WO2013067300A1 - Method of treatment - Google Patents

Method of treatment Download PDF

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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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alkyl
methyl
mmol
indazole
cycloalkyl
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PCT/US2012/063239
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French (fr)
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Anna K. BASSIL
Soren BEINKE
Rabinder Kumar Prinjha
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Glaxosmithkline Intellectual Property (No. 2) Limited
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Publication of WO2013067300A1 publication Critical patent/WO2013067300A1/en

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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

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.

Description

METHOD OF TREATMENT
Field of the Invention
This invention relates to compounds which inhibit EZH2/EZH1 and their uses for treating T cell mediated inflammatory immune diseases.
Background of the Invention
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)
EZH1 and EZH2 play a critical role in the epigenetic long term silencing of gene expression by di- or tri-methylating lysine 27 of histone H3 (H3K27me2/3). 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. 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. Thus, inhibition of the enzymatic activity of EZH1 and EZH2 may result in a loss of H3K27me3 and up-regulation of target genes.
In addition to its nuclear function in histone H3 modification 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. In addition, 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. Furthermore, 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. Thus, 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. While such concerted immune responses can provide powerful protection against pathogens it can also result in inflammation associated with unwanted immune responses against self and environmental antigens and commensal microorganisms as well as collateral damage to the host as a side effect of immune responses against pathogens. 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. Thus, 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.
Summary of the Invention
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.
In a further aspect 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.
In a further aspect 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.
Brief Description of Drawings
Figure 1: EZH1/EZH2 inhibitors impair T cell receptor-induced CD4+ T cell
proliferation. Division index was calculated by CFSE fluorescence 6 days post stimulation with 10 μς/mL aCD3 + 2 μς/mL aCD28. Data are presented as mean ± standard error of the mean, n=4.
Figure 2: EZH1/EZH2 inhibitors impair T cell receptor-induced effector cytokine production in CD4+ T cells. Cytokine production was measured 72 h post stimulation with 10 μς/mL aCD3 + 2 μς/mL aCD28. Data are presented as means ± standard error of the mean, n=4.
Figure 3: EZHi/EZH2 inhibitors impair T cell receptor-induced IL-2 production in CD4+ T cells. IL-2 production was measured 18 h post stimulation with 10
Figure imgf000004_0001
aCD3 + 2 μς/mL aCD28. Data are presented as means ± standard error of the mean, n=4.
Table 1: EZHi/EZH2 inhibitors impair T cell receptor-induced effector cytokine
production in CD4+ T cells. Cytokine production was measured 72 h post stimulation with 10 μς/mL aCD3 + 2 μς/mL aCD28. Data are presented as p!C50 ± sem; n=4 Detailed Description of the Invention
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)
Figure imgf000005_0001
wherein
X and Z are selected independently from the group consisting of hydrogen, (d- C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, unsubstituted or substituted (C3-C8)cycloalkyl, unsubstituted or substituted (C3-C8)cycloalkyl-(CrC8)alkyl or -(C2-C8)alkenyl,
unsubstituted or substituted (C5-C8)cycloalkenyl, unsubstituted or substituted (C5- C8)cycloalkenyl-(Ci-C8)alkyl or -(C2-C8)alkenyl, (C6-Ci0)bicycloalkyl, unsubstituted or substituted heterocycloalkyi, unsubstituted or substituted heterocycloalkyl-(Ci-C8)alkyl or - (C2-C8)alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-(Ci- C8)alkyl or -(C2-C8)alkenyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-(C C8)alkyl or -(C2-C8)alkenyl, halo, cyano, -CORa, -C02Ra, - CONRaRb, -CONRaNRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, - NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -NRaNRaC(0)ORa, -ORa, -OC(0)Ra, and - OC(0)NRaRb;
Y is H or halo; R1 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, unsubstituted or substituted (C3- C8)cycloalkyl, unsubstituted or substituted (C3-C8)cycloalkyl-(C1-C8)alkyl or - (C2-C8)alkenyl, unsubstituted or substituted (C5-C8)cycloalkenyl, unsubstituted or substituted (C5-C8)cycloalkenyl-(Ci-C8)alkyl or -(C2-C8)alkenyl, unsubstituted or substituted (C6-Ci0)bicycloalkyl, unsubstituted or substituted heterocycloalkyi or - (C2-C8)alkenyl, unsubstituted or substituted heterocycloalkyl-(Ci-C8)alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-(Ci-C8)alkyl or -(C2-C8)alkenyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-(Ci- C8)alkyl or -(C2-C8)alkenyl, -CORa, -C02Ra, -CONRaRb, -CONRaNRaRb;
R3 is hydrogen, (Ci-C8)alkyl, cyano, trifluoromethyl, -NRaRb, or halo;
R6 is selected from the group consisting of hydrogen, halo, (Ci-C8)alkyl,
(C2-C8)alkenyl, -B(OH)2, substituted or unsubstituted (C2-C8)alkynyl, unsubstituted or substituted (C3-C8)cycloalkyl, unsubstituted or substituted (C3-C8)cycloalkyl-(d-C8)alkyl, unsubstituted or substituted (C5-C8)cycloalkenyl, unsubstituted or substituted (C5- C8)cycloalkenyl-(Ci-C8)alkyl, (C6-Ci0)bicycloalkyl, unsubstituted or substituted
heterocycloalkyi, unsubstituted or substituted heterocycloalkyl-(Ci-C8)alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-(C1-C8)alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-(C1-C8)alkyl, cyano, - CORa, -C02Ra, -CONRaRb, -CONRaNRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, - NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, - NRaNRaRb, -NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -NRaNRaC(0)ORa, -ORa, - OC(0)Ra, -OC(0)NRaRb;
wherein any (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)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- C6)alkyl(Rc)1-2, -S(Ci-C6)alkyl(Rc)1-2, -(Ci-C6)alkyl(Rc)1-2, (Ci-C8)alkyl- heterocycloalkyl, (C3-C8)cycloalkyl-heterocycloalkyl, halo, (CrC6)alkyl,
(C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (Ci-C6)haloalkyl, cyano, -CORa, -C02Ra - CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, - NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, - OC(0)NRaRb, heterocycloalkyi, aryl, heteroaryl, aryl(Ci-C4)alkyl, and
heteroaryl(Ci-C4)alkyl;
wherein any aryl or heteroaryl moiety of said aryl, heteroaryl, aryl(Ci-C4)alkyl, or heteroaryl(Ci-C4)alkyl is optionally substituted by 1 , 2 or 3 groups independently selected from the group consisting of halo, (d-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C C6)haloalkyl, cyano, -CORa, -C02Ra, -CONRaRb,
-SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb,
-NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, and -OC(0)NRaRb;
Ra and Rb are each independently hydrogen, (Ci-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C6-Ci0)bicycloalkyl,
heterocycloalkyi, aryl, heteroaryl, wherein said (Ci-C8)alkyl, (C2-C8)alkenyl, (C2- C8)alkynyl, cycloalkyi, cycloalkenyl, bicycloalkyi, heterocycloalkyi ,aryl or heteroaryl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, hydroxyl, (Ci-C4)alkoxy, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -C02H, - C02(CrC4)alkyl, -CONH2,-CONH(C C4)alkyl, -CON((Ci-C4)alkyl)((C C4)alkyl), - S02(CrC4)alkyl, -S02NH2,-S02NH(C C4)alkyl, or -S02N((C C4)alkyl)((Ci-C4)alkyl); or Ra and Rb taken together with the nitrogen to which they are attached represent a 5-8 membered saturated or unsaturated ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C4)alkyl, (C1-C4)haloalkyl, amino, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, hydroxyl, oxo, (C1-C4)alkoxy, and (C1-C4)alkoxy(C1-C4)alkyl, wherein said ring is optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyi, aryl, or heteroaryl ring;
or Ra and Rb taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyi, aryl, or heteroaryl ring;
each Rc is independently (Ci-C4)alkylamino, -NRaS02Rb, -SORa, -S02Ra, - NRaC(0)ORa, -NRaRb, or -C02Ra;
or a salt thereof.
The present invention also relates to the above method, wherein the compound of Formula (II) is further defined in one of the subgroups below:
Subgroup (I)(A)
X and Z are selected from the group consisting of (d-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyi, aryl, heteroaryl, -NRaRb, and -ORa;
Y is H or F;
R1 is selected from the group consisting of (Ci-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyi, aryl, and heteroaryl; R3 is selected from the group consisting of hydrogen, (Ci-C8)alkyl, cyano, trifluoromethyl, -NRaRb, and halo;
R6 is selected from the group consisting of hydrogen, halo, cyano, trifluoromethyl, amino, (Ci-C8)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl, acylamino; (C2-C8)alkynyl, arylalkynyl, heteroarylalkynyl, -S02Ra, -S02NRaRb , and -NRaS02Rb ;
wherein any (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkynyl, arylalkynyl, heteroarylalkynyl group is optionally substituted by 1 , 2 or 3 groups independently selected from -0(C1-C6)alkyl(Rc)1-2, -S(C1-C6)alkyl(Rc)1-2, -(C1-C6)alkyl(Rc)1-2, (C C8)alkyl-heterocycloalkyl, (C3-C8)cycloalkyl-heterocycloalkyl, halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C C6)haloalkyl, cyano, -CORa, -C02Ra, -CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, - NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, - OC(0)NRaRb, heterocycloalkyi, aryl, heteroaryl, aryl(d-C4)alkyl, and
heteroaryl(Ci-C4)alkyl;
each Rc is independently (C C4)alkylamino, -NRaS02Rb, -SORa, -S02Ra, - NRaC(0)ORa, -NRaRb, or -C02Ra;
Ra and Rb are each independently hydrogen, (Ci-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C6-Ci0)bicycloalkyl,
heterocycloalkyi, aryl, heteroaryl, wherein said (Ci-C8)alkyl, (C2-C8)alkenyl, (C2- C8)alkynyl, cycloalkyi, cycloalkenyl, bicycloalkyi, heterocycloalkyi ,aryl or heteroaryl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, hydroxyl, (Ci-C4)alkoxy, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -C02H, - C02(CrC4)alkyl, -CONH2, -CONH(C C4)alkyl, -CON((C C4)alkyl)((Ci-C4)alkyl), - S02(C C4)alkyl, -S02NH2,-S02NH(d-d)alkyl, and -S02N((d-d)alkyl)((d-d)alkyl); or Ra and Rb taken together with the nitrogen to which they are attached represent a 5-8 membered saturated or unsaturated ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by 1 , 2 or 3 groups independently selected from (d-d)alkyl, (d-d)haloalkyl, amino, (d-d)alkylamino, ((d-C4)alkyl)((d-C4)alkyl)amino, hydroxyl, oxo, (d-d)alkoxy, and (Ci-d)alkoxy(d-d)alkyl, wherein said ring is optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyi, aryl, or heteroaryl ring;
or Ra and Rb taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C3-C8)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:
Figure imgf000009_0001
wherein in (1),
A is 0 NH, or S; B is CH or N, and C is hydrogen or C1-C3 alkyl; or
Figure imgf000009_0002
wherein in (2),
D is N or C o tionally substituted by hydrogen or d-C8 alkyl; or
Figure imgf000009_0003
wherein in (3),
E is NH or CH2; F is 0 or CO; and
Figure imgf000009_0004
wherein in (4),
J is 0, S or CO; or
Figure imgf000009_0005
wherein in (5),
Q is CH or N;
M is CH or N; and
L7(5) is hydrogen, halo, amino, cyano, (Ci-C8)alkyl, (C3-C8)cycloalkyl, -CORa, - C02Ra, -CONRaRb, -CONRaNRaRb, -S02Ra, -S02NRaRb, -NRaRb, -NRaC(0)Rb,-NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -ORa, wherein any (C1-C8)alkyl, (C3-C8)cycloalkyl, group is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C1-C6)haloalkyl, cyano, -CORa, -C02Ra, -CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, - NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, -OC(0)NRaRb; wherein Ra and Rb are defined as above; or
Figure imgf000010_0001
wherein in 6,
L/(6) is NH or CH2; or
Figure imgf000010_0002
wherein in 7,
M/(7) is hydrogen, halo, amino, cyano, (Ci-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -CORa, -C02Ra, -CONRaRb, -CONRaNRaRb, -S02Ra, - S02NRaRb, -NRaRb, -NRaC(0)Rb,-NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, - NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -ORa,
wherein any (C1-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl group is optionally substituted by 1 , 2 or 3 groups independently selected from
(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (CrC6)haloalkyl, cyano, - CORa, -C02Ra, -CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, - ORa, -OC(0)Ra, -OC(0)NRaRb; wherein Ra and Rb are defined as above; or
Figure imgf000010_0003
wherein in (8), P is CH2, NH, 0, or S; Q/(8) is CH or N; and n is 0-2; or
Figure imgf000011_0001
wherein in (9),
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-C8)alkyl, (C3- C8)cycloalkyl, -CORa, -C02Ra, -CONRaRb, -S02Ra, -S02NRaRb, -NRaRb, - NRaC(0)Rb,-NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, , -ORa, 4-(1 H- pyrazol-4-yl),
wherein any (Ci-C8)alkyl, (C3-C8)cycloalkyl, group is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (Ci-C6)haloalkyl, cyano, -CORa, -C02Ra,-CONRaRb, -SRa, - SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, - NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, -OC(0)NRaRb; wherein Ra and Rb are defined as above.
Subgroup (I)(B)
X and Z are selected independently from the group consisting of (d-C8)alkyl, (C3- C8)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NRaRb, and -ORa;
Y is H;
R1 is (Ci-C8)alkyl, (C3-C8)cycloalkyl, or heterocycloalkyl;
R3 is hydrogen, (Ci-C8)alkyl or halo;
R6 is hydrogen, halo, cyano, trifluoromethyl, amino, (Ci-C8)alkyl, (C3- C8)cycloalkyl;, aryl, heteroaryl, acylamino; (C2-C8)alkynyl, arylalkynyl, heteroarylalkynyl; - S02Ra; -S02NRaRb, or -NRaS02Rb;
wherein any (Ci-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkynyl, arylalkynyl, heteroarylalkynyl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl,
(Ci-C6)haloalkyl, cyano, -CORa, -C02Ra, -CONRaRb, -SRa, -SORa, -S02Ra, - S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, - NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, -OC(0)NRaRb, heterocycloalkyi, aryl, heteroaryl, aryl(C1-C4)alkyl, and heteroaryl(C1-C4)alkyl;
Ra and Rb are each independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C6-Ci0)bicycloalkyl,
heterocycloalkyi, aryl, heteroaryl, wherein said (Ci-C8)alkyl, (C2-C8)alkenyl, (C2- C8)alkynyl, cycloalkyi, cycloalkenyl, bicycloalkyi, heterocycloalkyi ,aryl or heteroaryl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, hydroxyl, (Ci-C4)alkoxy, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -C02H, - C02(CrC4)alkyl, -CONH2,-CONH(C C4)alkyl, -CON((Ci-C4)alkyl)((C C4)alkyl), - S02(CrC4)alkyl, -S02NH2, -S02NH(Ci-C4)alkyl, and -S02N((Ci-C4)alkyl)((C C4)alkyl); or Ra and Rb taken together with the nitrogen to which they are attached represent a 5-8 membered saturated or unsaturated ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, (Ci-C4)haloalkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, hydroxyl, oxo, (CrC4)alkoxy, and (Ci-C4)alkoxy(Ci-C4)alkyl, wherein said ring is optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyi, aryl, or heteroaryl ring;
or Ra and Rb taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C3-C8)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
nother aryl or heteroaryl group as follows:
Figure imgf000012_0001
wherein in (1),
A is 0 NH, or S; B is CH or N, and C is hydrogen or C1-C3 alkyl; or
Figure imgf000012_0002
wherein in (2),
D is N or C optionally substituted by hydrogen or d-C8 alkyl; or
Figure imgf000013_0001
wherein in (3),
E is NH or CH2; F is 0 or CO; and
Figure imgf000013_0002
wherein in (4),
J is 0, S or CO; or
Figure imgf000013_0003
wherein in (5),
Q is CH or N;
M is CH or N; and
L7(5) is hydrogen, halo, amino, cyano, (d-C8)alkyl, (C3-C8)cycloalkyl, -CORa, - C02Ra, -CONRaRb, -CONRaNRaRb, -S02Ra, -S02NRaRb, -NRaRb, -NRaC(0)Rb,-NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -ORa,
wherein any (Ci-C8)alkyl, (C3-C8)cycloalkyl, group is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C6)alkyl, (C3-C8)cycloalkyl, (C5-Ce)cycloalkenyl, (Ci-C6)haloalkyl, cyano, -CORa, -C02Ra, -CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaR , nitro, -NRaR , -NRaC(0)R , -NRaC(0)NRaR , - NRaC(0)ORa, -NRaS02R , -NRaS02NRaR , -ORa, -OC(0)Ra, -OC(0)NRaR , wherein Ra and Rb are defined as above; or
Figure imgf000013_0004
wherein in 6,
L/(6) is NH or CH2; or
Figure imgf000014_0001
wherein in 7,
M/(7) is hydrogen, halo, amino, cyano, (C1-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -CORa, -C02Ra, -CONRaRb, -CONRaNRaRb, -S02Ra, - S02NRaRb, -NRaRb, -NRaC(0)Rb,-NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, - NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -ORa,
wherein any (d-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl group is optionally substituted by 1 , 2 or 3 groups independently selected from
(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (CrC6)haloalkyl, cyano, - CORa, -C02Ra, -CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, - ORa, -OC(0)Ra, -OC(0)NRaRb; wherein Ra and Rb are defined as above; or
Figure imgf000014_0002
wherein in (8),
P is CH2, NH, 0, or S; Q/(8) is CH or N; and n is 0-2; or
Figure imgf000014_0003
wherein in (9),
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-C8)alkyl, (C3- C8)cycloalkyl, -CORa, -C02Ra, -CONRaRb, -S02Ra, -S02NRaRb, -NRaRb, - NRaC(0)Rb,-NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, , -ORa, 4- pyrazol-4-yl), wherein any (C1-C8)alkyl, (C3-C8)cycloalkyl, group is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C1-C6)haloalkyl, cyano, -CORa, -C02Ra -CON RaRb, -SRa, - SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, - NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, -OC(0)NRaRb, wherein Ra and Rb are defined as above.
Subgroup (I)(C)
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;
R1 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;
R3 is H, methyl, or Br; and
R6 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, phenylethynyl, 2-furanyl, 3-thienyl; lH-pyrazol-4-yl, lH-indazol-5-yl, lH-indazol-6-yl, 3- methyl-lH-indazol-5-yl, lH-l,2,3-benzotriazol-5-yl, 2-oxo-2,3-dihydro-lH-benzimidazol-5- yl, 2-oxo-2,3-dihydro-lH-indol-5-yl, 2-oxo-2,3-dihydro-lH-indol-6-yl, 2,1,3-benzoxadiazol- 5-yl, 2-amino-6-quinazolinyl, 2,4-dioxo-l,2,3,4-tetrahydro-5-pyrimidinyl, 2-amino-5- pyrimidinyl, 7-oxo-l,5,6,7-tetrahydro-l,8-naphthyridin-3-yl, phenyl, 2-methylphenyl, 2- nitrophenyl, 2-phenylethyl, 3-aminophenyl, 4-aminophenyl, 4-chlorophenyl, 4- fluorophenyl, 4-(methyloxy)phenyl, 3-(acetylamino)phenyl, 4-(acetylamino)phenyl, 4- (aminocarbonyl)phenyl, 4-(lH-pyrazol-4-yl)phenyl, 4-(aminosulfonyl)phenyl, 4- (methylsulfonyl)phenyl, 4-[(dimethylamino)sulfonyl]phenyl, 4- [(methylamino)carbonyl]phenyl, 4-[(methylamino)sulfonyl]phenyl, 4- [(methylsulfonyl)amino]phenyl, 3-pyridinyl, 4-pyridinyl, 2-(4-morpholinyl)-4-pyridinyl, 2- amino-4-pyridinyl, 5-(methyloxy)-3-pyridinyl, 5-(methylsulfonyl)-3-pyridinyl, 5- [(cyclopropylsulfonyl)amino]-6-(methyloxy)-3-pyndinyl, 5-[(phenylsulfonyl)amino]-3- pyridinyl, 6-(4-methyl-l-piperazinyl)-3-pyridinyl, 6-(4-morpholinyl)-3-pyridinyl, 6- (acetylamino)-3-pyridinyl, 6-(dimethylamino)-3-pyridinyl, 6-(methyloxy)-3-pyridinyl, 6- [(methylamino)carbonyl]-3-pyridinyl, 6-[(methylamino)sulfonyl]-3-pyridinyl, 6-methyl-3- pyridinyl, 4-pyridinyloxy.
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:
6-chloro-1-(1-methylethyl)-/\/-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-1 H-indazole-4-carboxamide;
A/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-6-fluoro-1 -(1-methylethyl)- 1 H-indazole-4-carboxamide;
6-Bromo-/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)- 1 H-indazole-4-carboxamide;
6-bromo-N-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl- 1 H-indazole-4-carboxamide;
6-bromo-1-(1-methylethyl)-/\/-{[6-methyl-2-oxo-4-(phenylmethyl)-1 ,2-dihydro-3- pyridinyl]methyl}-1 H-indazole-4-carboxamide;
6-bromo-1-(1-methylethyl)-/\/-[(6-methyl-2-oxo-1 ,2-dihydro-4,4'-bipyridin-3- yl)methyl]-1 H-indazole-4-carboxamide;
1 -(1 -methylethyl)-/V-{[6-methyl-2-oxo-4-(phenylmethyl)-1 ,2-dihydro-3- pyridinyl]methyl}-1 H-indazole-4-carboxamide ;
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(4-(2- (dimethylamino)ethoxy)phenyl)-1-isopropyl-1 H-indazole-4-carboxamide;
N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[4-(1 - piperazinyl)phenyl]-1 H-indazole-4-carboxamide;
A/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(1 - piperazinyl)-3-pyridinyl]-1 H-indazole-4-carboxamide;
6-{4-[(dimethylamino)methyl]phenyl}-1-(1-methylethyl)-N-{[6-methyl-4-(1- methylethyl)-2-oxo-1 ,2-dihydro-3-pyridinyl]methyl}-1 H-indazole-4-carboxamide;
1-isopropyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperazin-1 -yl)pyridin-3-yl)-1 H-indazole-4-carboxamide;
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1 -methyl-1 H- pyrazol-4-yl)-1 H-indazole-4-carboxamide;
6-(4-((dimethylamino)methyl)phenyl)-N-((4-ethyl-6-methyl-2-oxo-1 ,2- dihydropyridin-3-yl)methyl)-1 -isopropyl-1 H-indazole-4-carboxamide;
1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-[6- (1 -piperazinyl)-3-pyridinyl]-1 H-indazole-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)-1 H-indazole-4-carboxamide;
1-isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(2- methylpyrimidin-5-yl)-1 H-indazole-4-carboxamide;
6-[6-(dimethylamino)-3-pyridinyl]-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl- 1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide;
1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-[6- (4-morpholinyl)-3-pyridinyl]-1 H-indazole-4-carboxamide;
6-(2-amino-5-pyrimidinyl)-1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2- dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide;
6-(6-amino-3-pyridinyl)-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro- 3-pyridinyl)methyl]-1 H-indazole-4-carboxamide;
1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-(5- pyrimidinyl)-1 H-indazole-4-carboxamide;
1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-[6- (methyloxy)-3-pyridinyl]-1 H-indazole-4-carboxamide;
1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-[6- (4-methyl-1 -piperazinyl)-3-pyridinyl]-1 /-/-indazole-4-carboxamide;
1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-(2- methyl-3-pyridinyl)-1 H-indazole-4-carboxamide;
1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-(6- methyl-3-pyridinyl)-1 H-indazole-4-carboxamide;
6-[6-(dimethylamino)-3-pyridinyl]-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide;
N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6- (trifluoromethyl)-3-pyridinyl]-1 H-indazole-4-carboxamide;
6-{3-[(dimethylamino)methyl]phenyl}-/\/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-1 /-/-indazole-4-carboxamide;
6-{4-[(dimethylamino)methyl]phenyl}-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1-(1-methylethyl)-1 H-indazole-4-carboxamide; N-((1 ,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-1-isopropyl-6- (thiophen-3-yl)-1 H-indazole-4-carboxamide;
1-isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6- (thiophen-3-yl)-1 H-indazole-4-carboxamide;
6-{4-[(dimethylamino)methyl]phenyl}-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4- propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide hydrochloride salt;
6-{3-[(dimethylamino)methyl]phenyl}-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4- propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide hydrochloride salt;
N-((1 ,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-1-isopropyl-6-(1 H- pyrazol-4-yl)-1 H-indazole-4-carboxamide;
N-((1 ,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-1-isopropyl-6-(1 H- pyrrolo[2,3-b]pyridin-5-yl)-1 H-indazole-4-carboxamide;
6-(4-(dimethylamino)piperidin-1-yl)-1 -isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)-1 H-indazole-4-carboxamide ;
6-(4-((dimethylamino)methyl)piperidin-1 -yl)-1-isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)-1 H-indazole-4-carboxamide ;
N-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6- morpholino-1 H-indazole-4-carboxamide;
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-morpholino- 1 H-indazole-4-carboxamide;
N-((4-cyclohexyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-cyclopropyl-1 - isopropyl-1 H-indazole-4-carboxamide;
6-bromo-1-ethyl-1 H-indazole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1 , 2- dihydro-pyridin-3-ylmethyl)-amide;
6-bromo-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-1 -propyl-1 H- indazole-4-carboxamide;
6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 H- indazole-4-carboxamide;
6-bromo-1-cyclopentyl-N-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)- 1 H-indazole-4-carboxamide;
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(2-(4- methylpiperazin-1 -yl)pyrimidin-5-yl)-1 H-indazole-4-carboxamide;
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(3- (pyrrolidin-1 -yl)phenyl)-1 H-indazole-4-carboxamide; 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- methylthiophen-2-yl)-1 H-indazole-4-carboxamide;
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(2- (piperazin-1 -yl)pyrimidin-5-yl)-1 H-indazole-4-carboxamide;
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(3-(3- hydroxypropyl)phenyl)-1 H-indazole-4-carboxamide;
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(3- (trifluoromethoxy)phenyl)-1 H-indazole-4-carboxamide;
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- methoxypyridin-3-yl)-1 H-indazole-4-carboxamide;
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- fluorophenyl)-1 H-indazole-4-carboxamide;
1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-6-(1-methyl- 1 H-pyrazol-4-yl)-1 H-indazole-4-carboxamide;
1-cyclopentyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)-1 H-indazole-4-carboxamide;
1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-6-[6-(1- piperazinyl)-3-pyridinyl]-1 H-indazole-4-carboxamide;
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- ((dimethylamino)methyl)phenyl)-1 H-indazole-4-carboxamide;
6-chloro-1-cyclopentyl-/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 /-/- indazole-4-carboxamide;
6-chloro-1-cyclopentyl-/\/-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-1 /-/-indazole-4-carboxamide;
6-cyano-1 -cyclopentyl-/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H- indazole-4-carboxamide;
6-(aminomethyl)-1 -cyclopentyl-/\/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 H-indazole-4-carboxamide;
6-amino-1-cyclopentyl-/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 /-/- indazole-4-carboxamide;
1-cyclopentyl-/\/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-6- [(phenylsulfonyl)amino]-1 /-/-indazole-4-carboxamide;
1-cyclopentyl-/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-6-(3-hydroxy- 3-methyl-1-butyn-1-yl)-1 H-indazole-4-carboxamide;
6-bromo-1-cyclopropyl-/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 /-/- indazole-4-carboxamide; 6-bromo-1-cyclopropyl-/\/-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-1 H-indazole-4-carboxamide;
1-cyclopropyl-6-{4-[(dimethylamino)methyl]phenyl}-/\/-[(4,6-dimethyl-2-oxo-1 ,2- dihydro-3-pyridinyl)methyl]-1 /-/-indazole-4-carboxamide;
1-cyclopropyl-6-{4-[(dimethylamino)methyl]phenyl}-/\/-[(6-methyl-2-oxo-4-propyl- 1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide;
6-bromo-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3- methyl-1 H-indazole-4-carboxamide ;
6-bromo-1-isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3- yl)methyl)-1 H-indazole-4-carboxamide;
1-isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)- 6-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1 H-indazole-4-carboxamide;
3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1 H-indazole-4-carboxamide;
6-(6-(dimethylamino)pyridin-3-yl)-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3- yl)methyl)-1 -isopropyl-3-methyl-1 H-indazole-4-carboxamide;
6-(3-((dimethylamino)methyl)phenyl)-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3- yl)methyl)-1 -isopropyl-1 H-indazole-4-carboxamide;
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(4-fluorophenyl)-1 - isopropyl-3-methyl-1 H-indazole-4-carboxamide;
N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6-(6- (4-methylpiperazin-1 -yl)pyridin-3-yl)-1 H-indazole-4-carboxamide;
6-(4-((dimethylamino)methyl)phenyl)-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3- yl)methyl)-1 -isopropyl-3-methyl-1 H-indazole-4-carboxamide;
N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6-(6- (piperazin-1 -yl)pyridin-3-yl)-1 H-indazole-4-carboxamide hydrochloride;
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-6-(6- (4-methylpiperazin-1 -yl)pyridin-2-yl)-1 H-indazole-4-carboxamide;
N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6- (pyridin-3-yl)-1 H-indazole-4-carboxamide;
N-((1 ,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-1 -isopropyl-3-methyl- 6-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-indazole-4-carboxamide;
N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6-(1 H- pyrazol-4-yl)-1 H-indazole-4-carboxamide; N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6- (pyridin-3-yl)-1 H-indazole-4-carboxamide;
/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)- 6-(6-methyl-3-pyridinyl)-1 H-indazole-4-carboxamide;
6-[6-(dimethylamino)-3-pyridinyl]-3-methyl-1 -(1 -methylethyl)-/V-[(6-methyl-2-oxo-4-propyl- 1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide;
6-{3-[(dimethylamino)methyl]phenyl}-3-methyl-1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4- propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 /-/-indazole-4-carboxamide
6-{4-[(dimethylamino)methyl]phenyl}-3-methyl-1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4- propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 /-/-indazole-4-carboxamide;
3-methyl-1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6- (3-pyridinyl)-1 -/-indazole-4-carboxamide;
3-methyl-1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6- [6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1 /-/-indazole-4-carboxamide;
6-cyano-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3- methyl-1 H-indazole-4-carboxamide;
1-cyclopentyl-6-(cyclopropylsulfonyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3- yl)methyl)-1 H-indazole-4-carboxamide ;
6-(cyclopropylsulfonyl)-N-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 - isopropyl-1 H-indazole-4-carboxamide ;
N-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(methylsulfonyl)- 1 H-indazole-4-carboxamide;
/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6- (methylsulfonyl)-1 H-indazole-4-carboxamide;
N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4- morpholinylsulfonyl)-1 H-indazole-4-carboxamide;
6-[(cyclopropylamino)sulfonyl]-/\/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide;
/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(1^
pyrrolidinylsulfonyl)-1 H-indazole-4-carboxamide ; 6-({[3-(dimethylamino)propyl]amino}sulfonyl)-/V-[(4,6-dimethyl-2-oxo-1 ,2-d
3-pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide ;
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-((4- methylpiperazin-1 -yl)sulfonyl)-1 H-indazole-4-carboxamide ;
6-bromo-N-((4-(sec-butyl)-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 - isopropyl 1 H-indazole-4-carboxamide;
6-Bromo-1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-1 H-indazole-4-carboxamide; or
6-Bromo-1 -(1 -methylethyl)-/V-{[6-methyl-4-(1 -methylethyl)-2-oxo-1 ,2-dihydro-3- pyridinyl]methyl}-1 H-indazole-4-carboxamide; and
or a pharmaceutically acceptable salt thereof.
As used herein, 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.
As used herein, unless otherwise defined, 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-C6alkyl, CrCsalkylsulfonyl, d-Csalkoxy, C
C3alkoxycarbonyl, cyano, halogen, haloalkyl, hydroxyl, oxo, and nitro.
The term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
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. Furthermore, the term "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.
As used herein the term "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.C8alkyr 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.
The term "alkoxy" as used herein means -0(Ci.C8alkyl) including -OCH3, -
OCH2CH3 and -OC(CH3)3 and the like per the definition of alky! above.
The term "alkylthio" as used herein is meant -S(Ci.C8alkyl) including -SCH3, -
SCH2CH3 and the like per the definition of alkyl above.
The term "acyloxy" means -OC(0)Ci.C8alkyl and the like per the definition of alkyl above.
"Acylamino" means-N(H)C(0)C1.C8alkyl 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.
When the term "alkenyl" (or "alkenylene") is used it 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).
When the term "alkynyl" (or "alkynylene") is used it 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.
When "cycloalkyl" is used it refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. So, for example, the term "C3-C8cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to eight carbon atoms. Exemplary "C3-C8cycloalkyl" groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term "C5-C8cycloalkenyl" 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.
Where "C3-C8heterocycloalkyl" is used, it 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.
As used herein, the term "aryl", unless otherwise defined, is meant aromatic, hydrocarbon, ring system. The ring system may be monocyclic or fused polycyclic (e.g., bicyclic, tricyclic, etc.), substituted or unsubstituted. In various embodiments, 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. In various embodiments, 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".
As used herein, the term "heteroaryl", unless otherwise defined, is meant 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). Exemplary 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"
Provided herein are methods of treatment or prevention of autoimmune and inflammatory conditions and diseases that can be improved by inhibiting EZH1 and / or EZH2 and thereby, e.g., modulate the level of expression of methylation activated and methylation repressed target genes, or modulate the activity of signalling proteins. A method may comprise administering to a human, e.g. a human in need thereof, a therapeutically effective amount of an agent described herein.
Thus in one aspect there is provided the use of use of a compound or a pharmaceutically acceptable salt thereof which inhibits EZH2 and/or EZH 1 (i.e. an EZH2 and/or EZH1 inhibitor) in the manufacture of a medicament for treating T cell mediated inflammatory immune diseases or T cell mediated hypersensitivity diseases. In a further aspect there is provided 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.
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.
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. Examples of musculoskeletal inflammation which may be treated with compounds of the invention 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).
Ocular inflammation refers to inflammation of any structure of the eye, including the eye lids. Examples of ocular inflammation which may be treated in this invention include blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis.
Examples of inflammation of the nervous system which may be treated in this invention include encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis and schizophrenia.
Examples of inflammation of the vasculature or lymphatic system which may be treated in this invention 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 nodosa, polymyalgia, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune haemolytic anemia, interstitial cystitis, lyme disease, morphea, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.
The agents may be used to treat 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).
Other inflammatory conditions which may be treated in this invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, 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 pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sexary's syndrome, congenital adrenal hyperplasis, nonsuppurative thyroiditis, hypercalcemia associated with cancer, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, astopic dermatitis, drug hypersensistivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and oiridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) haemolytic anemia, leukaemia and lymphomas in adults, acute leukaemia of childhood, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis.
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).
Typically, but not absolutely, the salts of the compounds for use in the inevntion are pharmaceutically acceptable salts. Salts encompassed within the term
"pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts. In general, 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.
Other representative 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, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.
Other 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.
Pharmaceutical 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).
Pharmaceutical 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.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. 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. 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.
Where appropriate, 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.
Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or as enemas.
Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations 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.
It should be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical 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. However, 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. For a 70kg adult mammal, 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.
