[go: up one dir, main page]

WO2020021024A1 - Composés bicycliques substitués en tant que modulateurs du récepteur d'hydrocarbures aryle (ahr) - Google Patents

Composés bicycliques substitués en tant que modulateurs du récepteur d'hydrocarbures aryle (ahr) Download PDF

Info

Publication number
WO2020021024A1
WO2020021024A1 PCT/EP2019/070066 EP2019070066W WO2020021024A1 WO 2020021024 A1 WO2020021024 A1 WO 2020021024A1 EP 2019070066 W EP2019070066 W EP 2019070066W WO 2020021024 A1 WO2020021024 A1 WO 2020021024A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
independently selected
halogen
cycloalkyl
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2019/070066
Other languages
English (en)
Inventor
Christoph Steeneck
Sheena PINTO
Simon ANDERHUB
Christian Gege
Ulrich Deuschle
Thomas Hoffmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Phenex Pharmaceuticals AG
Original Assignee
Phenex Pharmaceuticals AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Phenex Pharmaceuticals AG filed Critical Phenex Pharmaceuticals AG
Publication of WO2020021024A1 publication Critical patent/WO2020021024A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds which can act as aryl hydrocarbon receptor (AhR) modulators and, in particular, as AhR antagonists.
  • the invention further relates to the use of the compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said aryl hydrocarbon receptor by said compounds.
  • the aryl hydrocarbon receptor is a ligand-modulated transcription factor, belonging to the basic helix-loop-helix PAS (Per-Arnt-Sim homology domain) family, that is expressed in most tissues in mice and humans and known to mediate many of the toxicities of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in mice.
  • the AhR protein is localized in the cytoplasm of eukaryotic cells in complexes with HSP90 and other proteins. Binding of agonistic ligands, such as TCDD, leads to dissociation of AhR from the HSP90 containing complex, transport to the nucleus and association with its heterodimeric partner ARNT.
  • This heterodimeric complex can bind to AhR response elements located in promoter regions of genes such as CYP1A1 , CYP1 B1 , ALDH3A1 , NQ01 , UGT1A1 etc. and induces the transcription of such genes in case of very potent and efficacious AhR agonists, such as TCDD.
  • CYP1 A1 By regulating the expression of genes involved in xenobiotic transformation (e.g. CYP1 A1 ), the AhR plays a significant role in the detoxification of xenobiotic substances in liver and intestine, which are prominent locations of AhR expression. This activity might be underlying some of the described chemoprevention and tumor suppression effects exerted by AhR.
  • CYP1A1 is known to metabolize some pro- cancerogens, such as benzo(a)pyrene into DNA reactive intermediates leading to mutagenesis and tumor formation (Murray et al. Nat Rev Cancer. 2014 Dec; 14(12):801 - 14; Safe et al Toxicol Sci. 2013 Sep; 135(1 ):1 -16).
  • the AhR is relatively strongly expressed in intestinal epithelial tissues, lung epithelium and skin. In these tissues the AhR expression is particularly high in cells of lymphoid origin such as T-cells, Dendritic Cells, Langerhans Cells, Macrophages, Mast cells etc.
  • One possible function in these compartments is to integrate signals from the commensal microbiomes in the intestine, the lung and the skin, which are known to produce diverse mixtures of indolic AhR modulators that are thought to balance the responses of the immune system towards the microbiome (Bessede et al., Nature. 2014 Jul 10; 511 (7508):184-90, Zelante et al. Immunity. 2013 Aug 22;39(2):372-85, Romani et al., Eur J Immunol. 2014 Nov;44(11 ):3192-200).
  • AhR AhR ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • AhR modulators and in particular modulators with primarily antagonistic activities might be useful as medicaments for the treatment of solid tumors (e.g. pancreatic cancer, prostate cancer, breast cancer, colon cancer).
  • solid tumors e.g. pancreatic cancer, prostate cancer, breast cancer, colon cancer.
  • the problem underlying the present invention is to provide compounds which have a AhR-antagonistic activity and can be used in the treatment and/or prophylaxis of AhR- mediated diseases.
  • A represents a 6- to 10-membered mono- or bicyclic aryl or a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of halogen, OH, CN, Ci- 6 -alkyl, O-C1- 6 -alkyl, oxo, C(0)OR a , OC(0)R a , S-Ci -6 -alkyl, S(0)-Ci -6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a ) 2 , C(0)N(R a ) 2 , NR a C(0)-Ci -6 -alkyl, S(0) 2 N(R a ) 2 , NR a S(0) 2 -Ci -6 -alkyl and C 3-6 -cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl,
  • substituents on the aryl or heteroaryl group together with the atoms they are attached to may form a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, oxo, OH, Ci- 6 -alkyl and halo-Ci- 6 -alkyl;
  • R a is independently selected from hydrogen and Ci- 6 -alkyl
  • B represents a 8- to 10- membered bicyclic aryl or heteroaryl ring, wherein the heteroaryl ring contains up to 6 heteroatoms independently selected from N, O and S,
  • bicyclic aryl or heteroaryl ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci-3-alkyl, OH, C 3-6 -cycloalkyl, OH, O-Ci-3-alkyl, oxo and CN, wherein cycloalkyl or alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, Ci-3-alkyl and halo-Ci-3-alkyl;
  • alkylene is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, Ci-3-alkyl and halo-Ci-3-alkyl;
  • R b is independently selected from hydrogen and Ci- 6 -alkyl
  • R c is hydrogen, OH, Ci- 6 -alkyl, O-Ci- 6 -alkyl, CN or S0 2 -Ci- 6 -alkyl;
  • C represents a Ci- 6 -alkyl, C3-io-cycloalkyl, 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, 6- to 10- membered mono- or bicyclic aryl or a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,
  • cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of halogen, OH, CN, Ci- 6 -alkyl, O-Ci-e-alkyl, C(0)OR a , OC(0)R a , S(0)-Ci- 6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a ) 2 , C(0)N(R a ) 2 , NR a C(0)-Ci- 6 -alkyl, S(0) 2 N(R a ) 2, NR a S(0) 2 -Ci -6 -alkyl and C 3-6 - cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl, halo-C
  • x 0, 1 or 2;
  • L represents a -NR bb C(0)- group
  • R bb is hydrogen or Ci- 6 -alkyl
  • C is 6- to 10-membered mono- or bicyclic aryl and 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of halogen, OH, CN, Ci- 6 -alkyl, O-C-i- 6 -alkyl, C(0)OR aa , OC(0)R aa , S(0)-Ci -6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R aa ) 2 , C(0)N(R aa ) 2 , NR aa C(0)-Ci- 6 -alkyl, S(0) 2 N(R aa ) 2, NR aa S(0) 2 -Ci- 6 -alkyl and C3-6-cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl, halo-Ci-3-alkyl,
  • substituents on the aryl or heteroaryl group together with the atoms they are attached to may form a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl and halo-Ci- 6 -alkyl, and
  • R aa is hydrogen or Ci- 6 -alkyl
  • R 100 to R 400 is independently selected from the group consisting of hydrogen, halogen, Ci -4 -alkyl, halo-Ci-3-alkyl, OH, O-Ci-3-alkyl, and CN, and R bb is hydrogen or Ci- 6 -alkyl.
  • R 100 to R 400 is independently selected from the group consisting of hydrogen, halogen, Ci -4 -alkyl, halo-Ci-3-alkyl, OH, O-Ci-3-alkyl, and CN
  • R bb is hydrogen or Ci- 6 -alkyl.
  • A represents a 6- to 10-membered mono- or bicyclic aryl or a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of halogen, OH, CN, Ci- 6 -alkyl, O-C-i- 6 -alkyl, C(0)OR a , OC(0)R a , S(0)-Ci -6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a ) 2 , C(0)N(R a ) 2 , NR a C(0)-Ci- 6 -alkyl, S(0) 2 N(R a ) 2 , NR a S(0) 2 -Ci- 6 -alkyl and C3-6-cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl, halo-Ci-3-alkyl, OH, CN and
  • substituents on the aryl or heteroaryl group together with the atoms they are attached to may form a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl and halo-Ci- 6 -alkyl;
  • R a is independently selected from hydrogen and Ci- 6 -alkyl
  • B represents a 8- to 10- membered bicyclic aryl or heteroaryl ring, wherein the heteroaryl ring contains up to 6 heteroatoms independently selected from N, O and S,
