US20210107863A2 - Novel aromatic compounds - Google Patents

Novel aromatic compounds Download PDF

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US20210107863A2
US20210107863A2 US16/488,458 US201816488458A US2021107863A2 US 20210107863 A2 US20210107863 A2 US 20210107863A2 US 201816488458 A US201816488458 A US 201816488458A US 2021107863 A2 US2021107863 A2 US 2021107863A2
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alkyl
perhalogenated
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substituted
optionally halogenated
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US20200031763A1 (en
US11591289B2 (en
US20220348535A2 (en
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Viktoria REINMÜLLER
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Xeniopro GmbH Germany
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Xeniopro GmbH Germany
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • the present invention relates to novel aromatic compounds and their use as therapeutic agents, which can be used in the treatment of pathological conditions, such as cancer, skin disorders, muscle disorders, and immune system-related disorders such as disorders of the hematopoietic system including the hematologic system in human and veterinary medicine.
  • Notch signaling is a fundamental cell-to-cell communication pathway that regulates central processes in embryonic development as well as in the maintenance of adult tissues.
  • the effect of a Notch signal is highly dependent on the signal strength, duration, and most importantly on the cellular context.
  • Notch activity leads to numerous cell-type specific responses, which implicate for example cell fate decisions, the induction or inhibition of differentiation, and the regulation of cell proliferation.
  • Notch signaling was discovered as an oncogenic pathway. Corresponding pathological conditions are linked to abnormally augmented signaling levels. In these particular cases, the use of Notch inhibiting agents represents a promising strategy for therapeutic intervention and numerous corresponding drugs are currently in development.
  • Prominent examples comprise non-melanoma skin cancer, neuroendocrine tumors and certain cancers of the hematopoietic system.
  • Notch enhancers are not only limited to the treatment of cancer, but likewise expected to be beneficial in other pathologic conditions that have been shown to be responsive to Notch induction, such as diseases of the skin, muscle or immune system.
  • Notch enhancers comprise resveratrol (Pinchot et al., Cancer 2011, 117, 1386-1398; Truong et al., Ann. Surg. Oncol. 2011, 18, 1506-1511; Yu et al., Mol. Cancer Ther.
  • the present invention covers refined structures to the initially discovered limited set of Notch enhancer molecules. These second generation compounds have been designed and are supposed to exhibit increased potency and greater metabolic stability. Alternatively, they present specific modifications of chemical residues, which are supposed to not impair the Notch-augmenting activity, but yet provide novel molecular features that may turn out to beneficially influence pharmacological and physicochemical parameters addressed in the general drug development process.
  • the present invention relates to compounds as defined herein that feature Notch enhancing activity, which can be used in the treatment of pathological conditions that are responsive for Notch-regulation, such as cancer, skin diseases, muscle disorders, and immune system-related disorders such as disorders of the hematopoietic system including the hematologic system in human and veterinary medicine.
  • the biological activity e.g. the antiproliferative activity of the claimed compounds can be attributed to but may not be limited to Notch signaling enhancing activity.
  • the present invention also relates to compounds as defined herein that feature antiproliferative activity, which can be used in the treatment of benign and malignant hyperproliferative disorders in human and veterinary medicine.
  • the present invention relates to compounds as defined herein for the treatment of immune system-related disorders such as disorders of the hematopoietic system including the hematologic system, such as malignancies of the myeloid lineage, malignant and non-malignant disorders of the skin and mucosa, such as squamous and basal cell carcinoma, actinic keratosis, and hyperproliferative disorders of the skin and mucosa, e.g.
  • immune system-related disorders such as disorders of the hematopoietic system including the hematologic system, such as malignancies of the myeloid lineage, malignant and non-malignant disorders of the skin and mucosa, such as squamous and basal cell carcinoma, actinic keratosis, and hyperproliferative disorders of the skin and mucosa, e.g.
  • cornification disorders malignant and non-malignant disorders of the muscle, including hyperproliferative disorders of the muscle, such as muscle hyperplasia and muscle hypertrophy, disorders of the neuroendocrine system, such as medullary thyroid cancer, and hyperproliferative disorders of the genitourinary tract, e.g. cervical cancer in human and veterinary medicine.
  • hyperproliferative disorders of the muscle such as muscle hyperplasia and muscle hypertrophy
  • disorders of the neuroendocrine system such as medullary thyroid cancer
  • hyperproliferative disorders of the genitourinary tract e.g. cervical cancer in human and veterinary medicine.
  • a first aspect of the present invention relates to compounds of formula I and salts and solvates thereof:
  • R 1 ⁇ C 1 -C 12 preferably C 1 -C 6 alkyl, C 2 -C 12 preferably C 2 -C 6 alkenyl, C 2 -C 12 preferably C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 4 -C 12 bicycloalkyl, C 6 -C 12 bicycloalkenyl, C 5 -C 14 tricycloalkyl,
  • alkyl, alkenyl and alkynyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, ⁇ Cl, —Br, —I, —CN, —NCO, —NCS; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C 1 -C 3 alkyl such as —CH 3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues can be perhalogenated, particularly perfluorinated;
  • R 1 is preferably selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, tert-butyl, tert-pentyl, 3-pentyl, —CF 3 , —CF 2 CF 3 , —(CF 2 ) 2 CF 3 , —(CF 2 ) 3 CF 3 , —CH(CF 3 ) 2 , —CF(CF 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, and 9-methylbicyclo[3.3.1]nonyl;
  • R 2 ⁇ H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,
  • alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C 1 -C 3 alkyl such as —CH 3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated;
  • R 2 is preferably selected from H, methyl and ethyl.
  • isomers e.g. enantiomers or diastereomers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
  • a second aspect of the present invention relates to compounds of formula II and salts and solvates thereof:
  • R 3 ⁇ H, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl
  • alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C 1 -C 3 alkyl such as —CH 3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C 1 -C 3 alkyl such as —CH 3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated;
  • R 3 is preferably H or methyl
  • R 4 ⁇ H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, OH or OC 1 -C 6 alkyl, wherein all alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C 1 -C 3 alkyl such as —CH 3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C 1 -C 3 alkyl such as —CH 3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated;
  • R 4 is preferably H, OH or methyl.
  • R 3 and R 4 are in each case H; H and OH; H and —CH 3 ; or in each case —CH 3 .
  • Table IIb Specific examples of compounds falling under the scope of formula II are shown in Table IIb.
  • the compounds in Table IIb are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes.
  • isomers e.g. enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
  • a third aspect of the present invention relates to compounds of formula III and salts and solvates thereof:
  • R 1 and R 2 are defined as in formula I, including the preferred definitions of R 1 and R 2 .
  • Table IIIb Specific examples of compounds falling under the scope of formula III are shown in Table IIIb.
  • the compounds in Table IIIb are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes.
  • isomers e.g. enantiomers or diastereomers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
  • a fourth aspect of the present invention relates to compounds of formula IV and salts and solvates thereof:
  • R 3 and R 4 are defined as in formula II, including the preferred definitions of R 3 and R 4 .
  • isomers e.g. enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
  • a fifth aspect of the present invention relates to compounds of formula V and salts and solvates thereof:
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C 1 -C 3 alkyl such as —CH 3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups can be perhalogenated, particularly perfluorinated;
  • n is preferably 0 as constituting cyclopropyl, particularly as constituting cyclopropyl being unsubstituted;
  • R 5 ⁇ C 1 -C 12 preferably C 1 -C 6 alkyl, C 2 -C 12 preferably C 2 -C 6 alkenyl, C 2 -C 12 preferably C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl,
  • alkyl, alkenyl and alkynyl residues can be linear or branched, and are perhalogenated, particularly perfluorinated,
  • alkyl, alkenyl and alkynyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • cycloalkyl and cycloalkenyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C 1 -C 3 alkyl such as —CH 3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • R 5 is preferably —CF 3 or —CF 2 CF 3 ;
  • R 6 -R 9 are independently from each other selected from —H, —F, —Cl, —Br, —I, linear or branched C 1 -C 4 alkyl, linear or branched C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 5 cycloalkyl, and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C 1 -C 3 alkyl such as —CH 3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • R 6 -R 8 each are preferably H, and R 9 is preferably —H, —F, —Cl, or —CH 3 ;
  • Y a six-membered aromatic ring selected from benzene, pyridine, pyrimidine, pyridazine or pyrazine;
  • the pyridine ring is not substituted, or it is substituted at the carbon positions with one to three of the substituents independently selected from R 10 -R 12 , and wherein preferably the N-atom of the pyridine ring is in ortho-position relative to the ether bond,
  • the pyrimidine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R 10 -R 11 , and wherein preferably an N-atom of the pyrimidine ring is in ortho-position relative to the ether bond,
  • the pyridazine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R 10 -R 11 , and wherein preferably an N-atom of the pyridazine ring is in ortho-position relative to the ether bond,
  • the pyrazine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R 10 -R 11 , and wherein preferably an N-atom of the pyrazine ring is in ortho-position relative to the ether bond,
  • Y benzene or pyridine being not substituted with any of the residues selected from R 10 -R 13 , or being substituted with one of the substituents selected from R 10 -R 13 being F at the carbon atom in ortho-position relative to the ether bond;
  • R 10 -R 13 are independently from each other selected from —F, —Cl, —Br, —I, linear or branched C 1 -C 4 alkyl, linear or branched C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 5 cycloalkyl, and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from —F, —Cl, —Br, —I; and C 1 -C 3 alkyl such as —CH 3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • R 14 ⁇ OR 2 or NR 3 R 4
  • R 2 is defined as in formula I including the preferred definition of R 2 as H, methyl or ethyl;
  • R 3 and R 4 are defined as in formula II, including the preferred definitions of R 3 as H or —CH 3 and R 4 as H, OH or —CH 3 ;
  • the present invention relates to compounds of formula Va and salts and solvates thereof:
  • Z is defined as in formula V, including the preferred definition of Z as Z ⁇ O,
  • R 5 is defined as in formula V, including all preferred definitions of R 5 ,
  • R 6 -R 9 are defined as in formula V, including all preferred definitions of R 6 -R 9 ,
  • R 14 is defined as in formula V
  • R 10 -R 13 are independently from each other selected from —H, —F, —Cl, —Br, —I, linear or branched C 1 -C 4 alkyl, linear or branched C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 5 cycloalkyl, and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from —F, —Cl, —Br, —I; and C 1 -C 3 alkyl such as —CH 3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated.