Experimentals:
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(4-(2- (dimethylamino)ethoxy)phenyl)-1 -isopropyl-1 H-indazole-4-carboxamide
Figure imgf000031_0001
6-bromo-N-(4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1 H-indazole-4- carboxamide (80 mg, 0.19 mmol), N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)ethanamine (84 mg, 0.29 mmol) and PdCl2(dppf)-CH2Cl2 adduct (7.8 mg, 0.009 mmol) in dioxane/water (3 ml:1 ml) were stirred for 10 min under nitrogen. Sodium bicarbonate (48.3 mg, 0.58 mmol) was added and the insoluble mixture was irradiated in a microwave at 100 °C for 20 min. The reaction mixture was evaporated, dissolved in DCM/MeOH (1 :1 ), and preabsorbed on silica gel and purified using silica gel chromatography (eluent: DCM/MeOH/NH4OH; gradient 0 to 80:20:2 in DCM). The isolated product was dissolved in hot DMSO/MeOH and purified using reversed-phase HPLC (25-80% gradient of MeCN in water with 0.1 % TFA). Most of the solvent from the combined product fractions were evaporated and sat. sol. NaHC03 was added, solids that crashed out were filtered, air-dried for 15 min, and dried in vaccum-oven overnight. The product was collected as a white solid (56 mg, 56%). 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 1 .54 (br. s., 1 H) 8.64 (t, J=4.80 Hz, 1 H) 8.35 (s, 1 H) 8.05 (s, 1 H) 7.81 - 7.84 (m, 2 H). LC-MS (ES) m/z = 528.1 [M+H]+ Example 9
N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)-6-[4-(1 - piperazinyl)phenyl]-1 H-indazole-4-carboxamide
Figure imgf000032_0001
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 (80 mg, 0.192 mmol) and [4-(1 -piperazinyl)phenyl]boronic acid (59 mg, 0.288 mmol). The product was collected as a white solid (34 mg, 35%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .53 (br. s., 1 H) 8.66 (br. s., 1 H) 8.33 (s, 1 H) 8.00 (s, 1 H) 7.82 (s, 1 H) 7.73 - 7.76 (m, 1 H) 7.72 (s, 1 H) 7.01 - 7.09 (m, 2 H) 5.89 (s, 1 H) 5.14 (dt, J=13.33, 6.60 Hz, 1 H) 4.39 (br. s., 1 H) 4.38 (br. s., 1 H) 3.38 - 3.52 (m, 4 H) 3.09 - 3.14 (m, 1 H) 3.00 - 3.09 (m, 3 H) 2.81 - 2.90 (m, 1 H) 2.21 (s, 3 H) 2.13 (s, 3 H) 1.50 (s, 3 H) 1.48 (s, 3 H). LC-MS (ES) m/z = 499.4 [M+H]+
Example 10
W-[(4,6-di methyl -2 -oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)-6-[6-(1 - piperazinyl)-3-pyridinyl]-1 H-indazole-4-carboxamide
Figure imgf000032_0002
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 NaHC03, and solids that crashed out were filtered . The product was evaporated from MeOH, triturated from ether and then CH3CN. After drying in vacuum oven overnight, the final product was collected as a white solid (87 mg, 78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.53 (br. s., 1 H) 8.59 - 8.67 (m, 2 H) 8.54 (s, 1 H) 8.35 (s, 1 H) 8.02 - 8.09 (m, 2 H) 7.84 (s, 1 H) 6.94 (d, J=9.09 Hz, 1 H) 5.89 (s, 1 H) 5.14 (dt, J=13.07, 6.47 Hz, 1 H) 4.39 (br. s., 1 H) 4.38 (br. s., 1 H) 3.41 - 3.47 (m, 4 H) 3.17 (s, 1 H) 2.22 (s, 3 H) 2.13 (s, 3 H) 1.50 (s, 3 H) 1 .49 (s, 3 H). LC-MS (ES) m/z = 500.4 [M+H]+ Note: some piperinzyl proton atoms hidden under water peak.
Example 11
6-{4-[(dimethylamino)methyl]phenyl}-1 -(1 -methylethyl)-N-{[6-methyl-4-(1 - methylethyl)-2-oxo- dazole-4-carboxamide
Figure imgf000033_0001
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%). 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 1 .48 (br. s., 1 H) 8.69 (br. s., 1 H) 8.37 (s, 1 H) 8.10 (s, 1 H) 7.86 (s, 1 H) 7.82 (s, 1 H) 7.80 (s, 1 H) 7.42 (s, 1 H) 7.40 (s, 1 H) 6.02 (s, 1 H) 5.17 (dt, J=13.14, 6.57 Hz, 1 H) 4.47 (d, J=4.80 Hz, 2 H) 3.44 (s, 2 H) 3.24 (dt, J=13.71 , 6.92 Hz, 1 H) 2.17 (s, 6 H) 2.15 (s, 3 H) 1.51 (s, 3 H) 1.49 (s, 3 H) 1.1 1 (s, 3 H) 1.09 (s, 3 H). LC-MS (ES) m/z = 500.1 [M+H]+ Example 12
1 -isopropyl-N-((4-isopropyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6- (piperazin-1 -yl)pyridin-3-yl)-1 H-indazole-4-carboxamide
Figure imgf000034_0001
In a 25 ml. sealable tube under nitrogen were combined 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, 0.2 mmol), {1-[5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- pyridinyl]piperazine (88 mg, 0.3 mmol) in dioxane/water (3 mL:1 ml_). PdCl2(dppf)-CH2Cl2 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 Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). 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 MgS04, filtered, and concentrated. DMF was added along with some water, and after sitting overnight, the solids that precipitated were filtered. EtOAc was added along with some hexanes, the contents sonicated, and the solids that precipitated were filtered and dried to afford the title compound as an off-white solid (29.5 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .54 (br. s., 1 H) 8.59 - 8.68 (m, 2 H) 8.35 (s, 1 H) 8.00 - 8.12 (m, 2 H) 7.83 (s, 1 H) 6.92 (d, J=8.84 Hz, 1 H) 6.03 (s, 1 H) 5.13 (quin, J=6.63 Hz, 1 H) 4.47 (br. s., 1 H) 4.46 (br. s., 1 H) 3.42 - 3.56 (m, 4 H) 3.20 - 3.27 (m, 1 H) 2.76 - 2.85 (m, 4 H) 2.16 (s, 3 H) 1 .50 (s, 3 H) 1 .49 (s, 3 H) 1.1 1 (s, 3 H) 1.09 (s, 3 H). LC-MS (ES) m/z = 528.1 [M+H]+ Example 13
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-(1 -methyl-1 H- pyrazol-4-yl)-1 H-indazole-4-carboxamide
Figure imgf000035_0001
In a 25 mL sealable tube under nitrogen were combined 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, 0.26 mmol), 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (82 mg, 0.4 mmol) in dioxane/water (3 mL:1 ml_). PdCI2(dppf)-CH2CI2 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 Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH).
The collected product was suspended in EtOAc along with some hexanes, it was sonicated, and the solids that precipitated were filtered. Acetonitrile was added, solids that precipitated were filtered, and further washed with acetonitrile/ether (2:8) and dried to afford the title compound as an off-white solid (84 mg, 76 %). 1H NMR (400 MHz, DMSO- d6) δ ppm 1 1.54 (s, 1 H) 8.48 (t, J=4.93 Hz, 1 H) 8.31 (s, 1 H) 8.26 (s, 1 H) 8.04 (s, 1 H) 8.03 (s, 1 H) 7.81 (d, J=1.01 Hz, 1 H) 5.90 (s, 1 H) 5.06 (quin, J=6.57 Hz, 1 H) 4.39 (s, 1 H) 4.38 (s, 1 H) 3.90 (s, 3 H) 2.23 (s, 3 H) 2.13 (s, 3 H) 1.50 (s, 3 H) 1.48 (s, 3 H); LC-MS (ES) m/z = 419.0
Example 14
6-(4-((dimethylamino)methyl)phenyl)-N-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin 3-yl)methyl)-1 -isopropyl-1 H-indazole-4-carboxamide
Figure imgf000036_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4-ethyl-6-methyl-2- oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide (90 mg, 0.21 mmol), dimethyl{[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}amine.HCI (93 mg, 0.31 mmol) in dioxane/water (3 mL:1 ml_). PdCl2(dppf)-CH2Cl2 adduct (8.52 mg, 0.01 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (52.6 mg, 0.63 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 ) added, and the contents pre-absorbed on silica gel and purified by Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The collected product was further purified by reversed-phase HPLC (15% 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 along with EtOAc. The organic layer was separated, and the aqueous layer was further extracted with EtOAc, DCM and DCM/isopropanol (8:2). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated. The solid was triturated in ether and dried to afford the title compound as an-off-white solid (40 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 8.67 (t, J=4.93 Hz, 1 H) 8.38 (s, 1 H) 8.1 1 (s, 1 H) 7.86 (s, 1 H) 7.82 (s, 1 H) 7.80 (s, 1 H) 7.42 (s, 1 H) 7.40 (s, 1 H) 5.93 (s, 1 H) 5.17 (quin, J=6.57 Hz, 1 H) 4.43 (s, 1 H) 4.41 (s, 1 H) 3.44 (s, 2 H) 2.57 (q, J=7.58 Hz, 2 H) 2.17 (s, 6 H) 2.14 (s, 3H), 1.51 (s, 3 H) 1.49 (s, 3 H) 1.10 (t, J=7.58 Hz, 3 H); LC-MS (ES) m/z = 486.3 [M+H]+ Example 15
1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-[6- (1 -piperazinyl)-3-pyridinyl]-1 H-indazole-4-carboxamide
Figure imgf000037_0001
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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .54 (br. s., 1 H) 8.65 (d, J=2.53 Hz, 1 H) 8.61 (t, J=4.80 Hz, 1 H) 8.36 (s, 1 H) 8.03 - 8.07 (m, 2 H) 7.83 (s, 1 H) 6.92 (d, J=9.09 Hz, 1 H) 5.92 (s, 1 H) 5.14 (quin, J=6.63 Hz, 1 H) 4.42 (br. s., 1 H) 4.41 (br. s., 1 H) 3.45 - 3.51 (m, 4 H) 2.75 - 2.84 (m, 4 H) 2.54 (m, 2 H) 2.14 (s, 3 H) 1.51 - 1.58 (m, 2 H) 1 .50 (s, 3 H) 1 .49 (s, 3 H) 0.88 (t, J=7.33 Hz, 3 H). LC-MS (ES) m/z = 528.0 [M+H]+
Example 16
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-indazole-4-carboxamide
Figure imgf000037_0002
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4-ethyl-6-methyl-2- oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide (90 mg, 0.21 mmol), 1 -methyl-4-[5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- pyridinyl]piperazine (95 mg, 0.31 mmol) in dioxane/water (3 mL:1 ml_). PdCI2(dppf)-CH2Cl2 adduct (8.52 mg, 0.01 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (52.6 mg, 0.63 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 Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NI-^OH). The collected product was further purified by reversed-phase
HPLC (15% 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 along with EtOAc. The organic layer was separated, and the aqueous layer was further extracted with EtOAc, DCM and DCM/isopropanol (8:2). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated. EtOAc was added along with some hexanes, and the contents were sonicated and then allowed sit overnight at room temperature. Solids that precipitated were filtered and dried to afford the title compound (84 mg, 76%) as a white solid. 1H NMR (400 MHz, DMSO- cfe) δ ppm 1 1.54 (br. s., 1 H) 8.65 (d, J=2.27 Hz, 1 H) 8.62 (t, J=4.80 Hz, 1 H) 8.36 (s, 1 H) 8.04 - 8.08 (m, 2 H) 7.82 - 7.85 (m, 1 H) 6.97 (d, J=8.84 Hz, 1 H) 5.94 (s, 1 H) 5.14 (quin, J=6.57 Hz, 1 H) 4.42 (s, 1 H) 4.41 (s, 1 H) 3.52 - 3.59 (m, 4 H) 2.56 (q, J=7.58 Hz, 2 H) 2.39 - 2.44 (m, 4 H) 2.23 (s, 3 H) 2.14 (s, 3 H) 1.50 (s, 3 H) 1.49 (s, 3 H) 1.10 (t, J=7.58 Hz, 3 H); LC-MS (ES) m/z = 486.3
Example 17
1 -isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(2- methylpyrimidin-5-yl)-1 H-indazole-4-carboxamide
Figure imgf000038_0001
In a 25 ml. sealable tube under nitrogen were combined 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, 0.23 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (64.2 mg, 0.29 mmol) in dioxane/water (3 mL:1 ml_). PdCI2(dppf)-CH2CI2 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 Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH).
The collected product was suspended in acetonitrile along with a few drops of EtOH and some hexanes. The contents were sonicated, and solids that precipitated were filtered and dried to afford the title compound as an off-white solid (44 mg, 42%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1.55 (s, 1 H) 9.21 (s, 2 H) 8.63 (t, J=4.80 Hz, 1 H) 8.43 (s, 1 H) 8.32 (s, 1 H) 7.94 - 7.96 (m, 1 H) 5.92 (s, 1 H) 5.17 (quin, J=6.63 Hz, 1 H) 4.43 (br. s., 1 H) 4.42 (br. s., 1 H) 2.69 (s, 3 H) 2.52 - 2.56 (m, 2 H) 2.14 (s, 3 H) 1.49 - 1 .55 (m, 8 H) 0.88 (t, J=7.33 Hz, 3 H); LC-MS (ES) m/z = 459.2
Example 18
6-[6-(dimethylamino)-3-pyridinyl]-1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2- dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide
Figure imgf000039_0001
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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .55 (s, 1 H) 8.57 - 8.65 (m, 2 H) 8.35 (s, 1 H) 8.01 - 8.06 (m, 2 H) 7.83 (s, 1 H) 6.76 (d, J=8.84 Hz, 1 H) 5.92 (s, 1 H) 5.13 (dt, J=13.14, 6.57 Hz, 1 H) 4.42 (br. s., 1 H) 4.41 (br. s., 1 H) 3.09 (s, 6 H) 2.54 (m, 2 H) 2.14 (s, 3 H) 1.51 - 1 .58 (m, 2 H) 1.50 (s, 3 H) 1 .49 (s, 3 H) 0.88 (t, J=7.33 Hz, 3 H). LC-MS (ES) m/z = 487.4 [M+H]+ Example 19
1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-[6- (4-morpholinyl)-3-pyridinyl]-1 H-indazole-4-carboxamide
Figure imgf000040_0001
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 (100 mg, 0.225 mmol) and [6-(4-morpholinyl)-3-pyridinyl]boronic acid (70 mg, 0.337 mmol). The final product was collected as a white solid (98 mg, 81 %). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .46 (br. s., 1 H) 8.68 (d, J=2.53 Hz, 2 H) 8.37 (s, 1 H) 8.07 - 8.12 (m, 2 H) 7.84 (d, J=1 .01 Hz, 1 H) 6.98 (d, J=8.84 Hz, 1 H) 5.91 (s, 1 H) 5.14 (quin, J=6.57 Hz, 1 H) 4.42 (d, J=4.80 Hz, 2 H) 3.71 - 3.76 (m, 4 H) 3.50 - 3.56 (m, 4 H) 2.52 - 2.56 (m, 2 H) 2.13 (s, 3 H) 1 .51 - 1 .58 (m, 2 H) 1 .51 (s, 3 H) 1 .49 (s, 3 H) 0.88 (t, J=7.33 Hz, 3 H). LC-MS (ES) m/z = 529.0 [M+H]+
Example 20
6-(2-amino-5-pyrimidinyl)-1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2- dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide
Figure imgf000040_0002
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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 8.78 (s, 2 H) 8.59 (t, J=4.80 Hz, 1 H) 8.37 (s, 1 H) 8.1 1 (s, 1 H) 7.82 (s, 1 H) 6.87 (s, 2 H) 5.91 (s, 1 H) 5.14 (quin, J=6.57 Hz, 1 H) 4.42 (s, 1 H) 4.41 (s, 1 H) 2.52 - 2.57 (m, 2 H) 2.13 (s, 3 H) 1.51 - 1.58 (m, 2 H) 1.50 (s, 3 H) 1.49 (s, 3 H) 0.88 (t, J=7.33 Hz, 3 H). LC- MS (ES) m/z = 460.7
Example 21
6-(6-amino-3-pyridinyl)-1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-1 H-indazole-4-carboxamide
Figure imgf000041_0001
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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.55 (s, 1 H) 8.61 (t, J=4.93 Hz, 1 H) 8.45 (d, J=2.27 Hz, 1 H) 8.34 (s, 1 H) 8.00 (s, 1 H) 7.90 (dd, J=8.59, 2.53 Hz, 1 H) 7.78 (s, 1 H) 6.55 (d, J=8.59 Hz, 1 H) 6.10 - 6.17 (m, 2 H) 5.91 (s, 1 H) 5.13 (quin, J=6.57 Hz, 1 H) 4.42 (br. s., 1 H) 4.41 (br. s., 1 H) 2.52 - 2.56 (m, 2 H) 2.13 (s, 3 H) 1.51 - 1.57 (m, 2 H) 1.50 (s, 3 H) 1.48 (s, 3 H) 0.88 (t, J=7.33 Hz, 3 H). LC-MS (ES) m/z = 459.2
Example 22
1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-(5- pyrimidinyl)-1 H-indazole-4-carboxamide
Figure imgf000041_0002
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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.55 (s, 1 H) 9.35 (s, 2 H) 9.21 - 9.26 (m, 1 H) 8.63 (t, J=4.93 Hz, 1 H) 8.45 (s, 1 H) 8.38 (s, 1 H) 7.99 (d, J=1.26 Hz, 1 H) 5.92 (s, 1 H) 5.18 (quin, J=6.57 Hz, 1 H) 4.44 (s, 1 H) 4.42 (s, 1 H) 2.52 - 2.56 (m, 2 H) 2.13 (s, 3 H) 1 .52 - 1.56 (m, 4 H) 1 .48 - 1 .52 (m, 4 H) 0.88 (t, J=7.33 Hz, 3 H). LC-MS (ES) m/z = 445.2
Example 23
1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-[6- (methyloxy)-3-pyridinyl]-1 H-indazole-4-carboxamide
Figure imgf000042_0001
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 [6-(methyloxy)-3-pyridinyl]boronic acid (52 mg, 0.337 mmol). The final product was collected as a white solid (72 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.55 (br. s., 1 H) 8.68 (br. s., 1 H) 8.62 (br. s., 1 H) 8.39 (s, 1 H) 8.21 (br. s., 1 H) 8.14 (s, 1 H) 7.86 (s, 1 H) 6.97 (d, J=8.59 Hz, 1 H) 5.92 (s, 1 H) 5.09 - 5.21 (m, 1 H) 4.37 - 4.48 (m, 2 H) 3.92 (s, 3 H) 2.54 (br. s., 2 H) 2.14 (s, 3 H) 1.55 (m, 2H) 1.51 (br. s., 3 H) 1 .50 (br. s., 3 H) 0.88 (t, J=7.20 Hz, 3 H). LC-MS (ES) m/z = 474.0
Example 24
1 -(1 -methylethyl)-W-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-[6- (4-methyl-1 -piperazinyl)-3-pyridinyl]-1 H-indazole-4-carboxamide
Figure imgf000043_0001
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%). 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 H NMR (400 MHz, DMSO-d6) 5ppm 1 1 .54 (br. s., 1 H) 8.65 (d, J=2.27 Hz, 1 H) 8.61 (t, J=4.80 Hz, 1 H) 8.36 (s, 1 H) 8.04 - 8.08 (m, 2 H) 7.83 (s, 1 H) 6.96 (d, J=9.09 Hz, 1 H) 5.92 (s, 1 H) 5.14 (quin, J=6.57 Hz, 1 H) 4.42 (d, J=4.80 Hz, 2 H) 3.53 - 3.59 (m, 4 H) 2.53 - 2.61 (m, 2 H) 2.40 - 2.45 (m, 4 H) 2.23 (s, 3 H) 2.14 (s, 3 H) 1 .51 - 1.58 (m, 2 H) 1.50 (s, 3 H) 1 .49 (s, 3 H) 0.88 (t, J=7.33 Hz, 3 H). LC-MS (ES) m/z = 542.2 [M+H]+
Example 25
1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-(2- methyl-3-pyridinyl)-1 H-indazole-4-carboxamide
Figure imgf000043_0002
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 (100 mg, 0.225mmol) and (2-methyl-3-pyridinyl)boronic acid (46 mg, 0.337 mmol). The product was collected as a white solid (68 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .44 (br. s., 1 H) 8.57 (br. s., 1 H) 8.50 (dd, J=4.93, 1 .64 Hz, 1 H) 8.43 (s, 1 H) 7.90 (s, 1 H) 7.73 (dd, J=7.71 , 1 .64 Hz, 1 H) 7.59 (d, J=1 .26 Hz, 1 H) 7.34 (dd, J=7.33, 4.80 Hz, 1 H) 5.90 (s, 1 H) 5.10 (quin, J=6.57 Hz, 1 H) 4.40 (s, 1 H) 4.38 (s, 1 H) 2.46 (s, 3 H) 2.12 (s, 3 H) 1.50 - 1 .58 (m, 2 H) 1.50 (s, 3 H) 1 .48 (s, 3 H) 0.88 (t, J=7.33 Hz, 3 H). LC-MS (ES) m/z = 458.3 [M+H]+
Example 26
1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-(6- methyl-3-pyridinyl)-1 H-indazole-4-carboxamide
Figure imgf000044_0001
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 (100 mg, 0.225mmol) and (6-methyl-3-pyridinyl)boronic acid (46 mg, 0.337 mmol). The product was collected as a white solid (99 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .47 (br. s., 1 H) 8.96 (d, J=2.02 Hz, 1 H) 8.67 (br. s., 1 H) 8.40 (s, 1 H) 8.20 (s, 1 H) 8.17 (dd, J=8.08, 2.53 Hz, 1 H) 7.89 (s, 1 H) 7.39 (d, J=8.08 Hz, 1 H) 5.91 (s, 1 H) 5.18 (quin, J=6.57 Hz, 1 H) 4.43 (br. s., 1 H) 4.42 (br. s., 1 H) 2.52 - 2.58 (m, 5 H) 2.13 (s, 3 H) 1.52 - 1.58 (m, 2 H) 1 .52 (s, 3 H) 1.50 (s, 3 H) 0.88 (t, J=7.33 Hz, 3 H). LC-MS (ES) m/z = 458.3 [M+H]+
Example 27
6-[6-(dimethylamino)-3-pyridinyl]-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide
Figure imgf000044_0002
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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 8.64 (d, J=2.27 Hz, 1 H) 8.60 (t, J=4.80 Hz, 1 H) 8.35 (s, 1 H) 8.02 - 8.06 (m, 2 H) 7.84 (s, 1 H) 6.77 (d, J=8.84 Hz, 1 H) 5.89 (s, 1 H) 5.13 (dt, J=13.14, 6.57 Hz, 1 H) 4.39 (br. s., 1 H) 4.38 (br. s., 1 H) 3.09 (s, 6 H) 2.22 (s, 3 H) 2.13 (s, 3 H) 1 .50 (s, 3 H) 1.49 (s, 3 H) LC-MS (ES) m/z = 459.2 [M+H]+
Example 28
N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)-6-[6- (trifluoromethyl)-3-pyridinyl]-1 H-indazole-4-carboxamide
Figure imgf000045_0001
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%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 9.30 (d, J=2.02 Hz, 1 H) 8.66 (t, J=4.93 Hz, 1 H) 8.58 (dd, J=8.08, 2.02 Hz, 1 H) 8.45 (s, 1 H) 8.38 (s, 1 H) 8.07 (d, J=8.34 Hz, 1 H) 7.98 - 8.01 (m, 1 H) 5.90 (s, 1 H) 5.20 (dt, J=13.14, 6.57 Hz, 1 H) 4.41 (br. s., 1 H) 4.40 (br. s., 1 H) 2.22 (s, 3 H) 2.13 (s, 3 H) 1.53 (s, 3 H) 1.51 (s, 3 H). LC-MS (ES) m/z = 484.1 [M+H]+ Example 29
6-{3-[(dimethylamino)methyl]phenyl}-A -[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide
Figure imgf000046_0001
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 NaHC03, solids that crashed out were filtered, and air-dried for 15 min. The product was then triturated first from EtOAc (containing EtOH) and then hexanes. The solid was then concentrated from MeOH, and triturated with ether, and then dried in vacuum oven overnight. The product was collected as a white solid (56 mg, 56%). 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 1.53 (s, 1 H) 8.66 (t, J=4.93 Hz, 1 H) 8.37 (s, 1 H) 8.09 (s, 1 H) 7.83 (s, 1 H) 7.71 - 7.76 (m, 2 H) 7.46 (t, J=7.96 Hz, 1 H) 7.33 (d, J=7.58 Hz, 1 H) 5.89 (s, 1 H) 5.19 (quin, J=6.63 Hz, 1 H) 4.40 (s, 1 H) 4.39 (s, 1 H) 3.49 (s, 2 H) 2.22 (s, 3 H) 2.19 (s, 6 H) 2.12 (s, 3 H) 1 .51 (s, 3 H) 1 .49 (s, 3 H); LC-MS (ES) m/z = 472.2 [M+H]+
Example 30
6-{4-[(dimethylamino) -1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 ide
Figure imgf000046_0002
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 NaHC03, solids that crashed out were filtered, and air-dried for 15 min. The product was then triturated first from EtOAc and then hexanes. The solid was washed with acetonitrile, filtered, and then dried in vacuum oven overnight. The product was collected as a white solid (80 mg, 69%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .53 (br. s., 1 H) 8.65 (t, J=4.93 Hz, 1 H) 8.38 (s, 1 H) 8.1 1 (s, 1 H) 7.87 (d, J=1.01 Hz, 1 H) 7.83 (s, 1 H) 7.81 (s, 1 H) 7.42 (s, 1 H) 7.40 (s, 1 H) 5.89 (s, 1 H) 5.12 - 5.21 (m, 1 H) 4.40 (s, 1 H) 4.39 (s, 1 H) 3.44 (s, 2 H) 2.22 (s, 3 H) 2.17 (s, 6 H) 2.12 (s, 3 H) 1 .51 (s, 3 H) 1 .49 (s, 3 H). LC-MS (ES) m/z = 472.2 [M+H]+ 472.2
Example 31
N-((1 ,2-dihydro-6-me ethyl)-1 -isopropyl-6- (thiophen-3-yl)-1 H-in
Figure imgf000047_0001
To a stirred solution of 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) in DMF (10 mL) was added 4,4,5,5-tetramethyl-2-(thiophen-3-yl)-1 ,3,2-dioxaborolane (0.1 13 g, 0.53 mmol) followed by PdCI2(PPh3)2 (0.06 g, 0.08 mmol) and the reaction mixture was stirred for 5 min. Sodium carbonate (0.1 19 g, 0.940 mmol) dissolved in water (2 mL) was added and the contents were stirred at 120 °C for 3 h. The reaction mixture was diluted with NaHC03 solution and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2S04 , filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by silica gel chromatography (eluent: 4% MeOH\EtOAc) to afford the title compound as an off white solid (75 mg, 38 %) . 1 H NMR (DMSO-d6, 400 MHz): δ 0.883 (t, J = 7.2 Hz, 3H), 1 .491-1 .550 (m, 8H), 2.13 (s, 3H), 2.501 (s, 2H), 4.419 (d, J = 3.6 Hz, 2H), 5.130 (t, J = 6.4 Hz, 1 H), 5.912 (s, 1 H), 7.691 (s, 1 H), 7.766 (d, J = 4.4 Hz, 1 H), 7.930 (s, 1 H), 8.041 (s, 1 H), 8.171 (s, 1 H), 8.353 (s, 1 H), 8.563 (s, 1 H), 1 1 .530 (s, 1 H). LCMS (ES+) m/z: 449.09.
Example 32
1 -isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6- (thiophen-3-yl)-1 H-indazole-4-carboxamide
Figure imgf000048_0001
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 %). 1H NMR (DMSO-d6, 400 MHz): 50.896 (t, J = 7.2 Hz, 3H), 1.483-1.576 (m, 8H), 2.138 (s, 3H), 2.533 (s, 2H), 4.408 (d, J = 4.4 Hz, 2H), 5.076-5.140 (m, 1 H), 5.915 (s, 1 H), 6.656 (s, 1 H), 7.105 (d, J = 2.8 Hz, 1 H), 7.814 (s, 1 H), 7.909 (s, 1 H), 8.092 (s, 1 H), 8.340 (s, 1 H), 8.573 (s, 1 H), 1 1 .540 (s, 1 H). LCMS (ES+) m/z: 433.1
Example 33
6-{4-[(dimethylamino)methyl]phenyl}-1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl- 1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide hydrochloride salt
Figure imgf000048_0002
In a glass pressure tube was added 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), 4-(N,N-dimethylaminomethyl)phenylboronic acid pinacol ester hydrochloride (170 mg, 0.571 mmol), potassium phosphate (300 mg, 1 .413 mmol), dioxane (12 mL) and water (3 mL). The suspension was stirred and purged with N2 then PdCI2(dppf)-CH2Cl2 adduct (50 mg, 0.061 mmol) was added. The reaction mixture was capped and stirred at 1 10 °C for 4 hr. The dark black reaction mixture was evaporated to dryness. The crude product was purified by silica gel chromatography (eluent: 0 to 70%, 20% (5% NH4OH in MeOH) / CH2CI2) in CH2CI2). The pure fractions were combined and evaporated to dryness to give the product as a very dark brown-black solid. The solid was taken up in CH2CI2 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 CH2CI2, 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. with Et20, triturated, filtered and dried under vacuum to give the product 6-{4-[(dimethylamino)methyl]phenyl}-1 -(1 - methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4- carboxamide hydrochloride salt as a light tan solid (205 mg, 85 % yield). 1 H NMR (400MHz ,DMSO-d6) δ = 1 1.60 (br. s., 1 H), 10.81 (br. s., 1 H), 8.69 (t, J = 4.9 Hz, 1 H), 8.40 (s, 1 H), 8.19 (s, 1 H), 7.97 (d, J = 8.3 Hz, 2 H), 7.90 (d, J = 1.0 Hz, 1 H), 7.71 (d, J = 8.3 Hz, 2 H), 5.94 (s, 1 H), 5.18 (dt, J = 6.7, 13.2 Hz, 1 H), 4.43 (d, J = 4.8 Hz, 2 H), 4.34 (d, J = 5.3 Hz, 2 H), 2.72 (d, J = 5.1 Hz, 6 H), 2.58 - 2.52 (m, 2 H), 2.14 (s, 3 H), 1 .59 - 1.52 (m, 2 H), 1 .51 (d, J = 6.6 Hz, 6 H), 0.89 (t, J = 7.3 Hz, 3 H); LC-MS(ES)+ m/e 500.2
[M+H]+. Example 34
6-{3-[(dimethylamino)methyl]phenyl}-1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl- 1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide hydrochloride salt
Figure imgf000049_0001
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 PdCl2(dppf)-CH2CI2 adduct (50 mg, 0.061 mmol). The product was obtained as a light tan solid (204 mg, 85 % yield). 1H NMR (400MHz ,DMSO-d6) δ = 1 1 .67 (br. s., 1 H), 10.97 (br. s., 1 H), 8.68 (t, J = 5.1 Hz, 1 H), 8.38 (s, 1 H), 8.30 (s, 1 H), 8.16 (s, 1 H), 8.00 - 7.94 (m, 1 H), 7.92 (d, J = 1.0 Hz, 1 H), 7.65 - 7.53 (m, 2 H), 5.96 (s, 1 H), 5.18 (dt, J = 6.6, 13.3 Hz, 1 H), 4.43 (d, J = 5.1 Hz, 2 H), 4.38 (d, J = 5.6 Hz, 2 H), 2.74 (d, J = 4.8 Hz, 6 H), 2.61 - 2.52 (m, 2 H), 2.15 (s, 3 H), 1 .59 - 1.52 (m, 2 H), 1 .51 (d, J = 6.6 Hz, 6 H), 0.90
(t, J = 7.3 Hz, 3 H); LC-MS(ES)+ m/e 500.2 [M+H]+. Example 35
N-((1 ,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-1 -isopropyl-6-(1 H- pyrazol-4-yl)-1 H-indazole-4-carboxamide
Figure imgf000050_0001
a) Methyl 1 -isopropyl-6-(1 H-pyraz le-4-carboxylate
Figure imgf000050_0002
To a stirred solution of methyl 6-bromo-1 -isopropyl-1 H-indazole-4-carboxylate, 1 (0.8 g, 2.7 mmol) in 1 ,4-dioxane (20 mL) were added 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 H-pyrazole (0.576 g, 2.97 mmol) and NaHC03 (0.567 g, 6.75 mmol) dissolved in water (8 mL). The reaction mixture was degassed with argon gas for 30 min. To the resulting mixture was added PdCI2(dppf)-CH2Cl2 adduct (0.1 10 g, 0.135mmol) and the mixture heated at reflux for 3 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to afford 800 mg of crude product. The crude compound was purified by silica gel chromatography (eluent: 5% MeOH/DCM) to the title compound as a pale liquid (375 mg, 47% ). LCMS (ES-) m/z = 283.1 1. b) 1 -isopropyl-6-(1 H-pyrazol-4-yl)-1 H-indazole-4-carboxylic acid
Figure imgf000051_0001
To a stirred solution of methyl 1 -isopropyl-6-(1 H-pyrazol-4-yl)-1 H-indazole-4-carboxylate (750 mg, 2.64 mmol) in THF:H20 (30 ml.) was added LiOH H20 (330 mg, 7.85 mmol) and the resulting mixture was refluxed at 80 °C for 8 h. THF was distilled off under reduced pressure and the aqueous layer was acidified with 10% HCI (to pH ~5 ) at 0 °C. The precipitated solid was collected by filtration and dried to afford the title compound 1- isopropyl-6-(1 H-pyrazol-4-yl)-1 H-indazole-4-carboxylic acid as an off-white solid (540 mg, 76%). LCMS (ES+) m/z = 271.09. c) N-((1 ,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-1 -isopropyl-6-(1 H- pyrazol-4-yl)-1 H-indazole-4-carboxamide
To a stirred solution of N-((1 ,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-1 - isopropyl-6-(1 H-pyrazol-4-yl)-1 H-indazole-4-carboxamide (550 mg, 2.037mmol) in DCM (20 ml.) were added EDC HCI (466 mg, 2.44 mmol), HOBT (374 mg, 2.44 mmol) and DIPEA (1.8 ml_, 10.18 mmol) and the contents stirred at room temperature for 15 min. To the resulting mixture 3-(amino methyl)-4,6-dimethylpyridin-2(1 H)-one (338 mg, 2.037 mmol) was added and stirred at RT for 3 h. The reaction mixture was diluted with DCM (50 ml.) and washed with water (20 ml_). The DCM layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford 200 mg of crude product. The crude product was diluted with DCM (5 ml_), filtered, and dried to afford N-((1 ,2-dihydro-6- methyl-2-oxo-4-propylpyridin-3-yl)methyl)-1 -isopropyl-6-(1 H-pyrazol-4-yl)-1 H-indazole-4- carboxamide as an off-white solid (80 mg, 10%).1H NMR(DMSO-d6, 400 MHz): 50.907- 0.871 (t, 3H, J = 14.4 Hz), 1 .55-1.48 (m, 8H), 2.134 (s, 3H), 2.555 (s, 2H), 4.417-4.406 (d, 1 H, J = 4.4 Hz), 5.059 (m, 1 H), 5.913 (s, 1 H), 7.830 (s, 1 H), 8.047 (s, 1 H), 8.080 (s, 1 H), 8.306 (s, 2H), 8.462 (s, 1 H), 1 1 .53 (s, 1 H), 13 (bs, 1 H). LCMS (ES+) m/z = 433.17. Example 36
N-((1 ,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-1 -isopropyl-6-(1 H- pyrrolo[2,3-b]pyridin-5-yl)-1 H-indazole-4-carboxamide
Figure imgf000052_0001
a) Methyl 1 -isopropyl-6-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-indazole-4-carboxylate
Figure imgf000052_0002
The title compound was prepared in the same manner as described for example 35 (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
Figure imgf000052_0003
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 H20 (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%). 1H NMR (DMSO-d6, 400 MHz) : 51.530 (d, J = 6.4 Hz, 6H), 5.199-5.265 (m, 1 H), 6.552 (d, J = 1.6 Hz, 1H), 7.550 (t, J = 2.4 Hz, 1H), 8.11 (s, 1H), 8.328 (s, 1H), 8.383 (d, J = 1.6 Hz, 1H ), 8.401 (s, 1H), 8.671 (d, J = 1.6 Hz, 1H), 11.77 (brs, 1H). LCMS (ES+) m/z: 321.24. c) N-((1,2-dihydro-6-methyl-2-oxo-4^ropylpyridin-3-yl)methyl)-1-isopropyl-6-(1H- pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-4-carboxamide
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 %).1H NMR (DMSO-d6, 400 MHz) : 50.886 (t, J = 7.2 Hz, 3H), 1.513 (d, J = 6.4 Hz, 8H), 2.131 (s, 3H), 2.552 (s, 2H), 4.431 (d, J = 4.4 Hz, 1H), 5.153-5.216 (m, 1H), 5.911 (s, 1H), 6.535 (d, J = 2Hz, 2H), 7.535 (s, 1H), 7.930 (s, 1H), 8.174 (s, 1H), 8.40 (d, J = 9.6 Hz, 2H), 8.656 (s, 1H), 8.730 (s, 1H), 11.526 (brs, 1H), 11.756 (brs, 1 H); LC-MS (ES+) m/z: 483.19.