  • bicyclic aryl or heteroaryl ring is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, Ci- 6 -alkyl, halo-Ci-3-alkyl, C3-6- cycloalkyl, OH, O-C-i-3-alkyl and CN, wherein cycloalkyl or alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, OH, C-i-3-alkyl and halo-Ci-3-alkyl;
  • R b is independently selected from hydrogen and Ci- 6 -alkyl
  • R c is hydrogen, OH, Ci- 6 -alkyl, O-Ci- 6 -alkyl, CN or S0 2 -Ci- 6 -alkyl;
  • C represents a Ci- 6 -alkyl, C3-io-cycloalkyl, 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, 6- to 10- membered mono- or bicyclic aryl or a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,
  • cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of halogen, OH, CN, Ci- 6 -alkyl, O-Ci-e-alkyl, C(0)OR a , OC(0)R a , S(0)-Ci- 6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a ) 2 , C(0)N(R a ) 2 , NR a C(0)-Ci -6 -alkyl, S(0) 2 N(R a ) 2, NR a S(0) 2 -Ci -6 -alkyl and C 3-6 - cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl, halo-
  • two substituents on the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group together with the atoms they are attached to may form a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl and halo-Ci- 6 -alkyl;
  • x 0, 1 or 2;
  • L represents a -NR bb C(0)- group
  • R bb is hydrogen or Ci- 6 -alkyl
  • C is 6- to 10-membered mono- or bicyclic aryl and 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of halogen, OH, CN, Ci- 6 -alkyl, O-C-i- 6 -alkyl, C(0)OR aa , OC(0)R aa , S(0)-Ci- 6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a a ) 2 , C(0)N(R aa ) 2 , NR aa C(0)-Ci- 6 -alkyl, S(0) 2 N(R aa ) 2, NR aa S(0) 2 -Ci- 6 -alkyl and C3-6-cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl, halo-Ci-3-alkyl,
  • substituents on the aryl or heteroaryl group together with the atoms they are attached to may form a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl and halo-Ci- 6 -alkyl, and wherein R aa is hydrogen or Ci- 6 -alkyl,
  • R 100 to R 400 is independently hydrogen, halogen, Ci -4 -alkyl, halo-Ci-3-alkyl, OH, O-Ci-3-alkyl and CN, and R bb is hydrogen or Ci-6-alkyl.
  • A represents a 6- to 10-membered mono- or bicyclic aryl or a 5- to 10- membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of halogen, OH, CN, Ci- 6 -alkyl, O-C1- e-alkyl, C(0)0R a , 0C(0)R a , S(0)-Ci- 6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a ) 2 , C(0)N(R a ) 2 ,
  • substituents on the aryl or heteroaryl group together with the atoms they are attached to may form a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl and halo-Ci- 6 -alkyl; and
  • R a is independently selected from hydrogen and Ci- 6 -alkyl.
  • R 4 is independently selected from halogen, OH, CN, Ci- 6 -alkyl, O-Ci- 6 -alkyl, C(0)OR a , OC(0)R a , S(0)-Ci- 6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a ) 2 , C(0)N(R a ) 2 , S(0) 2 N(R a ) 2 , NR a S(0) 2 - Ci- 6 -alkyl and C3-6-cycloalkyl,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl, halo-Ci-3-alkyl, OH, CN and oxo;
  • R a is independently selected from hydrogen and Ci- 6 -alkyl
  • n 0 to 5.
  • R 4 is independently selected from halogen, OH, CN, Ci- 6 -alkyl, O-Ci- 6 -alkyl, C(0)0R a , 0C(0)R a , S(0)-Ci- 6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a ) 2 , C(0)N(R a ) 2 , S(0) 2 N(R a ) 2 , NR a S(0) 2 - Ci- 6 -alkyl and C3-6-cycloalkyl,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl, halo-Ci-3-alkyl, OH, CN and oxo;
  • R a is independently selected from hydrogen and Ci- 6 -alkyl
  • n 0 to 5.
  • X is halogen, Ci- 6 -alkyl or C3-6-cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl and halo-Ci-3-alkyl;
  • R 5 is independently selected from halogen and CN
  • n 0 to 4.
  • X is F, Cl, CH3, CH2CH3, CHF2 or CF3;
  • R 5 is independently selected from halogen and CN
  • m 0 to 4.
  • A is In an equally most preferred embodiment in combination with any of the above or below embodiments, A is
  • B represents a 8- to 10-membered bicyclic aryl or heteroaryl ring, wherein the heteroaryl ring contains up to 6 heteroatoms independently selected from N, O and S, and wherein the bicyclic ring is connected to A and L-C in the following configurations
  • bicyclic aryl or heteroaryl ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci-3-alkyl, OH, C3-6-cycloalkyl, O-Ci-3-alkyl and CN,
  • cycloalkyl or alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, Ci-3-alkyl and halo-Ci- 3-alkyl.
  • X 1 is independently selected from N and OR 1 ;
  • X 2 is independently selected from NR 2 , O and S;
  • Y is independently selected from N and OR 1 ;
  • R 1 is independently selected from hydrogen, halogen, Ci- 6 -alkyl, halo-Ci-3-alkyl, OH, C3- 6 -cycloalkyl, O-C-i-3-alkyl and CN,
  • cycloalkyl or alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, OH, C-i-3-alkyl and halo-C-i-3-alkyl;
  • R 2 is independently selected from hydrogen and Ci-6-alkyl.
  • X 1 is independently selected from N and CR 1 ;
  • X 2 is independently selected from NR 2 , O and S;
  • Y is independently selected from N and CR 1 ;
  • R 1 is independently selected from hydrogen, halogen, Ci- 3 -alkyl, halo-Ci- 3 -alkyl, C 3-6 - cycloalkyl, OH, O-C-i- 3 -alkyl and CN,
  • cycloalkyl or alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, OH, C-i-3-alkyl and halo-C-i-3-alkyl;
  • R 2 is independently selected from hydrogen and Ci-6-alkyl.
  • X 1 is independently selected from N and CR 1 ;
  • X 2 is independently selected from NR 2 , O and S;
  • Y is independently selected from N and CR 1 ;
  • R 1 is independently selected from hydrogen, halogen, C-i- 3 -alkyl, halo-C-i- 3 -alkyl, OH, C 3 - 6-cycloalkyl, O-C-i- 3 -alkyl and CN,
  • cycloalkyl or alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, OH, C-i-3-alkyl and halo-C-i-3-alkyl;
  • R 2 is independently selected from hydrogen and Ci-6-alkyl.
  • B is independently selected from hydrogen and Ci-6-alkyl.
  • X 1 is independently selected from N and CR 1 ;
  • X 2 is independently selected from NR 2 , O and S;
  • Y is independently selected from N and CR 1 ;
  • R 1 is independently selected from hydrogen, halogen, Ci- 3 -alkyl, halo-Ci- 3 -alkyl, OH, C 3 - 6-cycloalkyl, O-C-i- 3 -alkyl, and CN,
  • cycloalkyl or alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, OH, C-i-3-alkyl and halo-C-i-3-alkyl;
  • R 2 is independently selected from hydrogen and Ci-6-alkyl.
  • B is In a preferred embodiment in combination with any of the above or below embodiments, R 1 is hydrogen or Ci-3-alkyl.
  • R 1 is hydrogen or methyl, most preferably R 1 is hydrogen.
  • C represents a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, more preferably the 6-membered heteroaryl is pyridine, wherein the heteroaryl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of OH, halogen, CN, Ci- 6 -alkyl, O-C1- 6 -alkyl, OC(0)R a , S(0)-Ci -6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a ) 2 , NR a C(0)-Ci -6 -alkyl, S(0) 2 N(R a ) 2 , NR a S(0) 2 -Ci- 6 -alkyl and C3-6-cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituent
  • heteroaryl group wherein two substituents on the heteroaryl group together with the atoms they are attached to may form a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl and halo-Ci- 6 -alkyl.
  • C represents a Ci- 6 -alkyl, C3-io-cycloalkyl, 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, 6- to 10-membered mono- or bicyclic aryl or a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of OH, CN, Ci- 6 -alkyl, O-Ci-e-alkyl, OC(0)R a , S(0)-Ci -6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a ) 2 , NR a C(0)-Ci -6 -
  • two substituents on the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group together with the atoms they are attached to may form a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl and halo-Ci- 6 -alkyl.
  • C represents a 6- to 10-membered mono- or bicyclic aryl or a 5- to 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of OH, CN, Ci- 6 -alkyl, O- Ci- 6 -alkyl, OC(0)R a , S(0)-Ci -6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a ) 2 , NR a C(0)-Ci -6 -alkyl, S(0) 2 N(R a ) 2 , NR a S(0) 2 -Ci- 6 -alkyl and C3-6-cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to