  • isomers e.g. enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
  • C 1 -C 12 alkyl comprises all isomers of the corresponding saturated aliphatic hydrocarbon groups containing one to twelve carbon atoms; this includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methylbutyl, iso-pentyl, 2-methylbut-2-yl, 3-methylbut-2-yl, all hexyl-isomers, all heptyl-isomers, all octyl-isomers, all nonyl-isomers, all decyl-isomers, all undecyl-isomers and all dodecyl-isomers.
  • C 2 -C 12 alkenyl comprises all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing two to twelve carbon atoms linked by one or more double bonds; this includes vinyl, all propenyl-isomers, all butenyl-isomers, all pentenyl-isomers, all hexenyl-isomers, all heptenyl-isomers, all octenyl-isomers, all nonenyl-isomers, all decenyl-isomers, all undecenyl-isomers and all dodecenyl-isomers.
  • C 2 -C 12 alkynyl comprises all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing two to twelve carbon atoms linked by one or more triple bonds; this includes ethynyl, all propynyl-isomers, all butynyl-isomers, all pentynyl-isomers, all hexynyl-isomers, all heptynyl-isomers, all octynyl-isomers, all nonynyl-isomers, all decynyl-isomers, all undecynyl-isomers and all dodecynyl-isomers.
  • alkynyl also includes compounds having one or more triple bonds and one or more double bonds.
  • C 3 -C 8 cycloalkyl comprises the corresponding saturated hydrocarbon groups containing three to eight carbon atoms arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
  • C 3 -C 8 cycloalkenyl comprises the corresponding unsaturated non-aromatic, anti-aromatic or aromatic hydrocarbon groups containing three to eight carbon atoms arranged in a monocyclic ring structure and linked by one or more double bonds; this includes cyclopropenyl, all cyclobutenyl-isomers, all cyclopentenyl-isomers, all cyclohexenyl-isomers, all cycloheptenyl-isomers, all cyclooctenyl-isomers.
  • C 4 -C 12 bicycloalkyl comprises the corresponding saturated hydrocarbon groups containing four to twelve carbon atoms arranged in a bicyclic ring structure
  • C 6 -C 12 bicycloalkenyl comprises the corresponding unsaturated hydrocarbon groups containing six to twelve carbon atoms arranged in a bicyclic ring structure and linked by one or more double bonds;
  • C 5 -C 14 tricycloalkyl comprises the corresponding saturated hydrocarbon groups containing five to fourteen carbon atoms arranged in a tricyclic ring structure
  • perhalogenated relates to the exhaustive halogenation of the carbon scaffold; according residues comprise the corresponding perfluorinated, perchlorinated, perbrominated and periodinated groups.
  • perhalogenated relates to perfluorinated or perchlorinated groups, more preferably to perfluorinated groups.
  • the compounds of the present invention may form salts, which are also within the scope of this invention.
  • Reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterions (internal or inner salts) are included within the term “salt(s)” as used herein (and may be formed, for example, where the substituents comprise an acid moiety such as a carboxyl group). Also included herein are quaternary ammonium salts such as alkylammonium salts. Salts of the compounds may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxal
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, tert-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • organic bases for example, organic amines
  • organic bases for example, organic amines
  • benzathines dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, tert-butyl amines
  • amino acids such as arginine, lysine and the like.
  • the basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science 1977, 66 (2), each of which is incorporated herein by reference in its entirety.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the invention relates to the D form, the L form and D,L mixtures and also, where more than one asymmetric carbon atom is present, to the diastereomeric forms.
  • Those compounds of the invention which contain asymmetric carbon atoms, and which as a rule accrue as racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • solvates and hydrates of the compounds of the invention and solvates and hydrates of their pharmaceutically acceptable salts.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers, rotamers, and isotopes of the structures depicted, unless otherwise indicated.
  • the compound can be provided as a prodrug.
  • prodrug denotes a compound, which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the invention, or a salt and/or solvate thereof.
  • the compounds of the invention, and salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof.
  • the compounds according to the invention have been found to have pharmacologically important properties, which can be used therapeutically.
  • the compounds of the invention can be used alone, in combination with each other or in combination with other active compounds.
  • compounds of the present invention may be enhancers of Notch signalling.
  • Notch signaling The communication between cells via Notch signaling (reviewed in Kopan et al., Cell 2009, 137, 216-233; Bray, Nat. Rev. Mol. Cell Biol. 2016, 17, 722-735) is in the first step mediated by two types of transmembrane proteins: The Notch receptors being distributed within the cell membrane of the signal-receiving cell and the Notch ligands covering the membrane of the signal-sending cell.
  • Notch signaling is activated by receptor-ligand interaction, which leads to the proteolytic release of the intra cellular domain (NICD) of the membrane bound Notch receptor into the inside of the signal receiving cell.
  • NBD intra cellular domain
  • the activation level of Notch signaling can be quantified in vitro most reliably by measuring the expression levels of Notch specific target genes. This can be accomplished by the quantification of corresponding mRNA or protein of a particular Notch target gene. Alternatively, cells can be genetically modified to carry a luciferase gene as an artificial Notch target gene, which is expressed in dependence of Notch activity. In this setting, Notch signaling levels can be quantified by measuring the luciferase-derived bioluminescence values.
  • Notch-reporter assay i.e. a luciferase-based luminescence readout
  • a luciferase-based luminescence readout was used here to quantify the ability of the claimed small molecules to augment Notch signaling in a cellular system.
  • HeLa cells obtainable from the American Type Culture Collection (ATCC) under the accession number ATCC-CCL-2, were transiently transfected for 24 hours using FuGENE® HD (Promega, #E2311) as transfection reagent with expression vectors of a membrane-tethered form of the constitutively active intracellular domain of the human Notch1 receptor (hNotch1 ⁇ E) to activate the signaling cascade (BPS Bioscience, human analogue to Notch Pathway Reporter Kit #60509 component C), a Firefly luciferase being expressed under the control of a Notch-responsive promoter to monitor Notch signaling (BPS Bioscience, Notch Pathway Reporter Kit #60509, CSL luci
  • HeLa cells were cultivated according to the protocol of the provider in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • the transfection was carried out in a 100 mm-culture dish (StarLab, #CC7682-3394) with cells being properly attached to the plate at a cell confluency of 80-90% in a total volume of 7 mL culture medium.
  • a transfection mix was prepared by adding to 238 ⁇ L Opti-MEM (Fisherscientific, #10149832) 40 ⁇ L of the hNotch1 ⁇ E expression vector (100 ng/ ⁇ L), 80 ⁇ L of the CSL luciferase reporter vector (40 ng/ ⁇ L), 4 ⁇ L of the pRL-SV40- Renilla luciferase vector (10 ng/ ⁇ L), and in the last step 18.1 ⁇ L of FuGENE® HD. After addition of FuGENE® HD the transfection mix was let stand for 15 min at room temperature and hereafter equally distributed into the culture dish. Subsequently, i.e.
  • the transfected cells (10.000 cells per well) were incubated with the test-compounds at a final concentration of 10 ⁇ M (diluted from 10 mM stock-solutions in DMSO to a final DMSO concentration of 0.1% v/v) or with the empty carrier DMSO at 0.1% v/v as control for 20 hours in 96-well plates suitable for luminescence readouts (CORNING, #3610).
  • the cells were lysed with 30 ⁇ L per well of Passive Lysis Buffer (Promega, #E194A, component of Dual-Luciferase® Reporter Assay System, #E1910) and the Firefly as well as Renilla luciferase values were measured with a luminescence reader with applying 15 ⁇ L per well each of the corresponding enzyme substrates needed to create the luminescence signals (Promega, Dual-Luciferase® Reporter Assay System, #E1910).
  • Passive Lysis Buffer Promega, #E194A, component of Dual-Luciferase® Reporter Assay System, #E1910
  • Renilla luciferase values were measured with a luminescence reader with applying 15 ⁇ L per well each of the corresponding enzyme substrates needed to create the luminescence signals.