Example 37
6-(4-(dimethylamino)piperidin-1 -yl)-1 -isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide
Figure imgf000053_0001
a) Methyl 6-(4-(dimethylamino)piperidin-1 -yl)-1 -isopropyl-1 H-indazole-4-carboxylate
Figure imgf000053_0002
To a 10-mL microwave tube were added methyl 6-bromo-1-(1-methylethyl)-1 H-indazole- 4-carboxylate (200 mg, 0.673 mmol), N,N-dimethyl-4-piperidinamine (95 mg, 0.740 mmol), toluene (3 mL), and cesium carbonate (329 mg, 1 .010 mmol), and the mixture was degassed for 5 min by bubbling N2. BINAP (62.9 mg, 0.101 mmol) and Pd2(dba)3 (30.8 mg, 0.034 mmol) were added. The tube was sealed and the mixture was heated at 1 15 °C with stirring for 15h. The mixture was diluted with methanol (5 mL) and filtered.
The filtrate was concentrated and the residue was purified using reverse-phase HPLC to give 58 mg of product as an off-white solid. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .45 (d, J = 8.0 Hz, 6 H), 1.54 - 1.61 (m, 2 H), 1.87 - 1.96 (m, 2 H), 2.31 (m, 6H), 2.80-2.83 (m, 2H), 3.83-3.86 (m, 2H), 3.93 (s, 3H), 4.98-5.04 (m, 1 H), 7.29 (s, 1 H), 7.57 (s, 1 H), 8.17 (s, 1 H). LCMS: (M+H)+=345.2 b) 6-(4-(dimethylamino)piperidin-1 -yl)-1 -isopropyl-1 H-indazole-4-carboxylic acid
Figure imgf000054_0001
To a solution of methyl 6-bromo-3-methyl-1-(1-methylethyl)-1 H-indole-4-carboxylate (520 mg 1.676 mmol) in methanol (8 mL) and tetrahydrofuran (3.00 mL) was added sodium hydroxid< (2.79 mL, 8.38 mmol), and the mixture was stirred overnight. The mixture was concentrated t( remove organic solvents and diluted with water (5 mL). The aqueous solution was acidified t( ~pH 3 using 1 N HCI and the precipitate was collected by filtration and dried under high vacuun to give 480 mg of product as a white solid. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .45- 1.46 (d, . = 8.0 Hz, 6H), 1.75 - 1.78 (m, 2 H), 2.10-2.12 (m, 2H), 2.80-2.89 (m, 8H), 3.35-3.40 (m, 1 H) 3.97-4.00 (m, 2H), 4.97-5.04 (m, 1 H), 7.34 (s, 1 H), 7.58 (s, 1 H), 8.18 (s, 1 H); LCMS (M+H)+=296.3 c) 6-(4-(dimethylamino)piperidin-1 -yl)-1 -isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)-1 H-indazole-4-carboxamide
To a solution of 6-[4-(dimethylamino)-1 -piperidinyl]-1-(1-methylethyl)-1 H-indazole-4- carboxylic acid (34 mg, 0.103 mmol) in DMSO (1 mL) were added 3-(aminomethyl)-6- methyl-4-propyl-2(1 H)-pyridinone (29.0 mg, 0.134 mmol), N-methylmorpholine (0.045 mL, 0.412 mmol), 1 -hydroxy-7-azabenzotriazole (28.0 mg, 0.206 mmol) and EDC (39.5 mg, 0.206 mmol), and the mixture was stirred for 48h. The mixture was purified using reverse-phase HPLC to afford the title compound as a pale yellow solid (34 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.77 - 0.96 (m, 3 H), 1.43 (d, J = 6.57 Hz, 6 H), 1.46 - 1 .66 (m, 4 H), 1.89 (m, 2 H), 2.13 (s, 3 H), 2.31 (s, 6H), 2.33( m, 2 H), 2.55 (s, 3 H), 2.65 - 2.84 (m, 2 H), 3.86 (m. 2 H), 4.38 (m, 2 H), 4.85 - 5.04 (m, 1 H), 5.91 (s, 1 H), 7.07 (s, 1 H), 7.32 (m, 1 H), 8.15 (m, 1 H), 8.25 (br. s., 1 H), 8.44 (t, J = 4.93 Hz, 1 H); LCMS:
(M+H)+=493.2
Example 38
6-(4-((dimethylamino)methyl)piperidin-1 -yl)-1 -isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)-1 H-indazole-4-carboxamide
Figure imgf000055_0001
a) Methyl 6-(4-((dimethylamino)methyl)piperidin-1 -yl)-1 -isopropyl-1 H-indazole-4- carboxylate
Figure imgf000055_0002
To a 10-mL microwave tube were added methyl 6-bromo-1 -(1 -methylethyl)-1 H-indazole-4 carboxylate (250 mg, 0.841 mmol), N,N-dimethyl-1-(4-piperidinyl)methanamine (132 mg, 0.92! mmol), Toluene (3 mL), and cesium carbonate (41 1 mg, 1.262 mmol), and the mixture was degassed for 5 min by bubbling N2 through. BINAP (79 mg, 0.126 mmol) and Pd2(dba)3 (38.! mg, 0.042 mmol) were added. The tube was sealed and the mixture was heated at 1 15 °C wit! stirring for 15h. The mixture was diluted with methanol (5 mL) and filtered. The fitrate was concentrated and the residue was purified using reverse-phase HPLC to give 35 mg of produc as a off-white solid. LCMS MH+ = 359.3 b) 6-(4-((dimethylamino)methyl)piperidin-1 -yl)-1 -isopropyl-1 H-indazole-4-carboxylic acid
Figure imgf000056_0001
The title compound was prepared using the procedure described for example 37 (step b) 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .26-1.29 (m, 2 H), 1.43-1 .45 (m, 6 H), 2.27-2.30 (m, 8 H), 2.76-2.78 (m, 2 H), 3.77-3.81 (m, 2 H), 3.97-4.00 (m, 2 H), 4.97-5.03 (m, 1 H), 7.20 (s, 1 H), 7.53 (s, 1 H), 8.16 (s, 1 H); LCMS: (M+H)+=345.2 c) 6-(4-((dimethylamino)methyl)piperidin-1 -yl)-1 -isopropyl-N-((6-methyl-2-oxo-4-propyl-1 ,2- dihydropyridin-3-yl)methyl)-1 H-indazole-4-carboxamide
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. 1H NMR (400 MHz, DMSO-c/6) δ ppm 0.89 (t J = 7.33 Hz, 3 H), 1 .14 - 1.32 (m, 2 H), 1.42 (m, 6 H), 1.45 - 1 .55 (m, 2 H), 1.57 - 1.68 (m, 1 H) 1.72 - 1 .89 (m, 3 H), 2.03 - 2.21 (m, 12 H), 2.63 - 2.79 (m, 2 H), 3.54 - 3.66 (m, 1 H), 3.81 (m, . H), 4.37 (d, J = 4.80 Hz, 2 H), 4.94 (quin, J = 6.63 Hz, 1 H), 5.91 (s, 1 H), 7.05 (s, 1 H), 7.32 (d, . = 1.77 Hz, 1 H), 8.14 (s, 1 H), 8.44 (t, J = 5.05 Hz, 2 H), 1 1.24 - 1 1 .80 (m, 1 H); LCMS (M+H)+=507.1
Example 39
N-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6- morpholino-1 H-indazole-4-carboxamide
Figure imgf000057_0001
In a 25 mL sealable tube under nitrogen were combined methyl 6-bromo-1-(1- methylethyl)-1 H-indazole-4-carboxylate (250 mg, 0.84 mmol), sodium tert-butoxide (178 mg, 1 .85 mmol), Pd-XPhos precatalyst (chloro(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1 , 1 '-biphenyl)[2-(2-aminoethyl)phenyl]Pd(ll); Me-t-butylether adduct) (34.8 mg, 0.042 mmol) and morpholine (81 mg, 0.93 mmol) in Dioxane (4 mL). The resulting mixture was degassed with nitrogen for 10 minutes. The vessel was sealed and the mixture was heated at 98 °C for 20 hours. The contents were diluted with water and 1 N HCI was added to adjust the pH~3-4. The contents were extracted with EtOAc and DCM/isopropanol (8:2), and the combined organic layers were washed with brine, dried over MgS04, filtered and concentrated. The residue was dissolved in DCM and purified by Si02 chromatography (eluent: Hexanes/EtOAc gradient 0 to 100% EtOAc). Fractions were evaporated and solids were dried to afford the title compound as a light yellow solid (1 15 mg, 46%). LC-MS (ES) m/z = 290.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (br. s., 1 H) 8.18 (s, 1 H) 7.56 (d, J=2.02 Hz, 1 H) 7.26 - 7.29 (m, 1 H) 5.00 (quin, J=6.57 Hz, 1 H) 3.77 - 3.81 (m, 4 H) 3.22 - 3.26 (m, 4 H) 1.46 (s, 3 H) 1.44 (s, 3 H) b) In a 25 mL sealable tube under nitrogen were combined 1-(1-methylethyl)-6-(4- morpholinyl)-1 H-indazole-4-carboxylic acid (55 mg, 0.19 mmol) and 3- (aminomethyl)-4-ethyl-6-methyl-2(1 H)-pyridinone.HCI (57.8 mg, 0.29 mmol) in DMSO (2 mL). 1-hydroxy-7-azabenzotriazole (44 mg, 0.32 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. N- methylmorpholine (0.088 ml, 0.8 mmol) and EDC (62 mg, 0.32 mmol) were added, the vessel was sealed, and the mixture was stirred at room temperature overnight. The crude product was purified by reversed-phase HPLC (15% to 80% CH3CN in water with 0.1 % TFA) which afforded the TFA salt. CH3CN was evaporated, a saturated solution of sodium bicarbonate was added, and solids that precipitated were filtered. EtOAc was added along with some hexanes and the contents were sonicated. Solids that precipitated were filtered and dried to afford the title compound as an off-white solid (47.5 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.46 (br. s., 1 H) 8.48 (br. s., 1 H) 8.18 (s, 1 H) 7.32 - 7.37 (m, 1 H) 7.10 (s, 1 H) 5.93 (s, 1 H) 4.95 (dt, J=13.14, 6.57 Hz, 1 H) 4.38 (br. s., 1 H) 4.37 (br. s., 1 H) 3.74 - 3.81 (m, 4 H) 3.20 - 3.25 (m, 4 H) 2.53 - 2.60 (m, 2 H) 2.14 (s, 3 H) 1.45 (s, 3 H) 1 .43 (s, 3 H) 1.09 (t, J=7.45 Hz, 3 H); LC-MS (ES) m/z = 437.9
Example 40
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-morpholino- 1 H-indazole-4-carboxamide
Figure imgf000058_0001
The title compound was prepared in the same manner as described for example 39 from 1-(1-methylethyl)-6-(4-morpholinyl)-1 H-indazole-4-carboxylic acid (55 mg, 0.19 mmol) and 3-(aminomethyl)-4,6-dimethyl-2(1 H)-pyridinone.HCI (53.8 mg, 0.29 mmol) The product was collected as an off-white solid (48 mg, 57%). 1 H NMR (400 MHz, DMSO-c/6) δ ppm 1 1.44 (br. s., 1 H) 8.49 (br. s., 1 H) 8.18 (s, 1 H) 7.35 (d, J=1 .77 Hz, 1 H) 7.10 (s, 1 H) 5.88 (s, 1 H) 4.95 (quin, J=6.57 Hz, 1 H) 4.36 (br. s., 1 H) 4.34 (br. s., 1 H) 3.75 - 3.80 (m, 4 H) 3.21 - 3.25 (m, 4 H) 2.20 (s, 3 H) 2.12 (s, 3 H) 1 .44 (s, 3 H) 1.43 (s, 3 H); LC-MS (ES) m/z = 423.9
Example 41
N-((4-cyclohexyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-cyclopropyl-1 - isopropyl-1 H-indazole-4-carboxamide
Figure imgf000059_0001
a) 6-bromo-N-((4-cyclohexyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 - isopropyl-1 H-indazole-4-carboxamide
Figure imgf000059_0002
6-bromo-1-(1-methylethyl)-1 H-indazole-4-carboxylic acid (237 mg, 0.84 mmol), 3- (aminomethyl)-4-cyclohexyl-6-methyl-2(1 H)-pyridinone TFA (378 mg, 1 .13 mmol) and 1- hydroxy-7-azabenzotriazole (171 mg, 1.26 mmol) were stirred in 10 mL of DMSO for 10 min under nitrogen. N-methylmorpholine (0.37 ml, 3.35 mmol) was added along with EDC (241 mg, 1.26 mmol) and the mixture was stirred at rt overnight. An additional 0.2 eq of pyrdinone, HOAt, NMM and EDC were added and the contents were stirred at rt overnight. The reaction mixture was then poured onto ice-water . A solution of 10% K2C03 in water was added to afford a pH ~ 8-9 solution. The reaction mixture was stirred at rt for 30 min and then allowed to stand at rt for 30 min. Precipitated solids were filtered and air-dried. The collected solid was treated with EtOAc (not soluble) and hexanes, and then concentrated in vacuo. To the isolated solid was then added DMF followed by heating and sonication. Water was added and beige solids crashed out. The precipitated solids were filtered, washed with water, air-dried, and dried in vaccum oven for 2 hours. The title compound was collected as a solid (308 mg, 74%). 1H NMR (400 MHz, DMSO- d6) δ ppm 1 1.53 (s, 1 H) 8.63 (t, J=4.80 Hz, 1 H) 8.37 (s, 1 H) 8.20 (s, 1 H) 7.68 (d, J=1.26 Hz, 1 H) 6.01 (s, 1 H) 5.05 (dt, J=13.14, 6.57 Hz, 1 H) 4.43 (d, J=4.80 Hz, 2 H) 2.84 (t, J=1 1.24 Hz, 1 H) 2.15 (s, 3 H) 1 .70 (d, J=13.39 Hz, 2 H) 1.60 (d, J=12.13 Hz, 3 H) 1.47 (s, 3 H) 1 .45 (s, 3 H) 1.42 (br. s., 1 H) 1 .17 - 1 .39 (m, 4 H); LCMS:485.2/487.2 (Br pattern).
b) N-((4-cyclohexyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-cyclopropyl-1 - isopropyl-1 H-indazole-4-carboxamide
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4-cyclohexyl-6- methyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1 H-indazole-4- carboxamide (98 mg, 0.2 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (50.9 mg, 0.3 mmol) in dioxane/water (3 mL:1 ml_). PdCI2(dppf)-CH2CI2 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. DCM/MeOH (1 :1 ) was added, the contents pre-absorbed on silica gel, and purified by Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH40H). The collected product was further purified by reverse-phase HPLC
(15% to 80% CH3CN in water with 0.1 % TFA) which afforded the TFA salt. CH3CN was evaporated, a saturated solution of sodium bicarbonate was added to the water layer and it was further concentrated. Upon sitting for 2 weeks, solids that precipitated were filtered and dried to afford the title compound as a light orange solid (17 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .48 (br. s., 1 H) 8.46 (br. s., 1 H) 8.25 (s, 1 H) 7.57 (s, 1 H) 7.16 (s, 1 H) 6.01 (s, 1 H) 4.93 - 5.04 (m, 1 H) 4.45 (br. s., 1 H) 4.43 (br. s., 1 H) 2.84 (t, J=1 1 .49 Hz, 1 H) 2.15 (s, 3 H) 2.03 - 2.10 (m, 1 H) 1 .60 (br. s., 5 H) 1 .47 (s, 3 H) 1.45 (s, 3 H) 1.16 - 1.42 (m, 5 H) 0.96 - 1 .02 (m, 2 H) 0.80 - 0.85 (m, 2 H). LC-MS (ES) m/z = 447 Example 42
6-bromo-1 -ethyl-1 H-indazole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1 , 2- dihydro-pyridin-3-ylmethyl)-amide
Figure imgf000061_0001
a) 6-bromo-1 -ethyl-1 H-indazole-4-carboxylic acid methyl ester and methyl 6-bromo- 2-ethyl-2H-indazole-4-carboxylate
Figure imgf000061_0002
To a stirred suspension of 6-bromo-1 H-indazole-4-carboxylic acid methyl ester (2.5 g, 9.8 mmol) and K2C03 (2 g, 14.7 mmol) in DMF (50 mL) was added 1 -bromoethane (1.28 g, 1 1.76 mmol) at RT. The contents were stirred for 2 h at 50 °C. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with water (3x30 mL), brine solution (2x30 mL), dried over anhydrous sodium sulphate, and 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. 1H NMR (400 MHz, DMSO-d6) (1 -ethyl isomer) : δ 1.41 - 1.37 (t, 3H), 3.95 (s, 3H), 4.51 -4.49 (m, 2H), 7.85-7.84 (d, J = 1.2 Hz, 1 H), 8.41 -8.39 (d, J = 10 Hz, 1 H). LCMS (ES+): m/z=283 [M+1 ], 285.02 [M+2]. b) 6-bromo-1 -ethyl-1 H-indazole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1 , 2- dihydro-pyridin-3-ylmethyl)-amide
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 H20 (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.H20 (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. The reaction mixture was diluted with DCM (50 mL) and washed with water (2x50 mL), 10% aq citric acid solution (2x50 mL), saturated aq NaHC03 solution (2x30 mL) and brine (2x50 mL). The organic layer was dried over Na2S04, 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 %). 1H NMR (400 MHz, DMSO-d6): δ 0.83-0.79 δ (t, 3H), 1.38 (t, 3H), 1 .55 (m, 2H), 2.15 (s, 3H), 2.49 (s, 2H), 4.38 (d, 2H), 4.43 (m, 2H), 5.90 (s, 1 H), 7.64 (d, 1 H), 8.19 (s, 1 H), 8.38 (s, 1 H), 8.61 (m, 1 H), 1 1.51 (bs, 1 H). LCMS (ES+): m/z = 431 .15.
Example 43
6-bromo-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-1 -propyl-1 H- indazole-4-carboxamide
Figure imgf000062_0001
a) 6-Bromo-1 -propyl-1 H-indazole-4-carboxylic acid methyl ester
Figure imgf000062_0002
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. The obtained crude products were purified by silica gel chromatography (eluent: 10 % ethyl acetate in petroleum ether) to afford the title compounds 6-bromo-1- propyl-1 H-indazole-4-carboxylic acid methyl ester (700 mg, 20 %) and undesired isomer 6-bromo-2-propyl-2H-indazole-4-carboxylic acid methyl ester (700 mg, 20 %) as white solids. 1H NMR (400 MHz, DMSO-d6): (N1-propyl isomer): δ 0.83-0.80 δ (t, J=7.6, 3H), 1.84-1 .81 (t, J=14.4 Hz, 2H), 3.95-3.94 (d, J=5.2 Hz 3H), 4.45-4.43 (t, 2H), 7.84 (d, J=1 .2 Hz, 1 H), 8.43 (d, J= 14 Hz, 2H). LCMS (ES+): m/z= 297.06. b) 6-bromo-1 -propyl-1 H-indazole-4-carboxylic acid
Figure imgf000063_0001
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.H20 (290 mg, 7.07 mmol). The product was collected as an off-white solid (600 mg, 90 %). 1H NMR (400 MHz, DMSO-d6): δ 0.83-0.80 δ (t, 3H), 1.86-1 .81 (m, 2H), 4.44-4.40 (t, 2H), 7.81 (d, J=1 .2 Hz, 1 H), 8.38 (d, J= 4.4 Hz, 2H). LCMS (ES-): m/z= 281.14 [M-2H]. c) 6-bromo-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-1 -propyl- 1 H-indazole-4-carboxamide
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 %). 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H), 0.90 (t, 3H), 1.48-1.46 (t, 2H), 1.86-1 .80 (m, 2H), 2.13 (s, 3H), 2.50-2.32 (t, 2H), 4.40-4.35 (m, 4H), 5.90 (s, 1 H), 7.69 (s, 1 H), 8.20 (s, 1 H), 8.35 (s, 1 H), 8.62 (s, 1 H), 1 1 .52 (s, 1 H). LCMS (ES+): m/z= 445.17. Example 44
6-bromo-1 -cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 H- indazole-4-carboxamide
Figure imgf000064_0001
a) methyl 6-bromo-1 -cyclopentyl-1 H-indazole-4-carboxylate
Figure imgf000064_0002
Ice-cooled methyl 6-bromo-1 H-indazole-4-carboxylate (2 g, 7.84 mmol) in 30 ml. of DMF was treated with NaH (60%, 345 mg, 8.63 mmol) and the mixture was stirred for 1 hr at 0 °C. lodocyclopentane (2.31 g, 1 1 .8 mmol) was then added and the mixture was stirred at 100 °C overnight. After cooling to RT, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, dried over MgS04, filtered and evaporated. 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%). 1H NMR (400 MHz, DMSO-d6): δ 8.40 (s, 1 H) 8.37 (s, 1 H) 7.81 (d, J=1 .52 Hz, 1 H) 5.26 (quin, J=7.07 Hz, 1 H) 3.95 (s, 3 H) 2.08 - 2.17 (m, 2 H) 1.93 - 2.01 (m, 2 H) 1 .82 - 1 .92 (m, 2 H) 1.64 - 1.73 (m, 2 H); LCMS (ES+): m/z= 323.3/325.3 b) 6-bromo-1 -cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)- 1 H-indazole-4-carboxamide
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 reaction mixture was stirred at room temperature overnight to afford a slurry. The slurry was diluted with DMSO (10 mL) and added dropwise to a ice-chilled aqueous solution of 1 N Na2C03 (50 ml) and water (200 mL), and stirred rapidly for 30 min. The precipitate was collected by vacuum filtration and washed with water. The cake was dried in the vacuum oven at 60 °C overnight (16h). The title compound was obtained as a pale yellow-white solid (2.05 g, 98 % yield). 1H NMR (400 MHz, DMSO-56) δ 1 1.50 (br. s., 1 H), 8.64 (br. s., 1 H), 8.37 (s, 1 H), 8.20 (s, 1 H), 7.70 (d, J = 1.52 Hz, 1 H), 5.89 (s, 1 H), 5.22 (quin, J = 7.01 Hz, 1 H), 4.34 (d, J = 4.55 Hz, 2H), 2.20 (s, 3H), 2.13 (s, 3H), 2.06 - 2.1 1 (m, 2H), 1.91 - 2.03 (m, 2H), 1 .80 - 1 .91 (m, 2H), 1.61 - 1 .75 (m, 2H). LC-MS(ES) [M+H]+ 443.0.
Example 45
6-bromo-1 -cyclopentyl-N-((4-ethyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)- 1 H-indazole-4-carboxamide
Figure imgf000066_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-1-cyclopentyl-1 H- indazole-4-carboxylic acid (370 mg, 1.2 mmol) and 3-(aminomethyl)-4-ethyl-6-methyl- 2(1 H)-pyridinone.HCI (340 mg, 1.68 mmol) in DMSO (3 ml_). 1 -hydroxy-7- azabenzotriazole (277 mg, 2.04 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. N-methylmorpholine (0.55 ml, 5 mmol) and EDC (390 mg, 2 mmol) were added, the vessel was sealed, and the mixture was stirred at room temperature overnight. The mixture was poured onto 10 mL of ice-water and solids crashed out. 10% K2C03 was added to adjust the pH~8-9. The mixture was stirred for 4 hours and then allowed to stand for another 2 hours. Solids were filtered and air-dried. DMF along with some water was then added. Solids that precipitated were filtered and dried to afford the title compound as a light orange solid (515 mg, 91 %). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 8.63 (t, J=4.80 Hz, 1 H) 8.36 (s, 1 H) 8.20 (s, 1 H) 7.70 (d, J=1.52 Hz, 1 H) 5.93 (s, 1 H) 5.23 (t, J=7.07 Hz, 1 H) 4.36 (s, 1 H) 4.35 (s, 1 H) 2.53 - 2.59 (m, 2 H) 2.14 (s, 3 H) 2.07 - 2.13 (m, 2 H) 1 .93 - 2.01 (m, 2 H) 1.83 - 1.91 (m, 2 H) 1 .65 - 1 .73 (m, 2 H) 1.10 (t, J=7.58 Hz, 3 H); LC-MS (ES) m/z = 456.9/459.1
Example 46
1 -cyclopentyl-N-(( hyl)-6-(2-(^ methylpiperazin-1
Figure imgf000067_0001
To a 2 mL microwave vial were added 6-bromo-1 -cyclopentyl-N-[(4,6-dimethyl-2-oxo-1 ,2- dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide (150 mg, 0.338 mmol), 2-(4- methyl-1 -piperazinyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (134 mg, 0.440 mmol), Na2C03 (108 mg, 1.015 mmol), PdCI2(dppf)-CH2CI2 adduct (27.6 mg, 0.034 mmol), 1 ,2-Dimethoxyethane (1269 μΙ) and water (423 μΙ). 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). 1H NMR (400 MHz, CHLOROFORM-δ) δ 8.62 (s, 2H), 8.39 (s, 1 H), 7.99 (t, J = 5.56 Hz, 1 H), 7.71 (s, 1 H), 7.57 (s, 1 H), 5.98 (s, 1 H), 5.03 (quin, J = 7.14 Hz, 1 H), 4.66 (d, J = 5.81 Hz, 2H), 3.97 (br. s., 4H), 2.64 (br. s., 4H), 2.44 (s, 6H), 2.12 - 2.25 (m, 7H), 1 .89 - 2.07 (m, 2H), 1 .67 - 1.85 (m, 2H). LCMS(ES) [M+H]+ 541.5.
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
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(3- (pyrrolidin-1 -yl)phenyl)-1 H-indazole-4-carboxamide
Figure imgf000068_0001
1H NMR (400 MHz, MeOD) 58.35 (s, 1H), 7.93 (s, 1H), 7.81 (d, J = 1.26 Hz, 1H), 7.29 (t, J = 7.96 Hz, 1H), 6.99 (d, J = 8.08 Hz, 1H), 6.91 (t, J = 2.02 Hz, 1H), 6.63 (dd, J = 1.77, 8.08 Hz, 1H), 6.14 (s, 1H), 5.27 (quin, J = 7.26 Hz, 1H), 4.60 (s, 2H), 3.36 - 3.44 (m, 4H), 2.45 (s, 3H), 2.27 (s, 8H), 2.07 (dt, J = 3.38, 6.63 Hz, 3H), 1.90 - 2.05 (m, 2H), 1.74 - 1.88 (m, 2H). LCMS(ES) [M+H]+ 510.1.
Example 48
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4- methylthiophen-2-yl)-1H-indazole-4-carboxamide
Figure imgf000068_0002
1H NMR (400 MHz, DMSO-56) 511.55 (s, 1H), 8.64 (t, J = 4.93 Hz, 1H), 8.32 (s, 1H), 8.05 (s, 1H), 7.80 (d, J = 1.26 Hz, 1H), 7.55 (d, J = 1.26 Hz, 1H), 7.19 (t, J = 1.26 Hz, 1H), 5.90 (s, 1H), 5.30 (s, 1H), 4.38 (d, J = 4.80 Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 2.13 (s, 5H), 1.95 - 2.06 (m, J = 6.32 Hz, 2H), 1.82 - 1.94 (m, 2H), 1.64 - 1.77 (m, J = 4.55 Hz, 2H). LCMS(ES) [M+H]+ 461.1. Example 49
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2- (piperazin-1 -yl)pyrimidin-5-yl)-1 H-indazole-4-carboxamide
Figure imgf000069_0001
1H NMR (400 MHz, MeOD) δ 8.97 (s, 2H), 8.43 (s, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 6.99 (br. s., 1H), 5.31 (qd, J = 6.69, 6.86 Hz, 1H), 4.72 (br. s., 2H), 4.21 (br. s., 4H), 3.38 (br. s., 4H), 2.69 (s, 3H), 2.53 (s, 3H), 2.20 - 2.32 (m, 2H), 2.07 - 2.20 (m, 2H), 2.03 (d, J = 18.19 Hz, 2H), 1.73 - 1.90 (m, 2H). LCMS(ES) [M+H]+ 527.2.
Example 50
1-cyclopentyl-N-((4,6-d -3-yl)methyl)-6-(3-(3- hydroxypropyl)phenyl)
Figure imgf000069_0002
1H NMR (400 MHz, MeOD) δ 8.37 (s, 1H), 7.97 (s, 1H), 7.83 (d, J = 1.26 Hz, 1H), 7.64 (s, 1H), 7.60 (d, J = 7.83 Hz, 1H), 7.41 (t, J = 7.58 Hz, 1H), 7.27 (d, J = 7.58 Hz, 1H), 6.15 (s, 1H), 5.28 (quin, J = 7.26 Hz, 1H), 4.57 - 4.62 (m, 2H), 3.63 (t, J = 6.44 Hz, 2H), 2.77 - 2.85 (m, 2H), 2.45 (s, 3H), 2.27 (s, 3H), 2.19 - 2.26 (m, 2H), 2.09 - 2.20 (m, 2H), 1.87 - 2.07 (m, 4H), 1.74 - 1.87 (m, 2H). LCMS(ES) [M+H]+ 499.5. Example 51
1-cyclopentyl-N-((4,6 n-3-yl)methyl)-6-(3- (trifluoromethoxy)ph
Figure imgf000070_0001
1H NMR (400 MHz, MeOD) δ 8.39 (s, 1H), 8.04 (s, 1H), 7.79 - 7.85 (m, 2H), 7.73 (s, 1H), 7.61 (t, J = 7.96 Hz, 1H), 7.34 (dt, J = 1.17, 8.27 Hz, 1H), 6.15 (s, 1H), 5.26 - 5.35 (m, 1H), 4.60 (s, 2H), 2.45 (s, 3H), 2.27 (s, 3H), 2.24 (br. s., 2H), 2.09 - 2.20 (m, 2H), 1.94 - 2.07 (m, 2H), 1.81 (d, J = 4.55 Hz, 2H). LCMS(ES) [M+H]+ 525.2.
Example 52
1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6- methoxypyridin-3-yl)-1H-indazole-4-carboxamide
Figure imgf000070_0002
1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.69 (d, J = 1.77 Hz, 1H), 8.61 (t, J = 4.93 Hz, 1H), 8.38 (s, 1H), 8.22 (dd, J = 2.65, 8.72 Hz, 1H), 8.16 (s, 1H), 7.87 (d, J = 1.26 Hz, 1H), 6.97 (d, J = 8.59 Hz, 1H), 5.89 (s, 1H), 5.32 (quin, J = 7.14 Hz, 1H), 4.39 (d, J = 4.80 Hz, 2H), 3.92 (s, 3H), 2.22 (s, 3H), 2.13 (s, 5H), 1.99 (s, 2H), 1.84 - 1.95 (m, 2H), 1.65 - 1.78 (m, 2H). LCMS(ES) [M+H]+ 472.4. Example 53
1 -cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- fluorophenyl)-1 H-indazole-4-carboxamide
Figure imgf000071_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-1-cyclopentyl-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide (100 mg, 0.23 mmol) and (4-fluorophenyl)boronic acid (47.3 mg, 0.34 mmol) in dioxane/water (3 ml_:1 ml_). PdCI2(dppf)-CH2Cl2 adduct (9.2 mg, 0.01 1 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (56.8 mg, 0.68 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, water was added, and solids that crashed out were filtered. DCM/MeOH (1 :1 ) was added, the contents pre-absorbed on silica gel and purified by Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NI-^OH). The collected product was suspended in EtOAc along with some hexanes. The mixture was sonicated, and the solids that precipitated were filtered and dried to afford the title compound as a light grey solid (78 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 8.64 (t, J=4.80 Hz, 1 H) 8.37 (s, 1 H) 8.13 (s, 1 H) 7.89 - 7.94 (m, 2 H) 7.85 (s, 1 H) 7.35 (t, J=8.97 Hz, 2 H) 5.89 (s, 1 H) 5.34 (quin, J=7A4 Hz, 1 H) 4.40 (br. s., 1 H) 4.38 (br. s., 1 H) 2.22 (s, 3 H) 2.1 1 - 2.18 (m, 5 H) 1.98 - 2.06 (m, 2 H) 1 .86 - 1.94 (m, 2 H) 1.66 - 1 .75 (m, 2 H). LC-MS (ES) m/z = 459.1
Example 54
1 -cyclopentyl-N-[(4,6-dimethyl-2 nyl)methyl]-6-(1 -methyl- 1 H-pyrazol-4-yl)-1 H-indazole-4-c
Figure imgf000072_0001
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 %). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.53 (br. s., 1 H) 8.48 (t, J=4.93 Hz, 1 H) 8.30 (s, 1 H) 8.26 (s, 1 H) 8.04 (s, 2 H) 7.81 (s, 1 H) 5.90 (s, 1 H) 5.22 (quin, J=7.14 Hz, 1 H) 4.39 (s, 1 H) 4.38 (s, 1 H) 3.87 - 3.92 (m, 3 H) 2.23 (s, 3 H) 2.14 - 2.19 (m, 1 H) 2.13 (s, 4 H) 1 .96 - 2.05 (m, 2 H) 1 .84 - 1.94 (m, 2 H) 1 .66 - 1.76 (m, 2 H). LC-MS (ES) m/z = 445.2 [M+H]+
Example 55
1 -cyclopentyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-1 -yl)pyridin-3-yl)-1 H-indazole-4-carboxamide
Figure imgf000072_0002
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-1-cyclopentyl-N-[(6- methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide (100 mg, 0.21 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- pyridinyl]piperazine (96 mg, 0.32 mmol) in DME/water (3 mL:1 ml_). PdCI2(dppf)-CH2CI2 adduct (8.7 mg, 0.01 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (53.5 mg, 0.64 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 Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NI-^OH). The collected product was further purified by reversed-phase
HPLC (15% 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.