  • C represents a 5-membered heteroaryl containing 2 to 4 nitrogen atoms, which is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of OH, CN, Ci- 6 -alkyl, O-Ci- 6 -alkyl, OC(0)R a , S(0)-Ci- 6 -alkyl, S(0) 2 - Ci- 6 -alkyl, N(R a ) 2 , NR a C(0)-Ci -6 -alkyl, S(0) 2 N(R a ) 2 , NR a S(0) 2 -Ci -6 -alkyl and C 3-6 - cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl, halo-Ci-3-al
  • heteroaryl group wherein two substituents on the heteroaryl group together with the atoms they are attached to may form a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl and halo-Ci- 6 -alkyl.
  • C represents a 5-membered heteroaryl containing 2 or 3 nitrogen atoms, which is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of OH, CN, Ci- 6 -alkyl, O-Ci- 6 -alkyl, OC(0)R a , S(0)-Ci- 6 -alkyl, S(0) 2 - Ci- 6 -alkyl, N(R a ) 2 , NR a C(0)-Ci -6 -alkyl, S(0) 2 N(R a ) 2 , NR a S(0) 2 -Ci -6 -alkyl and C 3-6 - cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl, halo-Ci-3-
  • R 3 is Ci- 6 -alkyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of OH, halogen and CN.
  • R 3 is Ci- 6 -alkyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of OH, halogen and CN.
  • R 3 is Ci-6-alkyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of OH, halogen and CN.
  • R 3 is Ci- 6 -alkyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of OH, halogen and CN.
  • C is which is not further substituted or substituted with 1 substituent selected from the group consisting of OH, CN, Ci- 6 -alkyl, O-Ci- 6 -alkyl, OC(0)R a , S(0)-Ci- 6 -alkyl, S(0) 2 -Ci- 6 -alkyl, N(R a ) 2 , NR a C(0)-Ci- 6 -alkyl, S(0) 2 N(R a ) 2, NR a S(0) 2 -Ci- 6 -aikyl and Cs-e-cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-3-alkyl, halo-Ci-3-alkyl, OH, CN and oxo.
  • C is In an equally utmost preferred embodiment in combination with any of the above or below embodiments, C is In a further equally utmost preferred embodiment in combination with any of the above or below embodiments, C is
  • X is F, Cl, CF , CH2CH3, CHF2 or CF3;
  • R 5 is independently halogen or CN
  • m is 0 or 1 , and wherein the ring is not further substituted or substituted with 1 or 2 substituents independently selected from the group consisting of OH, CN, Ci- 6 -alkyl, 0-Ci -6 -alkyl, OC(0)R a , S(0)-Ci -6 -alkyl, S(0) 2 -Ci -6 -alkyl, N(R a ) 2 , NR a C(0)-Ci- 6 -alkyl, S(0) 2 N(R a ) 2 , NR a S(0) 2 -Ci- 6 -alkyl and C3-6-cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C-i-3-alkyl, halo-C-i-3-alkyl, OH, CN and oxo.
  • substituents independently selected from the group consist
  • R b is independently selected from hydrogen and Ci- 6 -alkyl
  • R c is hydrogen, OH, Ci- 6 -alkyl, O-Ci- 6 -alkyl or CN.
  • L is -NR b C(0)-.
  • L is -NR b C(0)C(0)NR b -.
  • L is -NR b S02-.
  • L is -C(0)NR b -.
  • L is -NR b -Ci-2-alkylene-.
  • L is -NR b C(0)-, wherein R b is hydrogen or Ci- 6 -alkyl, more R b is hydrogen.
  • the compound according to Formula (I) is selected from
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to Formula (I) and a physiologically acceptable excipient.
  • the present invention is directed to the compound according to Formula (I) for use as a medicament.
  • the present invention is directed to the compound according to Formula (I) or a pharmaceutical composition containing same and a physiologically acceptable excipient for use in the prophylaxis and/or treatment of a disease or condition mediated by aryl hydrocarbon receptor (AhR).
  • aryl hydrocarbon receptor AhR
  • the disease or condition mediated by aryl hydrocarbon receptor (AhR) is cancer.
  • the compound according to Formula (I) is administered with one or more therapeutic agents for cancer selected from the group consisting of PD-1 agent, PD-L1 agent, CTLA-4 agent, ID01 inhibitor, chemotherapeutic agent, anticancer vaccine, Toll like receptor agonist, oncolytic virus, STING agonist and cytokine therapy, or wherein the compound is administered under irradiation therapy.
  • one or more therapeutic agents for cancer selected from the group consisting of PD-1 agent, PD-L1 agent, CTLA-4 agent, ID01 inhibitor, chemotherapeutic agent, anticancer vaccine, Toll like receptor agonist, oncolytic virus, STING agonist and cytokine therapy, or wherein the compound is administered under irradiation therapy.
  • Ci- 6 -alkyl means a saturated alkyl chain having 1 to 6 carbon atoms which may be straight chained or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, ferf-butyl, n-pentyl, isopentyl, neopentyl, and hexyl.
  • A“Co-2-alkylene” means that the respective group is divalent and connects the attached residue with the remaining part of the molecule. Moreover, in the context of the present invention,“Co-alkylene” is meant to represent a bond, whereas Ci-alkylene means a methylene linker, C 2 -alkylene means an ethylene linker or a methyl-substituted methylene linker and so on. In the context of the present invention, a Co-2-alkylene preferably represents a bond or a methylene group.
  • O-Ci- 6 -alkyl means that the alkyl chain is connected via an oxygen atom with the remainder of the molecule.
  • halo-Ci- 6 -alkyl means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen.
  • a preferred example thereof is CF 3 .
  • a C3-6-cycloalkyl group means a saturated or partially unsaturated mono- or bicyclic ring system comprising 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl.
  • a 3- to 10-membered heterocycloalkyl group means a saturated or partially unsaturated 3 to 10 membered carbon mono-, bi-, spiro- or multicyclic ring wherein 1 , 2, 3 or 4 carbon atoms are replaced by 1 , 2, 3 or 4 heteroatoms, respectively, wherein the heteroatoms are independently selected from N, O, S, SO and SO2.
  • Examples thereof include epoxidyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, 1 ,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1 ,4-dihydropyridinyl and 6- azabicyclo[3.2.1]octanyl.
  • the heterocycloalkyl group can be connected with the remaining part of the molecule via a carbon, nitrogen (e.g. in morpholine or piperidine) or sulfur atom.
  • a 5-10-membered mono- or bicyclic heteroaromatic ring system (within the application also referred to as heteroaryl) containing up to 6 heteroatoms means a monocyclic heteroaromatic ring such as pyrrolyl, imidazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl. It further means a bicyclic ring system wherein the heteroatom(s) may be present in one or both rings including the bridgehead atoms.
  • Examples thereof include, benzimidazolyl, benzisoxazolyl, benzodioxanyl, benzofuranyl, benzoxazolyl, imidazo[1 ,2-a]pyridinyl, imidazo[1 ,2-c]pyrimidinyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, pyrazolo[1 ,5- a]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-d]thiazolyl, quinolinyl, quinoxalinyl, pyrazolo[1 ,5-a]pyrimidinyl, thiazolo[4,5-b]pyridinyl and [1 ,2,4]triazolo[1 ,5-a]pyrimidinyl.
  • the nitrogen or sulphur atom of the heteroaryl system may also be optionally oxidized to the corresponding N- oxide, S-oxide or S,S-dioxide. If not stated otherwise, the heteroaryl system can be connected via a carbon or nitrogen atom. Examples for /V-linked heterocycles are
  • heteroaryl contains 1 to 6 heteroatoms independently selected from the group consisting of N, O and S.
  • a 6-10-membered mono- or bicyclic aromatic ring system (within the application also referred to as aryl) means an aromatic carbon cycle such as phenyl or naphthyl.
  • halogen comprises the specific halogen atoms fluorine, bromine, chlorine and iodine.
  • any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 35 S, 36 CI and 125 l.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the disclosure also includes“deuterated analogs” of compounds of Formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Such compounds may exhibit increased resistance to metabolism and thus be useful for increasing the half-life of any compound of Formula (I) when administered to a mammal, e.g. a human. See, for example, Foster in Trends Pharmacol. Sci. 1984:5;524.