  • a compound is considered as a Notch augmenting molecule, i.e. an enhancer of Notch signaling, if the weighted arithmetic mean of the luminescence values after subtraction of the corresponding combined standard deviation amounts to 1.1 or higher, in particular to 1.2 or higher, 1.3 or higher, 1.4 or higher, 1.5 or higher, 1.7 or higher, and 2.0 or higher relative to the overall basis level of 1.0.
  • the overall basis level was calculated as the weighted arithmetic mean of all double-normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds.
  • the corresponding combined standard deviation for the DMSO values amounts to less than 1 ⁇ 10 ⁇ 2 .
  • results indicate that compounds of said molecule families exhibit growth inhibiting properties in hyperproliferative processes.
  • the growth inhibiting properties correlate with Notch enhancing properties, in other cases the growth inhibiting properties do not correlate with Notch enhancing properties.
  • the biological activity of the claimed compounds can be attributed to but may not be limited to Notch signaling enhancing activity.
  • the secondary mechanisms of the claimed compounds leading to antiproliferative effects can be used alternatively or in combination with the Notch enhancing properties in medicinal treatments, preferably in the treatment of hyperproliferative disorders including cancer and non-malignant hyperproliferative disorders.
  • HL-60 cells, TT cells, HeLa cells, CAL-27 cells and human primary epidermal keratinocytes (HPEK) were seeded into 96-well plates suitable for fluorescence assays (CORNING #3598) at following initial cell numbers: 1000 cells per well for HL-60; 9000 cells per well for TT; 2000 cells per well for HeLa, 2000 cells per well for CAL-27, 2000 cells per well for HPEK.
  • the cells were treated with compounds at indicated final concentrations (diluted from the 1000 ⁇ stock-solutions in DMSO to a final DMSO concentration of 0.1% v/v) or with the empty carrier DMSO at 0.1% v/v as control for 5 days.
  • the cells were subjected to the alamarBlue® Proliferation Assay (Bio-Rad Serotec GmbH, BUF012B) according to the protocol of the manufacturer.
  • the readout was taken with a multi-well plate-reader in the fluorescence mode with applying a filter for excitation at 560 nm (band width 10 nm) and for emission at 590 nm (band width 10 nm).
  • Resveratrol (RES) treatment was included as control for growth inhibition.
  • the assays were performed in duplicate or more replicates of independent single experiments each containing a six-fold replicate for every condition. For every individual plate, the measured fluorescence intensity values of the conditions with compound treatment were normalized against the corresponding equally weighted arithmetic mean of the fluorescence intensity values of the six DMSO treated control wells in order to obtain the relative values to a baseline level of 1.0.
  • the statistical calculations were performed in analogy to the luciferase assay as described above. To this end, two independent outlier analyses were performed according to the methods by Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12). Outliers confirmed by at least one of the methods were excluded from the calculations but not more than one value out of six per compound within a single experiment.
  • the weighted arithmetic mean AVE w for each compound was calculated from the normalized values over all independent replicates of the single experiments comprising the six replicates each.
  • the corresponding standard deviation for the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Mühlig, Taschenbuch der Mathematik, 5 th edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and was combined with the Gauß′ error propagation associated with the performed calculation for the normalization.
  • the resulting standard deviation is herein referred to as “combined standard deviation”.
  • the compounds of the present invention may be growth inhibitors in hyperproliferative processes, including malignant and non-malignant hyperproliferative processes.
  • HL-60 cells human acute myeloid leukemia cells
  • DSMZ Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH
  • a compound is considered as a growth inhibitor of HL-60 cells, if—at a reference concentration of 20 ⁇ M—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0.
  • the overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds.
  • the corresponding combined standard deviation for the DMSO values amounts to less than 1 ⁇ 10 ⁇ 2 .
  • CAL-27 cells human tongue squamous cell carcinoma cells
  • DSMZ Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH
  • CAL-27 cells were cultivated according to the protocol of the provider (but at 5% instead of 10% CO 2 ) in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • a compound is considered as a growth inhibitor of CAL-27 cells, if—at a reference concentration of 20 ⁇ M—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0.
  • the overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds.
  • the corresponding combined standard deviation for the DMSO values amounts to less than 1 ⁇ 10 ⁇ 2 .
  • TT cells human medullary thyroid carcinoma cells
  • ATCC American Type Culture Collection
  • ATCC-CRL-1803 TT cells were cultivated according to the protocol of the provider in F-12K medium (Fisherscientific, #11580556, or ATCC, #ATCC-30-2004) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • a compound is considered as a growth inhibitor of TT cells, if—at a reference concentration of 40 ⁇ M—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0.
  • the overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds.
  • the corresponding combined standard deviation for the DMSO values amounts to less than 1 ⁇ 10 ⁇ 2 .
  • TT growth inhibitors relate to the compounds listed in Table IX.
  • Table IX The entries of Table IX are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated.
  • HeLa cells human cervical adenocarcinoma cells
  • ATCC American Type Culture Collection
  • HeLa cells were cultivated according to the protocol of the provider in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • a compound is considered as a growth inhibitor of HeLa cells, if—at a reference concentration of 40 ⁇ M—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0.
  • the overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds.
  • the corresponding combined standard deviation for the DMSO values amounts to less than 1 ⁇ 10 ⁇ 2 .
  • HPEKp human epidermal keratinocyte progenitors
  • CELLnTEC CnT-Prime epithelial culture medium
  • a compound is considered as a growth inhibitor of HPEKp cells, if—at a reference concentration of 10 ⁇ M—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0.
  • the overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds.
  • the corresponding combined standard deviation for the DMSO values amounts to less than 1 ⁇ 10 ⁇ 2 .
  • HPEKp growth inhibitors relate to the compounds listed in Table XI.
  • Table XI The entries of Table XI are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated.
  • C2C12 cells murine myoblast cells
  • DSMZ Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH
  • C2C12 cells were cultivated according to the protocol of the provider in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • a compound is considered as a growth inhibitor of C2C12 cells, if—at a reference concentration of 40 ⁇ M—the equally weighted arithmetic mean (AVE) of the six normalized fluorescence intensity values after addition of the corresponding standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0.
  • the overall basis level was calculated as the equally weighted arithmetic mean (AVE) of the six normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds.
  • the corresponding standard deviations for the tested compounds were calculated including the Gauß′ error propagation associated with the performed calculation for the normalization and amounts for the DMSO values to less than 3 ⁇ 10 ⁇ 2 .
  • Outlier analyses were performed as described above.
  • SCC squamous cell carcinoma
  • BHY cells human oral squamous cell carcinoma cells
  • DSMZ Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH
  • BHY cells were cultivated according to the protocol of the provider (but at 5% instead of 10% CO 2 ) in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • a compound is considered as a growth inhibitor of BHY cells, if—at a reference concentration of 40 ⁇ M—the equally weighted arithmetic mean (AVE) of the six normalized fluorescence intensity values after addition of the corresponding standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0.
  • the overall basis level was calculated as the weighted arithmetic mean (AVE w ) of all normalized values from the DMSO control measurements.
  • the corresponding combined standard deviation for the DMSO values amounts to less than 1 ⁇ 10 ⁇ 2 .
  • the corresponding standard deviations for the tested compounds were calculated including the Gauß′ error propagation associated with the performed calculation for the normalization.
  • the weighted arithmetic mean (AVE w ) and the combined standard deviation for RES was calculated in analogy to DMSO. Outlier analyses were performed as described above.
  • BHY growth inhibitors relate to the compounds listed in Table XIII.
  • Table XIII The entries of Table XIII are categorized by the corresponding equally weighted arithmetic means of the compounds falling into the activity ranges as indicated.
  • the present invention relates to the treatment of skin, skin appendages, mucosa, mucosal appendages, cornea, and all kinds of epithelial tissue.
  • skin relates to tissue including epidermis and dermis.
  • mucosa relates to mucous and submucous tissues including oral mucosa, nasal mucosa, ocular mucosa, mucosa of the ear, respiratory mucosa, genital mucosa, urothelial mucosa, anal mucosa and rectal mucosa.
  • tissue including hair follicles, hair, fingernails, toenails and glands including sebaceous glands, sweat glands, e.g. apocrine or eccrine sweat glands and mammary glands.
  • the present invention relates to treatment of non-melanoma skin cancer and pre-cancerous lesions, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), e.g. cutaneous SCC, lung SCC, head and neck SCC, oral SCC, esophageal SCC, cervical SCC, periocular SCC, SCC of the thyroid, SCC of the penis, SCC of the vagina, SCC of the prostate, SCC of the bladder, sebaceous gland carcinoma, Merkel cell carcinoma, angiosarcoma, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, dermatofibrosarcoma, actinic keratosis (AK) or Bowen's disease (BD).
  • BCC basal cell carcinoma
  • SCC squamous cell carcinoma
  • oral SCC esophageal SCC
  • cervical SCC periocular SCC
  • the present invention relates to the treatment of skin and mucosal disorders with cornification defects (keratoses) and/or abnormal keratinocyte proliferation, such as Psoriasis, Darier's disease, Lichen planus, Lupus erythematosus , Ichthyosis or Verruca vulgaris (senilis).