Solids that precipitated were filtered and dried to afford the title compound as a white solid (87 mg, 71 %). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.45 (br. s., 1 H) 8.68 (br. s., 1 H) 8.39 (s, 1 H) 8.24 (s, 1 H) 8.21 (d, J=5.30 Hz, 1 H) 7.84 - 7.88 (m, 1 H) 7.20 (s, 1 H) 7.13 (dd, J=5.31 , 1 .26 Hz, 1 H) 5.91 (s, 1 H) 5.38 (quin, J=7.07 Hz, 1 H) 4.43 (br. s., 1 H) 4.42 (br. s., 1 H) 3.55 - 3.63 (m, 4 H) 2.53 - 2.56 (m, 2 H) 2.41 - 2.46 (m, 4 H) 2.24 (s, 3 H) 2.12 - 2.20 (m, 5 H) 1.97 - 2.06 (m, 2 H) 1 .86 - 1 .95 (m, 2 H) 1.67 - 1 .76 (m, 2 H) 1.48 - 1.57 (m, 2 H) 0.89 (t, J=7.33 Hz, 3 H); LC-MS (ES) m/z = 568.3
Example 56
1 -cyclopentyl-N-[(4,6-dimethyl-2 -oxo-1 ,2-dihydro-3-pyridinyl)methyl]-6-[6-(1 - piperazinyl)-3-pyridinyl]-1 H-indazole-4-carboxamide
Figure imgf000073_0001
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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (br. s., 1 H) 8.64 - 8.67 (m, 1 H) 8.60 (t, J=4.80 Hz, 1 H) 8.35 (s, 1 H) 8.03 - 8.09 (m, 2 H) 7.84 (d, J=1.26 Hz, 1 H) 6.89 - 6.99 (m, 1 H) 5.89 (s, 1 H) 5.27 - 5.35 (m, 1 H) 4.39 (br. s., 1 H) 4.38 (br. s., 1 H) 3.41 - 3.56 (m, 4 H) 2.69 - 2.91 (m, 4 H) 2.22 (s, 3 H) 2.07 - 2.20 (m, 6 H) 1.97 - 2.06 (m, 2 H) 1 .85 - 1 .93 (m, 2 H) 1 .65 - 1 .74 (m, 2 H). LC-MS (ES) m/z = 526.3 [M+H]+ Example 57
1 -cyclopentyl-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(4- ((dimethylamino)methyl)phenyl)-1 H-indazole-4-carboxamide
Figure imgf000074_0001
To a sealed tube were added 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), and potassium phosphate (tribasic) (0.192 g, 0.902 mmol) followed by 1 ,4-Dioxane (2.0 ml.) and water (.5 ml_). The suspension was stirred with degassing under N2 for 10 min, followed by addition of PdCI2(dppf)-CH2CI2 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. The title compound was collected as an off-white solid (45 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .65 - 1 .76 (m, 2 H), 1.83 - 1 .94 (m, 2 H), 1 .97 - 2.07 (m, 2 H), 2.09 - 2.19 (m, 1 1 H), 2.21 (s, 3 H), 3.44 (s, 2H), 4.39 (d, J=4.80 Hz, 2 H), 5.34 (quin, J=7A4 Hz, 1 H), 5.88 (s, 1 H), 7.41 (m, J=8.34 Hz, 2 H), 7.81 (m, J=8.08 Hz, 2 H), 7.87 (d, J=1.01 Hz, 1 H), 8.12 (s, 1 H), 8.36 (s, 1 H), 8.65 (t, J=4.93 Hz, 1 H), 1 1 .53 (s, 1 H); LC- MS (ES) m/z = 498.3 [M+H]+ Example 58
6-chloro-1 -cyclopentyl-A -[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3^yridinyl)methyl]-1H- indazole-4-carboxamide
Figure imgf000075_0001
a) Methyl 6-chloro-1 -cyclopentyl-1 H-indazole-4-carboxylate
Figure imgf000075_0002
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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .64 - 1 .74 (m, 2 H), 1 .82 - 1 .93 (m, 2 H), 1.94 - 2.04 (m, 2 H), 2.09 - 2.19 (m, 2 H), 3.96 (s, 3 H), 5.27 (t, J=7.07 Hz, 1 H), 7.72 (d, J=1 .77 Hz, 1 H), 8.28 (s, 1 H), 8.40 (s, 1 H); LC-MS (ES) m/z = 278.7 [M+H]+ b) 6-chloro-1 -cyclopentyl-1 H-indazole-4-carboxylic acid
Figure imgf000076_0001
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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.63 - 1 .75 (m, 2 H) 1 .82 - 1 .93 (m, 2 H) 1.93 - 2.05 (m, 2 H) 2.08 - 2.19 (m, 2 H) 5.25 (quin, J=7.07 Hz, 1 H) 7.69 (d, J=1.77 Hz, 1 H) 8.20 (s, 1 H) 8.40 (s, 1 H) 1 1.88 - 15.25 (m, 1 H); LC-MS (ES) m/z = 264.9 [M+H]+ c) 6-chloro-1 -cyclopentyl-A -[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H- indazole-4-carboxamide
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. The final product was collected as 0.165g (89%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .62 - 1.74 (m, 2 H) 1 .81 - 1.91 (m, 2 H) 1 .91 - 2.02 (m, 2 H) 2.06 - 2.17 (m, 5 H) 2.20 (s, 3 H) 4.34 (d,
J=4.80 Hz, 2 H) 5.16 - 5.28 (m, 1 H) 5.88 (s, 1 H) 7.60 (d, J=1 .52 Hz, 1 H) 8.05 (s, 1 H) 8.37 (s, 1 H) 8.61 (t, J=4.93 Hz, 1 H) 1 1 .54 (s, 1 H); LC-MS (ES) m/z = 398.8 [M+H]+
Example 59
6-chloro-1 -cyclopentyl-A -[(6-methyl-2-oxo-4^ropyl-1 ,2-dihydro-3^yridinyl)methyl]- 1 H-indazole-4-carboxamide
Figure imgf000077_0001
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 final product was collected as 0.170g (86%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.33 Hz, 3 H), 1.45 - 1.57 (m, 2 H), 1.61 - 1.74 (m, 2 H), 1 .80 - 1.92 (m, 2 H), 1.92 - 2.03 (m, 2 H), 2.05 - 2.19 (m, 5 H), 4.36 (d, J=5.05 Hz, 2 H), 5.21 (t, J=7.07 Hz, 1 H), 5.91 (s, 1 H), 7.59 (d, J=1.52 Hz, 1 H), 8.06 (s, 1 H), 8.37 (s, 1 H), 8.62 (t, J=4.80 Hz, 1 H), 1 1 .55 (s, 1 H); LC-MS (ES) m/z = 426.7 [M+H]+
Example 60
6-cyano-1 -cyclopentyl-A -[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H- indazole-4-carboxamide
Figure imgf000077_0002
To 20 ml. microwave vial containing a mixture of 6-bromo-1 -cyclopentyl-N-[(4,6-dimethyl- 2-OXO-1 , 2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide (0.25g, 0.564 mmol), zinc cyanide (0.066 g, 0.564 mmol), zinc (7.37 mg, 0.1 13 mmol), and dppf (0.063 g, 0.1 13 mmol) was added Ν,Ν-Dimethylacetamide (DMA) (5.0 ml_). The suspension was stirred with degassing under nitrogen for 5 min. Next added PdCI2(dppf)-CH2Cl2 adduct (0.046 g, 0.056 mmol). The reaction contents were sealed and stirred with heating at 135 °C (heat block) for 16 h. The reaction mixture was allowed to cool to RT, diluted with 80 mL of water, and adjusted to pH~8 with sat NaHC03. The contents were stirred for 30 min, filtered, and the filter cake was washed with water. The collected solid was dried under hi vacuum for 4 h. The crude product was dissolved in DCM/MeOH followed by addition of silica gel, and concentrated in vacuo to dryness. 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 %) . 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.64 - 1 .75 (m, 2 H) 1 .83 - 1 .93 (m, 2 H) 1.94 - 2.06 (m, 2 H) 2.10 - 2.19 (m, 5 H) 2.21 (s, 3 H) 4.35 (d, J=4.80 Hz, 2 H) 5.31 (t, J=7.07 Hz, 1 H) 5.89 (s, 1 H) 7.91 (d, J=1 .26 Hz, 1 H) 8.51 (s, 1 H) 8.60 (s, 1 H) 8.66 (t, J=4.93 Hz, 1 H) 1 1.54 (s, 1 H) ; LC-MS (ES) m/z = 390.2 [M+H]+
Example 61
6-(aminomethyl)-1 -cyclopentyl-A -[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 H-indazole-4-carboxamide
Figure imgf000078_0001
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 title compound was collected as 68 mg (66 %); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64 - 1 .75 (m, 2 H), 1.82 - 1 .93 (m, 2 H), 1.94 - 2.04 (m, 2 H), 2.06 - 2.17 (m, 6 H), 2.21 (s, 3 H), 3.85 (s, 2 H), 4.35 (d, J=5.05 Hz, 2 H), 5.14 (t, J=7.07 Hz, 1 H), 5.89 (s, 1 H), 7.54 (s, 1 H), 7.76 (s, 1 H), 8.27 (s, 1 H), 8.32 (t, J=5.05 Hz, 1 H),
; LC-MS (ES) m/z = 394.0 [M+H]+ Example 62
6-amino-1 -cyclopentyl-A -[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3^yridinyl)methyl]-1H- indazole-4-carboxamide
Figure imgf000079_0001
To a 20 mL microwave vial containing a mixture of 6-bromo-1-cyclopentyl-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide (0.25g, 0.564 mmol), benzophenone imine (0.142 mL, 0.846 mmol) and Cs2C03 (0.735 g, 2.256 mmol) was added 1 ,4-dioxane (5 mL) and the suspension stirred with degassing under N2 for 5 min. Next added Xantphos (0.098 g, 0.169 mmol), degassed for 5 min, and then added Pd2(dba)3 (0.077 g, 0.085 mmol) and degassed for 1 min. The reaction vial was sealed and the mixture heated at 100 °C (heat block) with stirring for 2h. The contents were cooled to RT, diluted with water (80 mL), and extracted with EtOAc (2x). The combined organic layers were dried over MgS04, filtered through Celite, and concentrated in vacuo. The crude solid was dissolved in THF (5 mL) and treated with HCI (0.564 mL, 1 .692 mmol). The volatiles were removed in vacuo. 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. The title compound was collected as 90 mg (41 %); 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .60 - 1 .72 (m, 2 H), 1.78 - 1.89 (m, 2 H), 1 .91 - 2.00 (m, 2 H), 2.01 - 2.10 (m, 2 H), 2.12 (s, 3 H), 2.22 (s, 3 H), 4.32 (d, J=5.05 Hz, 2 H), 4.84 (t, J=7.07 Hz, 1 H), 5.41 (s, 2 H), 5.88 (s, 1 H), 6.65 (s, 1 H), 6.88 (d, J=1.52 Hz, 1 H), 7.95 (s, 1 H), 8.14 (t, J=5.18 Hz, 1 H), 1 1 .53 (s, 1 H) ; LC-MS (ES) m/z = 379.2 [M+H] Example 63
1 -cyclopentyl-A -[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-6- [(phenylsulfonyl)amino]-1H-indazole-4-carboxamide
Figure imgf000080_0001
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 MgS04, filtered, and concentrated in vacuo. The solid was concentrated from DCM and dried in vacuum oven for 4 h at 45 °C. The title compound was collected as 30 mg (72%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .68 (td, J=5.49, 3.41 Hz, 2 H), 1.75 - 1 .94 (m, 4 H), 1.99 - 2.10 (m, 2 H), 2.12 (s, 3 H), 2.20 (s, 3 H), 4.30 (d,J=5.05 Hz, 2 H), 4.89 - 5.04 (m, 1 H), 5.89 (s, 1 H), 7.22 (d, J=1.52 Hz, 1 H), 7.36 (s, 1 H), 7.48 - 7.63 (m, 3 H), 7.77 - 7.84 (m, 2 H), 8.1 1 (s, 1 H), 8.36 (t, J=5.05 Hz, 1 H), 10.56 (s, 1 H), 1 1 .55 (s, 1 H); LC-MS (ES) m/z = 519.2 [M+H]
Example 64
1 -cyclopentyl-A -[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3^yridinyl)methyl]-6-(3-hydroxy- 3-methyl-1 -butyn-1 -yl)-1H-indazole-4-carboxamide
Figure imgf000081_0001
To a 10 mL microwave vial containing a mixture of 6-bromo-1-cyclopentyl-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide (0.12 g, 0.271 mmol), sodium iodide (8.1 1 mg, 0.054 mmol) and zinc (3.54 mg, 0.054 mmol) were added DMSO (2.5 mL), TEA (0.075 mL, 0.541 mmol), and DBU (0.082 mL, 0.541 mmol). The suspension was stirred and degassed with N2 for 5 min. Next added in 2-methyl-3-butyn- 2-o\ (0.131 mL, 1 .353 mmol) and Pd(Ph3P)4 (0.031 g, 0.027 mmol). The reaction vial was sealed and stirred with heating at 85 °C (heat block) for 3h. The mixture was then diluted into water and 20% THF/ EtOAc. The contents were stirred and the layers were separated. The organic layer was washed with brine, dried over MgS04, filtered through Celite, and concentrated in vacuo. The residue was dried on hi-vacuum pump overnight. 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/CHCI3. Next added 0.5g Silicycle carbonate resin and stirred for 15 min. After standing for 10 min, the contents were filtered through celite and concentrated in vacuo. The product was further concentrated from DCM and MTBE and then dried in hi-vac oven at 45 °C overnight. The title compound was collected as a white solid (38mg, 30%); 1 H NMR (400 MHz, DMSO- d6) δ ppm 1.47 - 1 .52 (m, 6 H), 1.64 - 1.73 (m, 2 H), 1 .80 - 1 .91 (m, 2 H), 1.92 - 2.02 (m, 2 H), 2.06 - 2.15 (m, 5 H), 2.18 -2.23 (m, 3 H), 4.28 - 4.38 (m, 2 H), 5.25 (quin, J=7.07 Hz, 1 H), 5.52 (s, 1 H), 5.84 - 5.91 (m, 1 H), 7.54 (d, J=1 .01 Hz, 1 H), 7.93 (s, 1 H), 8.35 (s, 1 H), 8.60 (t, J=4.93 Hz, 1 H), 1 1.51 (br. s., 1 H); LC-MS (ES) m/z = 446.9 [M+H] Example 65
6-bromo-1 -cyclopropyl-A -[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H- indazole-4-carboxamide
Figure imgf000082_0001
a) Methyl 6-bromo-1 -cyclopropyl-1 H-indazole-4-carboxylate
Figure imgf000082_0002
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. The contents were stirred with heating at 70 °C overnight. After cooling to RT, the reaction mixture was poured onto sat. NH4CI and ice. Next added DCM and stirred for 10 min. The contents were filtered through Celite, washing with water and DCM. The layers were separated and the aq. layer was extracted with DCM (1 x). The combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (3-25% gradient ethyl acetate in hexanes) wherein the less polar product was observed to be the title compound, and was collected as a yellow solid (0.54g, 46%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .10 - 1 .20 (m, 4 H), 3.81 - 3.90 (m, 1 H), 3.95 (s, 3 H), 7.86 (d, J=1.52 Hz, 1 H), 8.30 (d, J=1 .77 Hz, 1 H), 8.32 (d, J=1.01 Hz, 1 H); LC-MS (ES) m/z = 295.1 [M+H] b) 6-bromo-1 -cyclopropyl-1 H-indazole-4-carboxylate6-bromo-1 -cyclopropyl-1 H- indazole-4-carboxylic acid
Figure imgf000083_0001
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). The combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated in vacuo to a solid to which was dried under vacuum for 1 h. The title compound was collected as a white solid (0.48g, 91 %); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 - 1.17 (m, 4 H), 3.80 - 3.89 (m, 1 H), 7.84 (d, J=1.77 Hz, 1 H), 8.26 (s, 1 H), 8.31 (s, 1 H), 13.60 (br. s., 1 H); LC-MS (ES) m/z = 281.1 [M+H].
c) 6-bromo-1 -cyclopropyl-A -[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide
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. The title compound was collected as a white solid (0.27g, 81 %); 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .06 - 1 .17 (m, 4 H), 2.12 (s, 3 H), 2.20 (s, 3 H), 3.76 - 3.85 (m, 1 H), 4.33 (d, J=5.05 Hz, 2 H), 5.88 (s, 1 H), 7.76 (d, J=1.52 Hz, 1 H), 8.10 (s, 1 H), 8.30 (d, J=1 .01 Hz, 1 H), 8.64 (t, J=4.93 Hz, 1 H), 1 1.54 (s, 1 H); LC-MS (ES) m/z = 414.8 [M+H]. Example 66
6^romo-1 -cyclopropyl-A -[(6-methyl-2-oxo-4^ropyl-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-indazole-4-carboxamide
Figure imgf000084_0001
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 collected as a white solid (0.36g, 91 %); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.33 Hz, 3 H), 1 .06 - 1 .16 (m, 4 H), 1.50 (sxt, J=7.53 Hz, 2 H), 2.13 (s, 3 H), 3.76 - 3.86 (m, 1 H), 4.36 (d, J=5.05 Hz, 2 H), 5.90 (s, 1 H), 7.74 (d, J=1.52 Hz, 1 H), 8.09 (s, 1 H), 8.31 (s, 1 H), 8.64 (t, J=4.80 Hz, 1 H), 1 1 .54 (br. s., 1 H) ; LC-MS (ES) m/z = 443.0 [M+H].
Example 67
1 -cyclopropyl-6-{4- henyl}-A -[(4,6-dimethyl-2-oxo-1 ,2- dihydro-3-pyridinyl rboxamide
Figure imgf000084_0002
To a 20 mL microwave vial containing a mixture of 6-bromo-1 -cyclopropyl-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide (.070g, 0.169 mmol), N,N-dimethyl-1 -[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methanamine (0.060 g, 0.202 mmol), and potassium phosphate (tribasic) (0.107 g, 0.506 mmol) were added 1 ,4-dioxane (2.0 mL) and water (0.5 mL). The suspension was stirred with degassing under N2 for 10 min. (emulsion), and then PdCI2(dppf)-CH2Cl2 adduct (0.021 g, 0.025 mmol) was added. The contents were sealed and heated at 100 °C (heat block) for 2h. After cooling to RT, the reaction mixture was diluted with EtOAc. Silica gel was added the mixture was concentrated in vacuo to dryness. The contents were purified by silica gel chromatography (dry loaded, eluent : 8- 95% gradient chloroform (containing 10% 2M Ammonia in Methanol) and DCM). The collected product was concentrated from MTBE and dried in a vacuum oven for 2h. The title compound was collected as a white solid (67 mg, 81 %); 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .12 - 1.20 (m, 4 H), 2.12 (s, 3 H), 2.15 - 2.24 (m, 9 H), 3.44 (s, 2 H), 3.87 (t, J=5.31 Hz, 1 H), 4.38 (d, J=4.80 Hz, 2 H), 5.88 (s, 1 H), 7.42 (m, J=8.34 Hz, 2 H), 7.80 (m, J=8.08 Hz, 2 H), 7.90 (s, 1 H), 8.04 (s, 1 H), 8.31 (s, 1 H), 8.67 (t, J=4.93 Hz, 1 H), 1 1 .53 (s, 1 H); LC-MS (ES) m/z = 470.3 [M+H].
Example 68
1 -cyclopropyl-6-{4-[(dimeth [(6-methyl-2-oxo-4-propyl- 1 ,2-dihydro-3-pyridinyl)met mide
Figure imgf000085_0001
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 title compound was collected as a white solid (59 mg, 69 %); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.33 Hz, 3 H), 1.12 - 1 .21 (m, 4 H), 1.45 - 1.58 (m, 2 H), 2.13 (s, 3 H), 2.18 (s, 6 H), 3.45 (s, 2 H), 3.88 (quin, J=5.37 Hz, 1 H), 4.41 (d, J=5.05 Hz, 2 H), 5.91 (s, 1 H), 7.43 (m, J=8.34 Hz, 2 H), 7.80 (m, J=8.08 Hz, 2 H), 7.89 (d, J=1.26 Hz, 1 H), 8.04 (s, 1 H), 8.32 (s, 1 H), 8.68 (t, J=4.93 Hz, 1 H), 1 1.54 (s, 1 H); LC-MS (ES) m/z = 498.4 [M+H]. Example 69
6^romo-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3- methyl-1 H-indazole-4-carboxami
Figure imgf000086_0001
a) 5-Bromo~2~meihy1~3-nitro~benzosc acid
Figure imgf000086_0002
To a stirred solution of 2-methyl-3-nitro benzoic acid (300 g, 1647 mmol) in cone. H2S04 (1 .5 L) was added 1 ,3-dibromo-5,5 dimethyl -2,4-imadazolidinedione (258 g, 906 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was slowly added to ice water (4 L), and solid was precipitated out. The solid was filtered off and washed with water (1.2 L), pet ether (1 I) and dried to afford the title compound as a white solid (41 1 g, 96 %), which was used without further purification. 1 H NMR (DMSO, 400 MHz) : δ 2.446 (s, 3H), 8.136 (s, 1 H), 8.294 (s, 1 H). LCMS (ES-) m/z = 257.93 (M-H)- b) Methyl 6-bromo-1 H-indole-4-carboxylate
Figure imgf000086_0003
To a stirred solution of 5-Bromo-2-methy!-3-nitro-benzoic acid (140 g, 538.4 mmol) in DMF (550 ml) was added DMF-DMA (599 ml_, 4846 mmol) at room temperature. The reaction mixture was stirred at 1 15 °C for 18 h. The reaction mixture was then concentrated in vacuo. The residual contents (176 g, 536.5 mmol) were dissolved in acetic acid (696 mL) and added to a suspension of Iron (329.2 g, 5902 mmol) in acetic acid (1.4 L) at 50 °C. After completion of addition, the reaction mixture was stirred at 80- 90 °C for 4 h. 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 NaHC03, brine, and dried over anhydrous Na2S04, 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%). 1H NMR (DMSO-d6, 400 MHz) δ: 3.980 (s, 3H), 7.168 (d, J = 3.2 Hz, 1 H), 7.334 (d, J = 3.2 Hz, 1 H), 7.734 (s, 1 H), 8.017 (s, 1 H), 8.384 (brs, 1 H); LCMS (ES-) m/z = 251.9 (M-H). c) Methyl 8-bromo-3-formyl-1 H-!ndazole-4-carboxyiate
Figure imgf000087_0001
To a stirred solution of sodium nitrite (68.4 g, 991.3 mmol) in water (1425 mL) was added methyl 6-bromo-1 /-/-indole-4-carboxylate (20.64 g, 81.25 mmol) at RT and the mixture stirred for 15 min at RT. To the mixture was added 6N HCI (159.6 mL) slowly dropwise over a period of 1 h and the reaction mixture was then stirred at room temperature for 48 h. The reaction mixture was extracted with 10% THF in ethyl acetate (5 x 500 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2S04 , and filtered. The filtrate was concentrated to 1/3 volume and cooled in freezer for 4 h. Precipitated solids were filtered and washed with cold ethyl acetate and dried under high vacuum to afford the title compound as an off white solid (13.7g, 59.6%). 1H NMR (DMSO-d6, 400 MHz): δ ~ ~ (s, 3H), 7.754 (s, 1 H), 8.183 (s, 1 H), 10.274 (s, 1 H), 14.563 (brs, 1 H). LCMS (ES+): 281 .06 [M-H] ion present. d) Methyl 6-bromo-3-formyl-1 -isopropyl-1 H-indazole-4-carboxylate
Figure imgf000088_0001
To a stirred solution of methyl 6-bromo-3-formyi-1 H-indazole-4-carboxylate 1 (1 1.5 g, 40.63 mmol) in DMF (230 mL)) was added K2C03 (14.08 g, 102.02 mmol) at RT under argon, and stirred for 10 min. Then 2~iodopropane (7.24 g, 42.58 mmol) was added at RT and the mixture stirred at 40 °C for 2 h. The reaction mixture was diluted with cold water and extracted with ethyl acetate (4 x 300 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2S04 , filtered, and concentrated. The crude residue (12.4 g) was purified by silica gel chromatography (eluent: 0-10% ethyl acetate: pet ether) to afford the title compound as an off white solid (5.55 g, 42 %). 1 H NMR (CDCIs, 400 MHz): δι d, J = 6.4 Hz, 6Η. (s, 3H), 4.862-4.960 (m, 1 H), 7.807 (s, 1 H), 7.854 (s, 1 H), 10.375 (s, 1 H). HPLC: 98.66 %. e) Methyl 6-bromo-1 -isopropyl-3-methyl-1 H-indazole-4-carboxylate
Figure imgf000088_0002
To a stirred solution of methyl 6-bromo-3-formyl-1 -isopropyl-1 H-indazole-4-carboxylate (4.5 g, 13.84 mmol) in DMF (31.5 mL) was added p-toluenesulfonic acid monohydrate (0.342 g, 1.8 mmol), p-toluenesulfonyl hydrazide (3.35 g, 18.0 mmol) followed by sulfolane (31.5 mL), and the reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (3.489 g, 55.0 mmol) was added portion wise over a period of 25 min. 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 Na2S04 , 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 % ). 1 H NMR (CDCI3, 400 MHz): δ 1.559 (d, J = 6.8 Hz, 6H), 2.674 (s, 3H), 3.976 (s, 3H), 4.667- 4.767 ( m, 1 H), 7.715 (d, J=1.6 Hz, 1 H), 7.761 (d, J=1.6 Hz, 1 H).-LCMS (ES+): 98.63 %, 313.06 [M+H] ion present. f) 6-bromo-1 -isopropyl-3-methyl-1 H-indazole-4-carboxylic acid
Figure imgf000089_0001
To a stirred solution of methyl 6-bromo-1 -isopropyl-3-methyl-1 H-indazole-4-carboxylate (7.5 g, 24.1 1 mmol) in ethanol (400 mL) was added sodium hydroxide (1 .45 g, 36.17 mmol) in water (60 mL) and the reaction mixture was stirred at reflux for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (150 mL), and acidified with 2N HCI to pH~2. The precipitated acid was collected by filtration, washed with ether (200 mL, and dried to afford 6-bromo-1-isopropyl-3-methyl- 1 H-indazole-4-carboxylic acid as an off white solid (6.85 g, 95.6%). LCMS (ES-): 294.9 [M-H]. g) 6-bromo-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3- methyl-I H-indazole-4-carboxamide
To a stirred solution of 6-bromo-1-isopropyl-3-methyl-1 H-indazole-4-carboxylic acid, 1 (6.5 g, 21 .88 mmol) in DCM (250 mL) was added EDC HCI (5.01 g, 26.23 mmol), HOBt (3.545 g, 26.20 mmol) followed by diisopropyl ethyl amine (14.1 1 g, 109.37 mmol) and stirred at room temperature for 15 min. To the resulting mixture, 3-(amino methyl)-4,6- dimethylpyridin-2(1 H)-one (3.32 g, 21.84 mmol) followed by DMAP (catalytic amount) was added and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with DCM (300 mL) and washed with 1 N HCI solution (250 mL), saturated NaHC03 solution (250 mL) and brine solution. The organic layer was dried over anhydrous Na2S04 , filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether (100 mL), filtered, and dried to afford 6-bromo-N-((1 ,2-dihydro- 4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-1 H-indazole-4-carboxamide as an off white solid (5.5 g, 58 %). 1H NMR (DMSO-d6, 400 MHz): δ 1.412 (d, J = 6.4 Hz, 6H), 2.1 12 (s, 3H), 2.215 (s, 3H), 2.383 (s, 3H), 4.319 (d, J = 5.2 Hz, 2H), 4.907 - 4.972 (m, 1 H), 5.864 (s, 1 H), 7.129 (d, J = 1.2 Hz, 1 H), 8.01 1 (d, J = 1 .2 Hz, 1 H), 8.473 (t, J = 5 Hz, 1 H), 1 1 .479 (brs, 1 H). LCMS (ES+): 431.02 [M+H]. Example 70
6^romo-1 -isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3- yl)methyl)-1 H-indazole-4-carboxamide
Figure imgf000090_0001
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 title compound was collected as a white solid (0.35g, 92%); 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.33 Hz, 3 H) 1 .41 (d, J=6.57 Hz, 6 H) 1.49 - 1 .60 (m, 2 H) 2.12 (s, 3 H) 2.39 (s, 3 H) 2.53 (s, 1
H) 4.33 (d, J=5.05 Hz, 2 H) 4.88 - 5.00 (m, 1 H) 5.89 (s, 1 H) 7.12 (d, J=1.52 Hz, 1 H) 8.02 (d, J=1 .77 Hz, 1 H) 8.48 (t, J=4.93 Hz, 1 H) 1 1 .50 (s, 1 H); LCMS (ES+): 459.1 [M+H].
Example 71
1 -isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl-1 ,2-dihydropyridin-3-yl)methyl)-6- (2-(4-methylpiperazin-1 -yl)pyridin-4-yl)-1 H-indazole-4-carboxamide
Figure imgf000090_0002
In a 25 ml. sealable tube under nitrogen were combined 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 (85 mg, 0.19 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2- yl)-2-pyridinyl]piperazine (72.9 mg, 0.24 mmol) in dioxane/water (3 mL:1 ml_). PdCI2(dppf)-CH2Cl2 adduct (7.6 mg, 0.0093 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (46.6 mg, 0.55 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 was added and the contents purified by Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH).
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%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .50 (s, 1 H) 8.45 (t, J=4.93 Hz, 1 H) 8.19 (d, J=5.31 Hz, 1 H) 8.06 - 8.09 (m, 1 H) 7.40 (s, 1 H) 7.17 (s, 1 H) 7.08 (d, J=5.05 Hz, 1 H) 5.91 (s, 1 H) 5.1 1 (quin, J=6.57 Hz, 1 H) 4.39 (br. s., 1 H) 4.38 (br. s., 1 H) 3.55 - 3.62 (m, 4 H) 2.53 - 2.57 (m, 2 H) 2.41 - 2.46 (m, 7 H) 2.24 (s, 3 H) 2.13 (s, 3 H) 1.53 - 1.61 (m, 2 H) 1.47 (s, 3 H) 1.46 (s, 3 H) 0.93 (t, J=7.33 Hz, 3 H); LC- MS (ES) m/z = 459.2
Example 72
3- methyl-1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-6-[6-(1 ^iperazinyl)-3^yridinyl]-1 H-indazole-4-carboxamide
Figure imgf000091_0001
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%). 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 1.54 (br. s., 1 H) 8.49 - 8.63 (m, 2 H) 8.43 (br. s., 1 H) 7.97 (dd, J=8.84, 2.53 Hz, 1 H) 7.89 (s, 1 H) 7.32 (s, 1 H) 6.87 - 6.96 (m, 1 H) 5.91 (s, 1 H) 5.03 (dt, J=13.07, 6.47 Hz, 1 H) 4.38 (d, J=4.55 Hz, 2 H) 3.40 - 3.61 (m, 5 H) 2.77 - 2.82 (m, 3 H) 2.53 - 2.57 (m, 2 H) 2.43 (s, 3 H) 2.13 (s, 3 H) 1 .53 - 1.60 (m, 2 H) 1.46 (s, 3 H) 1.44 (s, 3 H) 0.93 (t, J=7.33 Hz, 3 H); LC-MS (ES) m/z = 542.2 [M+H]+
Example 73
6-(6-(dimethylamino)pyridin-3-yl)-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3- yl)methyl)-1 -isopropyl-3-methyl-1 H-indazole-4-carboxamide
Figure imgf000092_0001
To a stirred solution of 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) in DMF (30 mL) was added 6-(dimethylamino)pyridin-3-yl-3-boronic acid, 1 (127 mg, 0.765 mmol) followed by sodium carbonate (184.4 mg, 1.74 mmol) dissolved in water (3 mL) and degassed with argon for 1 h. Then PdCI2(PPh3)2 (48.8 mg, 0.069 mmol) was added and again degassed with argon for 15 min and stirred at 1 10°C for 4 h. The reaction mixture was filtered through Celite pad and washed with ethyl acetate (50 mL). The filtrate was diluted with water and extracted with ethyl acetate (4x90 mL). The combined organic layers were separated and washed with cold water (2x50 mL), brine solution (50 mL), dried over anhydrous Na2S04, filtered, and concentrated to afford the crude product (450 mg). The crude compound was purified by silica gel chromatography (eluent: 5% MeOH: DCM) to afford 100 mg of desired product which was triturated with hexane and the solid was filtered and dried to afford the title compound as an off white solid (100 mg, 30%). 1H NMR (DMSO-d6, 400 MHz) : δ 1 .559 (d, J = 6.8 Hz, 6H), 2.102 (s, 3H), 2.403 (s, 3H), 2.539 (s, 3H), 3.125 (s, 6H), 4.616 (s, 2H), 4.754 - 4.820 (m, 1 H), 5.893 (s, 1 H), 6.557 (d, J = 8.8 Hz, 1 H),7.313 (s, 1 H),7.401 (d, J = 5.2 Hz, 1 H), 7.448 (s, 1 H), 7.707 (d, J = 8.8 Hz, 1 H), 8.438 (s, 1 H), 1 1.502 (brs, 1 H). 1H NMR (D20 Ex in DMSO, 400 MHz) : δ 1.559 (d, J = 6.8 Hz, 6H), 2.1 15 (s,3H), 2.408 (s, 3H), 2.538 (s, 3H), 3.124 (s, 6H), 4.616 (s, 2H), 4.754 - 4.820 (m, 1 H), 5.899 (s, 1 H), 6.557 (d, J = 8.8 Hz, 1 H), 7.318 (s, 1 H), 7.450 (s, 1 H), 7.718 (d, J = 8.8 Hz, 1 H), 8.438 (s, 1 H). LCMS (ES+): 473.19. Example 74
6-(3-((dimethylamino)methyl)phenyl)-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3- yl)methyl)-1 -isopropyl-1 H-indazole-4-carboxamide
Figure imgf000093_0001
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 %). 1HNMR (CDCIs, 400 MHz): 51.568 (d, J = 6.8 Hz, 6H), 2.12 (s, 3H), 2.41 (s, 8H), 2.55 (s, 3H), 3.67 (s, 2H), 4.614 (d, J = 5.2 Hz, 2H), 4.899-4.834 (m, 1 H), 5.90 (s, 1 H), 7.326-7.308 (m, 1 H),7.408-7.368 (m, 3H), 7.558 (d, J = 7.6 Hz, 1 H, ), 7.639 (s, 1 H), 7.699 (s, 1 H), 1 1 .193 (brs, 1 H). LCMS (ES+) m/z: 486.31.
Example 75
N-((4,6-dimethyl-2-oxo-1 ,2-dih )-6-(4-fluorophenyl)-1 - isopropyl-3-methyl-1 H-indazo
Figure imgf000093_0002
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo- 1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1 -(1-methylethyl)-1 H-indazole-4-carboxamide (90 mg, 0.21 mmol), (4-fluorophenyl)boronic acid (43.8 mg, 0.31 mmol) in dioxane/water (3 mL:1 ml_). PdCI2(dppf)-CH2CI2 adduct (5.1 1 mg, 0.006 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (52.6 mg, 0.63 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, the contents pre-absorbed on silica gel and purified by Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The collected product was suspended in EtOAc along with some hexanes. The mixture was sonicated, and the solids that precipitated were filtered and dried to afford the title compound as a white solid (73 mg, 77%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1.50 (s, 1 H) 8.46 (t, J=5.05 Hz, 1 H) 7.94 (d, J=1.26 Hz, 1 H) 7.83 - 7.88 (m, 2 H) 7.31 - 7.36 (m, 3 H) 5.88 (s, 1 H) 5.06 (quin, J=6.63 Hz, 1 H) 4.38 (s, 1 H) 4.36 (s, 1 H) 2.43 (s, 3 H) 2.24 (s, 3 H) 2.12 (s, 3 H) 1.47 (s, 3 H) 1.45 (s, 3 H). LC-MS (ES) m/z = 446.9
Example 76
N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6-(6 methylpiperazin-1 -yl)pyridin-3-yl)-1 H-indazole-4-carboxamide
Figure imgf000094_0001
To a stirred solution of 6-bromo-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 - isopropyl-3-methyl-1 H-indazole-4-carboxamide (0.3 g, 0.69 mmol) in DMF (15 mL) was added 1-methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.25 g, 0.82 mmol) followed by PdCI2(PPh3)2 (0.097 g, 0.13 mmol) and the mixture stirred 5 min. Sodium carbonate (0.184 g, 1 .73 mmol) dissolved in water (2 mL) was added and the resulting reaction mixture was stirred at 1 10 °C for 4 h. The contents were then diluted with sodium bicarbonate solution and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2S04, filtered, and concentrated to afford the crude product. The crude compound was purified by silica gel chromatography (eluent: 5% MeOH\DCM). The desired product was isolated as an off white solid with trace impurities. The impure compound was washed several times with cold water and triturated with hexane to afford the title compound as an off-white solid (80 mg, 22%). 1H NMR (DMSO-d6, 400 MHz) : δ 1.447 (d, J = 6.4 Hz, 6H), 2.1 12 (s, 3H), 2.235 (s, 6H), 2.41 1 (s, 7H), 3.551 (s, 4H), 4.363 (d, J = 4.4 Hz, 2H), 4.991-5.054 (m, 1 H), 5.870 (s, 1 H), 6.942 (d, J = 9.2 Hz, 1 H), 7.321 (s, 1 H), 7.880 (s, 1 H), 7.99 (d, J = 8.8 Hz, 1 H), 8.403 (s, 1 H ), 8.569 (s, 1 H), 1 1 .483 (brs, 1 H). LCMS (ES+) m/z: 528.29. Example 77
6-(4-((dimethylamino)methyl)phenyl)-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-^ yl)methyl)-1 -isopropyl-3-methyl-1 H-indazole-4-carboxamide
Figure imgf000095_0001
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%). 1HNMR (DMSO-d6, 400 ΜΗζ):δ1.458 (d, J = 6.4 Hz, 6H), 2.108 (s, 3H), 2.176 (s, 8H), 2.55 (s, 3H), 3.67 (s, 2H), 4.614 (d, J = 5.2 Hz, 2H), 4.899-4.834 (m, 1 H), 5.90 (s, 1 H), 7.326-7.308 (m, 1 H), 7.408-7.368 (m, 3H), 7.558 (d, J = 7.6 Hz, 1 H), 7.639 (s, 1 H), 7.699 (s, 1 H), 1 1 .193 (brs, 1 H). LCMS (ES+) m/z: 486.20 (M+H).