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F labeled compound may be useful for PET or SPECT studies.
  • the concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as“FI” or“hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • the compounds of the present invention can be in the form of a prodrug compound.
  • Prodrug compound means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • prodrug examples include compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated.
  • these compounds can be produced from compounds of the present invention according to well-known methods.
  • prodrug examples are compounds, wherein the carboxylate in a compound of the present invention is, for example, converted into an alkyl-, aryl-, choline-, amino, acyloxymethylester, linolenoylester.
  • Metabolites of compounds of the present invention are also within the scope of the present invention.
  • tautomerism like e.g. keto-enol tautomerism
  • compounds of the present invention or their prodrugs may occur
  • the individual forms like e.g. the keto and enol form, are each within the scope of the invention as well as their mixtures in any ratio.
  • stereoisomers like e.g. enantiomers, cis/trans isomers, conformers and the like.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of the present invention may be obtained from stereoselective synthesis using optically pure starting materials. Another way to obtain pure enantiomers from racemic mixtures would use enantioselective crystallization with chiral counterions.
  • the compounds of the present invention can be in the form of a pharmaceutically acceptable salt or a solvate.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the present invention which contain acidic groups can be present on these groups and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts.
  • salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • the compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • inner salts or betaines can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • solvates such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol.
  • the present invention provides pharmaceutical compositions comprising at least one compound of the present invention, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients like a prodrug compound or other nuclear receptor modulators.
  • the compound of the present invention can be administered with one or more therapeutic agents for cancer selected from the group consisting of PD-1 agent, PD-L1 agent, CTLA-4 agent, ID01 inhibitor, chemotherapeutic agent, anticancer vaccine, Toll like receptor agonist, oncolytic virus, STING agonist and cytokine therapy, or the compound is administered under irradiation therapy.
  • one or more therapeutic agents for cancer selected from the group consisting of PD-1 agent, PD-L1 agent, CTLA-4 agent, ID01 inhibitor, chemotherapeutic agent, anticancer vaccine, Toll like receptor agonist, oncolytic virus, STING agonist and cytokine therapy, or the compound is administered under irradiation therapy.
  • Examples of PD-1 agents include, but are not limited to, Pembrolizumab and Nivolumab.
  • Examples of PD-L1 agents include, but are not limited to, Atezolizumab, Avelumab and Durvalumab.
  • CTLA-4 agents examples include, but are not limited to, Ipilimumab.
  • ID01 inhibitors include, but are not limited to, Epacadostat, Navoximod and BMS-986205.
  • chemotherapeutic agents include, but are not limited to, Cyclophosphamide, Busulfan, Carmustin, Temozolimide, Procarbazin,Trabectedin, Cisplatin, Carboplatin, Methotrexat, Pemetrexed, 6-Mercatopurine, 6-Thioguanine, Cladibine, Clofarabine, Nelarabine, Pentostatine, 5-Fluorouracil, Cytarabine, Gemcitabine, Azacitidine, Vincristine, Vinblastine, Vindesine, Paclitaxel, Docetaxel, Cabazitaxel, Ixabepilone, Eribulin, Estramustine phosphate, Topotecan, Irinotecan, Etoposide, Teniposide, Dactinomycin, Bleomycin, Doxorubicin, Daunorubicin, Epirubicin, Idarubicin, Mitoxantron, all-trans retinoic acid, Bexa
  • anticancer vaccines include, but are not limited to, Flepa-VAC-101 and Sipuleucel-T.
  • Toll like receptor agonists include, but are not limited to Imiquimod, Resiquimod, monophosphoryl lipid A, BCG , CpG ODNs and Motolimod.
  • oncolytic viruses include, but are not limited to H101 , Talimogene laherparepvec.
  • STING agonists include, but are not limited to, ADU-S100 and MK-1454.
  • cytokine therapy examples include, but are not limited to IL-2, GM-CSF, IL-12 and IL- 10.
  • Immune-Oncology therapeutics examples include, but are not limited to Chimeric antigen receptor, or CAR T-cell therapy, such as Tisagenlecleucel, Axicabtagen Ciloleucel and immune response modifying enzymes such as Asparaginase or Kynureninase.
  • the compounds used in the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non- aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatine; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavouring such as cherry or orange flavour.
  • the compounds used in the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral including intravenous, intramuscular and subcutaneous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), nasal and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of the present invention are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds When treating or preventing AhR-mediated conditions for which compounds of Formula (I) are indicated, generally satisfactory results are obtained when the compounds are administered at a daily dosage of from about 0.1 mg to about 100 mg per kilogram of mammal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 350 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention can be prepared by a combination of methods known in the art including the procedures described in schemes 1 to 14 below.
  • the following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.
  • Scheme 1 describes the preparation of examples of the present invention from bicyclic scaffold intermediates.
  • these intermediates contain an amino functional group (A-1 ) amide coupling with a carboxylic acid and for example HATU affords compounds of structure A-2.
  • Coupling of A-1 with a sulfonylchloride affords sulfonamide compounds of structure A-3.
  • Intermediates containing a halogen (A-4) can be transformed into A-5 by Pd-catalysed coupling with an amine.
  • Intermediate A-4 can also be transformed into A-2 by Pd-catalysed coupling with a carboxylic acid amide as an alternative synthesis route.
  • Intermediates containing a carboxylic acid can be converted to compounds of structure A-7 by amide coupling with an amine using for example HATU as reagent.
  • Intermediates with a halogen substituent at B can be converted to compounds of structure A-2 by Suzuki coupling as a third alternative synthesis route for A-2.
  • Intermediates with an alkylene linker between the bicyclic scaffold and an amino group can be converted to compounds of structure A-10 by amide coupling.
  • Scheme 2 describes the preparation of 2/-/-indazole derived intermediates used in the coupling reactions described in Scheme 1.
  • a substituted or unsubstituted chloro nitrobenzaldehyde intermediate B-1 can be converted into azide B-2 using sodium azide.
  • Cyclocondensation reaction of B-2 with an amine at high temperature leads to the nitro intermediate B-3.
  • Reduction of the nitro group with for example iron powder and ammoniumchloride affords intermediate B-4.
  • Scheme 3 describes the preparation of imidazo[1 ,2-c]pyrimidine derived intermediates used in the coupling reactions described in Scheme 1.
  • a substituted or unsubstituted diaminopyrimidine C-1 can react with an a-bromo ketone C-2 in the presence of sodium bicarbonate at higher temperature to give a bicyclic intermediate of structure C-3.
  • Scheme 4 describes the preparation of [1 ,2,4]triazolo[1 ,5-a]pyrimidine derived intermediates used in the coupling reactions described in Scheme 1.
