibb Company Inhibitors of lysine methyl transferase
WO2015077194A1 (fr) * 2013-11-22 2015-05-28 Bristol-Myers Squibb Company Inhibiteurs de la lysine méthyltransférase
US11236082B2 (en) 2014-11-06 2022-02-01 Dana-Farber Cancer Institute, Inc. EZH2 inhibitors and uses thereof
EP3885343A1 (fr) 2014-11-06 2021-09-29 Dana-Farber Cancer Institute, Inc. Composés d'indole comme inhibiteurs de ezh2 et utilisations associées
US9527837B2 (en) 2014-12-05 2016-12-27 Eli Lilly And Company Inhibitors of EZH2
US10239843B2 (en) 2014-12-12 2019-03-26 Cancer Research Technology Limited 2,4-dioxo-quinazoline-6-sulfonamide derivatives as inhibitors of PARG
US10508086B2 (en) 2014-12-19 2019-12-17 Cancer Research Technology Limited PARG inhibitory compounds
US12129236B2 (en) 2014-12-19 2024-10-29 Cancer Research Technology Limited PARG inhibitory compounds
US10995073B2 (en) 2014-12-19 2021-05-04 Cancer Research Technology Limited PARG inhibitory compounds
US9718838B2 (en) 2015-08-27 2017-08-01 Eli Lilly And Company Inhibitors of EZH2
US10577350B2 (en) 2015-08-28 2020-03-03 Constellation Pharmaceuticals, Inc. Crystalline forms of (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide
US11059811B2 (en) 2015-11-19 2021-07-13 Jiangsu Hengrui Medicine Co., Ltd. Benzofuran derivative, preparation method thereof and use thereof in medicine
US10759787B2 (en) 2015-11-19 2020-09-01 Jiangsu Hengrui Medicine Co., Ltd. Benzofuran derivative, preparation method thereof and use thereof in medicine
US10633371B2 (en) 2016-04-22 2020-04-28 Dana-Farber Cancer Institute, Inc. EZH2 inhibitors and uses thereof
US10457640B2 (en) 2016-10-19 2019-10-29 Constellation Pharmaceuticals, Inc. Synthesis of inhibitors of EZH2
US11155537B2 (en) 2017-05-18 2021-10-26 Jiangsu Hengrui Medicine Co., Ltd. Crystal of benzofuran derivative free base and preparation method
KR102635949B1 (ko) 2017-05-18 2024-02-14 지앙수 헨그루이 파마슈티컬스 컴퍼니 리미티드 종양 치료용 약물의 제조에 있어서의 ezh2 억제제 및 btk 억제제의 조합물의 용도
CN109937041A (zh) * 2017-05-18 2019-06-25 江苏恒瑞医药股份有限公司 一种ezh2抑制剂与btk抑制剂联合在制备治疗肿瘤的药物中的用途
KR20200007851A (ko) * 2017-05-18 2020-01-22 지앙수 헨그루이 메디슨 컴퍼니 리미티드 종양 치료용 약물의 제조에 있어서의 ezh2 억제제 및 btk 억제제의 조합물의 용도
RU2762893C2 (ru) * 2017-05-18 2021-12-23 Цзянсу Хэнжуй Медсин Ко., Лтд. Применение ингибитора ezh2 в комбинации с ингибитором btk в получении лекарственного средства для лечения опухоли
WO2018210302A1 (fr) 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 Formes cristallines du chlore libre dérivé du benzofurane et son procédé de préparation
CN109937041B (zh) * 2017-05-18 2022-04-12 江苏恒瑞医药股份有限公司 一种ezh2抑制剂与btk抑制剂联合在制备治疗肿瘤的药物中的用途
WO2018210296A1 (fr) * 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 Utilisation d'un inhibiteur d'ezh2 combiné à un inhibiteur de btk dans la préparation d'un médicament pour le traitement d'une tumeur
US11065239B2 (en) 2017-05-18 2021-07-20 Jiangsu Hengrui Medicine Co., Ltd. Use of EZH2 inhibitor combined with BTK inhibitor in preparing drug for treating tumor
US12269820B2 (en) 2022-03-23 2025-04-08 Ideaya Biosciences, Inc. Piperazine substituted indazole compounds as inhibitors of PARG
WO2023244918A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents de dégradation bifonctionnels de quinolone bcl6
WO2023244917A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents dégradant bcl6 hétérobifonctionnels 1,8-naphthyridin-2-one
WO2024108691A1 (fr) * 2022-11-25 2024-05-30 深圳先进技术研究院 Lymphocyte t régulateur et son procédé de préparation
CN117362277A (zh) * 2023-10-13 2024-01-09 沈阳药科大学 含咪唑啉酮结构的苯甲酰胺类化合物及其制备方法和应用

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