Example 78
N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl -3 -methyl -6-(6- (piperazin-1 -yl)pyridin-3-yl)-1 H-indazole-4-carboxamide hydrochloride
Figure imgf000095_0002
.HCI a) tert-butyl 4-(5-(4-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methylcarbamoyl)- 1 -isopropyl-3-methyl-1 H-indazol-6-yl)pyridin-2-yl)piperazine-1 -carboxylate
Figure imgf000096_0001
To a stirred solution of 6-bromo-N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 - isopropyl-3-methyl-1 H-indazole-4-carboxamide (400 mg, 0.928 mmol) in DMF (20 mL) was added tert-butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2- yl)piperazine-1 -carboxylate (397 mg, 1 .02 mmol) followed by sodium carbonate (246 mg, 2.32 mmol) dissolved in water (4 mL) and degassed with argon for 30 min. PdCI2(PPh3)2 (65 mg, 0.092 mmol) was added and the mixture again degassed with argon for 10 min. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3x150 mL). The combined organic layers were dried over anhydrous Na2S04 , filtered, and concentrated to afford the crude product (650 mg). The crude compound was purified by silica gel chromatography (eluent: 0-10% MeOH: DCM). The product was triturated with diethyl ether (150 mL) to afford the title compound as an off white solid (270 mg, 47%). 1H NMR (DMSO-d6, 400 MHz): δ 1.498 (s, 9H), 1 .560 (d, J = 6.4 Hz, 6H), 2.128 (s, 3H), 2.413 (s, 3H), 2.526 (s, 3H), 3.579 (s, 8H), 4.610 (d, J = 5.6 Hz, 2H), 4.760-4.824 (m, 1 H), 5.907 (s, 1 H), 6.70 (d, J = 8.8 Hz, 1 H ), 7.31 1-7.346 (m, 2H),7.454 (s, 1 H), 7.735 (d, J = 8.8 Hz, 1 H ), 8.463 (s, 1 H), 10.991 (brs, 1 H). LCMS (ES+): 614.25. b) N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6-(6- (piperazin-1 -yl)pyridin-3-yl)-1 H-indazole-4-carboxamide hydrochloride
To a stirred solution of tert-butyl 4-(5-(4-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3- yl)methylcarbamoyl)-1 -isopropyl-3-methyl-1 H-indazol-6-yl)pyridin-2-yl)piperazine-1- carboxylate (250 mg, 0.407 mmol) in DCM (50 mL) was added 4M HCI in 1 ,4-dioxane (6 mL) at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated and then co-distilled with toluene (50 mL). The residue was dried under reduced pressure to get the crude HCI salt (195 mg). The residue was triturated with diethyl ether (100 mL), DCM (100 mL) and n-hexane (100 mL) to afford the title compound as a pale brown solid (135 mg, 60%). 1H NMR (DMSO-d6, 400 MHz): δ 1.454 (d, J = 6.4 Hz, 6H), 2.1 19 (s, 3H), 2.244 (s, 3H), 2.412 (s, 3H), 3.222 (s, 4H), 3.839 (s, 4H), 4.369 (d, J= 4.4 Hz, 2H), 5.005-5.071 (m, 1 H), 5.888 (s, 1 H), 7.125 (d, J = 8.8 Hz, 1 H ), 7.348 (s, 1 H), 7.942 (s, 1 H), 8.158 (d, J = 8 Hz, 1 H), 8.429 (t, J = 4.6 Hz, 1 H ), 8.613 (d, J = 2.0 Hz, 1 H), 9.145 (s, 2H), 1 1.519 (brs, 1 H).LCMS (ES+): 514.24 [M+H].
Example 79
N -((4, 6 -d i methy I -2 -oxo -1 , 2 -d i hy d ro ^
methylpiperazin-1 -yl)pyridin-2-yl)-1 H-indazole-4-carboxamide
Figure imgf000097_0001
A stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 - isopropyl-3-methyl-1 H-indazole-4-carboxamide, 3 (200 mg, 0.464 mmol), 1 -methyl-4-(4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (154 mg, 0.510 mmol) and Na2C03 (123 mg, 1.160 mmol) in a mixture of water (3 mL) and DMF (15 mL) was degassed with argon gas for 30 min. Then PdCI2(PPh3)2 (16.28 mg, 0.023 mmol) was added and heated to 120 °C for 3 h. Then the reaction mixture was filtered through Celite bed and the Celite bed was washed with ice cold water (2x100 mL). The filtrate was extracted with EtOAc (20 mL), dried over anhydrous sodium sulphate, filtered, and concentrated to afford 150 mg of crude product. The crude product was purified by silica gel chromatography over (eluent: 5% MeOH/DCM) to afford the title compound as an off- white solid (85 mg, 32%).1HNMR(DMSO-d6, 400MHz): δ 0.889 (t, J = 14.4 Hz, 3H),
I .554-1.483 (m, 8H), 2.134 (s, 3H), 2.55 (s, 3H), 4.41 1 (d, J = 1.6 Hz, 2H), 5.059 (m, 1 H), 5.913 (s, 1 H), 7.830 (s, 1 H), 8.047 (s, 1 H), 8.08 (s, 1 H), 8.306 (s, 1 H), 8.462 (s, 1 H),
I I .53 (s, 1 H), 13 (brs, 1 H). LCMS (ES+) m/z = 528.2. Example 80
N-((1 ,2-dihydro-4,6-di )-1 -isopropyl-3-methyl-6- (pyridin-3-yl)-1 H-inda
Figure imgf000098_0001
a) methyl 3-methyl-1 -(1 -methylethyl)-6-(3-pyridinyl)-1 H-indazole-4-carboxylate
Figure imgf000098_0002
To a stirred solution of methyl 6-bromo-1 -isopropyl-3-methyl-1 H-indazole-4-carboxylate (0.5 g, 1.60 mmol) in 1 ,4-dioxane (25 mL) was added 3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine (0.39 g, 1 .92 mmol) followed by PdCI2(dppf)-CH2CI2 adduct (0.26 g, 0.32 mmol). 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 Na2S04, 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%). 1 H NMR (DMSO-d6, 400 MHz): 51 .485 (d, J = 6.4 Hz, 6H), 2.601 (s, 3H), 3.945 (s, 3H), 5.121 -5.186 (m, 1 H), 7.523-7.554 (m, 1 H), 7.902 (s, 1 H) , 8.232 (d, J = 7.6 Hz, 1 H), 8.316 (s, 1 H), 8.625 (d, J = 4Hz, 1 H), 9.045 (s, 1 H). b) 1 -isopropyl-3-methyl-6-(pyridin-3-yl)-1 H-indazole-4-carboxylic acid
Figure imgf000099_0001
To a stirred solution of methyl 1 -isopropyl-3-methyl-6-(pyridin-3-yl)-1 H-indazole-4- carboxylate, 1 (0.5 g, 1.618 mmol) in a mixture of THF and H20 (30 mL) was added LiOH H20 (0.2 g, 4.85 mmol) and the mixture was refluxed at 80 °C for 8 h. THF was distilled off and the aqueous layer was adjusted to pH~5 with 10% HCI at 0 °C and the precipitated solid was collected by filtration and dried to afford 1-isopropyl-3-methyl-6- (pyridin-3-yl)-1 H-indazole-4-carboxylic acid as an off-white solid (0.51 g). LCMS (ES+) m/z: 296.7. c) N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6- (pyridin-3-yl)-1 H-indazole-4-carboxamide
To a stirred solution of 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1 H-indazole-4-carboxylic acid (0.5 g, 1 .69 mmol) in DCM (30 mL) was added EDC HCI (0.39 g, 2.03 mmol), HOBT (2.74 g, 2.03 mmol) followed by DIPEA (1.47 mL, 8.45 mmol) and stirred at room temperature for 15 min. To the resulting reaction mixture, 3-(amino methyl)-4,6-dimethylpyridin-2(1 H)- one (0.257 g, 1 .69 mmol) was added and stirred at room temperature for overnight. 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 %). 1H NMR (DMSO-d6, 400 MHz): 51.461 (d, J = 6.4 Hz, 6H), 2.109 (s, 3H), 2.240 (s, 3H), 2.438 (s, 3H), 4.372 (d, J = 4.8 Hz, 2H), 5.042-5.107 (m, 1 H), 5.870 (s, 1 H), 7.410 (s, 1 H), 7.501 -7.533 (m, 1 H), 8.061 (s, 1 H), 8.215 (d, J = 8 Hz, 1 H ), 8.461 (t, J = 4.8 Hz, 1 H), 8.593 (d, J = 4.8 Hz, 1 H), 9.036 (s, 1 H), 1 1 .489 (brs, 1 H). LCMS (ES+) m/z: 430.12
Example 81
N-((1 ,2-dihydro-6-methyl-2-oxo-4^ropylpyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6- (1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-indazole-4-carboxamide
Figure imgf000100_0001
a) Methyl 1 -isopropyl-3-methyl-6-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-indazole-4- carboxylate
Figure imgf000100_0002
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%). 1H NMR (DMSO-d6, 400 MHz) : 51.489 (d, J = 6.4 Hz, 6H), 2.603 (s, 3H), 3.949 (s, 3H), 5.140-5.172 (m, 1 H), 6.547 (s, 1 H), 7.545 (s, 1 H), 7.935 (s, 1 H), 8.253 (s, 1 H), 8.377 (s, 1 H), 8.667 (s, 1 H), 1 1 .774 (s, 1 H). LCMS (ES+) m/z: 349. b) 1 -isopropyl-3-methyl-6-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-indazole-4-carboxylic acid
Figure imgf000100_0003
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 H20 (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. LCMS (ES+) m/z: 335.15. c) N-((1 ,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-1 -isopropyl-3- methyl-6-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-indazole-4-carboxamide
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 %). 1 H NMR (DMSO-d6, 400 MHz) : 50.930 (t, J = 7.6 Hz, 3H), 1.468 (d, J = 6.4 Hz, 6H), 1 .544-1 .601 (m, 2H), 2.123 (s, 3H), 2.452 (s, 3H), 2.501 (s, 2H), 4.394 (d, J = 4 Hz, 2H), 5.060-5.093 (m, 1 H), 5.902 (s, 1 H), 6.526 (s, 1 H), 7.420 (s, 1 H), 7.528 (s, 1 H), 7.996 (s, 1 H), 8.348 (s, 1 H), 8.445 (s, 1 H), 8.656 (s, 1 H), 1 1 .490 (brs, 1 H), 1 1 .735 (brs, 1 H). LCMS (ES+) m/z: 497.49
Example 82
N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6-(1 H- pyrazol-4-yl)-1 H-indazole-4-carboxamide
Figure imgf000101_0001
a) Methyl 1 -isopropyl-3-methyl-6-(1 H-pyrazol-4-yl)-1 H-indazole-4-carboxylate
Figure imgf000101_0002
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. 1H NMR (DMSO-d6, 400 MHz) : 51.470 (d, J = 6.4 Hz, 6H), 2.543 (s, 3H), 3.928 (s, 3H), 5.000 - 5.063 (m, 1 H), 7.822 (s, 1 H), 8.102 (d, J = 9.6 Hz, 2H), 8.374 (s, 1 H), 13.030 (brs, 1 H). LCMS (ES+) m/z: 299.25. b) 1 -isopropyl-3-methyl-6-(1 H-pyrazol-4-yl)-1 H-indazole-4-carboxylic acid
Figure imgf000102_0001
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.H20 (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). 1H NMR (DMSO-d6, 400 MHz) : 51.467 (d, J = 6.4 Hz, 6H), 2.568 (s,3H), 4.984-5.048 (m, 1 H), 7.790 (s, 1 H), 8.058 (s, 1 H), 8.219 (brs, 2H), 13.05 (brs, 2H). LCMS (ES+) m/z: 285.10 [M+H]. c) N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6- (1 H-pyrazol-4-yl)-1 H-indazole-4-carboxamide
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%). 1H NMR (DMSO-d6, 400 MHz): 51 .563 (d, J = 6.8 Hz, 6H), 2.207 (s, 3H), 2.455 (s, 3H), 2.556 (s, 3H), 4.616 (d, J = 6 Hz, 2H), 4.781 - 4.798 (m, 1 H), 5.899 (s, 1 H), 7.236 (s, 1 H), 7.488 (s, 1 H) 7.522 (s, 1 H), 7.797 (d, J = 9.6 Hz, 2H).LCMS (ES+) m/z: 419.45.
Example 83
N-((1 ,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1 -isopropyl-3-methyl-6- (pyridin-3-yl)-1 H-indazole-4-carboxamide
Figure imgf000102_0002
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%). 1H NMR (DMSO-d6, 400 MHz): 50.938 (t, J = 7.2 Hz, 3H), 1.447 (d, J = 6.8 Hz, 6H), 1.540-1.597 (m, 2H), 2.122 (s, 3H), 2.380 (s, 3H), 2.548 (t, J = 3.6 Hz, 2H), 4.369 (d, J = 5.2 Hz, 2H), 4.920 - 4.987 (m, 1 H), 5.899 (s, 1 H), 7.330 (s, 1 H), 7.869 (s, 1 H), 8.021 (s, 1 H), 8.293 (t, J = 4.8 Hz, 2H), 1 1.483 (brs, 1 H), 12.963 (brs, 1 H).-LCMS (ES+) m/z: 447.48.
Example 84
W-[(4,6-di methyl -2 -oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1 -(1 -methylethyl)-6- (6-methyl-3-pyridinyl)-1 H-indazole-4-carboxamide
Figure imgf000103_0001
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 collected as 75 mg (24%); 1H NMR (DMSO-d6, 400 MHz): 51 ,45 (d, J = 6.4 Hz, 3H), 2.1 1 (s, 3H), 2.24 (s, 3H), 2.49 (s, 3H), 2.51 (s, 3H), 4.36-4.38 (m, 2H), 5.03-5.09 (m, 1 H), 5.87 (s, 1 H), 7.36 (s, 1 H), 7.38 (s, 1 H), 8.01 (s, 1 H), 8.1 1 (d, J = 2.4 Hz, 1 H), 8.45 (s, 1 H), 8.89 (s, 1 H), 1 1 .48 (s, 1 H); LCMS (ES+) m/z: 444.21 . Example 85
6-[6-(dimethylamino)-3^yridinyl]-3-methyl-1 -(1 -m
1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide
Figure imgf000104_0001
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 collected as a white solid (49 mg, 56%); 1h NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3 H), 1 .45 (d, J=6.57 Hz, 6 H), 1 .51 - 1.6' (m, 2 H), 2.12 (s, 3 H), 2.42 (s, 3 H), 2.52 - 2.59 (m, 2 H), 3.08 (s, 6 H), 4.38 (d, J=5.05 Hz, 2 H) 4.96 - 5.09 (m, 1 H), 5.90 (s, 1 H), 6.75 (d, J=9.09 Hz, 1 H), 7.31 (d, J=1.26 Hz, 1 H), 7.86 (d J=1.26 Hz, 1 H), 7.96 (dd, J=8.97, 2.65 Hz, 1 H), 8.40 (t, J=4.93 Hz, 1 H), 8.55 (d, J=2.27 Hz, ' H), 1 1 .50 (s, 1 H); LCMS (ES+) m/z: 501 .1 .
Example 86
6-{3-[(dimethylamino)methyl]phenyl}-3-methyl-1 -(1 -methylethyl)-A -[(6-methyl-2-oxo-4- propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide
Figure imgf000104_0002
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 product was collected as a white solid (58 mg, 57 %) 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3 H) 1 .46 (d, J=6.57 Hz, 6 H) 1 .52 1.63 (m, 2 H) 2.10 - 2.21 (m, 9 H) 2.44 (s, 3 H) 2.52 - 2.59 (m, 2 H) 3.47 (s, 2 H) 4.38 (d, J=5.0! Hz, 2 H) 5.02 - 5.14 (m, 1 H) 5.90 (s, 1 H) 7.28 - 7.36 (m, 2 H) 7.44 (t, J=7.58 Hz, 1 H) 7.63 7.73 (m, 2 H) 7.92 (d, J=1 .26 Hz, 1 H) 8.47 (t, J=4.93 Hz, 1 H) 1 1.50 (s, 1 H); LCMS (ES+) m/z 514.3.
Example 87
6-{4-[(dimethylamino)methyl]phenyl}-3-methyl-1 -(1 -methylethyl)-A -[(6-methyl-2-oxo-4- propyl-1 ,2-dihydro-3^yridinyl)methyl]-1 H-indazole-4-carboxamide
Figure imgf000105_0001
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 product was collectec as a white solid (72 mg, 70%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3 H) 1.45 (d, J=6.57 Hz, 6 H), 1 .56 (sxt, J=7.53 Hz, 2 H), 2.07 - 2.23 (m, 9 H), 2.44 (s, 3H), 2.52 - 2.5< (m, 2 H), 3.43 (s, 2 H), 4.38 (d, J=5.05 Hz, 2 H), 5.06 (quin, J=6.63 Hz, 1 H), 5.90 (s, 1 H), 7.33 7.45 (m, 3 H), 7.75 (d, J=8.08 Hz, 2 H), 7.93 (d, J=1.26 Hz, 1 H), 8.45 (t, J=4.93 Hz, 1 H), 1 1.5( (s, 1 H); LCMS (ES+) m/z: 514.5. Example 88
3-methyl-1 -(1 -methylethyl)-A -[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6- (3-pyridinyl)-1 H-indazole-4-carboxamide
Figure imgf000106_0001
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 product was collected as a white solid (.097g, 95%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.33 Hz, 3 H), 1.46 (d, J=6.57 Hz, 6 H), 1 .51 - 1.64 (m, 2 H), 2.12 (s, 3 H), 2.45 (s, 3 H), 2.54 (dd, J=8.72, 6.95 Hz, 2 H), 4.38 (d, J=5.05 Hz, 2 H), 5.08 (quin, J=6.57 Hz, 1 H) ,5.90 (s, 1 H), 7.40 (d, J=1.52 Hz, 1 H), 7.52 (dd, J=8.46, 5.18 Hz, 1 H), 8.07 (d, J=1 .52 Hz, 1 H), 8.21 (dt, J=8.27, 1 .80 Hz, 1 H), 8.46 (t, J=4.93 Hz, 1 H), 8.59 (dd, J=4.67, 1 .64 Hz, 1 H), 9.03 (d, J=1 .52 Hz, 1 H), 1 1 .51 (s, 1 H); LCMS (ES+) m/z: 457.2.
Example 89
3-methyl-1 -(1 -methylethyl)-A -[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6- [6-(4-methyl-1 -piperazinyl)-3-pyridinyl]-1H-indazole-4-carboxamide
Figure imgf000106_0002
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 title compound was collected as a white solid (0.105 g, 84%); 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.33 Hz, 3 H), 1.45 (d, J=6.57 Hz, 6 H), 1.50 - 1 .63 (m, 2 H), 2.12 (s, 3 H), 2.22 (s, 3 H), 2.38 - 2.45 (m, 7 H), 2.52 - 2.59 (m, 2 H), 3.51 - 3.60 (m, 4 H), 4.37 (d, J=5.05 Hz, 2 H), 4.96 - 5.10 (m, 1 H), 5.90 (s, 1 H), 6.94 (d, J=8.84 Hz, 1 H), 7.32 (d, J=1 .26 Hz, 1 H), 7.89 (d, J=1.26 Hz, 1 H), 7.98 (dd, J=8.84, 2.53 Hz, 1 H), 8.40 (t, J=5.05 Hz, 1 H), 8.56 (d, J=2.27 Hz, 1 H), 1 1.50 (s, 1 H); LCMS (ES+) m/z: 556.1.
Example 90
6-cyano-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-3- methyl-1 H-indazole-4-carboxamide
Figure imgf000107_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo- 1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1 -(1-methylethyl)-1 H-indazole-4-carboxamide (130 mg, 0.3 mmol), dicyanozinc (40.7 mg, 0.35 mmol), Pd2(dba)3 (317 mg, 0.35 mmol), dppf (21.7 mg, 0.04 mmol) and zinc (4.9 mg, 0.08 mmol) in DMF (4 ml.) and the resulting mixture was degassed with nitrogen for 10 min. 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 Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). 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 solids that precipitated were filtered and dried to afford the title compound as a white solid (70.3 mg, 60%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1.39 (br. s., 1 H) 8.56 (t, J=4.80 Hz, 1 H) 8.43 (d, J=1.01 Hz, 1 H) 7.35 (d, J=1.01 Hz, 1 H) 5.88 (s, 1 H) 5.04 (quin, J=6.57 Hz, 1 H) 4.35 (s, 1 H) 4.34 (s, 1 H) 2.43 (s, 3 H) 2.23 (s, 3 H) 2.12 (s, 3 H) 1.46 (s, 3 H) 1.44 (s, 3 H); LC-MS (ES) m/z = 378.3[M+H]+ Example 91
1 -cyclopentyl-6-(cycl thyl-2-oxo-1 ,2-dihydropyridin-3- yl)methyl)-1 H-indazo
Figure imgf000108_0001
To a 10-mL microwave tube were added 6-bromo-1 -cyclopentyl-N-[(4,6-dimethyl-2-oxo- 1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4-carboxamide (70 mg, 0.158 mmol), cyclopropanesulfinic acid (40.8 mg, 0.316 mmol), dimethyl sulfoxide (3 ml_), Ν,Ν'- dimethyl-1 ,2-ethanediamine methyl[2-(methylamino)ethyl]amine (55.7 mg, 0.632 mmol), and copper(ll) trifluoromethanesulfonate (57.1 mg, 0.158 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. The tube was sealed and the mixture irradiated at 120 °C (microwave) for 3h. The mixture was filtered and the DMSO solution was purified using reverse-phase HPLC to give 45 mg of product. The product was collected as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .00 - 1.12 (m, 2 H), 1.15 - 1.31 (m, 2 H), 1.67 - 1.79 (m, 2 H), 1 .84 - 1.94 (m, 2 H), 1 .96 - 2.08 (m, 2 H), 2.12 - 2.28 (m, 8 H), 2.93 - 3.05 (m, 1 H), 4.38 (d, J = 5.05 Hz, 2 H), 5.43 (quin, J = 7.01 Hz, 1 H), 5.90 (s, 1 H), 8.01 (d, J=1 .26 Hz, 1 H), 8.44 (s, 1 H), 8.52 (s, 1 H), 8.83 (t, J = 4.93 Hz, 1 H) , 1 1 .57 (s, 1 H); LCMS: (M+H)+=469.0
Example 92
6-(cyclopropylsulfonyl)- -1 ,2-dihydropyridin-3-yl)methyl)-1 - isopropyl-1 H-indazole-4
Figure imgf000108_0002
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). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 - 1 .16 (m, 5 H), 1.19 - 1.27 (m, 2 H), 1 .50 (d, J = 6.57 Hz, 6 H), 2.15 (s, 3 H), 2.58 (m, 2 H), 2.97 (m, 1 H), 4.41 (d, J = 4.80 Hz, 2 H), 5.26 (m, 1 H), 5.94 (s, 1 H), 8.01 (d, J = 1.26 Hz, 1 H), 8.43 (s, 1 H), 8.53 (s, 1 H), 8.83 (m, 1 H), 1 1 .58 (s, 1 H); LCMS: (M+H)+=457.0
Example 93
N -((4-ethy I -6-methy I -2 -oxo-1 ,2 -d i hyd
1 H-indazole-4-carboxamide
Figure imgf000109_0001
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. The product was collected as a white solid (21 mg) 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.06 - 1.17 (m, 3 H), 1.47 - 1.56 (m, 6 H), 2.15 (s, 3 H) ,2.58 (q, J = 7.58 Hz, 2 H), 3.03 (s, 3 H), 4.33 - 4.47 (m, 2 H), 5.17 - 5.30 (m, 1 H), 5.94 (s, 1 H), 8.01 (d, J = 1.26 Hz, 1 H), 8.45 (m, 1 H), 8.53 (s, 1 H), 8.78 (t, J = 4.93 Hz, 1 H); LCMS: (M+H)+=431.1
Example 94
W-[(4,6-di methyl -2 -oxo-1 ,2 ethyl]-1 -(1 -methylethyl)-6- (methylsulfonyl)-1 H-indaz
Figure imgf000109_0002
To a 10 mL microwave vial containing a stirring mixture of L-valine (8.42 mg, 0.072 mmol), NaOH (0.024 mL, 0.072 mmol), and DMSO (1.6 mL) were added sodium methanesulfinate (0.065 g, 0.539 mmol), copper(l) iodide (6.85 mg, 0.036 mmol) and 1 -Ethyl-3-methylimidazoliym bromide (0.014 g, 0.072 mmol). After stirring for 15 min, 6-bromo-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide (0.15 g, 0.359 mmol) was added. The reaction vial was sealed and the mixture was stirred with heating at 90 °C (heat block) for 18h. The contents were then irradiated (microwave) at 130 °C for 2hr. After cooling to RT, the reaction mixture was poured onto 50 mL of water and stirred. The contents were extracted with hot 30%THF/EtOAc (2x) (need to heat to break up emulsion). The combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: 5-75% chloroform (containing 10% 2M ammonia in methanol) and dichloromethane. The isolated product was concentrated from DCM and MTBE, and dried under hi vacuum. The title compound was collected as 75 mg (49%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.57 Hz, 6 H) 2.13 (s, 3 H) 2.22 (s, 3 H) 3.30 (s, 3 H) 4.38 (d, J=4.80 Hz, 2 H) 5.23 (quin, J=6.57 Hz, 1 H) 5.90 (s, 1 H) 8.02 (d, J=1 .01 Hz, 1 H) 8.45 (s, 1 H) 8.52 (s, 1 H) 8.77 (t, J=4.80 Hz, 1 H) 1 1 .56 (s, 1 H); LCMS: (M+H)+= 417.1.
Methyl 1 -(1 -methylethyl)-6-nitro-1 H-indazole-4-carboxylate
Figure imgf000110_0001
Sodium hydride (1 .142 g, 45.2 mmol) was added to Ν,Ν-Dimethylformamide (DMF) (100 mL) which was cooled in a ice water bath. A DMSO solution (20 mL) of methyl 6-nitro- 1 H-indazole-4-carboxylate (5 g, 22.61 mmol) was then added dropwise. After 15 minutes was added 2-bromopropane (4.25 mL, 45.2 mmol) dropwise and the contents were stirred at room temperature for 16 hours. Next added iodomethane (2.83 mL, 45.2 mmol) and let stir at room temperature for 3 hours followed by heating at 50 °C for 3 hours. The solvent was removed in vacuo. The residue was purified via silica gel chromatography (eluent: 0% to 25% EtOAc:Hex) to afford the product as 1.39 g (23%). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.07 (s, 3 H), 8.61 - 8.63 (m, 1 H), 8.64 (s, 1 H), 8.73 (d, J=2.02 Hz, 1 H) ; LCMS(ES) [M+H]+264.0 Methyl 6-amino-1 -(1 -methylethyl)-1 H-indazole-4-carboxylate
Figure imgf000111_0001
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 H2 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%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.58 (d, J=6.57 Hz, 6 H), 4.00 (s, 5 H), 4.70 (dt, J=13.39, 6.69 Hz, 1 H), 6.80 (s, 1 H), 7.37 (d, J=2.02 Hz, 1 H), 8.30 (s, 1 H). LCMS(ES) [M+H]+234.0
Methyl 6-(chlorosulfonyl)-1 -(1 -methylethyl)-1 H-indazole-4-carboxylate
Figure imgf000111_0002
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 S02, 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. The residue was suspended in 100 mL DCM, washed with water (2 x 50 mL), dried (MgS04), filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (eluent : 0% to 10 gradient EtOAc:Hex). The product was collected as 510 mg (75%). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.68 (d, 6 H), 4.09 (s, 3 H), 5.01 (dt, J=13.33, 6.60 Hz, 1 H), 8.40 (s, 1 H), 8.51 (d, J=1.52 Hz, 1 H), 8.70 (s, 1 H). LCMS(ES) [M+H]+317.0 Methyl 1 -(1 -methylethyl)-6-(4-morpholinylsulfonyl)-1 H-indazole-4-carboxylate
Figure imgf000112_0001
A solution of morpholine (0.030 mL, 0.347 mmol), triethylamine (0.055 mL, 0.395 mmol) and dichloromethane (DCM) (20 mL) were cooled in an ice-water bath. A DCM solution (5 mL) of methyl 6-(chlorosulfonyl)-1 -(1 -methylethyl)-1 H-indazole-4-carboxylate (100 mg, 0.316 mmol) was added dropwise. The contents were stirred at room temperature for 10 min. The contents were then washed with water, brine, dried over MgS04, filtered, and concentrated in vacuo. The product was collected as 90 mg (77%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67 (d, 6 H), 2.99 - 3.19 (m, 4 H), 3.75 - 3.86 (m, 4 H), 4.08 (s, 3 H), 4.98 (ddd, J=13.26, 6.82, 6.69 Hz, 1 H), 8.14 (s, 1 H), 8.22 (d, J=1.26 Hz, 1 H), 8.65 (s, 1 H); LCMS(ES) [M+H]+368.0
The following intermediates were prepared using the general procedures outlined for the above compound from methyl 6-(chlorosulfonyl)-1-(1-methylethyl)-1 H-indazole-4- carboxylate and the appropriate amine.
Methyl 6-[(cyclopropylamino)s yl)-1H-indazole-4-carboxylate
Figure imgf000112_0002
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.57 - 0.76 (m, 4 H), 1.66 (d, J=6.82 Hz, 6 H), 2.22 - 2.39 (m, 1 H), 4.07 (s, 3 H), 4.89 - 5.17 (m, 2 H), 8.33 (s, 1 H), 8.36 (d, J=1.26 Hz, 1 H), 8.63 (s, 1 H); LCMS(ES) [M+H]+324.4
Methyl 1 -(1 -methylethyl)-6-(1 -pyrrolidinylsulfonyl)-1 H-indazole-4-carboxylate
Figure imgf000112_0003
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .62 - 1.74 (m, 6 H), 1.85 (ddd, J=6.57, 3.66, 3.41 Hz, 4 H), 3.37 (t, J=6.69 Hz, 4 H), 5.01 (spt, J=6.65 Hz, 1 H), 8.30 (s, 1 H), 8.42 (d, J=1.26 Hz, 1 H), 8.69 (s, 1 H); LCMS(ES) [M+H]+338.3
Methyl 6-({[3-(dimethylamino)propyl]amino}sulfonyl)-1 -(1 -methylethyl)-1 H-indazole- 4-carboxylate
Figure imgf000113_0001
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .60 - 1.67 (m, 6 H), 1.74 (quin, J=5.81 Hz, 2 H), 2.37 (s, 6 H), 2.55 (t, J=5.81 Hz, 2 H), 3.07 - 3.16 (m, 2 H), 4.04 (s, 3 H), 4.98 (dt, J=13.33, 6.60 Hz, 1 H), 8.30 (d, J=1.77 Hz, 2 H), 8.59 (s, 1 H). LCMS(ES) [M+H]+383.1
Methyl 1 -(1 -methylethyl)-6-[(p indazole-4-carboxylate
Figure imgf000113_0002
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .53 (d, 6 H), 4.01 (s, 3 H), 4.81 (dt, J=13.33, 6.60 Hz, 1 H), 6.94 (s, 1 H), 7.02 - 7.16 (m, 3 H), 7.20 - 7.26 (m, 2 H), 8.04 (s, 1 H), 8.32 (d, J=1.26 Hz, 1 H), 8.55 (s, 1 H). LCMS(ES) [M+H]+ 373.9
1 -(1 -methylethyl)-6-(4-morpholinylsulfonyl)-1 H-indazole-4-carboxylic acid
Figure imgf000113_0003
Sodium hydroxide (0.980 mL, 0.980 mmol) was added to a solution of methyl 1-(1- methylethyl)-6-(4-morpholinylsulfonyl)-1 H-indazole-4-carboxylate (90 mg, 0.245 mmol) in ethanol (30 mL) and heated at reflux for 1 hour. The solvent was removed in vacuo and the residue suspended in water (20 mL). The contents were acidifed by addition of acetic acid, and extracted with DCM (4 x 30 mL). The combined organic layers were washed with water, brine, dried over MgS04, filtered, and concentrated in vacuo. The product was collected as 90 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .63 - 1.78 (m, 6 H), 3.02 - 3.24 (m, 4 H), 3.67 - 3.88 (m, 4 H), 5.00 (dt, J=13.20, 6.66 Hz, 1 H), 8.21 (s, 1 H), 8.31 (s, 1 H), 8.71 (s, 1 H), LCMS(ES) [M+H]+354.2
The following intermediates were prepared using the general procedure outlined for the above compound.
6-[(cyclopropylamino)sulfonyl]-1 -(1 -methylethyl)-1H-indazole-4-carboxylic acid
Figure imgf000114_0001
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.62 - 0.72 (m, 4 H), 1.67 (d, J=6.57 Hz, 6 H), 2.27 - 2.44 (m, 1 H), 5.02 (spt, J=6.61 Hz, 1 H), 5.37 (s, 1 H), 8.41 (s, 1 H), 8.44 (d, J=1.52 Hz, 1 H), 8.65 (s, 1 H); LCMS(ES) [M+H]+324.4
1 -(1 -methylethyl)-6-(1 -pyrrolidinylsulfonyl)-1 H-indazole-4-carboxylic acid
Figure imgf000114_0002
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .62 - 1.74 (m, 6 H), 1.85 (ddd, J=6.57, 3.66, 3.41 Hz, 4 H), 3.37 (t, J=6.69 Hz, 4 H), 5.01 (spt, J=6.65 Hz, 1 H), 8.30 (s, 1 H), 8.42 (d, J=1.26 Hz, 1 H), 8.69 (s, 1 H); LCMS(ES) [M+H]+338.3
6-({[3-(dimethylamino)propyl]amino}sulfonyl)-1 -(1 -methylethyl)-1H-indazole-4- carboxylic acid
Figure imgf000114_0003
1H NMR (400 MHz, DMSO-d6) δ ppm 1 .50 (d, 6 H), 1.62 (qd, J=7.07, 6.82 Hz, 2 H), 2.30 (s, 6 H), 2.82 (t, J=6.82 Hz, 2 H), 5.19 (dt, J=13.14, 6.57 Hz, 1 H), 7.98 (d, J=8.59 Hz, 1 H), 8.13 (d, J=1.26 Hz, 1 H), 8.32 (s, 1 H), 8.55 (s, 1 H); LCMS(ES) [M+H]+ 368.9
1 -(1 -methylethyl)-6-[(phenylamino)sulfonyl]-1 H-indazole-4-carboxylic acid
Figure imgf000115_0001
1H NMR (400 MHz, MeOD) δ ppm 1 .52 (d, J=6.82 Hz, 6 H), 4.98 (ddd, J=13.26, 6.82, 6.69 Hz, 1 H), 7.00 - 7.16 (m, 3 H), 7.18 - 7.28 (m, 2 H), 8.15 (s, 1 H), 8.25 (d, J=1.52 Hz, 1 H), 8.52 (s, 1 H); LCMS(ES) [M+H]+ 360.1
Example 95
N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)-6-(4- morpholinylsulfonyl)-1 H-indazole-4-carboxamide
Figure imgf000115_0002
1-(1-methylethyl)-6-(4-morpholinylsulfonyl)-1 H-indazole-4-carboxylic acid (90 mg, 0.255 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1 H)-pyridinone (62.5 mg, 0.331 mmol), 1- hydroxy-7-azabenzotriazole (69.3 mg, 0.509 mmol), EDC (98 mg, 0.509 mmol) and N- methylmorpholine (0.1 12 mL, 1 .019 mmol) were added to Dimethyl Sulfoxide (DMSO) (10 mL) and stirred at room temperature for 16 hours. Next added 40 mL of water and stirred for 10 minutes. The contents were extracted with DCM (5 x 30 mL), washed with water, dried (MgS04), filtered, and concentrated in vacuo. The residue was purified via chromatography (eluent : 0% to 100% gradient Hex:EtOAc then 0 to 10% MeOH:EtOAc). The product was collected as 1 10 mg (88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .50 (d, 6 H), 2.13 (s, 3 H), 2.23 (s, 3 H), 2.89 - 3.05 (m, 4 H), 3.54 - 3.71 (m, 4 H), 4.38 (d, J=4.80 Hz, 2 H), 5.27 (dt, J=13.07, 6.47 Hz, 1 H), 5.90 (s, 1 H), 7.80 (d, J=1.01 Hz, 1 H), 8.29 (s, 1 H), 8.52 (s, 1 H), 8.88 (t, J=5.05 Hz, 1 H), 1 1.56 (br. s., 1 H); LCMS(ES) [M+H]+488.3
Examples 96-99 were prepared using the general procedures outlined for the above compound.