  • Treatment of intermediate D-3 with Zn-Cu couple affords a bicyclic intermediate of structure D-4.
  • Scheme 5 describes the preparation of indole-derived intermediates used in the coupling reactions described in Scheme 1.
  • a substituted or unsubstituted indole boronic acid E-1 can be coupled with an aryl halide in a Suzuki reaction to afford intermediate E-2.
  • Ester saponification and deprotection affords the corresponding carboxylic acid E-3.
  • Scheme 5 describes the preparation of indole-derived intermediates used in the coupling reactions described in Scheme 1.
  • a substituted or unsubstituted 5-nitroindolin-2-one F- 1 can be converted to the corresponding 2-bromo-5-nitro-1 /-/-indole F-2 with phosphoryl bromide.
  • Suzuki coupling affords intermediate F-3, which can be reduced with iron powder and ammoniumchloride to give intermediate F-4.
  • Scheme 7 describes the preparation of 1 /-/-pyrrolo[2,3-b]pyridine derived intermediates used in the coupling reactions described in Scheme 1.
  • a substituted or unsubstituted 6- chloro-3-iodopyridin-2-amine G-1 is converted to the corresponding bis methylsulfonamide G-2 with methylsulfonylchloride in the presence of triethylamine.
  • Treatment of G-2 with NaOH affords the corresponding mono-methylsulfonamide G-3 which is converted to azaindole G-4 via Pd/Cu(l) catalysed coupling/cyclisation reaction with an appropriately substituted alkyne.
  • Boc-protection using di-ferf-butyl dicarbonate affords the corresponding intermediate G-5.
  • Scheme 8 describes the preparation of 1 /-/-pyrrolo[3,2-c]pyridine derived intermediates used in the coupling reactions described in Scheme 1.
  • a substituted or unsubstituted 2- chloro-5-iodopyridin-4-amine H-1 is converted to the corresponding bis- methylsulfonamide H-2 with methylsulfonylchloride in the presence of triethylamine.
  • Treatment of H-2 with NaOH affords the corresponding mono methylsulfonamide H-3 which is converted to azaindole H-4 via Pd/Cu(l) catalysed coupling/cyclisation reaction with an appropriately substituted alkyne.
  • Boc-protection using di-ferf-butyl dicarbonate affords the corresponding intermediate H-5.
  • Scheme 9 describes the preparation of indole-derived intermediates used in the coupling reactions described in Scheme 1.
  • a substituted or unsubstituted (6-bromo-1 -(ferf- butoxycarbonyl)-1 /-/-indol-2-yl)boronic acid 1-1 is submitted to a Suzuki coupling with an aryl halide to give intermediate I-2.
  • Intermediate I-2 can be coupled with ferf-butyl carbamate under Pd catalysis to give a Boc-protected aryl amine I-3, which is converted to intermediate I-4 through deprotection with for example TFA.
  • Scheme 9 I-4 Scheme 10 describes the preparation of quinoline-derived intermediates used in the coupling reactions described in Scheme 1.
  • Substituted or unsubstituted quinoline J-1 is submitted to a Suzuki coupling with an aryl boronic acid to give intermediate J-2.
  • Pd catalyzed hydrogenation of the nitro group affords intermediate J-3.
  • substituted or unsubstituted indole J-4 is converted into intermediate J-6.
  • Scheme 11 describes the preparation of thiazolo[4,5-b]pyridine derived intermediates used in the coupling reactions described in Scheme 1.
  • a substituted or unsubstituted 6- chloro-3-iodopyridin-2-amine is treated with benzoyl isothiocyanate to afford intermediate K-2.
  • Cyclisation of K-2 with potassium carbonate and catalytic amounts of L-proline and copper(l) iodide at elevated temperatures leads to intermediate K-3.
  • Amide cleavage of K-3 using sulfuric acid at high temperatures affords the amino intermediate K-4 which can be coupled to a carboxylic acid using for example PyBOP.
  • Scheme 12 describes the preparation of 1 /-/-indazole derived intermediates used in the coupling reactions described in Scheme 1.
  • a substituted or unsubstituted 6-bromo-1/-/- indazole (L-1 ) is treated with an aryl-fluoride in the presence of a base to afford intermediate L-2.
  • Scheme 13 describes the preparation of pyrazolo[1 ,5-a]pyridine derived intermediates used in the coupling reactions described in Scheme 1.
  • a substituted or unsubstituted 5- bromo-2-methylpyridine (M-2) is deprotonated with lithium hexamethyldisilazide and the resulting metallated intermediate is treated with an ester intermediate M-1 to afford the intermediate M-3.
  • Treatment of M-3 with 0-(mesitylsulfonyl)hydroxylamine affords intermediates of structure M-4.
  • Scheme 13 describes the preparation of indole derived intermediates bearing a methylene linker united L in 5- or 6-position of the indole used in the coupling reactions described in Scheme 1.
  • the iodoaniline intermediate N-1 is converted into N-2 by Sonogashira reaction.
  • Treatment with TFAA and DMAP affords the corresponding trifluoroacetamide derivative N-3, which is cyclized to the indole intermediate N-4 under Pd catalysis.
  • Ester saponification using for example LiOH is followed by amide coupling with L/,O-dimethylhydroxylamine to afford intermediate N-6.
  • Grignard reaction is followed by condensation reaction with hydroxylamine to afford oxime intermediate N-8. Reduction of N-8 with Pd on charcoal under an atmosphere of hydrogen affords intermediates of structure N-9.
  • Step 3 2-(o-Tolyl)-2/-/-indazol-5-amine (Int 1 )
  • Step 1 3-(2-(Trifluoromethyl)phenyl)-1 /-/-1 ,2,4-triazol-5-amine (Int 3b)
  • hydrazinecarboximidamide (14.5 g, 196 mmol)
  • methyl 2-(trifluoromethyl)benzoate (10.0 g, 49 mmol)
  • the pH of the mixture was adjusted to pH 3 - 4 with 1 M HCI.
  • Step 3 5-Chloro-2-(2-(trifluoromethyl)phenyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine (Int 3)
  • Step 2 2-(o-Tolyl)-1 /-/-indole-6-carboxylic acid (Int 4)
  • Step 1 2-Bromo-5-nitro-1 /-/-indole (Int 5b)
  • Step 3 2-(o-Tolyl)-1 /-/-indol-5-amine (Int 5)
  • Step 1 7-Nitro-2-(2-(trifluoromethyl)phenyl)quinoline (Int 6b)
  • Step 2 2-(2-(Trifluoromethyl)phenyl)quinolin-7-amine (Int 6)
  • the crude product was dissolved in DCM/MeOH (5 mL, 25:1 ) and filtered through a plug of silica. The plug was extracted with DCM/MeOH (6:4) and the combined organic layers were concentrated to dryness to give the title compound as a brown solid.
  • Step 4 A/-(5-Chlorothiazolo[4,5-b]pyridin-2-yl)-1 -methyl-1 A7-1 ,2,4-triazole-5- carboxamide (Int 7)
  • Step 1 2-Methyl-/V-((1 -methyl-1 /-/-pyrazol-5-yl)methylene)propane-2-sulfinamide (Int 12b)
  • Step 2 2-Methyl-/V-(2,2,2-trifluoro-1 -(1 -methyl-1 /-/-pyrazol-5-yl)ethyl)propane-2- sulfinamide (Int 12c)
  • Step 3 2,2,2-Trifluoro-1 -(1 -methyl-1 /-/-pyrazol-5-yl)ethan-1 -amine (Int 12)
  • Step 1 1 -Methyl-1 /-/-pyrazole-5-carbaldehyde oxime (Int 13b)
  • Step 2 4-Chloro-/V-hydroxy-1 -methyl-1 /-/-pyrazole-5-carbimidoyl chloride (Int 13)
  • Step 1 2-Bromo-1 -(difluoromethyl)-4-fluorobenzene (Int 20b)
  • Int 21a The title compound was prepared similar as described for intermediate 20, step 1 (Int 20b) using methyl 2-formyl benzoate in place of 2-bromo-4-fluorobenzaldehyde.
  • Step 1 2-(5-Bromopyridin-2-yl)-1 -(2-(trifluoromethyl)phenyl)ethan-1 -one (Int 23b)
  • Step 1 Methyl 3-amino-4-(o-tolylethynyl)benzoate (Int 24b)
  • Step 2 Methyl 4-(o-tolylethynyl)-3-(2,2,2-trifluoroacetamido)benzoate (Int 24c)
  • TFAA methyl 3-amino-4-(o-tolylethynyl)benzoate
  • pyridine a solution of methyl 3-amino-4-(o-tolylethynyl)benzoate (Int 24b)
  • DMAP 50 mg
  • the mixture was stirred at 40 °C overnight.
  • DCM (50 ml_) was added and the mixture was washed with 1 M HCI (2 x 30 ml_) and brine (1 x 40 ml_).
  • the combined organic layers were dried over Na 2 S0 4 , filtered and concentrated to dryness.
  • Step 4 2-(o-Tolyl)-1 /-/-indole-6-carboxylic acid (Int 24e)
  • Step 5 A/-Methoxy-/V-methyl-2-(o-tolyl)-1 /-/-indole-6-carboxamide (Int 24f)
  • Step 7 1 -(2-(o-Tolyl)-1 /-/-indol-6-yl)ethan-1 -one oxime (Int 24h)
  • Step 8 1 -(2-(o-Tolyl)-1 /-/-indol-6-yl)ethan-1 -amine (Int 24)
  • Step 1 A/-(5-Methylthiazol-2-yl)acetamide (Int 25b)
  • Step 3 (E)-/V-(4-Nitro-5-(2-(trifluoromethyl)styryl)thiazol-2-yl)acetamide (Int 25d)