  • cornification defects keratoses
  • abnormal keratinocyte proliferation such as Psoriasis, Darier's disease, Lichen planus, Lupus erythematosus , Ichthyosis or Verruca vulgaris (senilis).
  • the invention relates to the treatment of skin and mucosal diseases related to and caused by viral infections, such as warts, HPV-related warts, papillomas, HPV-related papillomas, papillomatoses and HPV-related papillomatoses, e.g.
  • Verruca plantar warts
  • Verruca plana flat warts/plane warts
  • Verruca filiformis filiform warts
  • mosaic warts periungual warts, subungual warts
  • oral warts genital warts
  • fibroepithelial papilloma intracanalicular papilloma, intraductal papilloma, inverted papilloma, basal cell papilloma, squamous papilloma, cutaneous papilloma, fibrovasular papilloma, plexus papilloma, nasal papilloma, pharyngeal papilloma, Papillomatosis cutis carcinoides, Papillomatosis cutis lymphostatica, Papillomatosis confluens et reticularis or laryngeal papillomatosis (respiratory papillomatosis
  • the invention relates to the treatment of atopic dermatitis.
  • the invention relates to the treatment of acne.
  • the invention relates to the treatment of wounds of the skin, wherein the process of wound healing is accelerated.
  • a further aspect of the present invention relates to the treatment of immune system-related disorders.
  • immune system-related as used herein applies to a pathological condition of the hematopoietic system including the hematologic system, as well as to the intervention into proliferation, differentiation and/or activation of cell lineages of the hematopoietic system including the hematologic system in order to modulate an immune response (immune modulation).
  • diseases of the hematopoietic system including the hematologic system, such as malignancies of the myeloid lineage, e.g. chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML), including acute promyelocytic leukemia (APL); malignancies of the lymphoid lineage, e.g. B-cell acute lymphoblastic leukemia (B-ALL), pre-B-cell acute lymphoblastic leukemia (pre-B-ALL), Hodgkin lymphoma or myeloma; or acute lymphoblastic and acute myeloid mixed lineage leukemia with MLL gene translocation.
  • malignancies of the myeloid lineage e.g. chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML), including acute promyelocytic leukemia (APL); malignancies of the lymphoid lineage, e.g. B-
  • the compounds of the invention may be used in immunotherapy, alone or together with other immunotherapeutic methods or compounds, or as adjuvant for immunotherapy.
  • immunotherapy as used herein applies to activation-immunotherapy in patients without immune deficiency or with acquired or congenital immune deficiency, and as immune recovery to enhance the functionality of the immune system in the response against pathogens or pathologically transformed endogenous cells, such as cancer cells.
  • immunotherapy methods as used herein applies to vaccinations, antibody treatment, cytokine therapy, the use of immune checkpoint inhibitors and immune response-stimulating drugs, as well as to autologous transplantations of genetically modified or non-modified immune cells, which may be stimulated with intercellular signals, or signaling molecules, or antigens, or antibodies, i.e. adoptive immune-cell transfer.
  • peripheral T-lymphocytes in order to amplify an immune response, particularly the stimulation of proliferation and/or cytokine production and/or secretion upon antigen recognition in order to amplify an immune response
  • B-lymphocytes in order to amplify an immune response
  • stimulation of proliferation and/or antibody production and/or secretion such as the enhancement of an immune response through augmentation of the number of specific immune-cell subtypes, by regulation of differentiation and/or cell fate decision during immune-cell development, as for example to augment the number of marginal zone B-cells, or T-helper (Th) subsets in particular Th1, Th2 and regulatory T-cells; or the use as vaccine adjuvant.
  • Th T-helper
  • a still further aspect of the invention relates to the treatment of muscular diseases including diseases of skeletal muscle, cardiac muscle and smooth muscle.
  • the invention relates to the treatment of muscular dystrophies (MD).
  • MD muscular dystrophies
  • Duchenne MD Becker MD, congenital MD, Limb-Girdle MD, facioscapulohumeral MD, Emery-Dreifuss MD, distal MD, myotonic MD or oculopharyngeal MD.
  • the invention relates to the treatment of hyperproliferative disorders of the muscle, including myoblastoma, rhabdomyoma, and rhabdomyosarcoma, as well as muscle hyperplasia and muscle hypertrophy.
  • the compounds of the invention may be used for muscle regeneration after pathologic muscle degeneration or atrophy, e.g. caused by traumata, caused by muscle ischemia or caused by inflammation, in aging-related muscle-atrophy or in disease-related muscle atrophy such as myositis and fibromyositis or poliomyelitis.
  • pathologic muscle degeneration or atrophy e.g. caused by traumata, caused by muscle ischemia or caused by inflammation, in aging-related muscle-atrophy or in disease-related muscle atrophy such as myositis and fibromyositis or poliomyelitis.
  • a still further aspect relates to the treatment of disorders of the neuroendocrine system such as cancer of the neuroendocrine system, comprising neuroendocrine small cell carcinomas, neuroendocrine large cell carcinomas and carcinoid tumors, e.g. of the brain, thyroid, pancreas, gastrointestinal tract, liver, esophagus, and lung, such as neuroendocrine tumor of the pituitary gland, neuroendocrine tumor of the adrenal gland, medullary thyroid cancer (MTC), C-cell hyperplasia, anaplastic thyroid cancer (ATC), parathyroid adenoma, intrathyroidal nodules, insular carcinoma, hyalinizing trabecular neoplasm, paraganglioma, small-cell lung cancer (SCLC), lung carcinoid tumors, neuroblastoma, gastrointestinal carcinoid, Goblet-cell carcinoid, pancreatic carcinoid, gastrinoma, glucagenoma, somatostatinoma, VIPo
  • a still further aspect relates to the treatment of cancers or precancerous lesions of the brain, pancreas, liver, thyroid, genitourinary tract and endothelial tissue, including glioma, mixed glioma, glioblastoma multiforme, astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, ependymoma, anaplastic ependymoma, myxopapillary ependymoma, subependymoma, brain stem glioma, optic nerve glioma, and forebrain tumors, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma, pancreatic pseudopapillary ne
  • treating refers to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • the term “treating” also encompasses post-treatment care.
  • administration of a compound of the invention, or pharmaceutically acceptable salt thereof is effective in preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • the compounds of the invention may be used in human and veterinary medicine, which includes the treatment of companion animals, e.g. horses, dogs, cats, rabbits, guinea pigs, birds, fishes; and livestock, e.g. cattle, poultry, pig, sheep, goat, donkey, yak and camel.
  • companion animals e.g. horses, dogs, cats, rabbits, guinea pigs, birds, fishes
  • livestock e.g. cattle, poultry, pig, sheep, goat, donkey, yak and camel.
  • the present invention further provides pharmaceutical compositions comprising a compound as described herein or a pharmaceutically acceptable salt thereof for use in medicine, e.g. in human or veterinary medicine.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • An effective dose of the compounds according to the invention, or their salts, solvates or prodrugs thereof is used, in addition to physiologically acceptable carriers, diluents and/or adjuvants for producing a pharmaceutical composition.
  • the dose of the active compounds can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the diseases to be treated, and similar factors.
  • the daily dose can be given as a single dose, which is to be administered once, or be subdivided into two or more daily doses, and is as a rule 0.001-2000 mg. Particular preference is given to administering daily doses of 0.1-500 mg, e.g. 0.1-100 mg.
  • Suitable administration forms are topical or systemical including enteral, oral, rectal, and parenteral, as infusion and injection, intravenous, intra-arterial, intraperitoneal, intramuscular, intracardial, epidural, intracerebral, intracerebroventricular, intraosseous, intra-articular, intraocular, intravitreal, intrathecal, intravaginal, intracavernous, intravesical, subcutaneous, intradermal, transdermal, transmucosal, inhalative, intranasal, buccal, sublingual and intralesional preparations.
  • enteral, oral, rectal, and parenteral as infusion and injection, intravenous, intra-arterial, intraperitoneal, intramuscular, intracardial, epidural, intracerebral, intracerebroventricular, intraosseous, intra-articular, intraocular, intravitreal, intrathecal, intravaginal, intracavernous, intravesical, subcutaneous, intradermal, transdermal, transmu
  • the customary galenic preparation forms such as tablets, sugar-coated tablets, capsules, dispersible powders, granulates, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lip balms, mouthwashs, foams, pastes, tinctures, dermal patches and tapes, forms in occlusion or in combination with time release drug delivery systems, with electrophoretic dermal delivery systems including implants and devices, and with jet injectors, liposome and transfersome vesicles, vapors, sprays, syrups, juices or drops and eye drops, can be used.
  • Solid medicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminium stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gelatine, agar agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); preparations which are suitable for oral administration can comprise additional flavourings and/or sweetening agents, if desired.
  • carrier substances such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminium stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher mole
  • Liquid medicinal forms can be sterilized and/or, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators.
  • auxiliary substances such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators.
  • additives are tartrate and citrate buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its non-toxic salts).
  • High molecular weight polymers such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitable for regulating the viscosity.
  • solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.
  • Oily suspensions for parenteral or topical applications can be vegetable, synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol.
  • vegetable, synthetic or semisynthetic oils such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid,
  • fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, inter alia.