Example 96
6-[(cyclopropylamino)sulfonyl]-A -[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide
Figure imgf000116_0001
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.42 - 0.65 (m, 4 H), 1.61 (d, J=6.57 Hz, 6 H), 2.19 (dt, J=6.63, 3.38 Hz, 1 H), 2.25 (s, 3 H), 2.45 (s, 3 H), 4.63 (d, J=5.56 Hz, 2 H), 4.95 (quin, J=6.63 Hz, 1 H), 6.02 (s, 1 H), 6.32 (br. s., 1 H), 8.17 (s, 1 H), 8.20 (s, 1 H), 8.25 (t, J=5.18 Hz, 1 H), 8.60 (s, 1 H), 1 1.46 (br. s., 1 H); LCMS(ES) [M+H]+ 458.1
Example 97
W-[(4,6-di methyl -2 -oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)-6-(1 - pyrrolidinylsulfonyl)-1 H-indazole-4-carboxamide
Figure imgf000116_0002
1H NMR (400 MHz, DMSO-de) δ ppm 1 .49 (d, 6 H), 1 .58 - 1 .71 (m, 4 H), 2.13 (s, 3 H), 2.23 (s, 3 H), 3.18 - 3.29 (m, 4 H), 4.38 (d, J=5.05 Hz, 2 H), 5.28 (quin, J=6.57 Hz, 1 H), 5.90 (s, 1 H), 7.89 (d, J=1 .01 Hz, 1 H), 8.33 (s, 1 H), 8.51 (s, 1 H), 8.90 (t, J=4.93 Hz, 1 H), 1 1 .56 (s, 1 H); LCMS(ES) [M+H]+ 472.4 Example 98
6-({[3-(dimethylamino)propyl]amino}sulfonyl)-yV-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide
Figure imgf000117_0001
1H NMR (400 MHz, DMSO-de) δ ppm 1 .37 - 1.54 (m, 8 H), 1 .97 (s, 6 H), 2.05 - 2.17 (m, 5 H), 2.22 (s, 3 H), 2.78 (t, J=6.95 Hz, 2 H), 4.36 (d, J=4.55 Hz, 2 H), 5.16 (quin, J=6.57 Hz, 1 H), 5.89 (s, 1 H), 7.87 (s, 1 H), 8.25 (s, 1 H), 8.43 (s, 1 H), 8.53 (s, 0 H), 8.73 (br. s., 1 H); LCMS(ES) [M+H]+ 502.9
Example 99
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 -isopropyl-6-((4- methylpiperazin-1 -yl)sul
Figure imgf000117_0002
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .62 (d, J=6.82 Hz, 6 H), 2.27 (d, J=6.32 Hz, 6 H), 2.43 (s, 3 H), 2.52 (br. s., 4 H), 3.14 (br. s., 4 H), 4.65 (d, J=5.81 Hz, 2 H), 4.93 (dq, J=6.82, 6.65 Hz, 1 H), 5.99 (s, 1 H), 7.86 (s, 1 H), 8.01 (s, 1 H), 8.06 - 8.16 (m, 1 H), 8.56 (s, 1 H), 12.02 (br. s., 1 H); LCMS(ES) [M+H]+ 501 .0. Example 100
6^romo-N-((4-(sec-butyl)-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1 - isopropyl 1 H-indazole-4-carboxamide
Figure imgf000118_0001
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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.53 (s, 1 H), 8.62 (t, J=4.7 Hz, 1 H), 8.37 (s, 1 H), 8.20 (s, 1 H), 7.70 (d, J=1 .5 Hz, 1 H), 5.96 (s, 1 H), 5.05 (quin, J=6.6 Hz, 1 H), 4.41 (d, J=4.3 Hz, 2 H), 2.95 (q, J=7.1 Hz, 1 H), 2.15 (s, 3 H), 1 .48 (m, 8 H), 1 .07 (d, J=6.6 Hz, 3 H), 0.74 (t, J=7.3 Hz, 3 H). LC-MS(ES) [M+H]+ 459.2.
Example 101
6-Bromo-1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-1 H-indazol
Figure imgf000118_0002
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) and 1 -hydroxy-7- azabenzotriazole (57.7 mg, 0.42 mmol) were stirred in 3 mL of DMSO for 10 min under nitrogen. 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. Then 10% K2C03 was added to adjust the pH to about 8-9. Then the reaction was stirred at room temperature for 10 min and let stand for 10 min. Solids were filtered off, dissolved in DMF and water was added. Solids that precipitated out were filtered off, air-dried for 15 min and dried in vacuum oven for 2 h to give the title compound (94 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 8.62 (t, J=4.93 Hz, 1 H) 8.37 (s, 1 H) 8.20 (s, 1 H) 7.69 (d, J=1.26 Hz, 1 H) 5.91 (s, 1 H) 5.06 (dt, J=13.14, 6.57 Hz, 1 H) 4.36 (d, J=4.80 Hz, 2 H) 2.14 (s, 3 H) 1 .48 - 1.56 (m, 2 H) 1 .47 (s, 3 H) 1 .45 (s, 3 H) 0.89 (t, J=7.33 Hz, 3 H); MS(ES) [M+H]+ 445.1 , 446.9.
Example 102
6-Bromo-1 -(1 -methylethyl ylethyl)-2-oxo-1 ,2-dihydro-3- pyridinyl]methyl}-1 H-inda
Figure imgf000119_0001
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. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1.53 (s, 1 H) 8.63 (t, J=4.80 Hz, 1 H) 8.37 (s, 1 H) 8.20 (s, 1 H) 7.69 (d, J=1 .26 Hz, 1 H) 6.02 (s, 1 H) 5.05 (quin, J=6.57 Hz, 1 H) 4.41 (d, J=4.80 Hz, 2 H) 3.21 (quin, J=6.76 Hz, 1 H) 2.16 (s, 3 H) 1.47 (s, 3 H) 1.45 (s, 3 H) 1.1 1 (s, 3 H) 1.09 (s, 3 H); MS(ES) [M+H]+ 445.1 , 446.9.
Example 103
methyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1 -methylethyl)-6-phenyl-1 H- indazole-4-carboxamide
Figure imgf000119_0002
To a mixture of 6-bromo-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 - (1 -methylethyl)-1 H-indazole-4-carboxamide (0.15g, 0.359 mmol), phenylboronic acid (0.088 g, 0.719 mmol) and potassium phosphate (tribasic) (0.229 g, 1 .078 mmol) was added 1 ,4-dioxane (3 ml.) and water (0.75 ml_). The suspension was degassed with N2 for 10 min, at which time PdCI2(dppf)-CH2CI2 (0.044 g, 0.054 mmol) was added and the sealed reaction heated at 100 °C overnight. Diluted reaction with EtOAc and filtered through Celite, washing with EtOAc and concentrating in vacuo to a residue that was dissolve in a minimum amount of DCM. Purification by silica gel chromatography (12 gram Isco GOLD silica column; Gradient B: 5-80%; A: dichloromethane, B: 10% (2 M ammonia in methanol) in chloroform) gave N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-6-phenyl-1 H-indazole-4-carboxamide (0.105g, 0.248 mmol, 69.1 % yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.57 Hz, 6 H) 2.12 (s, 3 H) 2.22 (s, 3 H) 4.39 (d, J=4.80 Hz, 2 H) 5.10 - 5.24 (m, 1 H) 5.89 (s, 1 H) 7.37 - 7.46 (m, 1 H) 7.48 - 7.55 (m, 2 H) 7.82 - 7.93 (m, 3 H) 8.12 (s, 1 H) 8.38 (s, 1 H) 8.66 (t, J=4.93 Hz, 1 H) 1 1.54 (s, 1 H). MS(ES) [M+H]+ 415.1.
Example 104
methyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1 -methylethyl)-6-(4-pyridinyl)- 1 H-indazole-4-carboxamide
Figure imgf000120_0001
To a mixture of 6-bromo-N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 - (1 -methylethyl)-1 H-indazole-4-carboxamide (0.15g, 0.359 mmol),4-pyridinylboronic acid (0.088 g, 0.647 mmol) and potassium phosphate (tribasic) (0.229 g, 1 .078 mmol) was added 1 ,4-dioxane (3 ml.) and water (0.75 ml_). The suspension was degassed with N2 for 10 min, at which time PdCI2(dppf)-CH2CI2 (0.044 g, 0.054 mmol) was added and the sealed reaction heated at 100 °C overnight (reaction got very dark). Diluted reaction with EtOAc and filtered through Celite, washing with EtOAc and concentrated in vacuo to a residue that was dissolved in a minimum amount of DCM. Purification by silica gel chromatography (12 gram Isco GOLD silica column; Gradient B: 5-90%; A:
dichloromethane, B: 10% (2 M ammonia in methanol) in chloroform) gave N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1-methylethyl)-6-(4-pyridinyl)-1 H- indazole-4-carboxamide (1 12 mg, 0.264 mmol, 73.5 % yield). 1H NMR (400 MHz, DMSO- d6) δ ppm 1 .51 (d, J=6.57 Hz, 6 H) 2.12 (s, 3 H) 2.22 (s, 3 H) 4.40 (d, J=4.80 Hz, 2 H) 5.15 - 5.27 (m, 1 H) 5.89 (s, 1 H) 7.90 - 8.00 (m, 3 H) 8.34 (s, 1 H) 8.43 (s, 1 H) 8.65 - 8.75 (m, 3 H) 1 1.55 (s, 1 H). MS(ES) [M+H]+ 416.1. Example 105
/V-[(4,6-Dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-6-{4- [(methylamino)sulfonyl]phenyl}-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide
Figure imgf000121_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1 H-indazole-4- carboxamide (100 mg, 0.24 mmol), {4-[(methylamino)sulfonyl]phenyl}boronic acid (77 mg, 0.36 mmol) in DME/water (3 mL:1 ml_). PdCI2(dppf)-CH2CI2 (9.8 mg, 0.012 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (60.4 mg, 0.72 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 140 °C for 30 min. EtOAc was added and the solution was filtered thru Celite and evaporated. DCM/MeOH (1 :1 ) was added, it was pre- absorbed on silica gel and purified by Si02 chromatography (eluent: gradient 100% DCM to 90:10:1 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered, washed with DCM and dried to afford the title compound (67 mg, 54%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 9.87 (br. s., 1 H) 8.62 (t, J=4.80 Hz, 1 H) 8.37 (s, 1 H) 8.07 (s, 1 H) 7.82 - 7.86 (m, 3 H) 7.35 (s, 1 H) 7.32 (s, 1 H) 5.89 (s, 1 H) 5.15 (quin, J=6.63 Hz, 1 H) 4.39 (d, J=4.80 Hz, 2 H) 3.04 (s, 3 H) 2.22 (s, 3 H) 2.12 (s, 3 H) 1 .51 (s, 3 H) 1.49 (s, 3 H). MS(ES) [M+H]+ 507.9.
Example 106
W-[(4,6-Dimethyl-2-oxo-1 ,2-dihydro^
piperazinyl)-3-pyridinyl]-1 H-indazole-4-carboxamide
Figure imgf000122_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1 H-indazole-4- carboxamide (100 mg, 0.24 mmol), 1 -methyl-4-[5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-2-pyridinyl]piperazine (109 mg, 0.36 mmol) in DME/water (3 mL:1 ml_). PdCI2(dppf)- CH2CI2 (9.8 mg, 0.012 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (60.4 mg, 0.72 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 130 °C for 30 min. Solvent was evaporated, DCM was added and it was purified by Si02 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Further purification by reversed-phase HPLC (C18, 15% to 80% CH3CN in water with 0.1 % TFA, 12 minute gradient) afforded the TFA salt. The CH3CN was evaporated and the mixture was diluted with saturated sodium bicarbonate and EtOAc. The organic layer was separated and the aqueous layer was further extracted with DCM and DCM/isopropanol (80:20). The combined organic layers were washed with water, dried (MgS04), filtered and
concentrated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered and dried to afford the title compound (71 mg, 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.55 (br. s., 1 H) 8.66 (d, J=2.27 Hz, 1 H) 8.61 (t, J=4.93 Hz, 1 H) 8.36 (s, 1 H) 8.04 - 8.09 (m, 2 H) 7.84 (d, J=1.26 Hz, 1 H) 6.96 (d, J=8.84 Hz, 1 H) 5.89 (s, 1 H) 5.14 (quin, J=6.57 Hz, 1 H) 4.39 (d, J=5.05 Hz, 2 H) 3.52 - 3.60 (m, 4 H) 2.38 - 2.46 (m, 4 H) 2.22 (d, J=4.55 Hz, 6 H) 2.13 (s, 3 H) 1.50 (s, 3 H) 1 .49 (s, 3 H). MS(ES) [M+H]+ 514.5. Example 107
W-[(4,6-Dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1 -methylethyl)-6-(2-oxo-2,3- dihydro-1 H-ben -4-carboxamide
Figure imgf000123_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1 H-indazole-4- carboxamide (100 mg, 0.24 mmol), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3- dihydro-2H-benzimidazol-2-one (93 mg, 0.36 mmol) in dioxane/water (3 ml_:1 ml_).
PdCI2(dppf)-CH2Cl2 (9.8 mg, 0.012 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (60.4 mg, 0.72 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 130 °C for 20 min. DCM/MeOH (1 :1 ) was added, it was pre-absorbed on silica gel and purified by Si02 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH).
Fractions were evaporated. EtOH was added, it was sonicated and the solids that precipitated were filtered, washed with EtOH and DCM and dried to afford the title compound (43 mg, 37%) as a beige solid. 1H NMR (400 MHz, DMSO-c/6) 6ppm 1 1.53 (s, 1 H) 10.78 (s, 1 H) 10.74 (s, 1 H) 8.64 (t, J=4.80 Hz, 1 H) 8.35 (s, 1 H) 8.02 (s, 1 H) 7.81 (s, 1 H) 7.44 (dd, J=8.08, 1.77 Hz, 1 H) 7.36 - 7.39 (m, 1 H) 7.03 (d, J=8.08 Hz, 1 H) 5.89 (s, 1 H) 5.16 (quin, J=6.57 Hz, 1 H) 4.39 (d, J=4.80 Hz, 2 H) 2.21 (s, 3 H) 2.13 (s, 3 H) 1.50 (s, 3 H) 1.49 (s, 3 H). MS(ES) [M+H]+ 471 .3
Example 108
6-[6-(Acetylamino)-3-pyridinyl]-/\/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 - (1-methylethyl)-1 H-indazole-4-carboxamide
Figure imgf000123_0002
In a 25 ml. sealable tube under nitrogen were combined 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, 0.24 mmol), N-[5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- pyridinyl]acetamide (104 mg, 0.4 mmol) in DME/water (3 mL:1 ml_). PdCI2(dppf)-CH2CI2 (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 Si02 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added, it was sonicated and the solids that precipitated were filtered, washed with hexanes and dried to afford the title compound (91 mg, 72%) as a light beige solid. 1 H NMR (400 MHz, DMSO-c/6) δ ppm 1 1 .54 (s, 1 H) 10.65 (s, 1 H) 8.84 (d, J=2.27 Hz, 1 H) 8.64 (t, J=4.93 Hz, 1 H) 8.39 (s, 1 H) 8.25 - 8.30 (m, 1 H) 8.15 - 8.24 (m, 2 H) 7.89 - 7.93 (m, 1 H) 5.89 (s, 1 H) 5.18 (quin, J=6.63 Hz, 1 H) 4.40 (d, J=4.80 Hz, 2 H) 2.22 (s, 3 H) 2.13 (s, 3 H) 2.12 (s, 3 H) 1.51 (s, 3 H) 1 .50 (s, 3 H). MS(ES) [M+H]+ 473.1 .
Example 109
methyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1 -methylethyl)-6-(3-pyridinyl)- 1 H-indazole-4-carboxamide
Figure imgf000124_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1 H-indazole-4- carboxamide (120 mg, 0.29 mmol) and 3-pyridinylboronic acid (53 mg, 0.43 mmol) in DME/water (3 ml_:1 ml_). PdCI2(dppf)-CH2CI2 (1 1 .7 mg, 0.014 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (72.5 mg, 0.86 mmol) was added and the insoluble mixture was heated in a microwave at 120 °C for 20 min. It was evaporated and the residue was dissolved in DCM and purified by Si02 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. DMF was added along with some water and the solids that precipitated were filtered, washed with water and hexanes and dried to afford the title compound (74 mg, 61 %) as a light grey solid. 1H N MR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 9.1 1 (d, J=2.02 Hz, 1 H) 8.66 (t, J=4.80 Hz, 1 H) 8.61 (dd, J=4.80, 1.26 Hz, 1 H) 8.42 (s, 1 H) 8.28 (dt, J=8.02, 1 .93 Hz, 1 H) 8.25 (s, 1 H) 7.93 (s, 1 H) 7.54 (dd, J=7.83, 4.80 Hz, 1 H) 5.89 (s, 1 H) 5.19 (dt, J=13.14, 6.57 Hz, 1 H) 4.40 (d, J=4.80 Hz, 2 H) 2.22 (s, 3 H) 2.12 (s, 3 H) 1.52 (s, 3 H) 1.50 (s, 3 H). MS(ES) [M+H]+ 416.1.
Example 1 10
A/-[(4,6-Dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)-6-[6-(4- morpholinyl)-3-pyridinyl]-1 H-indazole-4-carboxamide
Figure imgf000125_0001
In a 25 mL sealable tube under nitrogen were combined 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, 0.26 mmol) and [6-(4-morpholinyl)-3-pyridinyl]boronic acid (82 mg, 0.39 mmol) in DME/water (3 ml_:1 mL). PdCI2(dppf)-CH2CI2 (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 and the insoluble mixture was heated in a microwave at 1 10 °C for 20 min. It was evaporated, DCM/MeOH (1 :1 ) was added, it was pre-absorbed on silica gel and purified by Si02 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOH was added, it was sonicated and the solids that precipitated were filtered, washed with hexanes and dried to afford the title compound (123 mg, 89%) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 8.69 (d, J=2.27 Hz, 1 H) 8.61 (t, J=4.93 Hz, 1 H) 8.36 (s, 1 H) 8.08 - 8.12 (m, 2 H) 7.85 (d, J=1.01 Hz, 1 H) 6.98 (d, J=8.84 Hz, 1 H) 5.89 (s, 1 H) 5.14 (quin, J=6.57 Hz, 1 H) 4.39 (d, J=5.05 Hz, 2 H) 3.71 - 3.75 (m, 4 H) 3.50 - 3.55 (m, 4 H) 2.22 (s, 3 H) 2.13 (s, 3 H) 1.50 (s, 3 H) 1.49 (s, 3 H). MS(ES) [M+H]+ 501.1. Example 1 1 1
A/-[(4,6-Dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)-6-[6-(methyloxy)-
3-pyridinyl]-1 H-indazole-4-carboxamide
Figure imgf000126_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1 H-indazole-4- carboxamide (120 mg, 0.29 mmol) and [6-(methyloxy)-3-pyridinyl]boronic acid (66 mg, 0.43 mmol) in DME/water (3 ml_:1 ml_). PdCI2(dppf)-CH2CI2 (1 1.7 mg, 0.014 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (72.5 mg, 0.86 mmol) was added and the insoluble mixture was heated in a microwave at 1 10 °C for 20 min. Water was added and the solids that precipitated were filtered. DCM was added and it was purified by Si02 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered. DMF was added along with some water and the solids that precipitated were filtered and dried to afford the title compound (57 mg, 43%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .54 (s, 1 H) 8.69 (d, J=2.27 Hz, 1 H) 8.62 (t, J=4.80 Hz, 1 H) 8.39 (s, 1 H) 8.22 (dd, J=8.72, 2.65 Hz, 1 H) 8.15 (s, 1 H) 7.87 (s, 1 H) 6.97 (d, J=8.59 Hz, 1 H) 5.89 (s, 1 H) 5.15 (dt, J=13.07, 6.47 Hz, 1 H) 4.39 (d, J=4.80 Hz, 2 H) 3.92 (s, 3 H) 2.22 (s, 3 H) 2.12 (s, 3 H) 1.51 (s, 3 H) 1.49 (s, 3 H). MS(ES) [M+H]+ 446.1 .
Example 1 12
/v-[(4,6-Dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)-6-[2- (trifluoromethyl)phenyl]-1 H-indazole-4-carboxamide
Figure imgf000126_0002
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1 H-indazole-4- carboxamide (100 mg, 0.24 mmol) and [2-(trifluoromethyl)phenyl]boronic acid (68.3 mg, 0.36 mmol) in dioxane/water (3 ml_:1 ml_). PdCI2(dppf)-CH2CI2 (9.78 mg, 0.012 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (60.4 mg, 0.72 mmol) was added and the insoluble mixture was heated in a microwave at 1 10 °C for 15 min. Water was added and the solids that precipitated were filtered off. DCM/MeOH (1 :1 ) was added, it was pre-absorbed on silica gel and purified by Si02 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered and dried to afford the title compound (87 mg, 74%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) 6ppm 1 1.52 (s, 1 H) 8.53 (t, J=4.80 Hz, 1 H) 8.43 (s, 1 H) 7.88 (d, J=7.83 Hz, 1 H) 7.81 (s, 1 H) 7.77 (t, J=7.45 Hz, 1 H) 7.66 (t, J=7.71 Hz, 1 H) 7.53 - 7.57 (m, 2 H) 5.87 (s, 1 H) 5.05 (dt, J=13.14, 6.57 Hz, 1 H) 4.35 (d, J=4.80 Hz, 2 H) 2.19 (s, 3 H) 2.10 (s, 3 H) 1.48 (s, 3 H) 1.47 (s, 3 H).
MS(ES) [M+H]+ 483.0.
Example 1 13
6-{4-[(Dimethylamino)sulfonyl]phenyl}-/\/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3- pyridinyl)methyl]-1 -(1 -methylethyl)-1 H-indazole-4-carboxamide
Figure imgf000127_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1 H-indazole-4- carboxamide (220 mg, 0.53 mmol) and {4-[(dimethylamino)sulfonyl]phenyl}boronic acid (181 mg, 0.79 mmol) in 3:1 dioxane/water (4 ml_). PdCI2(dppf)-CH2CI2 (21.5 mg, 0.026 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (133 mg, 1.58 mmol) was added and the insoluble mixture was heated in a microwave at 1 10 °C for 20 min. Water was added and the solids that precipitated were filtered. Purification by reversed-phase HPLC (C18, 15% to 80% CH3CN in water with 0.1 % TFA, 12 minute gradient) afforded the TFA salt. Acetonitrile was evaporated off and the resulting mixture was diluted with saturated sodium bicarbonate. The solids that precipitated were filtered off. EtOAc /EtOH (5:1 ) was added, along with some hexanes, and the mixture was sonicated. The solids that precipitated were filtered off and dried to afford the title compound (132 mg, 47%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .49 (br. s., 1 H) 8.71 (t, J=4.42 Hz, 1 H) 8.43 (s, 1 H) 8.27 (s, 1 H) 8.15 (s, 1 H) 8.13 (s, 1 H) 7.94 (d, J=1.26 Hz, 1 H) 7.88 (s, 1 H) 7.86 (s, 1 H) 5.89 (s, 1 H) 5.21 (quin, J=6.57 Hz, 1 H) 4.40 (d, J=4.80 Hz, 2 H) 2.66 (s, 6 H) 2.21 (s, 3 H) 2.12 (s, 3 H) 1.52 (s, 3 H) 1.50 (s, 3 H). MS(ES) [M+H]+ 522.
Example 1 14
/v-[(4,6-Dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1 -methylethyl)-6-(2- methylphenyl)-1 H-indazole-4-carboxamide
Figure imgf000128_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-N-[(4,6- dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1 H-indazole-4- carboxamide (120 mg, 0.29 mmol) and [(2-methylphenyl)boronic acid (58.6 mg, 0.43 mmol) in dioxane/water (3 ml_:1 ml_). PdCI2(dppf)-CH2CI2 (1 1.74 mg, 0.014 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (72.5 mg, 0.86 mmol) was added and the insoluble mixture was heated in a microwave at 100 °C for 15 min. DCM/MeOH (1 :1 ) was added, it was pre-absorbed on silica gel and purified by Si02 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered and dried to afford the title compound (84 mg, 66%) as an off-white solid. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 1 .51 (s, 1 H) 8.55 (t, J=4.80 Hz, 1 H) 8.41 (s, 1 H) 7.80 (s, 1 H) 7.55 (d, J=1 .01 Hz, 1 H) 7.27 - 7.35 (m, 4 H) 5.87 (s, 1 H) 5.09 (quin, J=6.57 Hz, 1 H) 4.36 (d, J=5.05 Hz, 2 H) 2.26 (s, 3 H) 2.20 (s, 3 H) 2.1 1 (s, 3 H) 1.49 (s, 3 H) 1.47 (s, 3 H). MS(ES) [M+H]+ 429.1 . Example 1 15
6-Bromo-/V-[(4-cyclohexyl-6-methyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1-(1- methyleth l)-1 H-indazole-4-carboxamide
Figure imgf000129_0001
In a 25 ml. sealable tube under nitrogen were combined 6-bromo-1-(1- methylethyl)-1 H-indazole-4-carboxylic acid (237 mg, 0.84 mmol) and 3-(aminomethyl)-4- cyclohexyl-6-methyl-2(1 H)-pyridinone.TFA (434 mg, 1.3 mmol) in DMSO (10 ml_). 1- hydroxy-7-azabenzotriazole (194 mg, 1 .42 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. N-methylmorpholine (0.39 ml_, 3.52 mmol) and EDC (273 mg, 1 .42 mmol) were added, the vessel was sealed, and the mixture was stirred at room temperature for 2 days. The mixture was poured into 10 mL of ice-water and beige solids crashed out. K2C03 (10%) was added to adjust the pH~8-9 and the mixture stirred for 30 min and let stand for another 30 min. Solids were filtered off and air- dried. DMF was added, it was heated and sonicated and some water was added. Solids that precipitated were filtered, washed with water and dried to afford the title compound (307 mg, 73%) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .53 (s, 1 H) 8.63 (t, J=4.80 Hz, 1 H) 8.37 (s, 1 H) 8.20 (s, 1 H) 7.68 (d, J=1.26 Hz, 1 H) 6.01 (s, 1 H) 5.05 (dt, J=13.14, 6.57 Hz, 1 H) 4.43 (d, J=4.80 Hz, 2 H) 2.84 (t, J=1 1 .24 Hz, 1 H) 2.15 (s, 3 H) 1 .70 (d, J=13.39 Hz, 2 H) 1 .60 (d, J=12.13 Hz, 3 H) 1 .47 (s, 3 H) 1 .45 (s, 3 H) 1 .42 (br. s., 1 H) 1.17 - 1.39 (m, 4 H). MS(ES) [M+H]+ 485.2, 487.2.
Example 1 16
1-(1-Methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 H inda mide
Figure imgf000130_0001
6-Bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-phenyl-1 ,2-dihydro-3- pyridinyl)methyl]-1 H-indazole-4-carboxamide (70.3 mg, 0.15 mmol) in 3:1 EtOH/THF (4 ml.) was hydrogenated using Pd/C (10% wet Degussa type) and a balloon of hydrogen. The reactin mixture was stirred at room temperature overnight. It was filtered through Celite, washed with EtOAc and EtOH and the solvent was evaporated. DMF was added with some water and white solids that crashed out were filtered off, air-dried for 15 min and dried in a vacuum oven for 3 h. The residue was purified by Gilson reversed-phase HPLC (30x100 Varian Polaris C18, 15-80% gradient of MeCN in water with 0.1 % TFA over 12 minutes). Most of the solvent was removed and saturated NaHC03 was added. The solids that crashed out were filtered off, air-dried for 15 min and dried in vacuum oven overnight to give the title compound (19 mg, 37%). 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 1 .75 (br. s., 1 H) 8.63 (br. s., 1 H) 8.34 (s, 1 H) 7.85 (d, J=8.34 Hz, 1 H) 7.39 - 7.51 (m, 7 H) 5.99 (s, 1 H) 5.03 (quin, J=6.57 Hz, 1 H) 4.22 (d, J=4.29 Hz, 2 H) 2.21 (s, 3 H) 1.49 (s, 3 H) 1.47 (s, 3 H). MS(ES) [M+H]+ 367.2.
The following compounds were prepared using the general procedures outlined for Examples 103 - 1 16:
Example 1 17
6-Bromo-1 -cyclopentyl-/\/-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-1 H- indazole-4-carboxamide
Figure imgf000131_0001
1H NMR (400 MHz, DMSO-d6) 6ppm 1 1.54 (s, 1 H) 8.62 (t, J=4.80 Hz, 1 H) 8.36 (s, 1 H) 8.20 (s, 1 H) 7.69 (d, J=1.26 Hz, 1 H) 5.91 (s, 1 H) 5.22 (quin, J=7.01 Hz, 1 H) 4.36 (d, J=4.80 Hz, 2 H) 2.07 - 2.15 (m, 5 H) 1 .93 - 2.01 (m, 2 H) 1 .83 - 1.91 (m, 2 H) 1.65 - 1.73 (m, 2 H) 1 .47 - 1 .56 (m, 2 H) 0.89 (t, J=7.33 Hz, 3 H). MS(ES) [M+H]+ 471.2, 473.0.
Example 1 18
6-Bromo-/V-[(4-cyclopropyl-6-methyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 -(1- methylethyl -1 H-indazole-4-carboxamide
Figure imgf000131_0002
1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.48 (br. s., 1 H) 8.66 (t, J=4.67 Hz, 1 H) 8.32 - 8.38 (m, 1 H) 8.20 (s, 1 H) 7.71 (d, J=1.26 Hz, 1 H) 5.52 (s, 1 H) 5.06 (quin, J=6.57 Hz, 1 H) 4.53 (d, J=4.80 Hz, 2 H) 2.06 - 2.17 (m, 4 H) 1.47 (s, 3 H) 1.45 (s, 3 H) 0.89 - 0.97 (m, 2 H) 0.68 - 0.78 (m, 2 H). MS(ES) [M+H]+ 443.0, 445.1 .
Example 1 19
1-cyclopentyl-/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-py
piperazinyl)-4-pyridinyl]-1 H-indazole-4-carboxamide
Figure imgf000132_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 8.65 (t, J=4.80 Hz, 1 H) 8.39 (s, 1 H) 8.24 (s, 1 H) 8.21 (d, J=5.05 Hz, 1 H) 7.87 (s, 1 H) 7.21 (s, 1 H) 7.14 (d, J=5.31 Hz, 1 H) 5.89 (s, 1 H) 5.38 (quin, J=7A 4 Hz, 1 H) 4.39 (d, J=5.05 Hz, 2 H) 3.56 - 3.63 (m, 4 H) 2.44 (t, J=4.80 Hz, 4 H) 2.24 (s, 3 H) 2.22 (s, 3 H) 2.14 - 2.20 (m, 2 H) 2.12 (s, 3 H) 1.98 - 2.05 (m, 2 H) 1 .91 (dd, J=8.84, 5.56 Hz, 2 H) 1.68 - 1 .75 (m, 2 H). MS(ES) [M+H]+ 540.3.
Example 120
1 -Cyclopentyl-/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-1 H-indazole-4- carboxamide
Figure imgf000132_0002
1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.39 (br. s., 1 H) 8.50 (br. s., 1 H) 8.35 (s, 1 H) 7.85 (d, J=8.59 Hz, 1 H) 7.54 (d, J=7.07 Hz, 1 H) 7.40 (dd, J=8.46, 7.20 Hz, 1 H) 5.88 (s, 1 H) 5.21 (quin, J=7.01 Hz, 1 H) 4.36 (d, J=4.80 Hz, 2 H) 2.22 (s, 3 H) 2.09 - 2.16 (m, 6 H) 1 .96 - 2.04 (m, 2 H) 1.84 - 1 .92 (m, 2 H) 1 .66 - 1 .74 (m, 2 H). MS(ES) [M+H]+ 365.3. Example 121
6-Bromo-1 -(1 -methylethyl)-/V-[(6-methyl-2-oxo-4-phenyl-1 ,2-dihydro-3-pyridinyl)m
1 H-indazole-4-carboxamide
Figure imgf000133_0001
1 H NMR (400 MHz, DMSO-d6) 6ppm 1 1 .86 (br. s., 1 H) 8.60 (t, J=4.04 Hz, 1 H) 8.34 (s, 1 H) 8.21 (s, 1 H) 7.64 (d, J=1 .26 Hz, 1 H) 7.39 - 7.47 (m, 5 H) 6.00 (s, 1 H) 5.06 (dt, J=13.14, 6.57 Hz, 1 H) 4.17 (d, J=4.04 Hz, 2 H) 2.22 (s, 3 H) 1 .47 (s, 3 H) 1 .45 (s, 3 H). MS(ES) [M+H]+ 478.9, 480.8.
Example 122
1 -Cyclopentyl-A/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-6-(2-oxo-2,3- dihydro-1 H-benzimidazol-5-yl)-1 H-indazole-4-carboxamide
Figure imgf000133_0002
1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .53 (s, 1 H) 10.78 (s, 1 H) 10.74 (s, 1 H) 8.64 (t, J=4.80 Hz, 1 H) 8.34 (s, 1 H) 8.03 (s, 1 H) 7.79 - 7.84 (m, 1 H) 7.44 (dd, =Q.2^ , 1 .64 Hz, 1 H) 7.37 (s, 1 H) 7.03 (d, J=8.08 Hz, 1 H) 5.89 (s, 1 H) 5.34 (quin, J=7.14 Hz, 1 H) 4.39 (d, J=4.80 Hz, 2 H) 2.21 (s, 3 H) 2.15 - 2.19 (m, 1 H) 2.13 (s, 4 H) 1 .98 - 2.06 (m, 2 H) 1 .85 - 1 .94 (m, 2 H) 1 .67 - 1 .76 (m, 2 H). MS(ES) [M+H]+ 497.3. Example 123
1 -(1 -methylethyl)-/V-{[6-methyl-4-(1-methylethyl)-2-oxo-1 ,2-dihydro-3-pyridi
[2-(4-methyl-1 -piperazin l)-4-pyridinyl]-1 /-/-indazole-4-carboxamide
Figure imgf000134_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.51 (br. s., 1 H) 8.67 (t, J=4.55 Hz, 1 H) 8.39 (s, 1 H) 8.24 (s, 1 H) 8.20 (d, J=5.31 Hz, 1 H) 7.85 (d, J=1.01 Hz, 1 H) 7.21 (s, 1 H) 7.14 (dd, J=5.31 , 1 .26 Hz, 1 H) 6.03 (s, 1 H) 5.21 (quin, J=6.63 Hz, 1 H) 4.48 (br. s., 1 H) 4.46 (br. s., 1 H) 3.54 - 3.64 (m, 4 H) 3.25 (dt, J=13.64, 6.82 Hz, 1 H) 2.41 - 2.46 (m, 4 H) 2.24 (s, 3 H) 2.16 (s, 3 H) 1 .52 (s, 3 H) 1 .50 (s, 3 H) 1 .12 (s, 3 H) 1 .10 (s, 3 H). MS(ES) [M+H]+ 542.3.
Example 124
1-(1-Methylethyl)-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-(2- 2,3-dihydro-1 /-/-benzimidazol-5-yl)-1 /-/-indazole-4-carboxamide
Figure imgf000134_0002
1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 10.79 (s, 1 H) 10.74 (s, 1 H) 8.65 (t, J=4.93 Hz, 1 H) 8.35 (s, 1 H) 8.02 (s, 1 H) 7.80 (s, 1 H) 7.43 (dd, J=8.08, 1 .77 Hz, 1 H) 7.37 (s, 1 H) 7.03 (d, J=8.08 Hz, 1 H) 5.91 (s, 1 H) 5.16 (quin, J=6.63 Hz, 1 H) 4.42 (d, J=4.80 Hz, 2 H) 2.52 - 2.57 (m, 1 H) 2.14 (s, 3 H) 1 .51 - 1 .59 (m, 2 H) 1 .50 (s, 3 H) 1 .49 (s, 3 H) 0.89 (t, J=7.33 Hz, 3 H). MS(ES) [M+H]+ 499.3. Example 125
1-Cyclopentyl-/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-6-(6-m
pyridinyl -1 H-indazole-4-carboxamide
Figure imgf000135_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.45 (br. s., 1 H) 8.97 (d, J=2.27 Hz, 1 H) 8.69 (br. s., 1 H) 8.39 (s, 1 H) 8.21 (s, 1 H) 8.17 (dd, J=8.08, 2.53 Hz, 1 H) 7.90 (s, 1 H) 7.40 (d, J=8.08 Hz, 1 H) 5.89 (s, 1 H) 5.35 (quin, J=7.14 Hz, 1 H) 4.39 (d, J=4.80 Hz, 2 H) 2.54 (s, 3 H) 2.22 (s, 3 H) 2.16 (d, J=7.58 Hz, 2 H) 2.12 (s, 3 H) 1.98 - 2.06 (m, 2 H) 1.86 - 1.94 (m, 2 H) 1 .68 - 1 .76 (m, 2 H). MS(ES) [M+H]+ 456.0.