  • Step 4 /V-(5-(2-(Trifluoromethyl)phenyl)-4/-/-pyrrolo[2,3-d]thiazol-2-yl)acetamide (Int 25e)
  • Step 5 5-(2-(Trifluoromethyl)phenyl)-4/-/-pyrrolo[2,3-d]thiazol-2-amine (Int 25)
  • Step 1 7-Nitro-3-(o-tolyl)quinoline (Int 26b)
  • Step 3 3-(o-Tolyl)-1 /-/-indol-6-amine (Int 27)
  • Step 1 /V-(6-Chloro-3-iodopyridin-2-yl)-/V-(methylsulfonyl)methanesulfonamide (Int 100b)
  • Methanesulfonyl chloride (26.7 ml_, 345 mmol) was added dropwise to a solution of 6- chloro-3-iodopyridin-2-amine (Int 100a) (25.0 g, 98.4 mmol) in pyridine (200 ml_) at 0 °C. The mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated to dryness and the residue was purified by column chromatography (gradient 5-100% EtOAc in DCM) to give the title compound as a yellow solid.
  • Step 2 /V-(6-Chloro-3-iodopyridin-2-yl)methanesulfonamide (Int 100c)
  • Step 3 6-Chloro-2-(2-(trifluoromethyl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridine (Int 100d)
  • Step 4 ferf-Butyl 6-chloro-2-(2-(trifluoromethyl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridine-1 - carboxylate (Int 100)
  • Step 1 /V-(2-Chloro-5-iodopyridin-4-yl)-/V-(methylsulfonyl)methanesulfonamide (Int 101 b)
  • Step 2 /V-(2-Chloro-5-iodopyridin-4-yl)methanesulfonamide (Int 101c)
  • Step 3 6-Chloro-2-(2-(trifluoromethyl)phenyl)-1 /-/-pyrrolo[3,2-c]pyridine (Int 101d)
  • Step 4 ferf-Butyl 6-chloro-2-(2-(trifluoromethyl)phenyl)-1 H-pyrrolo[3,2-c]pyridine-1 - carboxylate (Int 101 )
  • Step 2 2-(o-Tolyl)-1 /-/-indol-6-amine (Int 103)
  • Example 1/1 1 -Methyl-/V-(2-(o-tolyl)-1 /-/-indol-5-yl)-1 /-/-pyrazole-5-carboxamide (1/1 )
  • Example 3/1 1 -Methyl-/V-(2-(2-(trifluoromethyl)phenyl)imidazo[1 ,2-c]pyrimidin-7-yl)-1 H- pyrazole-5-carboxamide (3/1 )
  • Example 7 1 -Methyl-/V-(2-(2-(trifluoromethyl)phenyl)pyrazolo[1 ,5-a]pyridin-6-yl)-1 H-
  • Step 1 /V-(2-(5-Chloro-2-(trifluoromethyl)phenyl)pyrazolo[1 ,5-a]pyridin-6-yl)-1 ,1 - diphenylmethanimine (8a)
  • Step 3 /V-(2-(5-Chloro-2-(trifluoromethyl)phenyl)pyrazolo[1 ,5-a]pyridin-6- yl)picolinamide (8)
  • Example 100 1 -((2-(2-(T rifluoromethyl)phenyl)-1 -/-pyrrolo[2,3-b]pyridin-6- yl)carbamoyl)cyclopropane-1 -carboxylic acid (100)
  • Step 1 tert- Butyl 6-(1 -(methoxycarbonyl)cyclopropane-1 -carboxamido)-2-(2-
  • Step 2 Methyl 1 -((2-(2-(trifluoromethyl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridin-6-yl)carbamoyl) cyclopropane-1 -carboxylate (100b)
  • Step 3 1 -((2-(2-(Trifluoromethyl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridin-6-yl)carbamoyl) cyclopropane-1 -carboxylic acid (100)
  • Example 101 /V-(2-(2-(trifluoromethyl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridin-6- yl)cyclopropane-1 ,1 -dicarboxamide (101 )
  • Example 102 /V 1 -Methyl-/V 2 -(2-(2-(trifluoromethyl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridin-6- yl)oxalamide (102)
  • Step 1 Ethyl 2-oxo-2-((2-(2-(trifluoromethyl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridin-6- yl)amino)acetate (102a)
  • Pd 2 (dba)3 (463 mg, 0.50 mmol) was added to a mixture of 6-chloro-2-(2- (trifluoromethyl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridine (Int 100) (400 mg, 1.01 mmol), K 2 CO 3 (419 mg, 3.03 mmol), ethyl 2-amino-2-oxoacetate (130 mg, 1.1 1 mmol) and tBuXPhos (322 mg, 0.78 mmol) in 10 mL f-BuOH/water (20:1 ). The mixture was heated at 90 °C for
  • Step 2 A/ 1 -Methyl-/V 2 -(2-(2-(trifluoromethyl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridin-6- yl)oxalamide (102)
  • Step 1 ferf-Butyl 6-((pyridin-2-ylmethyl)amino)-2-(2-(trifluoromethyl)phenyl)-1 /-/- pyrrolo[2,3-b]pyridine-1 -carboxylate (103a)
  • Pd 2 (dba)3 (348 mg, 0.38 mmol) was added to a mixture of ferf-butyl 6-chloro-2-(2- (trifluoromethyl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (Int 100) (300 mg, 0.76 mmol), potassium carbonate (349 mg, 2.28 mmol), pyridin-2-ylmethanamine (164 mg, 1.52 mmol) and tBuXPhos (273 mg, 0.57 mmol) in 6 ml_ f-BuOH/water (30:1 ). The mixture was heated at 90 °C for 5 h under microwave irradiation.
  • Step 2 /V-(Pyridin-2-ylmethyl)-2-(2-(trifluoromethyl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridin-6- amine (103)
  • Example 104 L/-(1 -Methyl-1 /-/-pyrazol-5-yl)-2-(o-tolyl)-1 /-/-indole-6-carboxamide (104)
  • Example 105 2-(o-Tolyl)-/V-(2,2,2-trifluoro-1 -(1 -methyl-1 /-/-pyrazol-5-yl)ethyl)-1 /-/-indol e-amine (105)
  • Step 1 ferf-Butyl 2-(o-tolyl)-6-((2,2,2-trifluoro-1 -(1 -methyl-1 /-/-pyrazol-5-yl)ethyl)amino)- 1 /-/-indole-1 -carboxylate (105a) A mixture of ferf-butyl 6-bromo-2-(o-tolyl)-1 /-/-indole-1 -carboxylate (Int 102) (500 mg, 1.30 mmol), 2,2,2-trifluoro-1 -(1 -methyl-1 /-/-pyrazol-5-yl)ethan-1 -amine (Int 12) (419 mg, 1.95 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1 ,1 biphenyl][2-(2-aminoethyl)phenyl]palla
  • Step 2 2-(o-Tolyl)-/V-(2,2,2-trifluoro-1 -(1 -methyl-1 /-/-pyrazol-5-yl)ethyl)-1 /-/-indol-6- amine (105)
  • Example 106 4-Chloro-/V'-hydroxy-1 -methyl-/V-(2-(o-tolyl)-1 /-/-indol-6-yl)-1 /-/-pyrazole- 5-carboximidamide (106)
  • Example 106 The title compound was prepared similar as described for Example 106 using 1 -methyl- 1 /-/-pyrazole-5-sulfonyl chloride in place of 4-chloro-/V-hydroxy-1 -methyl-1 /-/-pyrazole-5- carbimidoyl chloride (Int 13).
  • Example 107 4-Fluoro-/V-(1 -(2-(o-tolyl)-1 /-/-indol-6-yl)ethyl)benzamide (107)
  • Example 107 The following Examples were prepared similar as described for Example 107 using the appropriate building blocks.
  • Example 200 1 -Methyl-/V-(5-(2-(trifluoromethyl)phenyl)thiazolo[4,5-b]pyridin-2-yl)-1 H- 1 ,2,4-triazole-5-carboxamide (200)
  • Example 200 A mixture of A/-(5-chlorothiazolo[4,5-b]pyridin-2-yl)-1 -methyl-1 A7-1 ,2, 4-triazole-5- carboxamide (Int 7) (160 mg, 0.544 mmol), (2-(trifluoromethyl)phenyl)boronic acid (310 mg, 1.63 mmol), Pd(dtbpf)Cl2 (35 mg, 0.054 mmol) and CS2CO3 (532 mg, 1.63 mmol) in 1 ,4-dioxane/H 2 0 (16 ml_, 3:1 ) was stirred at 100 °C under N2 overnight.
  • Example 201 1 -Methyl-/V-(5-(2-(trifluoromethyl)phenyl)-4 -/-pyrrolo[2,3-d]thiazol-2-yl)- 1 H- 1 ,2,4-triazole-5-carboxamide (201 )
  • Example 300 1 -Methyl-/V-(3-(o-tolyl)quinolin-7-yl)-1 H- 1 ,2,4-triazole-5-carboxamide
  • Example 300/1 1 -Methyl-/V-(3-(o-tolyl)-1 /-/-indol-6-yl)-1 H-1 ,2,4-triazole-5-carboxamide
  • AhR direct luciferase reporter assay in HepG2 cells.
  • HepG2 CYP1A1 -LUC A stable cell line (HepG2 CYP1A1 -LUC) was used in which part of the promoter region of the human CYP1A1 gene is stably integrated into the genome of human HepG2 hepatocytes (DSZM#ACC 180) in front of a Photinus pyralis Firefly Luciferase gene.
  • a 1210 bp fragment comprising part of the human CYP1A1 promoter was isolated via Sacl and Bglll restriction digestion from Lightswitch Clone S714555 (SwitchGearGenomics) and inserted between the Sacl and Bglll sites in pGL4.30 (Promega # E8481 ) in front of the Firefly Luciferase gene.
  • the resulting vector was linearized with Notl, transfected into FlepG2 cells (DSMZ#ACC 180) and stably transfected clones selected with 250pg/ml Flygromycin B. After repetitive rounds of subcloning and testing for robustly regulated luciferase activity after AhR agonist stimulation, a stable clonal FlepG2 CYP1A1 -Luc cell line was selected.
  • the FlepG2 CYP1A1 -Luc cells do express basal luciferase activity that can be increased via potent AhR agonists or decreased via potent AhR antagonists, added to the growth medium of the cells.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés bicycliques qui peuvent agir en tant que modulateurs du récepteur d'hydrocarbures aryle (AhR) et, en particulier, en tant qu'antagonistes d'AhR. L'invention concerne en outre l'utilisation des composés pour le traitement et/ou la prophylaxie de maladies et/ou d'états par liaison dudit récepteur d'hydrocarbure aryle par lesdits composés. A-B-L-C (I)
PCT/EP2019/070066 2018-07-26 2019-07-25 Composés bicycliques substitués en tant que modulateurs du récepteur d'hydrocarbures aryle (ahr) Ceased WO2020021024A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18185817 2018-07-26
EP18185817.6 2018-07-26