  • Silicone oils of differing viscosity are also suitable. It is furthermore possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil.
  • Suitable solvents, gelatinizing agents and solubilizers are water or water-miscible solvents.
  • suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.
  • Cellulose ethers which can dissolve or swell both in water or in organic solvents, such as hydroxypropylmethyl cellulose, methyl cellulose or ethyl cellulose, or soluble starches, can be used as film-forming agents.
  • gelatinizing agents and film-forming agents are also perfectly possible.
  • ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.
  • surfactants for example of Na lauryl sulphate, fatty alcohol ether sulphates, di-Na—N-lauryl- ⁇ -iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono-/dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts can also be required for the formulation.
  • surfactants for example of Na lauryl sulphate, fatty alcohol ether sulphates, di-Na—N-lauryl- ⁇ -iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. T
  • Stabilizers such as montmorillonites or colloidal silicic acids, for stabilizing emulsions or preventing the breakdown of active substances such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations.
  • Preparations for parenteral administration can be present in separate dose unit forms, such as ampoules or vials.
  • Use is preferably made of solutions of the active compound, preferably aqueous solution and, in particular, isotonic solutions and also suspensions.
  • These injection forms can be made available as ready-to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent.
  • Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilisates which are prepared before use using the suitable solvent or suspending agent.
  • inhalable preparations can present as powders, solutions or suspensions.
  • inhalable preparations are in the form of powders, e.g. as a mixture of the active ingredient with a suitable formulation aid such as lactose.
  • the preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions.
  • the compounds of the invention may be administered as a combination therapy, as sequence therapy or as simultaneous combination therapy, with further active agents, e.g. therapeutically active compounds useful in the treatment of the above indicated disorders.
  • therapeutically active compounds may include but are not limited to chemotherapeutic agents such as nucleoside analogs, e.g. Cytarabin, Gemcitabine, Azathioprine, Mercaptopurine, Fluorouracil, Thioguanine, Hydroxyurea, Azacitidine, Capecitabine, Doxifluridine, and Methotrexate; such as platinum-based drugs, e.g. Cisplatin, Oxaliplatin, Carboplatin and Nedaplatin; such as anthracyclines, e.g.
  • Docetaxel Paclitaxel, Abraxane, Cabazitaxel, Vinblastine, Vindesine, Vinorelbine and Vincristine; such as topoisomerase inhibitors, e.g. Irinotecan, Topotecan, Teniposide and Etoposide; and targeted therapeutic agents such as kinase inhibitors, regulators i.e. inhibitors and activators of signaling pathways including growth factor signaling, cytokine signaling, NF-kappaB signaling, AP1 signaling, JAK/STAT signaling, EGFR signaling, TGF-beta signaling, Notch signaling, Wnt signaling, Hedgehog signaling, hormone and nuclear receptor signaling, e.g.
  • topoisomerase inhibitors e.g. Irinotecan, Topotecan, Teniposide and Etoposide
  • targeted therapeutic agents such as kinase inhibitors, regulators i.e. inhibitors and activators of signaling pathways including growth
  • Raloxifene Tamoxifen, Fulvestrant, Lasofoxifene, Toremifene, Bicalutamide, Flutamide, Anastrozole, Letrozole and Exemestane; histone deacetylase inhibitors, e.g. Vorinostat, Romidepsin, Panobinostat, Belinostat and Chidamide; and Ingenol mebutate; and other Notch enhancers not encompassed by the compounds of the present invention, e.g.
  • Valproic acid Valproic acid, Resveratrol, hesperetin, chrysin, phenethyl isothiocyanate, thiocoraline, N-methylhemeanthidine chloride and Notch Signaling-activating peptides or antibodies; and immune response modulating agents e.g. Imiquimod, Ipilimumab, Atezolizumab, Ofatumumab, Rituximab, Nivolumab and Pembrolizumab; and anti-inflammatory agents including glucocorticoids and non-steroidal anti-inflammatory drugs, e.g.
  • cortisol-based preparations Dexamethason, Betamethason, Prednisone, Prednisolone, Methylprednisolone, Triamcinolon-hexacetonid, Mometasonfuroat, Clobetasolpropionat, acetylsalicylic acid, salicylic acid and other salicylates, Diflunisal, Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Loxoprofen, Flurbiprofen, Oxaprozin, Indomethacin, Ketorolac, Tolmetin, Diclofenac, Etodolac, Aceclofenac, Nabumetone, Sulindac, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Parecoxib, Etoricoxib and Fi
  • the compounds of the invention may be administered as antibody-drug conjugates.
  • the compounds of the invention may be administered in combination with surgery, cryotherapy, electrodessication, radiotherapy, photodynamic therapy, laser therapy, chemotherapy, targeted therapy, immunotherapy, gene therapy, antisense therapy, cell-based transplantation therapy, stem cell therapy, physical therapy and occupational therapy.
  • diaryl ether scaffold which can be prepared by a method of reacting a phenol and an electron-deficient aryl halide in the presence of a base such as potassium carbonate or cesium carbonate in a non-protic organic solvent such as DMSO or DMF at room temperature or at elevated temperature or reflux, preferably at 80° C. or 100° C., with optional assistance of microwave irradiation (Li et al., Org. Lett. 2003, 5, 2169-2171);
  • the corresponding carboxylic acids are synthesized by saponification of the corresponding benzoate esters, fluorobenzoate esters, nicotinate esters, or fluoronicotinate esters in the presence of potassium hydroxide or sodium hydroxide in a binary solvent mixture of water and an alcohol, preferably ethanol, or water and tetrahydrofuran at ambient or elevated temperature (Becker et al., Organikum, 22nd edition 2004 (German), pp. 488, publisher: Wiley-VCH Weinheim);
  • esters, primary amides, secondary amides, tertiary amides, and hydroxamic acids are synthesized by in situ transformation of the corresponding benzoic acid, fluorobenzoic acid, nicotinic acid, or fluoronicotinic acid to the corresponding acid chlorides in the presence of thionyl chloride and catalytic amounts of DMF in toluene at ambient or elevated temperature, preferably at 80° C., and under inert gas atmosphere, followed by the addition of the respective nucleophile, i.e.
  • perfluoroalkylcyclopropyl moiety associated with the compounds of the invention falling under the scope of formula V is synthesized in three steps according to the procedure described in Barnes-Seeman et al., ACS Med. Chem. Lett. 2013, 4, 514-516; first, a bromoperfluoroalkenylbenzene such as 1-bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene or 1-bromo-4-(3,3,4,4,4-pentafluorobut-1-en-2-yl)benzene is obtained by a method of reacting 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one or 1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropan-1-one, respectively, in the presence of methanesulfonyl chloride and a base such as potassium fluoride in a crown ether such as 18-crown-6 in a
  • a bromophenylperfluoroalkyldihydropyrazole such as 3-(4-bromophenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole or 3-(4-bromophenyl)-3-(perfluoroethyl)-4,5-dihydro-3H-pyrazole is obtained by a method of reacting a bromoperfluoroalkenylbenzene such as 1-bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene or 1-bromo-4-(3,3,4,4,4-pentafluorobut-1-en-2-yl)benzene, respectively, in the presence of diazomethane in an ether such as diethyl ether or methyl tert-butyl ether at ambient temperature;
  • the perfluoroalkylcyclopropylarylbromide such as 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene or 1-bromo-4-(1-(perfluoroethyl)cyclopropyl)benzene is obtained by a method of reacting 3-(4-bromophenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole or 3-(4-bromophenyl)-3-(perfluoroethyl)-4,5-dihydro-3H-pyrazole, respectively, in an organic solvent such as toluene or xylenes or a mixture thereof.
  • an organic solvent such as toluene or xylenes or a mixture thereof.
  • the obtained perfluoroalkylcyclopropylarylbromide can subsequently be converted into the corresponding phenol for one of the above said coupling reactions with an electron-deficient aryl halide, a nitroarene, a diaryliodonium triflate or tosylate by a method of reaction in the presence of a transition metal-based catalyst system such as Pd2dba3, an organophosphorus-based ligand such as 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-Bu XPhos), a base such as potassium hydroxide or sodium hydroxide in a biphasic solvent system such as water/dioxane or water/toluene at elevated temperature or reflux, preferably at 100° C., and under an inert gas atmosphere (Anderson et al., J. Am. Chem. Soc. 2006, 128, 10694-10695);
  • a copper-based catalyst system such as CuI
  • a pyridyl based ligand such as 2-methylquinolin-8-ol or preferably 8-hydroxyquinoline-N-oxide
  • tetrabutyl-ammonium hydroxide or preferably cesium hydroxide monohydrate in a non-protic organic solvent such as DMSO or DMF at elevated temperature or reflux, preferably at 110° C., and under an inert gas atmosphere
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • TLC thin layer chromatography
  • Diaryl ether esters according to formula I, formula III, and formula V can be prepared by nucleophilic aromatic substitution, e.g. by reaction of an alkyl 4-fluorobenzoate, or an alkyl 3,4-difluorobenzoate, or an alkyl 6-chloronicotinate, or an alkyl 6-chloro-5-fluoronicotinate, with a phenol derivative (nucleophile, see Table XIV) in the presence of a base like potassium carbonate in a solvent like dimethyl sulfoxide at a temperature between 80° C. and 150° C. and in an inert atmosphere such as argon.