Example 126
1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-[2-(4- methyl-1-piperazinyl)-4-pyridinyl]-1 /-/-indazole-4-carboxamide
Figure imgf000135_0002
1H NMR (400 MHz, DMSO-d6) 6ppm 1 1.54 (s, 1 H) 8.65 (t, J=4.80 Hz, 1 H) 8.40 (s, 1 H) 8.24 (s, 1 H) 8.21 (d, J=5.30 Hz, 1 H) 7.86 (s, 1 H) 7.21 (s, 1 H) 7.14 (d, J=5.31 Hz, 1 H) 5.91 (s, 1 H) 5.21 (dt, J=13.14, 6.57 Hz, 1 H) 4.42 (d, J=4.80 Hz, 2 H) 3.56 - 3.63 (m, 4 H) 2.53 - 2.56 (m, 2 H) 2.44 (t, J=4.93 Hz, 4 H) 2.24 (s, 3 H) 2.13 (s, 3 H) 1 .52 - 1 .61 (m, 2 H) 1 .52 (s, 3 H) 1.50 (s, 3 H) 0.89 (t, J=7.33 Hz, 3 H). MS(ES) [M+H]+ 542.2. Example 127
1-Cyclopentyl-/V-[(6-methyl-2-oxo-4-propyM
pyridinyl -1 H-indazole-4-carboxamide
Figure imgf000136_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.46 (br. s., 1 H) 8.96 (d, J=2.02 Hz, 1 H) 8.70 (br. s., 1 H) 8.40 (s, 1 H) 8.21 (s, 1 H) 8.17 (dd, J=8.08, 2.53 Hz, 1 H) 7.89 (s, 1 H) 7.40 (d, J=8.08 Hz, 1 H) 5.91 (s, 1 H) 5.31 - 5.39 (m, 1 H) 4.42 (d, J=4.55 Hz, 2 H) 2.54 (s, 5 H) 2.12 - 2.20 (m, 5 H) 2.05 (br. s., 2 H) 1 .90 (dd, J=8.97, 5.68 Hz, 2 H) 1.67 - 1.76 (m, 2 H) 1.48 - 1.57 (m, 2 H) 0.88 (t, J=7.33 Hz, 3 H). MS(ES) [M+H]+ 484.2.
Example 128
1 -Cyclopentyl-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-(3-pyridinyl)-
1 H-indazole-4-carboxamide
Figure imgf000136_0002
1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.55 (br. s., 1 H) 9.14 (s, 1 H) 8.60 - 8.70 (m, 2 H) 8.42 (s, 1 H) 8.35 (d, J=8.08 Hz, 1 H) 8.28 (s, 1 H) 7.93 (d, J=1 .01 Hz, 1 H) 7.61 (dd, J=7.83, 4.80 Hz, 1 H) 5.92 (s, 1 H) 5.36 (quin, J=7A 4 Hz, 1 H) 4.43 (d, J=4.80 Hz, 2 H) 2.54 (d, J=6.82 Hz, 2 H) 2.12 - 2.21 (m, 5 H) 1 .99 - 2.07 (m, 2 H) 1 .86 - 1 .95 (m, 2 H) 1.67 - 1.77 (m, 2 H) 1 .48 - 1.57 (m, 2 H) 0.88 (t, J=7.33 Hz, 3 H). MS(ES) [M+H]+ 470.2. Example 129
1-(1 -Methylethyl)-A -[(6-methyl-2-oxo^-propyl-1 ,2-dihydro-3-pyridinyl)methyl]-6-(3- pyridinyl)-1 H-indazole-4-carboxamide
Figure imgf000137_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H) 9.1 1 (br. s., 1 H) 8.66 (t, J=4.80 Hz, 1 H) 8.62 (d, J=4.04 Hz, 1 H) 8.42 (s, 1 H) 8.28 (dt, J=8.21 , 1 .83 Hz, 1 H) 8.25 (s, 1 H) 7.92 (d, J=1.01 Hz, 1 H) 7.55 (dd, J=7.96, 4.67 Hz, 1 H) 5.92 (s, 1 H) 5.19 (quin, J=6.63 Hz, 1 H) 4.43 (d, J=4.80 Hz, 2 H) 2.54 (d, J=7.07 Hz, 2 H) 2.13 (s, 3 H) 1 .52 - 1 .59 (m, 2 H) 1.52 (s, 3 H) 1.50 (s, 3 H) 0.88 (t, J=7.33 Hz, 3 H). MS(ES) [M+H]+ 444.3.
Example 130
1-Cyclopentyl-/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-6-[6-(4-morpholinyl)-
3-pyridiny -1 H-indazole-4-carboxamide
Figure imgf000137_0002
1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.54 (s, 1 H), 8.69 (d, J = 2.27 Hz, 1 H), 8.60 (t, J = 5.05 Hz, 1 H), 8.35 (s, 1 H), 8.10 (ddd, J = 2.78, 2.91 , 5.94 Hz, 2H), 7.85 (d, J = 1 .01 Hz, 1 H), 6.98 (d, J = 8.84 Hz, 1 H), 5.89 (s, 1 H), 5.31 (t, J = 7.07 Hz, 1 H), 4.39 (d, J = 4.80 Hz, 2H), 3.70 - 3.76 (m, 4H), 3.50 - 3.55 (m, 4H), 2.22 (s, 3H), 2.09 - 2.18 (m, 5H), 1.96 - 2.07 (m, 2H), 1 .89 (dd, J = 5.68, 9.22 Hz, 2H), 1 .66 - 1 .77 (m, 2H). MS(ES) [M+H]+ 527.1. Example 131
1-Cyclopentyl-/V-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridiny^
in e
Figure imgf000138_0001
1H NMR (400 MHz, DMSO-d6) 5ppm 1 1.54 (s, 1 H), 9.35 (s, 2H), 9.23 (s, 1 H), 8.63 (t, J = 4.93 Hz, 1 H), 8.44 (s, 1 H), 8.39 (s, 1 H), 8.01 (d, J = 1.26 Hz, 1 H), 5.90 (s, 1 H), 5.35 (dq, J = 7.07, 7.33 Hz, 1 H), 4.40 (d, J = 4.80 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 5H), 1 .98 - 2.08 (m, 2H), 1 .85 - 1 .96 (m, 2H), 1.67 - 1.77 (m, 2H). MS(ES) [M+H]+ 443.0.
Intermediates
Intermediate 1
3-(Aminomethyl)-4,6-dimethyl-2(1 H)-pyridinone hydrochloride
Figure imgf000138_0002
Palladium on carbon (10%) (3.24 g) was charged into a 2L dry Parr bottle and a small amount of acetic acid was added. Next added 4,6-dimethyl-2-oxo-1 ,2-dihydro- pyridine- 3-carbonitrile (30 g , 202.7 mmol), sodium acetate (30.75 g, 375.0 mmol), platinum oxide (0.218 g), and acetic acid (1 L).. The bottle was capped, placed on Parr apparatus, and shaken under an atmosphere of H2 (100 psi) for 2 days. The reaction mixture was filtered. The solvent was removed to give a residue, which was treated with 150 mL of cone. HCI, and the formed solids were filtered. The yellow filtrate was concentrated . To the crude compound was added 30 mL of cone. HCI and 150 mL EtOH, the contents cooled to 0 °C, and stirred at 0 °C for 2h. The formed solids were filtered, washed with cold EtOH, ether, and dried. The product was collected as 36 g. This batch was combined with other batches prepared on smaller scales and triturated with ether to give 51 g of pure compound.. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1.85 (br s, 1 H) 8.13 (br s, 3 H) 5.93 - 6.01 (m, 1 H) 3.72 - 3.80 (m, 2 H) 2.22 (s, 3 H) 2.16 (s, 3 H). Intermediate 2
3-(aminomethyl)-6-methyl-4-propyl-2(1 H)-pyridinone
Figure imgf000139_0001
Step 1
To a stirred solution of t-BuOK (20 g, 178.5 mmol) and cyanoacetamide (16.5 g, 196 mmol) in DMSO (300 mL) was added (3E)-3-hepten-2-one (20 g, 178.3 mmol) under argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 30 min and then additional t-BuOK (60 g,535.7 mmol) was added to the reaction mixture. The argon was then displaced by oxygen gas and stirred for 48 hrs at room temperature under oxygen. Reaction mixture was cooled to 0 °C and diluted with water (80 mL) followed by 4N HCI (120 mL). The mixture was stirred for 15 min and the solid was filtered. The solid was washed with water (1 L) and dried to afford 1 ,2-dihydro- 6-methyi-2-oxo-4-propylpyridine-3-carbonitrile as an off white solid (12 g, 38 %). 1H NMR (CDCIs ,400 MHz) : δ 1 .030 (t, 3H, J = 7.2 Hz), 1.728 (m, 2H),2.429 ( s, 3H), 2.701 (t, 2H, J=7.6 Hz), 6.083 (s, 1 H). LCMS E-S (M-H) = 175.1 1.
Step 2
To a suspension of Raney Ni (2 g) in methanol (250 mL) was added 1.2-dihydro-6- methyi-2-oxo-4-propylpyridine-3-carbonitri!e (5 g, 28.4 mmol) and methanolic ammonia (750 mL). The reaction mixture was stirred at room temperature under hydrogen pressure (60 psi) for 48 hrs. The reaction mixture was filtered through celite pad and washed with methanol (250 mL). The filtrate was concentrated under reduced pressure to afford the crude product (5.1 g). The crude product was purified by column chromatography by using a short column of silica gel (60-120 mesh) treated with methanolic NH3, (eluant: 0- 25% methanol in DCM) and isolated to afford the desired product 3-(amino methyl)-6- methyl-4-propylpyridin-2(1 H)-one as an off white solid (2 g , 39 % yield). 1H NMR (DMSO, 400 MHz) : δ 0.921 (t, 3H, J = 7.2 Hz), 1.518 (m, 2H),2.09 ( s, 3H), 2.418 (t, 2H,J=7.6 Hz), 3.451 (s,2H), 4-5.6 (br s, 2H, exchangeable), 5.822(s,1 H). LCMS E-S (M+H) = 181.22. Intermediate 3
3-(Aminomethyl)-6-methyl-4-(1 -methylethyl)-2(1H)-pyridinone
Figure imgf000140_0001
The title compound was prepared in the same manner as described for 3-(aminomethyl)- 6-methyl-4-propyl-2(1 H)-pyridinone (Intermediate 2, steps 1 and 2) from (3£)-5-methyl-3- hexen-2-one (20 g, 137 mmol). LCMS E-S (M+H) = 181 .1 . 1 H NMR (400 MHz, DMSO- cfe) δ ppm 1 1 .8 - 1 1 .9 (br s, 1 H), 7.86 - 7.96 (br s, 3H), 6..10 (s, 1 H), 3.82 - 3.86 (m, 2H), 3.02 - 3.09 (m, 1 H), 2.17 (s, 3H), 1 .08 (d, 6H).
Intermediate 4
3-(Aminomethyl)-4-cyclohexyl-6-methyl-2(1 H)-pyridinone
Figure imgf000140_0002
Step 1
To a stirred suspension of CrCI2 (58 g, 472.8 mmol in THF (1500 mL) was added a THF solution (500 mL) of 1 , 1 -dichloro-2-propanone ( 10 g, 78.8 mmol) and cyclohexanecarbaldehyde (8.84 g, 78.8 mmol). The reaction mixture was heated at reflux for 2 h, and then quenched by the addition of 1.0 M HCI. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude residue ( 10 g) was added to a solution of DMSO (150 mL) containing t-BuOK (7.5 g, 65.7 mmol) and cyanoacetamide (6.1 g, 72.3 mmol) and stirred at room temperature for 30 min. Additional t-BuOK (22.5 g, 197.1 mmol) was added and the reaction mixture was stirred under an atmosphere of oxygen for an additional 1 h. The contents were purged with argon, diluted with 4 volumes of H20, and then 5 volumes of 4 N HCI, which were added slowly. The reaction mixture was filtered, washed with water and dried to give 4- cyclohexyl-6-methyl-2-oxo-1 ,2-dihydro-3-pyridinecarbonitrile (4.5 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.25 (s, 1 H), 2.61-2.65 (m, 1 H), 2.22 (s, 3H), 1 .66-1.79 (m, 4H), 1.24-1 .46 (m, 6H). Step 2
To an ice-bath cooled THF (100 mL) solution of the product from step 1 (2 g, 9.26 mmol) were added NaBH4 (0.81 g, 21 .3 mmol), and l2 (2.3 g, 9.26 mmol), and the mixture stirred for 30 min. The reaction mixture was then heated at reflux for 3h, and then allowed to cool to room temperature. After cooling to 0 °C, the reaction mixture was acidified by slow addition of 3 N HCI (1 mL). The reaction mixture was concentrated in vacuo and the crude product purified by reverse phase HPLC to give the title compound as a solid (0.5 g, 25%). LCMS E-S (M+H) = 221.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .8 - 1 1 .9 (br s, 1 H), 7.80-7.93 (br s, 3H), 6.07 (s, 1 H), 3.69 (s, 2H), 2.67-2.75 (m, 1 H), 2.17 (s, 3H), 1.58-1 .72 (m, 5H), 1 .19 - 1.41 (m, 5H).
Intermediate 5
3-(Aminomethyl)-4-ethyl-6-methyl-2(1 H)-pyridinone hydrochloride
Figure imgf000141_0001
Hex-3-en-2-one
O
PP
To a stirred solution of 1-(triphenylphosphoranylidene)-2-propanone (100 g, 307 mmol) in DCM (500 mL) was added propionaldehyde (140 mL, 1929 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 18 hours. The reaction was monitored by TLC. The solvent (DCM) was distilled off using ordinary distillation. The residue was then distilled using fractional distillation under vacuum (-450 mbar) and the desired product was isolated. The title compound, hex-3-en-2-one (20 g, 66%), was collected at 1 10 °C. 1 H NMR (CDCI3 ,400 MHz) δ ppm 1.071-1.121 (t, 3H, J = 7.4 Hz), 2.250-2.299 (m, 5H), 6.054-6.094 (d, 1 H, J =16Hz), 6.823-6.895 (m, 1 H). Step2
4-EthyS-1 ,2-d5hydro-6-meihy!-2-oxopyndine-3-carbonitn!e
Figure imgf000142_0001
To a stirred solution of t-BuOK (22.85 g, 204.08 mmol) and cyanoacetamide (18.8 g, 224.1 mmol) in DMSO (300 mL) was added hex-3-en-2-one (20 g, 204.08 mmol) under argon atmosphere at room temperature. The reaction mixture was then stirred at room temperature for 30 min and then added additional t-BuOK (68.5 g, 612.05 mmol) was added. Argon gas was displaced by oxygen gas and the mixture stirred for 48 hrs at room temperature in presence of oxygen. Reaction was monitored by TLC. The reaction mixture was cooled to 0 °C and diluted with water (100 mL) followed by 4 N HCI (120 mL). The mixture was stirred for 15 min and the resulting solid was filtered. The solid was washed with water (1 L) and dried to afford the title compound, 4-ethy!-1 ,2-dihydro-6- methyi-2-oxopyridine-3-carbonitrile (10.5 g, 31 %), as an off white solid. 1H NMR (CDCI3 400 MHz) : δ ppm 1.148-1.185 (t, 3H, J = 7.4 Hz), 2.237 ( s, 3H), 2.557-2.614(m, 2H), 6.21 1 (s, 1 H), 12.330 (broad s, 1 H). MS(ES) [M+H]+ 161 .06.
Step 3
3-(Amino methyl)-4-ethyl-6-methylpyridin
Figure imgf000142_0002
To a suspension of Raney Nickel (6 g) in methanol (200 mL) was added 4-ethyi-1 ,2- dihydro-6-methy!-2-oxopyridine-3-carbonitrile (10 g, 61 .7 mmol) and methanolic ammonia (750 mL). The reaction mixture was stirred at room temperature under hydrogen pressure (80 psi) for 48 hrs. The reaction mixture was filtered through Celite and washed with methanol (250 mL). The filtrate was concentrated under reduced pressure and the residue purified by filter column using silica gel (60-120 mesh), eluted with 10% MeOH in CHCI3, to afford 3-(amino methyl)-4-ethyl-6-methylpyridin-2(1 H)-one (5.6 g, 54 %) as an off white solid. 1H NMR (DMSO-D6, 400 MHz) (free amine): δ ppm 1 .063-1 .101 (t, 3H, J = 7.6 Hz), 2.101 (s, 3H), 2.412-2.449 ( m, 2H), 3.448 (s, 2H), 5.835 (s, 1 H). MS(ES)
[M+H]+ 167.06. Step 4
3-(Aminomethyl)-4-ethyl-6-methylpyridin-2(1 H)-one hydrochloride
Figure imgf000143_0001
3-(Amino methyl)-4-ethyl-6-methylpyridin-2(1 H)-one, (5.6 g, 33 mmol) was suspended in DCM (560 mL) and the insoluble contents/particles were filtered. The filtrate was concentrated and dried. The residue was dissolved in DCM (10 mL) and 4 M HCI in1 ,4- dioxane (16 mL, 66 mmol) was added at 0 °C and stirred for 10 min, at which time the reaction mixture was concentrated under high-vacuum and dried. The resulting crude solid was triturated with hexane (150 mL) and filtered. The solid was dried under vacuum. Collected 3-(amino methyl)-4-ethyl-6-methylpyridin-2(1 H)-one hydrochloride (5.9 g, 86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .082-1 .120 (t, 3H, J = 7.6 Hz), 2.179 (s, 3H), 2.503-2.544 (m, 2H), 3.785-3.798 (d, 2H, J = 5.2 Hz), 6.024 (s, 1 H),7.985 (broad s,2H), 1 1 .858 (broad s, 1 H). MS(ES) [M+H]+ 167.2.
Intermediate 6
3-(aminomethyl)-6-methyl-4,4'-bipyridin-2(1 H)-one
Figure imgf000143_0002
Step 1
(Z)-3-hydroxy-1 -(pyridin-4-yl)but-2-en-1 -one
Figure imgf000143_0003
To a solution of ethyl 4-pyridinecarboxylate (30 g, 198 mmol) and acetone (34.58 g, 595 mmol) in THF (150 mL) was slowly added NaOMe (12.87 g, 238 mmol) at 35-40 °C. The mixture was stirred at room temperature for 0.5 h, and then heated at reflux for 3 h. The mixture was cooled to room temperature and filtered to give a solid, which was washed with f-BuOMe, and dissolved in H20. The solution was acidified with acetic acid and the resulting oily product was extracted with CHCI3. The solvent was removed in vacuo, and the crude product was obtained (12 g, 37%) and used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 2H), 7.76 (d, 2H), 6.63 (s, 1 H), 2.21 (s, 3H); note: enolic OH does not appear.
Step 2
6-methyl-2-oxo-1 ,2-dihydro-[4,4'-bi ridine]-3-carbonitrile
Figure imgf000144_0001
To a solution of (2Z)-3-hydroxy-1-(4-pyridinyl)-2-buten-1-one (8 g, crude, 49 mmol) and cyanoacetamide (4.12 g, 49 mmol) in anhydrous EtOH (100 mL) was added piperidine (4.17 g, 49 mmol) under N2 at 75 °C. The mixture was heated at reflux for 1 h, and then cooled to room temperature. After filtration, the solid was collected and washed with H20 to give the crude product (4 g) as two isomers. After separation by HPLC, 1.8 g of 6- methyl-2-oxo-1 ,2-dihydro-4,4'-bipyridine-3-carbonitrile and 1 .2 g of 4-methyl-6-oxo-1 ,6- dihydro-2,4'-bipyridine-5-carbonitrile were obtained. The identity of 6-methyl-2-oxo-1 ,2- dihydro-4,4'-bipyridine-3-carbonitrile was established by nOE analysis. 1H NMR (400 MHz, DMSO-d6) δ 12.79 (br. s., 1 H), 8.75 (d, 2H), 7.58 (d, 2 H), 6.37 (s, 1 H), 2.31 (s, 3H).
Step 3
3-(aminomethyl)-6-methyl-4,4'-bipyridin-2(1 H)-one
Figure imgf000144_0002
To an ice bath cooled THF (100 mL) solution of 6-methyl-2-oxo-1 ,2-dihydro-4,4'- bipyridine-3-carbonitrile (4 g, 18.9 mmol) was added NaBH4 (1 .43 g, 37.9 mmol), and l2 (4.81 g, 18.9 mmol), and the mixture was stirred for 0.5 h. The reaction mixture was then heated at reflux for 4 h. After cooling to 0 °C, the reaction mixture was adjusted to pH 5 with 4 N HCI. The mixture was concentrated in vacuo to give the crude compound, which was purified by HPLC to give 3-(aminomethyl)-6-methyl-4,4'-bipyridin-2(1 /-/)-one (1 .9 g, 31 %) as a TFA salt. LCMS MH+ = 216.0 1H NMR (400 MHz, DMSO-d6 in D20) δ 8.87 (d, 2H), 7.87 (d, 2H), 6.13 (s, 1 H), 3.65 (br s, 2H), 2.17 (s, 3H).
Intermediate 7
3- (aminomethyl)-6-methyl-4-(phenylmethyl)-2(1 H)-pyridinone and 3-(aminomethyl)-
4- methyl-6-(phenylmethyl)-2(1 H)-pyridinone
Figure imgf000145_0001
Step 1
1 -phenylpentane-2,4-dione
Figure imgf000145_0002
To a solution of NaNH2 (19.02 g, 480 mmol) in anhydrous ether (400 ml.) under N2 at - 5 °C was added dropwise ethyl phenylacetate (19.2 g , 150 mmol) and then acetone (21.23 g, 370 mmol) with vigorous stirring. After addition, the reaction mixture was stirred at room temperature overnight. The mixture was then acidified to pH 4.0 - 5.0 with 1 N HCI. The organic layer was separated and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 1 -phenyl-2,4-pentanedione (18.32 g, 44 %). 1H NMR (400 MHz, CDCI3-d3) δ 15.49 (br s, 1 H), 7.33-7.45 (m, 5H), 5.53 (s, 1 H), 3.66 (s, 2H), 2.10 (s, 3H). Step 2
4-benzyl-6-methyl-2-oxo-1 ,2-dihydropyridine-3-carbonitrile and 6-benzyl-4-methyl- 2-oxo-1 ,2-dihydropyridine-3-carbonitrile
Figure imgf000146_0001
1-phenyl-2,4-pentanedione (18.32 g, 104 mmol) and cyanoacetamide (8.74 g, 104 mmol) were dissolved in EtOH (104 mL) and heated until homogenous (ca. 75 °C). Piperidine (8.86 g, 104 mmol) was added and the reaction mixture heated at reflux for 15 -30 min. followed by cooling to room temperature, during which time precipitation occurred. The heterogenous contents were filtered to give a solid which was suspended in 200 mL water and stirred vigorously for 20 min. The heterogenous mixture was filtered to afford 6- methyl-2-oxo-4-(phenylmethyl)-1 ,2-dihydro-3-pyridinecarbonitrile and 4-methyl-2-oxo-6- (phenylmethyl)-1 ,2-dihydro-3-pyridinecarbonitrile (12.06 g, 52%). LCMS MH+ = 225.1 1H NMR (400 MHz, DMSO-d6) δ 7.21 -7.31 (m, 10H), 6.06 (s, 2H), 3.89 (s, 2H), 3.79 (s, 2H), 2.24 (s, 3H), 2.15 (s, 3H).
Step 3
tert-butyl ((4-benzyl-6-methyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)carbamate compound and tert-butyl ((6-benzyl-4-methyl-2-oxo-1 ,2-dihydropyridin-3- yl)methyl)carbamate
Figure imgf000146_0002
Sodium acetate (6.14 g, 74.8 mmol), Pd/C (0.65 g, 1 mmol), and platinum (II) oxide (45 mg, 1 mmol) were placed in a dried Parr bottle equipped with nitrogen inlet. A small amount of acetic acid was added to wet the catalysts. A solution of 6-methyl-2-oxo-4- (phenylmethyl)-l ,2-dihydro-3-pyridinecarbonitrile and 4-methyl-2-oxo-6-(phenylmethyl)- 1 ,2-dihydro-3-pyridinecarbonitrile (6 g, 26.7 mmol) in acetic acid (300 mL) was added to the vessel. The contents were sealed and hydrogenated on Parr shaker at 45 psi for 12 h. The reaction mixture was filtered and washed with acetic acid. The filtrate was removed under reduced pressure. The residue was washed with methanol and filtered to afford a crude mixture of 3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1 H)-pyridinone and 3-(aminomethyl)-4-methyl-6-(phenylmethyl)-2(1 H)-pyridinone. The reaction was run in duplicate to afford a total crude recovery of 14.5 g. To a solution of the above crude product mixture (4.0 g, 17.5 mmol) in THF (10 ml.) and DMF (10 ml.) was added di-tert- butoxycarbonyl anhydride (5.0 g, 23.4 mmoL) and triethylamine (5.2 g, 52.5 mmol) at 0 °C. The reaction mixture was stirred with warming to room temperature and then stirred for an additional 4 h. The contents were diluted with ice water and then filtered. The collected solid was dried and the products separated by HPLC to furnish 1.2 g of 1 , 1 - dimethylethyl {[4-methyl-2-oxo-6-(phenylmethyl)-1 ,2-dihydro-3-pyridinyl]methyl}carbamate (1 H NMR (400 MHz, DMSO-d6) δ 1 1 .55-1.60 (br s, 1 H), 7.20-7.29 (m, 5H), 5.85 (s, 1 H), 3.92 (s, 2H), 3.90 (s, 2H), 2.10 (s, 3H), 1 .32 (s, 9H) and 1 .0 g of 1 ,1 -dimethylethyl {[6- methyl-2-oxo-4-(phenylmethyl)-1 ,2-dihydro-3-pyridinyl]methyl}carbamate (1H NMR (400 MHz, DMSO-d6) δ 1 1 .50-1 1.55 (br s, 1 H), 7.18-7.25 (m, 5H), 5.75 (s, 1 H), 4.02 (s, 2H), 3.85 (s, 2H), 2.05 (s, 3H), 1.32 (s, 9H).
Step 4
3-(aminomethyl)-6-benzyl-4-methylpyridin
Figure imgf000147_0001
A solution of 1 , 1-dimethylethyl {[4-methyl-2-oxo-6-(phenylmethyl)-1 ,2-dihydro-3- pyridinyl]methyl}carbamate (1.2 g, 3.66 mmol) in 4N HCI (in 15 ml. 1 ,4 dioxane) was heated to 60 °C for 1 h. The mixture was cooled to room temperature. The mixture was filtered and dried to give 3-(aminomethyl)-4-methyl-6-(phenylmethyl)-2(1 /-/)-pyridinone as an HCI salt (0.725 g, 87%). LCMS MH+ = 229.1 1H NMR (400 MHz, DMSO-d6) δ 1 1 .9- 12.0 (br s, 1 H), 7.99 (br s, 3H), 7.20 (s, 5H), 5.97 (s, 1 H), 3.72-3.75 (m, 4H), 2.17 (s, 3H). 3-(aminomethyl)-4-benzyl-4-methylpyridin-2(1 H)-one
Figure imgf000148_0001
A solution of 1 , 1-dimethylethyl {[6-methyl-2-oxo-4-(phenylmethyl)-1 ,2-dihydro-3- pyridinyl]methyl}carbamate (1.0 g, 3.0 mmol) in 4N HCI (in 15 ml. 1 ,4 dioxane) was heated to 60 °C for 1 h. The mixture was cooled to room temperature. The mixture was filtered and dried to give 3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1 /-/)-pyridinone as an HCI salt (0.600 g, 86%). LCMS MH+ = 229.1 1H NMR (400 MHz, DMSO-d6) δ 1 1 .9- 12.0 (br s, 1 H), 8.03 (br s, 3H), 7.16-7.30 (m, 5H), 5.84 (s, 1 H), 3.91 (s, 2H), 3.81 (s, 2H), 2.10 (s, 3H).
Intermediate 8
3-(aminomethyl)-4-(sec-butyl)-6-methylpyridin-2(1 H)-one
Figure imgf000148_0002
a) (E)-5-methylhept-3-en-2-one
Figure imgf000148_0003
To a stirred solution of 1-(triphenylphosphoranylidene)-2-propanone (73.9 g, 232.55 mmol) in DCM (150 ml.) was added 2-methyl butanal (20 g, 232.55 mmol) and the resulting reaction mixture was stirred at room temperature for 16 h. DCM was distilled off from the reaction mixture using short path condenser and after that, the desired product (E)-5-methylhept-3-en-2-one, 2 (12 g, 41 %) was collected as colorless liquid by fractional distillation. 1H NMR (CDCI3 ,400 MHz): δ 0.909-0.891 (t, 3H, J = 7.2 Hz), 1.085-0.976 (m, 3H), 1.46-1 .103 (m, 2H), 1 .632-1 .606 (d, 1 H), 2.252-2.205 (m, 3H), 6.061-6.018 (dd, 1 H), 6.716-6.657 (m, 1 H). GCMS = 126.2 (M)-Purity 87%. b) 4-sec-butyl-1 ,2-dihydro-6-methyl-2-oxopyridine-3-carbonitrile
Figure imgf000149_0001
To a stirred solution of t-BuOK (8 g, 71.42 mmol) and cyanoacetamide (6.6 g, 78.57 mmol) in DMSO (80 mL) was added (E)-5-methylhept-3-en-2-one, 2 (9 g, 71 .42 mmol) under argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 1 h and then added additional t-BuOK (24 g, 214.28 mmol) was added. Then argon was displaced by oxygen and stirred at RT for 48 h. The reaction mixture was cooled to 0 °C, diluted with water (36 mL) followed by 4N HCI (up to pH~4) and the resulting reaction mixture was stirred for 15 min. The separated solid was collected by filtration, washed with water (10 mL), pet ether (100 mL) and dried to afford the title compound as yellow solid (7 g, 53 %). 1H NMR (DMSO-d6 ,400 MHz): δ 0.816-0.779 (t, 3H, J = 7.6 Hz), 1.178-1.161 (d, 3H, J=6.8Hz), 1637-1.505 (m, 2H), 2.24 (s, 3H), 2.814- 2.760 (m, 1 H), 6.239 (s, 1 H), 12.324 (bs, 1 H); LCMS (ES-) m/z = 189.20 (M-H) c) 4-sec-butyl-3-(aminomethyl)-6-methylpyridin-2(1 H)-one
To a suspension of Raney Ni (10 g) in methanol (50 mL) was added 4-sec-butyl-1 ,2- dihydro-6-methyl-2-oxopyridine-3-carbonitrile (7 g, 36.8 mmol) followed by methanolic ammonia (200 mL) and the resulting reaction mixture was stirred at room temperature under hydrogen pressure (80 psi) for 18 h. The reaction mixture was filtered through Celite pad and washed with methanol (250 mL). The filtrate was concentrated under reduced pressure to afford the crude product (7 g). The reaction was repeated again under same condition. The crude products were combined and purified by silica gel chromatography (eluent: 8% MeOH in CHCI3 , spiked with NH3) and the obtained solid was triturated with diethyl ether (50 mL) and dried under vacuum to afford the title compound as yellow solid (3.5 g, 28%). 1H NMR (DMSO-d6, 400 MHz): δ 0.809-0.774 (t, 3H, J = 6.8 Hz), 1 .1 13-1 .097 (d, 3H, J = 6.4 Hz), 1.504-1.468 (t, 2H, J =7.2 Hz), 2.184 (s, 3H), 2.839-2.822 (d, 1 H, J = 6.8 Hz), 3.822 (s, 2H), 6.059 (s, 1 H), 8.315 (bs, 2H); LCMS (ES+) m/z = 195.22 (M+H) Assay Protocol
Compounds contained herein were evaluated for their ability to inhibit the methyltransferase activity of EZH2 within the PRC2 complex. Human PRC2 complex was prepared by co-expressing each of the 5 member proteins (FLAG-EZH2, EED, SUZ12, RbAp48, AEBP2) in Sf9 cells followed by co-purification. Enzyme activity was measured in a scintillation proximity assay (SPA) where a tritiated methyl group is transferred from 3H-SAM to a lysine residue on Histone H3 of a mononucleosome, purified from HeLa cells. Mononucleosomes were captured on SPA beads and the resulting signal is read on a ViewLux plate reader.
Part A. Compound Preparation
1. Prepare 10 mM stock of compounds from solid in 100% DMSO.
2. Set up an 1 1 -point serial dilution (1 :3 dilution, top concentration 10 mM) in 100% DMSO for each test compound in a 384 well plate leaving columns 6 and 18 for DMSO controls.
3. Dispense 100 nl_ of compound from the dilution plate into reaction plates (Grenier Bio-One, 384-well, Cat# 784075).
Part B. Reagent Preparation
Prepare the following solutions:
1. 50 mM Tris-HCI, pH 8: Per 1 L of base buffer, combine 1 M Tris-HCI, pH 8 (50 ml.) and distilled water (950 ml_).
2. 1x Assay Buffer: Per 10 ml. of 1 x Assay Buffer, combine 50 mM Tris-HCI, pH 8 (9958 uL), 1 M MgCI2 (20 uL), 2 M DTT (20 uL), and 10% Tween-20 (2 uL) to provide a final concentration of 50 mM Tris-HCI, pH 8, 2 mM MgCI2, 4 mM DTT, 0.002% Tween-20.
3. 2x Enzyme Solution: Per 10 ml. of 2x Enzyme Solution, combine 1x Assay Buffer and PRC2 complex to provide a final enzyme concentration of 10 nM.
4. SPA Bead Suspension: Per 1 ml. of SPA Bead Suspension, combine PS-PEI coated LEADSeeker beads (40 mg) and ddH20 (1 ml.) to provide a final concentration of 40 mg/mL.
5. 2x Substrate Solution: Per 10 mL of 2x Substrate Solution, combine 1x Assay Buffer (9728.55 uL), 800 ug/mL mononucleosomes (125 uL), 1 mM cold SAM (4 uL), and 7.02 uM 3H-SAM (142.45 uL; 0.55 mCi/mL) to provide a final concentration of 5 ug/mL nucleosomes, 0.2 uM cold SAM, and 0.05 uM 3H-SAM. 6. 2.67x Quench/Bead Mixture: Per 10 mL of 2.67x Quench/Bead Mixture, combine ddH20 (9358 uL), 10 mM cold SAM (267 uL), 40 mg/mL Bead Suspension (375 uL) to provide a final concentration of 100 uM cold SAM and 0.5 mg/mL SPA beads.
Part C. Assay Reaction in 384-well Grenier Bio-One Plates
Compound Addition
1. Dispense 100 nL/well of 100x Compound to test wells (as noted above).
2. Dispense 100 nL/well of 100% DMSO to columns 6 & 18 for high and low controls, respectively.
Assay
1. Dispense 5 uL/well of 1 x Assay Buffer to column 18 (low control reactions).
2. Dispense 5 uL/well of 2x Enzyme Solution to columns 1 -17, 19-24.
3. Spin assay plates for ~1 minute at 500 rpm.
4. Stack the assay plates, covering the top plate.
5. Incubate the compound/DMSO with the enzyme for 30 minutes at room
temperature.
6. Dispense 5 uL/well of 2x Substrate Solution to columns 1-24.
7. Spin assay plates for ~1 minute at 500 rpm.
8. Stack the assay plates, covering the top plate.
9. Incubate the assay plates at room temperature for 1 hour.
Quench/Bead Addition
1. Dispense 5 uL/well of the 3x Quench/Bead Mixture to columns 1 -24.
2. Seal the top of each assay plate with adhesive TopSeal.
3. Spin assay plates for ~1 minute at 500 rpm.
4. Equilibrate the plates for > 20 min.
Read plates
1. Read the assay plates on the Viewlux Plate Reader utilizing the 613 nm emission filter with a 300 s read time.
Reagent addition can be done manually or with automated liquid handler.
*The final DMSO concentration in this assay is 1 %.
*The positive control is in column 6; negative control is in column 18.
*Final starting concentration of compounds is 100 μΜ. Part D. Data analysis
Percent inhibition was calculated relative to the DMSO control for each compound concentration and the resulting values were fit using standard IC50 fitting parameters within the ABASE data fitting software package.
Exemplified compounds of the present invention were generally tested according to the above or an analogous assay and were found to be inhibitors of EZH2. The IC50 values ranged from about 1 nM to about 10 μΜ; The IC50 values of the more active compounds range from about 1 nM to about 500 nM; The most active compounds are under 50 nM. As tested in the foregoing assay or an analogous assay, compounds of the various Examples gave the IC50 data (nM) in the paragraph below. Repeating the assay run(s) may result in a somewhat different.
Ex 1 , 32; Ex 3, 158; Ex 4, 25; Ex 5, 8; Ex 7, 40; Ex 8, 10; Ex 9, 16; Ex 10, 13; Ex 12, 4 ; Ex 13, 126; Ex 14, 5; Ex 15, 2; Ex 16, 3; Ex 17, 8; Ex 18, 10; Ex 19, 6; Ex 20, 10; Ex 21 , 5; Ex 22, 20; Ex 23, 8; Ex 24, 5; Ex 25,13; Ex 27, 32; Ex 29, 40; Ex 30, 32; Ex 31 , 20; Ex 32, 25; Ex 33, 5.