Publications (1)

Publication Number Publication Date
WO2020021024A1 true WO2020021024A1 (fr) 2020-01-30

Family

ID=63207518

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2019/070066 Ceased WO2020021024A1 (fr) 2018-07-26 2019-07-25 Composés bicycliques substitués en tant que modulateurs du récepteur d'hydrocarbures aryle (ahr)

Country Status (1)

Country Link
WO (1) WO2020021024A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020201825A2 (fr) 2019-03-29 2020-10-08 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Signature d'activation de récepteur d'hydrocarbures aryliques (ahr) et procédés de détermination d'état de signalisation d'ahr
WO2020208190A1 (fr) 2019-04-10 2020-10-15 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Gène 1 induit par l'interleukine 4 (il4i1) en tant que biomarqueur et ses utilisations
WO2021116357A1 (fr) 2019-12-10 2021-06-17 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Gène 1 induit par l'interleukine 4 (il4i1) et métabolites respectifs en tant que biomarqueurs pour le cancer
WO2021173082A1 (fr) 2020-02-26 2021-09-02 Jaguahr Therapeutics Pte Ltd Dérivés de pyridopyrimidine utiles dans la modulation de la signalisation de l'ahr
WO2021242955A1 (fr) * 2020-05-28 2021-12-02 Senda Biosciences, Inc. Hétérocycles azolés fusionnés utilisés en tant qu'antagonistes d'ahr
CN113831320A (zh) * 2020-06-23 2021-12-24 上海美悦生物科技发展有限公司 一种稠和吡唑类化合物的制备方法
CN114456178A (zh) * 2021-01-13 2022-05-10 重庆华森制药股份有限公司 四氢嘧啶[1,2-b]吲唑-4-胺类衍生物作为AhR抑制剂的用途及制备方法
CN115572282A (zh) * 2021-07-05 2023-01-06 华东理工大学 含芳杂环结构的吡唑酰胺类化合物及其制备方法和应用
US11767321B2 (en) 2020-10-05 2023-09-26 Enliven Inc. 5- and 6-azaindole compounds for inhibition of BCR-ABL tyrosine kinases
JP2024500989A (ja) * 2020-12-28 2024-01-10 セルジーン コーポレーション 寄生虫症のためのヘテロ環化合物およびそれらの使用
WO2024076300A1 (fr) 2022-10-03 2024-04-11 Jaguahr Therapeutics Pte Ltd Composés utiles dans la modulation de la signalisation d'ahr
WO2025034034A1 (fr) * 2023-08-09 2025-02-13 주식회사 대웅제약 Nouveau composé et composition pharmaceutique pour prévenir ou traiter le cancer ou des tumeurs le comprenant

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012076430A1 (fr) * 2010-12-07 2012-06-14 F. Hoffmann-La Roche Ag Composés de triazolopyridine
US20130338201A1 (en) * 2009-11-02 2013-12-19 Ahr Pharmaceuticals, Inc. Method of Cancer Treatment with 2-(1H-Indole-3-Carbonyl)-Thiazole-4-Carboxylic Acid Methyl Ester
WO2014100620A2 (fr) * 2012-12-21 2014-06-26 Plexxikon Inc. Composés et procédés pour la modulation de kinase, et indications associées
WO2014177493A1 (fr) * 2013-04-30 2014-11-06 F. Hoffmann-La Roche Ag Couplage de pyrazole-amides catalysé par pd
US20160175278A1 (en) 2010-07-27 2016-06-23 Trustees Of Boston University ARYL HYDROCARBON RECEPTOR (AhR) MODIFIERS AS NOVEL CANCER THERAPEUTICS
WO2018141857A1 (fr) * 2017-02-01 2018-08-09 Phenex Pharmaceuticals Ag Composés modulateurs du récepteur des hydrocarbures d'aryl (ahr)
WO2018141855A1 (fr) * 2017-02-01 2018-08-09 Phenex Pharmaceuticals Ag Composés modulateurs du récepteur des hydrocarbures d'aryl (ahr)
WO2018153893A1 (fr) * 2017-02-21 2018-08-30 Phenex Pharmaceuticals Ag Composés modulateurs du récepteur des hydrocarbures aryle (ahr)