  • a base like potassium carbonate in a solvent like dimethyl sulfoxide at a temperature between 80° C. and 150° C. and in an inert atmosphere such as argon.
  • Diaryl ether acids according to formula I, formula III, and formula V can be prepared by saponification, e.g. by reaction of the corresponding diaryl ether esters with an aqueous base solution like sodium hydroxide (nucleophile, see Table XIV) in a solvent like ethanol, methanol, tetrahydrofuran or a mixture thereof at a temperature between room temperature and reflux.
  • an aqueous base solution like sodium hydroxide (nucleophile, see Table XIV) in a solvent like ethanol, methanol, tetrahydrofuran or a mixture thereof at a temperature between room temperature and reflux.
  • Diaryl ether esters according to formula I, formula III, and formula V can be prepared by esterification via the corresponding acid chloride, e.g by reaction of a diaryl ether acid with thionyl chloride in the presence of catalytic amounts of DMF in a solvent like toluene at a temperature between 50° C. and 100° C. and in an inert atmosphere such as argon. After removal of the volatiles, the such obtained acid chloride intermediate is reacted with the alcohol corresponding to the desired ester (nucleophile, see Table XIV) in the presence of an organic base like triethylamine at a temperature between 0° C. and room temperature and in an inert atmosphere such as argon.
  • an organic base like triethylamine
  • diaryl ether esters according to formula I, formula III, and formula V can be prepared by esterification via the corresponding acid chloride, e.g. by reaction of a diaryl ether acid with thionyl chloride in the presence of the alcohol corresponding to the desired ester (nucleophile, see Table XIV), preferably as the solvent at a temperature between 50° C. and reflux.
  • Diaryl ether amides according to formula II, formula IV, and formula V can be prepared by amidation via the corresponding acid chloride, e.g by reaction of a diaryl ether acid with thionyl chloride in the presence of catalytic amounts of DMF in a solvent like toluene at a temperature between 50° C. and 100° C. and in an inert atmosphere such as argon. After removal of the volatiles, the such obtained acid chloride intermediate is reacted with the amine corresponding to the desired amide (nucleophile, see Table XIV) in a solvent like methanol, ethanol, or tetrahydrofuran at a temperature between 0° C. and room temperature and in an inert atmosphere such as argon. The presence of an organic base like triethylamine is needed if the hydrochloride salt of the amine is used.
  • reaction vessel was then sealed and immerged in a pre-heated oil bath at 100° C.
  • the reaction was stirred for 4-10 h.
  • the reaction was quenched with 1 M aqueous HCl.
  • the aqueous layer was extracted with EtOAc (3 ⁇ ).
  • the combined organics were washed with brine (1 ⁇ ), dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue was purified by silica gel flash chromatography eluting with 100% to 90% PE-EtOAc gradient to give the title compound as a yellow oil (3.0 g, 99%).
  • reaction mixture was quenched with saturated aqueous Na 2 S 2 O 3 and stirred 30 minutes. The mixture was filtered, then acidified to pH 2 with HCl 5 M. The aqueous layer was extracted with EtOAc (3 ⁇ ). The combined organics were washed with brine (1 ⁇ ), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 90% to 70% PE-EtOAc gradient to give the title compound as a white solid (300 mg, 49%).
  • reaction mixture was cooled down to 0° C., water (1.4 mL) and TBAF (1 M solution in THF, 1.4 mL, 1.4 mmol) were added and the reaction mixture was stirred at room temperature for 14 h. The reaction was quenched with water. The aqueous layer was extracted with EtOAc (3 ⁇ ). The combined organics were washed with brine (1 ⁇ ), dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • reaction vessel was then sealed and immerged in a pre-heated oil bath at 100° C.
  • the reaction was stirred for 4-10 h.
  • the reaction was quenched with 1 M aqueous HCl.
  • the aqueous layer was extracted with EtOAc (3 ⁇ ).
  • the combined organics were washed with brine (1 ⁇ ), dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue was purified by silica gel flash chromatography eluting with 100% to 90% PE-EtOAc gradient to give the title compound as a yellow oil (1.04 g, 29% over 4 steps, 44% BRSM).
  • the compounds listed in Table XIV have been identified by TLC using pre-coated silica TLC sheets and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, or acetic acids as eluent, preferably as binary or tertiary solvent mixtures thereof, UV light at a wavelength of 254 or 366 nm, and/or common staining solutions such as phosphomolybdic acid, potassium permanganate, or ninhydrin.
  • common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, or acetic acids as eluent, preferably as binary or tertiary solvent mixtures thereof, UV light at a wavelength of 254 or 366 nm, and/or common staining solutions such as phosphomolybdic acid, potassium permanganate, or ninhydrin.

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Abstract

The present invention comprises novel aromatic molecules, which can be used in the treatment of pathological conditions, such as cancer, skin diseases, muscle disorders, and immune system-related disorders such as disorders of the hematopoietic system including the hematologic system in human and veterinary medicine.

Description

  • The present invention relates to novel aromatic compounds and their use as therapeutic agents, which can be used in the treatment of pathological conditions, such as cancer, skin disorders, muscle disorders, and immune system-related disorders such as disorders of the hematopoietic system including the hematologic system in human and veterinary medicine.
    • BACKGROUND
  • Notch signaling is a fundamental cell-to-cell communication pathway that regulates central processes in embryonic development as well as in the maintenance of adult tissues. The effect of a Notch signal is highly dependent on the signal strength, duration, and most importantly on the cellular context. In this regard, Notch activity leads to numerous cell-type specific responses, which implicate for example cell fate decisions, the induction or inhibition of differentiation, and the regulation of cell proliferation.
  • If a signaling event is not correctly controlled, a consequent loss of balance in according cellular processes may drive abnormal cellular changes and finally end in diverse disease situations, such as cancer.
  • Initially, Notch signaling was discovered as an oncogenic pathway. Corresponding pathological conditions are linked to abnormally augmented signaling levels. In these particular cases, the use of Notch inhibiting agents represents a promising strategy for therapeutic intervention and numerous corresponding drugs are currently in development.
  • Conversely, there is increasing evidence for tumor-suppressor functions of the Notch pathway in other cellular contexts (Lobry et al., J. Exp. Med. 2011, 208, 1931-1935; South et al., Semin. Cell Dev. Biol. 2012, 23, 458-464), most notably concerning organs, in which Notch negatively impacts proliferation or triggers differentiation, such as in the skin or in the neuroendocrine system (Dotto, Oncogene 2008, 27, 5115-5123; Kunnimalaiyaan et al., The Oncologist 2007, 12, 535-542). This finding is not only based on observations that certain tumors display impairments in Notch activity. Additionally, various successful demonstrations confirmed that the artificial activation of Notch signaling has a beneficial impact on according malignant degenerations (Jaskula-Sztul et al, J. Surg. Res. 2011, 171, 23-27; Yu et al., Cancer 2013, 119, 774-781; Ye et al., Sci. Rep. 2016, 6, 26510). Prominent examples comprise non-melanoma skin cancer, neuroendocrine tumors and certain cancers of the hematopoietic system.
  • In a broader sense, due to the central role of this pathway, the potential use of Notch enhancers is not only limited to the treatment of cancer, but likewise expected to be beneficial in other pathologic conditions that have been shown to be responsive to Notch induction, such as diseases of the skin, muscle or immune system.
  • To this end, it is highly desirable to develop therapeutic agents that enhance Notch signaling.
  • Notch Enhancers State of the Art
  • Current methods to enhance Notch signaling for a potential therapeutic use entail the application of receptor-activating peptides or of small molecules that show Notch-augmenting properties. However, no approved Notch enhancer is available yet in the clinics. Besides, only a small number of according agents is known to date and much less have so far entered a drug development program. Reported small molecule Notch enhancers comprise resveratrol (Pinchot et al., Cancer 2011, 117, 1386-1398; Truong et al., Ann. Surg. Oncol. 2011, 18, 1506-1511; Yu et al., Mol. Cancer Ther. 2013, 12, 1276-1287), valproic acid (Greenblatt et al., Oncologist 2007, 12, 942-951; Platta et al., J. Surg. Res. 2008, 148, 31-37; Mohammed et al., Oncologist 2011, 16, 835-843), hesperetin (Patel et al., Ann. Surg. Oncol. 2014, 21, 497-504), chrysin (Yu et al., Cancer 2013, 119, 774-778), phenethyl isothiocyanate (Kim et al., PLoS One 2011, 6, 10), thiocoraline (Wyche et al., Cancer Gene Ther. 2014, 21, 518-525) and N-methylhemeanthidine chloride (Ye et al., Sci. Rep. 2016, 6, 26510).
  • A common drawback associated with most of the mentioned compounds is the lack of potency.
  • Hence, it is absolutely crucial to provide novel Notch enhancers with high therapeutic efficacy.
  • The screening of a small library of chemical molecules in a Notch-dependent luciferase reporter assay revealed a novel compound family with Notch-augmenting properties (Reinmüller et al., 2015, EPFL Thesis 6887, published in March 2016), the content of which is herein incorporated by reference.