Preparation of specific compounds (Compound A, B and C) that were tested in the T cell proliferation and cytokine production studies:
N-((4/6-dimethyl-2-oxo-l/2-dihydropyridin-3-yl)methyl)-6-(4-(2- (dimethylamino)ethoxy)phenyl)-l-isopropyl-lH-indazole-4-carboxamide
Figure imgf000152_0001
6-bromo-N-(4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-l-isopropyl-lH-indazole- 4-carboxamide (80 mg, 0.19 mmol), N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenoxy)ethanamine (84 mg, 0.29 mmol) and PdCI2(dppf)-CH2CI2 adduct (7.8 mg, 0.009 mmol) in dioxane/water (3 ml: l ml) were stirred for 10 min under nitrogen. Sodium bicarbonate (48.3 mg, 0.58 mmol) was added and the insoluble mixture was irradiated in a microwave at 100 °C for 20 min. The reaction mixture was evaporated, dissolved in DCM/MeOH (1 : 1), and preabsorbed on silica gel and purified using silica gel chromatography (eluent: DCM/MeOH/NH4OH; gradient 0 to 80:20:2 in
DCM). The isolated product was dissolved in hot DMSO/MeOH and purified using reversed-phase HPLC (25-80% gradient of MeCN in water with 0.1% TFA). Most of the solvent from the combined product fractions were evaporated and sat. sol. NaHC03 was added, solids that crashed out were filtered, air-dried for 15 min, and dried in vaccum- oven overnight. The product was collected as a white solid (56 mg, 56%). H NMR (400 MHz, DMSO-flfc)™ ppm 11.54 (br. s., 1 H) 8.64 (t, J=4.80 Hz, 1 H) 8.35 (s, 1 H) 8.05 (s, 1 H) 7.81 - 7.84 (m, 2 H). LC-MS (ES) m/z = 528.1 [M+H]+
Compound A can be prepared according to a procedure analogous to the above example:
Compound A: 1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3- pyridinyl)methyl]-6-[6-(4-methyl-1 -piperazinyl)-3-pyridinyl]-1 H-indazole-4- carboxamide
Figure imgf000153_0001
The title compound was prepared in a similar manner as described for the above example from 6-bromo-l-(l-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-l,2-dihydro-3- pyridinyl)methyl]-lH-indazole-4-carboxamide (90 mg, 0.202 mmol) and 1-methyl [5- (4,4,5,5-tetramethyl-l,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%). H NMR (400 MHz, DMSO- )™ ppm 1H NMR (400 MHz, DMSO-06)™ ppm 11.54 (br. s., 1 H) 8.65 (d, J=2.27 Hz, 1 H) 8.61 (t, J=4.80 Hz, 1 H) 8.36 (s, 1 H) 8.04 - 8.08 (m, 2 H) 7.83 (s, 1 H) 6.96 (d, J=9.09 Hz, 1 H) 5.92 (s, 1 H) 5.14 (quin, J=6.57 Hz, 1H) 4.42 (d, J=4.80 Hz, 2 H) 3.53 - 3.59 (m, 4 H) 2.53 - 2.61 (m, 2 H) 2.40 - 2.45 (m, 4 H) 2.23 (s, 3 H) 2.14 (s, 3 H) 1.51 - 1.58 (m, 2 H) 1.50 (s, 3 H) 1.49 (s, 3 H) 0.88 (t, J=7.33 Hz, 3 H). LC-MS (ES) m/z = 542.2 [M+H]+ Compound B: N-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1 -(1 - methylethyl)-6-[6-(4-methyl- -piperazinyl)-3-pyridinyl]-1 H-indole-4-carboxamide
Figure imgf000154_0001
Compound B can be prepared according to the general procedure described in the above experimental section.
6-Cyclopropyl-1 -(1 -methylethyl)-A -[(4-methyl-2-oxo-6-propyl-1 ,2-dihydro-3- pyridinyl)methy yridine-4-carboxamide
Figure imgf000154_0002
6-Cyclopropyl-1 -(1 -methylethyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (167 mg, 0.680 mmol), 3-(aminomethyl)-4-methyl-6-propyl-2(1 /-/)-pyridinone trifluoroacetate (200 mg, 0.680 mmol), HOAT (139 mg, 1 .019 mmol), EDC (195 mg, 1 .019 mmol), and N- methylmorpholine (0.299 mL, 2.72 mmol) were dissolved in DMF(6 mL) and stirred at 40 °C for 24 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to an orange oil. The residue was dissolved in DMSO, and purified by reverse phase HPLC (mobile phase: 40-60% ACN in H20, 0.1 % TFA). The isolated product was dried in a vacuum oven overnight and furnished the TFA salt of the title compound as a white solid, 0.1 13 g (32%). LCMS E-S (M+H) = 408.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 - 0.98 (m, 3 H), 1.06 (d, J = 7.07 Hz, 4 H), 1.46 (d, J = 6.82 Hz, 6 H), 1.52 - 1 .67 (m, 2 H), 2.17 - 2.31 (m, 4 H), 2.37 (t, J = 7.58 Hz, 2 H), 4.36 (d, J = 4.80 Hz, 2 H), 5.02 - 5.27 (m, 1 H), 5.91 (s, 1 H), 7.43 (s, 1 H), 8.21 (s, 1 H), 8.62 - 8.87 (m, 1 H), 1 1 .54 (br. s., 1 H). Compound C can be prepared according to a procedure analogous to the above example:
6-cyclopropyl-1 -(1 -methylethyl)-N-[(6-methyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]- 1 H-pyrazolo[3,4-b]pyridine-4-carboxamide
Figure imgf000155_0001
Examples
Proliferation Studies:
The EZH1/EZH2 inhibitors, Compound A and Compound B, concentration- dependently impaired T cell receptor-induced proliferation of CD4+ T cells with a plC50 of 5.30 ± 0.06 and 4.93 ± 0.05 respectively (n=4; Figure 1 ). In contrast, Compound C had no effect on T cell receptor-induced proliferation of CD4+ T cells (n=4).
Cytokine Production Studies:
The EZH1/EZH2 inhibitors, Compound A and Compound B, concentration- dependently impaired T cell receptor-induced production of IL-10, IL-13, IL-17, IFN & TNF in CD4+ T cells with plC50 values ranging between 5.65 ± 0.06 - 5.23 ± 0.03 and 5.21 ± 0.09 - 4.94 ± 0.03 respectively (n=4; Figure 2 & Table 1 ). In contrast, Compound C had no effect on T cell receptor-induced production of IL-17 or IFN in CD4+ T cells (n=4). High concentrations of Compound C (i.e. >15 μΜ) reduced IL-10, IL-13 & TNF production (n=4).
The EZH1/EZH2 inhibitors, Compound A and Compound B, concentration- dependently impaired T cell receptor-induced production of IL-2 in CD4+ T cells with plC50 values of 6.24 ± 0.24 and 5.76 ± 0.25 respectively (n=4; Figure 3). Compound C also impaired T cell receptor-induced production of IL-2 in CD4+ T cells, although a plC50 could not be calculated (n=4; Figure 3). Methods:
CD4 T cell isolation from human blood:
15 mis ficoll was added to 8 x 50ml_ accuspin tubes per donor and centrifuged at 2000RPM for 1 min. Whole blood samples (200 ml. + 1 % heparin) were collected from human donors. Approximately 25 ml blood was added to each ficoll pre-filled 50ml falcon tubes with filter and centrifuged at 1500 RPM for 20 min with the brake off to avoid disturbing cell separation. 45 ml with PBS was added to the PBMC fraction of each tube and centrifuged at 1500RPM for 10 min with brake. Supernatant were discarded and cell pellets resuspended in 2 ml PBS. Cell suspensions for each donor were recombined into a single falcon tube, made up to 45 ml with PBS and centrifuged at 1500RPM for 10 min. CD4+ T cells were isolated by negative depletion using a CD4 T cell Isolation Kit from Miltenyi Biotech according to manufacturers protocol.
Proliferation Studies:
96-well flat-bottom plates were coated with 10 μg/mL anti-CD3 + 2 μg/mL anti- CD28 at 4'C overnight. The following day, plates were washed with PBS. For proliferation studies, cells were stained with CFSE (Invitrogen) according to manufacturer's protocol. Cells were then added to anti-CD3 + anti-CD28 pre-coated 96- well plates at 0.2x106cells/well in the presence of EZH1/EZH2 inhibitors (Compound A & Compound B), an inactive control compound (Compound C) or vehicle (0.1 % DMSO) and incubated for 6 days at 37'C/ 5 % C02. Cells were then transferred to 96-well round- bottom plates, washed and then analysed by flow cytometry.
Cytokine Production Studies:
96-well flat-bottom plates were coated with 10 μg/mL anti-CD3 + 2 μg/mL anti- CD28 at 4'C overnight. The following day, plates were washed with PBS. For cytokine production studies, cells were added to anti-CD3 + anti-CD28 pre-coated 96-well plates at 0.4x106cells/well in the presence of EZH1/EZH2 inhibitors or vehicle and incubated at 37'C/ 5 % C02. Supernatants were taken 18 h (IL-2) or 72 h (IL-10, IL-13, IL-17, IFN, TNF) for determination of cytokine production by multiplex ELISA from Mesoscale discovery according to the manufacturers protocols. Drugs and Materials
Anti-CD3 (HU CD3 NALE MAB UCHT1 ; Cat # 555329) and anti-CD28 (HU CD28 NALE MAB CD28.2; Cat #: 555725), were obtained from BD Pharmingen and dissolved in Dulbecco's Phosphate Buffered Saline (with Ca2+/Mg2+; Gibco). Ficoll-paque (Cat # 17-1440-03) was obtained from GE Healthcare. The CD4+ T cell isolation kit (Cat # 130- 091-155) was obtained from Miltenyi Biotec. Cells were cultured in RPMI 1640 containing 10 % FCS + 1 % pen/strep + 1 % L-glutamine. The CellTrace CFSE cell proliferation kit (Cat # C34554) was obtained from Invitrogen.
Compound A, Compound B and Compound C were all synthesised in house and dissolved in 100 % DMSO.
Data Analysis
Proliferation Studies:
Flowjo Software was used to calculate a division index using fluorescence intensity. Data are expressed as mean ± standard error of the mean; n values are the numbers of human donors used. plC50 values were generated using GraphPad Prism software and non-linear sigmoid dose curve-fit.
Cytokine Production Studies:
Data were analysed using Excel and are expressed as mean ± standard error of the mean; n values are the numbers of human donors used. plC50 values were generated using GraphPad Prism software and non-linear sigmoid dose curve-fit.

Claims

Claims
1. A method of treating a T cell mediated inflammatory immune disease or a T cell mediated hypersensitivity disease, which comprises administering to a human in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, which inhibits EZH2 and/or EZH1 .
2. A method of treating T cell mediated inflammatory immune diseases, which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000158_0001
wherein
X and Z are selected independently from the group consisting of hydrogen, (d- C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, unsubstituted or substituted (C3-C8)cycloalkyl, unsubstituted or substituted (C3-C8)cycloalkyl-(C1-C8)alkyl or -(C2-C8)alkenyl,
unsubstituted or substituted (C5-C8)cycloalkenyl, unsubstituted or substituted (C5- C8)cycloalkenyl-(C1-C8)alkyl or -(C2-C8)alkenyl, (C6-C10)bicycloalkyl, unsubstituted or substituted heterocycloalkyi, unsubstituted or substituted heterocycloalkyl-(C1-C8)alkyl or - (C2-C8)alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-(d- C8)alkyl or -(C2-C8)alkenyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-(C C8)alkyl or -(C2-C8)alkenyl, halo, cyano, -CORa, -C02Ra, - CONRaRb, -CONRaNRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, - NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -NRaNRaC(0)ORa, -ORa, -OC(0)Ra, and - OC(0)NRaRb;
Y is H or halo;
R1 is (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, unsubstituted or substituted (C3- C8)cycloalkyl, unsubstituted or substituted (C3-C8)cycloalkyl-(CrC8)alkyl or - (C2-C8)alkenyl, unsubstituted or substituted (C5-C8)cycloalkenyl, unsubstituted or substituted (C5-C8)cycloalkenyl-(C1-C8)alkyl or -(C2-C8)alkenyl, unsubstituted or substituted (C6-C10)bicycloalkyl, unsubstituted or substituted heterocycloalkyi or - (C2-C8)alkenyl, unsubstituted or substituted heterocycloalkyl-(Ci-C8)alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-(Ci-C8)alkyl or -(C2-C8)alkenyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-(Ci- C8)alkyl or -(C2-C8)alkenyl, -CORa, -C02Ra, -CONRaRb, -CONRaNRaRb;
R3 is hydrogen, (Ci-C8)alkyl, cyano, trifluoromethyl, -NRaRb, or halo;
R6 is selected from the group consisting of hydrogen, halo, (Ci-C8)alkyl,
(C2-C8)alkenyl, -B(OH)2, substituted or unsubstituted (C2-C8)alkynyl, unsubstituted or substituted (C3-C8)cycloalkyl, unsubstituted or substituted (C3-C8)cycloalkyl-(d-C8)alkyl, unsubstituted or substituted (C5-C8)cycloalkenyl, unsubstituted or substituted (C5- C8)cycloalkenyl-(Ci-C8)alkyl, (C6-Ci0)bicycloalkyl, unsubstituted or substituted
heterocycloalkyi, unsubstituted or substituted heterocycloalkyl-(Ci-C8)alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-(Ci-C8)alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-(Ci-C8)alkyl, cyano, - CORa, -C02Ra, -CONRaRb, -CONRaNRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, - NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, - NRaNRaRb, -NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -NRaNRaC(0)ORa, -ORa, - OC(0)Ra, -OC(0)NRaRb;
wherein any (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)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- C6)alkyl(Rc)1-2, -S(Ci-C6)alkyl(Rc)1-2, -(Ci-C6)alkyl(Rc)1-2, (Ci-C8)alkyl- heterocycloalkyl, (C3-C8)cycloalkyl-heterocycloalkyl, halo, (CrC6)alkyl,
(C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (Ci-C6)haloalkyl, cyano, -CORa, -C02Ra - CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, - NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, - OC(0)NRaRb, heterocycloalkyi, aryl, heteroaryl, aryl(Ci-C4)alkyl, and
heteroaryl(Ci-C4)alkyl;
wherein any aryl or heteroaryl moiety of said aryl, heteroaryl, aryl(Ci-C4)alkyl, or heteroaryl(Ci-C4)alkyl is optionally substituted by 1 , 2 or 3 groups independently selected from the group consisting of halo, (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C C6)haloalkyl, cyano, -CORa, -C02Ra, -CONRaRb,
-SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, and -OC(0)NRaRb;
Ra and Rb are each independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C6-Ci0)bicycloalkyl,
heterocycloalkyi, aryl, heteroaryl, wherein said (Ci-C8)alkyl, (C2-C8)alkenyl, (C2- C8)alkynyl, cycloalkyi, cycloalkenyl, bicycloalkyi, heterocycloalkyi ,aryl or heteroaryl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, hydroxyl, (Ci-C4)alkoxy, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -C02H, - C02(CrC4)alkyl, -CONH2,-CONH(C C4)alkyl, -CON((Ci-C4)alkyl)((C C4)alkyl), - S02(CrC4)alkyl, -S02NH2,-S02NH(C C4)alkyl, or -S02N((C C4)alkyl)((Ci-C4)alkyl); or Ra and Rb taken together with the nitrogen to which they are attached represent a 5-8 membered saturated or unsaturated ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, (Ci-C4)haloalkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, hydroxyl, oxo, (CrC4)alkoxy, and (Ci-C4)alkoxy(Ci-C4)alkyl, wherein said ring is optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyi, aryl, or heteroaryl ring;
or Ra and Rb taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyi, aryl, or heteroaryl ring;
each Rc is independently (d^alkylamino, -NRaS02Rb, -SORa, -S02Ra, - NRaC(0)ORa, -NRaRb, or -C02Ra;
or a salt thereof.
3. A method of claim 2, wherein X and Z are selected from the group consisting of (Ci-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyi, aryl, heteroaryl, -NRaRb, and -ORa;
Y is H or F;
R1 is selected from the group consisting of (Ci-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyi, aryl, and heteroaryl;
R2 is hydrogen, (Ci-C8)alkyl, trifluoromethyl, alkoxy, or halo, in which said (C C8)alkyl maybe substituted with one to two groups selected from: amino, and (C
C3)alkylamino;
R7 is hydrogen, (Ci-C3)alkyl, or alkoxy; R3 is selected from the group consisting of hydrogen, (Ci-C8)alkyl, cyano, trifluoromethyl, -NRaRb, and halo; R6 is selected from the group consisting of hydrogen, halo, cyano, trifluoromethyl, amino, (C1-C8)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl, acylamino, (C2-C8)alkynyl, arylalkynyl, heteroarylalkynyl, -S02Ra, -S02NRaRb , and -NRaS02Rb ;
wherein any (d-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkynyl, arylalkynyl, heteroarylalkynyl group is optionally substituted by 1 , 2 or 3 groups independently selected from -0(Ci-C6)alkyl(Rc)1-2, -S(Ci-C6)alkyl(Rc)1-2, -(CrC6)alkyl(Rc)1-2, (C
C8)alkyl-heterocycloalkyl, (C3-C8)cycloalkyl-heterocycloalkyl, halo, (CrC6)alkyl,
(C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C C6)haloalkyl, cyano, -CORa, -C02Ra, - CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, - NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, - OC(0)NRaRb, heterocycloalkyi, aryl, heteroaryl, aryl(Ci-C4)alkyl, and
heteroaryl(Ci-C4)alkyl;
each Rc is independently (Ci-C4)alkylamino, -NRaS02Rb, -SORa, -S02Ra, - NRaC(0)ORa, -NRaRb, or -C02Ra;
Ra and Rb are each independently hydrogen, (Ci-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C6-Ci0)bicycloalkyl,
heterocycloalkyi, aryl, heteroaryl, wherein said (Ci-C8)alkyl, (C2-C8)alkenyl, (C2- C8)alkynyl, cycloalkyi, cycloalkenyl, bicycloalkyi, heterocycloalkyi ,aryl or heteroaryl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, hydroxyl, (C1-C4)alkoxy, amino, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, -C02H, - C02(C C4)alkyl, -CONH2, -CONH(C C4)alkyl, -CON((C1-C4)alkyl)((C1-C4)alkyl), - S02(CrC4)alkyl, -S02NH2,-S02NH(C C4)alkyl, and -S02N((Ci-C4)alkyl)((C C4)alkyl); or Ra and Rb taken together with the nitrogen to which they are attached represent a 5-8 membered saturated or unsaturated ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by 1 , 2 or 3 groups independently selected from (CrC4)alkyl, (Ci-C4)haloalkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, hydroxyl, oxo, (CrC4)alkoxy, and (Ci-C4)alkoxy(Ci-C4)alkyl, wherein said ring is optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyi, aryl, or heteroaryl ring;
or Ra and Rb taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C3-C8)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:
Figure imgf000162_0001
wherein in (1 ),
A is O, NH, or S; B is CH or N, and C is hydrogen or CrC8 alkyl; or
Figure imgf000162_0002
wherein in (2),
D is N or C optionally substituted by hydrogen or Ci-C8 alkyl; or
Figure imgf000162_0003
wherein in (3),
E is NH or CH2; F is O or CO; and G is NH or CH2; or
Figure imgf000162_0004
wherein in (4),
J is O, S or CO; or
Figure imgf000162_0005
wherein in (5),
Q is CH or N;
M is CH or N; and
L/(5) is hydrogen, halo, amino, cyano, (CrC8)alkyl, (C3-C8)cycloalkyl, -CORa, - C02Ra, -CONRaRb, -CONRaNRaRb, -S02Ra, -S02NRaRb, -NRaRb, -NRaC(0)Rb - NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, -N RaN RaC(0)N RaRb, -ORa, wherein any (Ci-C8)alkyl, (C3-C8)cycloalkyl, group is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C1-C6)haloalkyl, cyano, -CORa, -C02Ra, -CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, - NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, -OC(0)NRaRb; wherein Ra and Rb are defined as above; or
Figure imgf000163_0001
wherein in 6,
L/(6) is NH or CH2; or
Figure imgf000163_0002
wherein in 7,
M/(7) is hydrogen, halo, amino, cyano, (C1-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -CORa, -C02Ra, -CONRaRb, -CONRaNRaRb, -S02Ra, - S02NRaRb, -NRaRb, -NRaC(0)Rb,-NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, - NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -ORa,
wherein any (Ci-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl group is optionally substituted by 1 , 2 or 3 groups independently selected from
(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (CrC6)haloalkyl, cyano, - CORa, -C02Ra, -CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, - ORa, -OC(0)Ra, -OC(0)NRaRb; wherein Ra and Rb are defined as above; or
Figure imgf000163_0003
wherein in (8),
P is CH2, NH, O, or S; Q/(8) is CH or N; and n is 0-2; or
Figure imgf000164_0001
wherein in (9),
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-C8)alkyl, (C3- C8)cycloalkyl, -CORa, -C02Ra, -CONRaRb, -S02Ra, -S02NRaRb, -NRaRb, - NRaC(0)Rb,-NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, , -ORa, 4-(1 H- pyrazol-4-yl),
wherein any (Ci-C8)alkyl, (C3-C8)cycloalkyl, group is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C5-Ce)cycloalkenyl, (Ci-C6)haloalkyl, cyano, -CORa, -C02Ra,-CONRaRb, -SRa, - SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, - NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, -OC(0)NRaRb; wherein Ra and Rb are defined as above.
4. A method of claim 2, wherein X and Z are selected independently from the group consisting of (Ci-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NRaRb, and -ORa;
Y is H;
R1 is (Ci-C8)alkyl, (C3-C8)cycloalkyl, or heterocycloalkyl;
R2 is hydrogen, (Ci-C3)alkyl, or halo, in which said (Ci-C3)alkyl maybe substituted with one to two groups selected from: amino, and (Ci-C3)alkylamino;
R7 is hydrogen, (Ci-C3)alkyl, or alkoxy; R3 is hydrogen, (Ci-C8)alkyl or halo;
R6 is hydrogen, halo, cyano, trifluoromethyl, amino, (Ci-C8)alkyl, (C3- C8)cycloalkyl, aryl, heteroaryl, acylamino, (C2-C8)alkynyl, arylalkynyl, heteroarylalkynyl, - S02Ra, -S02NRaRb, or -NRaS02Rb;
wherein any (Ci-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkynyl, arylalkynyl, heteroarylalkynyl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl,
(Ci-C6)haloalkyl, cyano, -CORa, -C02Ra, -CONRaRb, -SRa, -SORa, -S02Ra, - S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, - NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, -OC(0)NRaRb, heterocycloalkyi, aryl, heteroaryl, aryl(C1-C4)alkyl, and heteroaryl(C1-C4)alkyl;
Ra and Rb are each independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C6-Ci0)bicycloalkyl,
heterocycloalkyi, aryl, heteroaryl, wherein said (Ci-C8)alkyl, (C2-C8)alkenyl, (C2- C8)alkynyl, cycloalkyi, cycloalkenyl, bicycloalkyi, heterocycloalkyi ,aryl or heteroaryl group is optionally substituted by 1 , 2 or 3 groups independently selected from halo, hydroxyl, (Ci-C4)alkoxy, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -C02H, - C02(CrC4)alkyl, -CONH2,-CONH(C C4)alkyl, -CON((Ci-C4)alkyl)((C C4)alkyl), - S02(CrC4)alkyl, -S02NH2, -S02NH(Ci-C4)alkyl, and -S02N((Ci-C4)alkyl)((C C4)alkyl); or Ra and Rb taken together with the nitrogen to which they are attached represent a 5-8 membered saturated or unsaturated ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, (Ci-C4)haloalkyl, amino, (Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, hydroxyl, oxo, (CrC4)alkoxy, and (Ci-C4)alkoxy(Ci-C4)alkyl, wherein said ring is optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyi, aryl, or heteroaryl ring;
or Ra and Rb taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C3-C8)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 compound of or another aryl or heteroaryl group as follows:
Figure imgf000165_0001
wherein in (1 ),
A is O, NH, or S; B is CH or N, and C is hydrogen or Ci-C8 alkyl; or
Figure imgf000165_0002
wherein in (2),
D is N or C optionally substituted by hydrogen or Ci-C8 alkyl; or
Figure imgf000166_0001
wherein in (3),
E is NH or CH2; F is O or CO; and G is NH or CH2; or
Figure imgf000166_0002
wherein in (4),
J is O, S or CO; or
Figure imgf000166_0003
wherein in (5),
Q is CH or N;
M is CH or N; and
L/(5) is hydrogen, halo, amino, cyano, (d-C8)alkyl, (C3-C8)cycloalkyl, -CORa, - C02Ra, -CONRaRb, -CONRaNRaRb, -S02Ra, -S02NRaRb, -NRaRb, -NRaC(0)Rb - NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -ORa, wherein any (Ci-C8)alkyl, (C3-C8)cycloalkyl, group is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (Ci-C6)haloalkyl, cyano, -CORa, -C02Ra, -CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, - NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, -OC(0)NRaRb, wherein Ra and Rb are defined as above; or
Figure imgf000166_0004
wherein in 6,
L/(6) is NH or CH2; or
Figure imgf000167_0001
wherein in 7,
M/(7) is hydrogen, halo, amino, cyano, (C1-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -CORa, -C02Ra, -CONRaRb, -CONRaNRaRb, -S02Ra, - S02NRaRb, -NRaRb, -NRaC(0)Rb,-NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, - NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -ORa,
wherein any (d-C8)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl group is optionally substituted by 1 , 2 or 3 groups independently selected from
(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (CrC6)haloalkyl, cyano, - CORa, -C02Ra, -CONRaRb, -SRa, -SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, - ORa, -OC(0)Ra, -OC(0)NRaRb; wherein Ra and Rb are defined as above; or
Figure imgf000167_0002
wherein in (8),
P is CH2, NH, O, or S; 0/(8) is CH or N; and n is 0-2; or
Figure imgf000167_0003
wherein in (9),
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-C8)alkyl, (C3- C8)cycloalkyl, -CORa, -C02Ra, -CONRaRb, -S02Ra, -S02NRaRb, -NRaRb, - NRaC(0)Rb,-NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, , -ORa, 4-(1 H- pyrazol-4-yl),
wherein any (Ci-C8)alkyl, (C3-C8)cycloalkyl, group is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (C1-C6)haloalkyl, cyano, -CORa, -C02Ra -CON RaRb, -SRa, - SORa, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, - NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, -OC(0)NRaRb, wherein Ra and Rb are defined as above.
5. A method of claim 2, wherein X is methyl, ethyl, n-propyl, isopropyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, trifluoromethyl, tetrahydropyran,
hydroxymethyl, methoxymethyl, or benzyl;
Y is H;
Z is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or benzyl;
R1 is isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, (1 - methylethyl)cyclopropyl, 1 , 1-dioxo-tetrahydrothiophene-3-yl, 1-Me-piperidin-4-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, /V,/V-dimethyl-1-propanaminyl, benzyl, or 4- pyridyl;
R2 is hydrogen, (d-C3)alkyl, or halo, in which said (CrC3)alkyl may be substituted with one to two groups selected from: amino, and (Ci-C3)alkylamino;
R7 is hydrogen, (C1-C3)alkyl, or alkoxy; R3 is H, methyl, or Br; and
R6 is methyl, bis(1 , 1-dimethylethyl), bis(l -methylethyl), cyclopropyl, propyl, dimethylamino, ethylamino, (2-hydroxyethyl)amino, 2-propen-1 -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-1-butyn-1 -yl, 4-pyridinylethynyl, phenylethynyl, 2-furanyl, 3-thienyl; 1 H-pyrazol-4-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 3- methyl-1 H-indazol-5-yl, 1 H-1 ,2,3-benzotriazol-5-yl, 2-oxo-2,3-dihydro-1 H-benzimidazol-5- yl, 2-0X0-2, 3-dihydro-1 H-indol-5-yl, 2-oxo-2,3-dihydro-1 H-indol-6-yl, 2,1 ,3-benzoxadiazol- 5-yl, 2-amino-6-quinazolinyl, 2,4-dioxo-1 ,2,3,4-tetrahydro-5-pyrimidinyl, 2-amino-5- pyrimidinyl, 7-oxo-1 ,5,6,7-tetrahydro-1 ,8-naphthyridin-3-yl, phenyl, 2-methylphenyl, 2- nitrophenyl, 2-phenylethyl, 3-aminophenyl, 4-aminophenyl, 4-chlorophenyl, 4- fluorophenyl, 4-(methyloxy)phenyl, 3-(acetylamino)phenyl, 4-(acetylamino)phenyl, 4- (aminocarbonyl)phenyl, 4-(1 H-pyrazol-4-yl)phenyl, 4-(aminosulfonyl)phenyl, 4- (methylsulfonyl)phenyl, 4-[(dimethylamino)sulfonyl]phenyl, 4- [(methylamino)carbonyl]phenyl, 4-[(methylamino)sulfonyl]phenyl, 4- [(methylsulfonyl)amino]phenyl, 3-pyridinyl, 4-pyridinyl, 2-(4-morpholinyl)-4-pyridinyl, 2- amino-4-pyridinyl, 5-(methyloxy)-3-pyridinyl, 5-(methylsulfonyl)-3-pyridinyl, 5- [(cyclopropylsulfonyl)amino]-6-(methyloxy)-3-pyridinyl, 5-[(phenylsulfonyl)amino]-3- pyridinyl, 6-(4-methyl-1-piperazinyl)-3-pyridinyl, 6-(4-morpholinyl)-3-pyridinyl, 6- (acetylamino)-3-pyridinyl, 6-(dimethylamino)-3-pyridinyl, 6-(methyloxy)-3-pyridinyl, 6- [(methylamino)carbonyl]-3-pyridinyl, 6-[(methylamino)sulfonyl]-3-pyridinyl, 6-methyl-3- pyridinyl, 4-pyridinyloxy.
6. A method of any one of the above claims, wherein said T cell mediated inflammatory immune disease is selected from a group consisting of: 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 nodosa, polymyalgia, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune haemolytic anemia, interstitial cystitis, lyme disease, morphea, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.
7. A method of any one of claims 1-5, wherein the T cell mediated hypersensitivity disease is selected from the group consisting of: contact hypersensitivity, contact dermatitis (including that due to poison ivy), uticaria, skin allergies, respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitive enteropathy (Celliac disease).
8. A method of treating a T cell mediated inflammatory immune disease or a T cell mediated hypersensitivity disease, which comprises administering to a human in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, which inhibits EZH2 and/or EZH1 , in a pharmaceutically acceptable composition.
9. A method of treating a T cell mediated inflammatory immune disease or a T cell mediated hypersensitivity disease, which comprises administering to a human in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 2-5, in a pharmaceutically acceptable composition.
10. 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.
1 1 . 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.
12. Compound or use according to claim 10 or claim 1 1 wherein said T cell mediated inflammatory immune disease is selected from a group consisting of: 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 nodosa, polymyalgia, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune haemolytic anemia, interstitial cystitis, lyme disease, morphea, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.
13. Compound or use according to claim 10 or claim 1 1 , wherein said T cell mediated hypersensitivity disease is selected from the group consisting of: contact hypersensitivity, contact dermatitis (including that due to poison ivy), uticaria, skin allergies, respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitive enteropathy (Celliac disease).
14. Compound or use according to any one of claims 10 to 13, wherein the compound is a compound as defined in any one of claims 2 to 5
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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015506985A (en) * 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． Methyl group-modifying enzyme regulator, composition and use thereof
WO2015077194A1 (en) * 2013-11-22 2015-05-28 Bristol-Myers Squibb Company Inhibitors of lysine methyl transferase
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 (en) * 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 Use of ezh2 inhibitor combined with btk inhibitor in preparing drug for treating tumor
WO2018210302A1 (en) 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 Crystal of benzofuran derivative free base and preparation method
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 (en) 2014-11-06 2021-09-29 Dana-Farber Cancer Institute, Inc. Indole compounds as ezh2 inhibitors and uses thereof
WO2023244917A1 (en) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. 1,8-naphthyridin-2-one heterobifunctional bcl6 degraders
WO2023244918A1 (en) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Quinolone bcl6 bifunctional degraders
WO2024108691A1 (en) * 2022-11-25 2024-05-30 深圳先进技术研究院 Regulatory t cell and preparation method therefor

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005034845A2 (en) * 2003-09-12 2005-04-21 Supergen, Inc. Compositions and methods for treatment of cancer
WO2007053114A1 (en) * 2005-10-31 2007-05-10 S*Bio Pte Ltd Method of predicting a response to hdac inhibitors
WO2010090723A2 (en) * 2009-02-04 2010-08-12 University Of Georgia Research Foundation, Inc. Methods of inhibiting fibrogenesis and treating fibrotic disease
US20110064664A1 (en) * 2007-10-08 2011-03-17 The Board Of Regents Of The University Of Texas System Methods and compositions involving chitosan nanoparticles

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005034845A2 (en) * 2003-09-12 2005-04-21 Supergen, Inc. Compositions and methods for treatment of cancer
WO2007053114A1 (en) * 2005-10-31 2007-05-10 S*Bio Pte Ltd Method of predicting a response to hdac inhibitors
US20110064664A1 (en) * 2007-10-08 2011-03-17 The Board Of Regents Of The University Of Texas System Methods and compositions involving chitosan nanoparticles
WO2010090723A2 (en) * 2009-02-04 2010-08-12 University Of Georgia Research Foundation, Inc. Methods of inhibiting fibrogenesis and treating fibrotic disease

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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 (en) * 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． Methyl group-modifying enzyme regulator, composition and use thereof
US10016405B2 (en) 2012-02-10 2018-07-10 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
US9371331B2 (en) 2012-02-10 2016-06-21 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9085583B2 (en) 2012-02-10 2015-07-21 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
US9980952B2 (en) 2012-02-10 2018-05-29 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US10150759B2 (en) 2012-12-21 2018-12-11 Epizyme, Inc. 1,4-pyridone bicycic heteroaryl compounds
US20150344459A1 (en) * 2012-12-21 2015-12-03 Epizyme, Inc. 1,4-pyridone bicyclic 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 (en) * 2013-11-22 2015-05-28 Bristol-Myers Squibb Company Inhibitors of lysine methyl transferase
US11236082B2 (en) 2014-11-06 2022-02-01 Dana-Farber Cancer Institute, Inc. EZH2 inhibitors and uses thereof
EP3885343A1 (en) 2014-11-06 2021-09-29 Dana-Farber Cancer Institute, Inc. Indole compounds as ezh2 inhibitors and uses thereof
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
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
WO2018210302A1 (en) 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 Crystal of benzofuran derivative free base and preparation method
CN109937041A (en) * 2017-05-18 2019-06-25 江苏恒瑞医药股份有限公司 A kind of EZH2 inhibitor combines the purposes in the drug of preparation treatment tumour with BTK inhibitor
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
KR20200007851A (en) * 2017-05-18 2020-01-22 지앙수 헨그루이 메디슨 컴퍼니 리미티드 Use of a combination of an EZH2 inhibitor and a BTK inhibitor in the manufacture of a drug for the treatment of tumors
US11155537B2 (en) 2017-05-18 2021-10-26 Jiangsu Hengrui Medicine Co., Ltd. Crystal of benzofuran derivative free base and preparation method
RU2762893C2 (en) * 2017-05-18 2021-12-23 Цзянсу Хэнжуй Медсин Ко., Лтд. Application of an ezh2 inhibitor in combination with a btk inhibitor in production of a medicinal product for treating a tumour
WO2018210296A1 (en) * 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 Use of ezh2 inhibitor combined with btk inhibitor in preparing drug for treating tumor
CN109937041B (en) * 2017-05-18 2022-04-12 江苏恒瑞医药股份有限公司 Application of EZH2 inhibitor and BTK inhibitor in preparation of medicine for treating tumors
KR102635949B1 (en) 2017-05-18 2024-02-14 지앙수 헨그루이 파마슈티컬스 컴퍼니 리미티드 Use of a combination of EZH2 inhibitors and BTK inhibitors in the manufacture of drugs for the treatment of tumors
WO2023244917A1 (en) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. 1,8-naphthyridin-2-one heterobifunctional bcl6 degraders
WO2023244918A1 (en) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Quinolone bcl6 bifunctional degraders
WO2024108691A1 (en) * 2022-11-25 2024-05-30 深圳先进技术研究院 Regulatory t cell and preparation method therefor

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