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130338201A1 (en) * 2009-11-02 2013-12-19 Ahr Pharmaceuticals, Inc. Method of Cancer Treatment with 2-(1H-Indole-3-Carbonyl)-Thiazole-4-Carboxylic Acid Methyl Ester
US20160175278A1 (en) 2010-07-27 2016-06-23 Trustees Of Boston University ARYL HYDROCARBON RECEPTOR (AhR) MODIFIERS AS NOVEL CANCER THERAPEUTICS
WO2012076430A1 (fr) * 2010-12-07 2012-06-14 F. Hoffmann-La Roche Ag Composés de triazolopyridine
WO2014100620A2 (fr) * 2012-12-21 2014-06-26 Plexxikon Inc. Composés et procédés pour la modulation de kinase, et indications associées
WO2014177493A1 (fr) * 2013-04-30 2014-11-06 F. Hoffmann-La Roche Ag Couplage de pyrazole-amides catalysé par pd
WO2018141857A1 (fr) * 2017-02-01 2018-08-09 Phenex Pharmaceuticals Ag Composés modulateurs du récepteur des hydrocarbures d'aryl (ahr)
WO2018141855A1 (fr) * 2017-02-01 2018-08-09 Phenex Pharmaceuticals Ag Composés modulateurs du récepteur des hydrocarbures d'aryl (ahr)
WO2018153893A1 (fr) * 2017-02-21 2018-08-30 Phenex Pharmaceuticals Ag Composés modulateurs du récepteur des hydrocarbures aryle (ahr)

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BESSEDE ET AL., NATURE, vol. 511, no. 7508, 10 July 2014 (2014-07-10), pages 184 - 90
KOLIOPANOS ET AL., ONCOGENE, vol. 21, no. 39, 5 September 2002 (2002-09-05), pages 6059 - 70
LI ET AL., INT J CLIN EXP PATHOL., vol. 7, no. 11, 15 October 2014 (2014-10-15), pages 7931
MURRAY ET AL., NAT REV CANCER, vol. 14, no. 12, December 2014 (2014-12-01), pages 801 - 14
RICHMOND ET AL., PLOS ONE, vol. 9, no. 4, 2014, pages e95058
ROMANI ET AL., EUR J IMMUNOL., vol. 44, no. 11, November 2014 (2014-11-01), pages 3192 - 200
SAFE ET AL., TOXICOL SCI., vol. 135, no. 1, September 2013 (2013-09-01), pages 1 - 16
ZELANTE ET AL., IMMUNITY, vol. 39, no. 2, 22 August 2013 (2013-08-22), pages 372 - 85

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020201825A2 (fr) 2019-03-29 2020-10-08 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Signature d'activation de récepteur d'hydrocarbures aryliques (ahr) et procédés de détermination d'état de signalisation d'ahr
WO2020208190A1 (fr) 2019-04-10 2020-10-15 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Gène 1 induit par l'interleukine 4 (il4i1) en tant que biomarqueur et ses utilisations
WO2021116357A1 (fr) 2019-12-10 2021-06-17 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Gène 1 induit par l'interleukine 4 (il4i1) et métabolites respectifs en tant que biomarqueurs pour le cancer
WO2021173082A1 (fr) 2020-02-26 2021-09-02 Jaguahr Therapeutics Pte Ltd Dérivés de pyridopyrimidine utiles dans la modulation de la signalisation de l'ahr
WO2021242955A1 (fr) * 2020-05-28 2021-12-02 Senda Biosciences, Inc. Hétérocycles azolés fusionnés utilisés en tant qu'antagonistes d'ahr
CN113831320B (zh) * 2020-06-23 2024-04-05 上海美悦生物科技发展有限公司 一种稠和吡唑类化合物的制备方法
WO2021259163A1 (fr) * 2020-06-23 2021-12-30 上海美悦生物科技发展有限公司 Procédé de préparation d'un composé de type pyrazole condensé
TWI896689B (zh) * 2020-06-23 2025-09-11 大陸商武漢朗來科技發展有限公司 稠和吡唑類化合物的製備方法
CN113831320A (zh) * 2020-06-23 2021-12-24 上海美悦生物科技发展有限公司 一种稠和吡唑类化合物的制备方法
US11767321B2 (en) 2020-10-05 2023-09-26 Enliven Inc. 5- and 6-azaindole compounds for inhibition of BCR-ABL tyrosine kinases
US11807638B2 (en) 2020-10-05 2023-11-07 Enliven Inc. 5- and 6-azaindole compounds for inhibition of Bcr-Abl tyrosine kinases
US12240846B2 (en) 2020-10-05 2025-03-04 Enliven Inc. 5- and 6-azaindole compounds for inhibition of Bcr-Abl tyrosine kinases
JP2024500989A (ja) * 2020-12-28 2024-01-10 セルジーン コーポレーション 寄生虫症のためのヘテロ環化合物およびそれらの使用
EP4267131A4 (fr) * 2020-12-28 2025-04-23 Celgene Corporation Composés hétérocycliques et leur utilisation pour des maladies parasitaires
CN114456178A (zh) * 2021-01-13 2022-05-10 重庆华森制药股份有限公司 四氢嘧啶[1,2-b]吲唑-4-胺类衍生物作为AhR抑制剂的用途及制备方法
CN115572282A (zh) * 2021-07-05 2023-01-06 华东理工大学 含芳杂环结构的吡唑酰胺类化合物及其制备方法和应用
CN115572282B (zh) * 2021-07-05 2024-07-09 华东理工大学 含芳杂环结构的吡唑酰胺类化合物及其制备方法和应用
WO2024076300A1 (fr) 2022-10-03 2024-04-11 Jaguahr Therapeutics Pte Ltd Composés utiles dans la modulation de la signalisation d'ahr
WO2025034034A1 (fr) * 2023-08-09 2025-02-13 주식회사 대웅제약 Nouveau composé et composition pharmaceutique pour prévenir ou traiter le cancer ou des tumeurs le comprenant

Similar Documents

Publication Publication Date Title
WO2020021024A1 (fr) Composés bicycliques substitués en tant que modulateurs du récepteur d'hydrocarbures aryle (ahr)
AU2018216955B2 (en) Aryl hydrocarbon receptor (AhR) modulator compounds
EP3577112B1 (fr) Composés modulateurs du récepteur des hydrocarbures d'aryle (ahr)
EP3585780A1 (fr) Composés modulateurs du récepteur des hydrocarbures aryle (ahr)
IL311024A (en) Substituted tricyclic compounds as parp inhibitors and use thereof
KR20220061958A (ko) Cd38의 억제제로서의 헤테로바이사이클릭 아미드
WO2016106266A1 (fr) Antagonistes des récepteurs tgfβ
JP2022551299A (ja) Ｂｒｄ４阻害活性を有する化合物、その調製方法および用途
EP3841102A1 (fr) Dérivés de tétrahydropyridopyrimidine utilisés comme modulateurs du ahr
WO2020116662A1 (fr) Dérivé de cycloalcane-1,3-diamine
JP2025521083A (ja) ＨＰＫ１阻害剤としてのテトラヒドロピリド［３，４－ｄ］ピリミジン化合物
KR20220073680A (ko) 다이아실글리세롤 키나아제 저해제로서 헤테로사이클 화합물 및 이의 용도
EP4093739A1 (fr) Composés hétérocycliques substitués par un oxalamide en tant que modulateurs du récepteur d'aryle hydrocarbone (ahr)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19742768

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19742768

Country of ref document: EP

Kind code of ref document: A1