    • DESCRIPTION OF THE INVENTION
  • The present invention covers refined structures to the initially discovered limited set of Notch enhancer molecules. These second generation compounds have been designed and are supposed to exhibit increased potency and greater metabolic stability. Alternatively, they present specific modifications of chemical residues, which are supposed to not impair the Notch-augmenting activity, but yet provide novel molecular features that may turn out to beneficially influence pharmacological and physicochemical parameters addressed in the general drug development process.
  • Thus, the present invention relates to compounds as defined herein that feature Notch enhancing activity, which can be used in the treatment of pathological conditions that are responsive for Notch-regulation, such as cancer, skin diseases, muscle disorders, and immune system-related disorders such as disorders of the hematopoietic system including the hematologic system in human and veterinary medicine.
  • The biological activity, e.g. the antiproliferative activity of the claimed compounds can be attributed to but may not be limited to Notch signaling enhancing activity. Thus, the present invention also relates to compounds as defined herein that feature antiproliferative activity, which can be used in the treatment of benign and malignant hyperproliferative disorders in human and veterinary medicine. In particular, the present invention relates to compounds as defined herein for the treatment of immune system-related disorders such as disorders of the hematopoietic system including the hematologic system, such as malignancies of the myeloid lineage, malignant and non-malignant disorders of the skin and mucosa, such as squamous and basal cell carcinoma, actinic keratosis, and hyperproliferative disorders of the skin and mucosa, e.g. cornification disorders, malignant and non-malignant disorders of the muscle, including hyperproliferative disorders of the muscle, such as muscle hyperplasia and muscle hypertrophy, disorders of the neuroendocrine system, such as medullary thyroid cancer, and hyperproliferative disorders of the genitourinary tract, e.g. cervical cancer in human and veterinary medicine.
  • A first aspect of the present invention relates to compounds of formula I and salts and solvates thereof:
  • Figure US20210107863A2-20210415-C00001
  • wherein X is CH or N,
  • R1═C1-C12 preferably C1-C6 alkyl, C2-C12 preferably C2-C6 alkenyl, C2-C12 preferably C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C4-C12 bicycloalkyl, C6-C12 bicycloalkenyl, C5-C14 tricycloalkyl,
  • wherein all alkyl, alkenyl and alkynyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, −Cl, —Br, —I, —CN, —NCO, —NCS; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues can be perhalogenated, particularly perfluorinated;
  • and wherein R1 is preferably selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, tert-butyl, tert-pentyl, 3-pentyl, —CF3, —CF2CF3, —(CF2)2CF3, —(CF2)3CF3, —CH(CF3)2, —CF(CF3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, and 9-methylbicyclo[3.3.1]nonyl;
  • R2═H, C1-C6 alkyl, C3-C6 cycloalkyl,
  • wherein all alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • wherein all cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • wherein all alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated;
  • and wherein R2 is preferably selected from H, methyl and ethyl.
  • In some embodiments, the following compounds shown in Table Ia are explicitly excluded from the scope of the invention:
  • TABLE Ia
    Compound R1 R2 X
    I-A tert-butyl H CH
    I-B tert-butyl ethyl CH
    I-C tert-pentyl H CH
    I-D tert-pentyl ethyl CH
    I-E cyclo-hexyl H CH
    I-F cyclo-hexyl ethyl CH
    I-G adamant-1-yl H CH
    I-H adamant-1-yl ethyl CH
    I-I methyl H N
    I-J methyl ethyl N
    I-K tert-butyl H N
    I-L tert-butyl ethyl N
    I-M tert-pentyl H N
    I-N tert-pentyl ethyl N
    I-O cyclo-hexyl H N
    I-P cyclo-hexyl ethyl N
    I-Q isopropyl H CH
    I-R phenyl H CH
    I-S methyl H CH
    I-T tert-butyl methyl N
    I-U methyl methyl N
    I-V methyl methyl CH
    I-W methyl ethyl CH
    I-X n-hexyl H CH
    I-Y n-octyl H CH
    I-Z n-dodecyl H CH
    I-AA iso-propyl H N
  • Compounds I-A to I-T of Table Ia are known in the art for certain applications in the field of medicine whereas to the best of the inventor's knowledge, compounds I-U to I-AA are not known for any use in medicine. Thus, the invention encompasses any medical use for compounds I-U to I-AA.
  • Specific examples of compounds falling under the scope of formula I are shown in Table Ib. The compounds in Table Ib are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes.
  • TABLE Ib
    X = CH, R2 = H
    Figure US20210107863A2-20210415-C00002
         		001
    4-(p-tolyloxy)benzoic acid
    Figure US20210107863A2-20210415-C00003
         		002
    4-(4-ethylphenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00004
         		003
    4-(4-propylphenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00005
         		004
    4-(4-butylphenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00006
         		005
    4-(4-pentylphenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00007
         		006
    4-(4-hexylphenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00008
         		007
    4-(4-isopropylphenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00009
         		008
    4-(4-(pentan-3-yl)phenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00010
         		009
    4-(4-(trifluoromethyl)phenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00011
         		010
    4-(4-(perfluoroethyl)phenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00012
         		011
    4-(4-(perfluoropropyl)phenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00013
         		012
    4-(4-(perfluorobutyl)phenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00014
         		013
    4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)
    benzoic acid
    Figure US20210107863A2-20210415-C00015
         		014
    4-(4-(perfluoropropan-2-yl)phenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00016
         		015
    4-(4-cyclopropylphenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00017
         		016
    4-(4-cyclobutylphenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00018
         		017
    4-(4-cyclopentylphenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00019
         		018
    4-(4-cycloheptylphenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00020
         		019
    4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00021
         		020
    4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00022
         		021
    4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)benzoic acid
    Figure US20210107863A2-20210415-C00023
         		022
    4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)
    benzoic acid
    X = CH, R2 = Me
    Figure US20210107863A2-20210415-C00024
         		023
    methyl 4-(p-tolyloxy)benzoate
    Figure US20210107863A2-20210415-C00025
         		024
    methyl 4-(4-ethylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00026
         		025
    methyl 4-(4-propylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00027
         		026
    methyl 4-(4-butylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00028
         		027
    methyl 4-(4-pentylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00029
         		028
    methyl 4-(4-hexylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00030
         		029
    methyl 4-(4-isopropylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00031
         		030
    methyl 4-(4-(tert-pentyl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00032
         		031
    methyl 4-(4-(pentan-3-yl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00033
         		032
    methyl 4-(4-(trifluoromethyl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00034
         		033
    methyl 4-(4-(perfluoroethyl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00035
         		034
    methyl 4-(4-(perfluoropropyl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00036
         		035
    methyl 4-(4-(perfluorobutyl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00037
         		036
    methyl 4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)
    benzoate
    Figure US20210107863A2-20210415-C00038
         		037
    methyl 4-(4-(perfluoropropan-2-yl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00039
         		038
    methyl 4-(4-cyclopropylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00040
         		039
    methyl 4-(4-cyclobutylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00041
         		040
    methyl 4-(4-cyclopentylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00042
         		041
    methyl 4-(4-cyclohexylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00043
         		042
    methyl 4-(4-cycloheptylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00044
         		043
    methyl 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)
    benzoate
    Figure US20210107863A2-20210415-C00045
         		044
    methyl 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)
    benzoate
    Figure US20210107863A2-20210415-C00046
         		045
    methyl 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00047
         		046
    methyl 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00048
         		047
    methyl 4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-
    yl)phenoxy)benzoate
    X = CH, R2 = Et
    Figure US20210107863A2-20210415-C00049
         		048
    ethyl 4-(p-tolyloxy)benzoate
    Figure US20210107863A2-20210415-C00050
         		049
    ethyl 4-(4-ethylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00051
         		050
    ethyl 4-(4-propylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00052
         		051
    ethyl 4-(4-butylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00053
         		052
    ethyl 4-(4-pentylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00054
         		053
    ethyl 4-(4-hexylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00055
         		054
    ethyl 4-(4-isopropylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00056
         		055
    ethyl 4-(4-(pentan-3-yl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00057
         		056
    ethyl 4-(4-(trifluoromethyl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00058
         		057
    ethyl 4-(4-(perfluoroethyl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00059
         		058
    ethyl 4-(4-(perfluoropropyl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00060
         		059
    ethyl 4-(4-(perfluorobutyl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00061
         		060
    ethyl 4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)
    benzoate
    Figure US20210107863A2-20210415-C00062
         		061
    ethyl 4-(4-(perfluoropropan-2-yl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00063
         		062
    ethyl 4-(4-cyclopropylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00064
         		063
    ethyl 4-(4-cyclobutylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00065
         		064
    ethyl 4-(4-cyclopentylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00066
         		065
    ethyl 4-(4-cycloheptylphenoxy)benzoate
    Figure US20210107863A2-20210415-C00067
         		066
    ethyl 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)
    benzoate
    Figure US20210107863A2-20210415-C00068
         		067
    ethyl 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00069
         		068
    ethyl 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)benzoate
    Figure US20210107863A2-20210415-C00070
         		069
    ethyl 4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)
    phenoxy)benzoate
    X = N, R2 = H
    Figure US20210107863A2-20210415-C00071
         		070
    6-(4-ethylphenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00072
         		071
    6-(4-propylphenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00073
         		072
    6-(4-butylphenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00074
         		073
    6-(4-pentylphenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00075
         		074
    6-(4-hexylphenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00076
         		075
    6-(4-isopropylphenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00077
         		076
    6-(4-(pentan-3-yl)phenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00078
         		077
    6-(4-(perfluoroethyl)phenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00079
         		078
    6-(4-(perfluoropropyl)phenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00080
         		079
    6-(4-(perfluorobutyl)phenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00081
         		080
    6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)
    nicotinic acid
    Figure US20210107863A2-20210415-C00082
         		081
    6-(4-(perfluoropropan-2-yl)phenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00083
         		082
    6-(4-cyclopropylphenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00084
         		083
    6-(4-cyclobutylphenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00085
         		084
    6-(4-cyclopentylphenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00086
         		085
    6-(4-cycloheptylphenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00087
         		086
    6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00088
         		087
    6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00089
         		088
    6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00090
         		089
    6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)nicotinic acid
    Figure US20210107863A2-20210415-C00091
         		090
    6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)
    nicotinic acid
    X = N, R2 = Me
    Figure US20210107863A2-20210415-C00092
         		091
    methyl 6-(p-tolyloxy)nicotinate
    Figure US20210107863A2-20210415-C00093
         		092
    methyl 6-(4-ethylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00094
         		093
    methyl 6-(4-propylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00095
         		094
    methyl 6-(4-butylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00096
         		095
    methyl 6-(4-pentylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00097
         		096
    methyl 6-(4-hexylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00098
         		097
    methyl 6-(4-isopropylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00099
         		099
    methyl 6-(4-(tert-pentyl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00100
         		100
    methyl 6-(4-(pentan-3-yl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00101
         		101
    methyl 6-(4-(trifluoromethyl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00102
         		102
    methyl 6-(4-(perfluoromethyl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00103
         		103
    methyl 6-(4-(perfluoropropyl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00104
         		104
    methyl 6-(4-(perfluorobutyl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00105
         		105
    methyl 6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)
    nicotinate
    Figure US20210107863A2-20210415-C00106
         		106
    methyl 6-(4-(perfluoropropan-2-yl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00107
         		107
    methyl 6-(4-cyclopropylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00108
         		108
    methyl 6-(4-cyclobutylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00109
         		109
    methyl 6-(4-cyclopentylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00110
         		110
    methyl 6-(4-cyclohexylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00111
         		111
    methyl 6-(4-cycloheptylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00112
         		112
    methyl 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)
    nicotinate
    Figure US20210107863A2-20210415-C00113
         		113
    methyl 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)
    nicotinate
    Figure US20210107863A2-20210415-C00114
         		114
    methyl 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00115
         		115
    methyl 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00116
         		116
    methyl 6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)
    phenoxy)nicotinate
    X = N, R2 = Et
    Figure US20210107863A2-20210415-C00117
         		117
    ethyl 6-(4-ethylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00118
         		118
    ethyl 6-(4-propylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00119
         		119
    ethyl 6-(4-butylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00120
         		120
    ethyl 6-(4-pentylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00121
         		121
    ethyl 6-(4-hexylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00122
         		122
    ethyl 6-(4-isopropylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00123
         		123
    ethyl 6-(4-(pentan-3-yl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00124
         		124
    ethyl 6-(4-(perfluoroethyl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00125
         		125
    ethyl 6-(4-(perfluoropropyl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00126
         		126
    ethyl 6-(4-(perfluorobutyl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00127
         		127
    ethyl 6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)
    nicotinate
    Figure US20210107863A2-20210415-C00128
         		128
    ethyl 6-(4-(perfluoropropan-2-yl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00129
         		129
    ethyl 6-(4-cyclopropylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00130
         		130
    ethyl 6-(4-cyclobutylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00131
         		131
    ethyl 6-(4-cyclopentylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00132
         		132
    ethyl 6-(4-cycloheptylphenoxy)nicotinate
    Figure US20210107863A2-20210415-C00133
         		133
    ethyl 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)
    nicotinate
    Figure US20210107863A2-20210415-C00134
         		134
    ethyl 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00135
         		135
    ethyl 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00136
         		136
    ethyl 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)nicotinate
    Figure US20210107863A2-20210415-C00137
         		137
    ethyl 6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)
    phenoxy)nicotinate
  • Also included are isomers, e.g. enantiomers or diastereomers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
  • A second aspect of the present invention relates to compounds of formula II and salts and solvates thereof:
  • Figure US20210107863A2-20210415-C00138
  • wherein X and R1 are defined as in formula I, including the preferred definition of R1,
  • R3═H, C1-C6 alkyl, or C3-C6 cycloalkyl,
  • wherein all alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • wherein all cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • wherein all alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated;
  • and wherein R3 is preferably H or methyl;
  • R4═H, C1-C6 alkyl, C3-C6 cycloalkyl, OH or OC1-C6 alkyl, wherein all alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • wherein all cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • wherein all alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated;
  • and wherein R4 is preferably H, OH or methyl.
  • In especially preferred embodiments, R3 and R4 are in each case H; H and OH; H and —CH3; or in each case —CH3.
  • In some embodiments, the following compounds shown in Table IIa are explicitly excluded from the scope of the invention:
  • TABLE IIa
    Compound R1 R3 R4 X
    II-A tert-butyl H H N
    II-B methyl H methyl CH
    II-C methyl methyl methyl CH
  • Compound II-A and II-B of Table IIa are known in the art for certain applications in the field of medicine whereas to the best of the inventor's knowledge, compound II-C is not known for any use in medicine. Thus, the invention encompasses any medical use for compound II-C.
  • Specific examples of compounds falling under the scope of formula II are shown in Table IIb. The compounds in Table IIb are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes.
  • TABLE IIb
    X = CH, R3 = H, R4 = H
    Figure US20210107863A2-20210415-C00139
         		138
    Figure US20210107863A2-20210415-C00140
         		139
    Figure US20210107863A2-20210415-C00141
         		140
    Figure US20210107863A2-20210415-C00142
         		141
    Figure US20210107863A2-20210415-C00143
         		142
    Figure US20210107863A2-20210415-C00144
         		143
    Figure US20210107863A2-20210415-C00145
         		144
    Figure US20210107863A2-20210415-C00146
         		145
    Figure US20210107863A2-20210415-C00147
         		146
    Figure US20210107863A2-20210415-C00148
         		147
    Figure US20210107863A2-20210415-C00149
         		148
    Figure US20210107863A2-20210415-C00150
         		149
    Figure US20210107863A2-20210415-C00151
         		150
    Figure US20210107863A2-20210415-C00152
         		151
    Figure US20210107863A2-20210415-C00153
         		152
    Figure US20210107863A2-20210415-C00154
         		153
    Figure US20210107863A2-20210415-C00155
         		154
    Figure US20210107863A2-20210415-C00156
         		155
    Figure US20210107863A2-20210415-C00157
         		156
    Figure US20210107863A2-20210415-C00158
         		157
    Figure US20210107863A2-20210415-C00159
         		158
    Figure US20210107863A2-20210415-C00160
         		159
    Figure US20210107863A2-20210415-C00161
         		160
    Figure US20210107863A2-20210415-C00162
         		161
    Figure US20210107863A2-20210415-C00163
         		162
    Figure US20210107863A2-20210415-C00164
         		163
    X = CH, R3 = H, R4 = OH
    Figure US20210107863A2-20210415-C00165
         		164
    Figure US20210107863A2-20210415-C00166
         		165
    Figure US20210107863A2-20210415-C00167
         		166
    Figure US20210107863A2-20210415-C00168
         		167
    Figure US20210107863A2-20210415-C00169
         		168
    Figure US20210107863A2-20210415-C00170
         		169
    Figure US20210107863A2-20210415-C00171
         		170
    Figure US20210107863A2-20210415-C00172
         		171
    Figure US20210107863A2-20210415-C00173
         		172
    Figure US20210107863A2-20210415-C00174
         		173
    Figure US20210107863A2-20210415-C00175
         		174
    Figure US20210107863A2-20210415-C00176
         		175
    Figure US20210107863A2-20210415-C00177
         		176
    Figure US20210107863A2-20210415-C00178
         		177
    Figure US20210107863A2-20210415-C00179
         		178
    Figure US20210107863A2-20210415-C00180
         		179
    Figure US20210107863A2-20210415-C00181
         		180
    Figure US20210107863A2-20210415-C00182
         		181
    Figure US20210107863A2-20210415-C00183
         		182
    Figure US20210107863A2-20210415-C00184
         		183
    Figure US20210107863A2-20210415-C00185
         		184
    Figure US20210107863A2-20210415-C00186
         		185
    Figure US20210107863A2-20210415-C00187
         		186
    Figure US20210107863A2-20210415-C00188
         		187
    Figure US20210107863A2-20210415-C00189
         		188
    X = CH, R3 = H, R4 = Me
    Figure US20210107863A2-20210415-C00190
         		189
    Figure US20210107863A2-20210415-C00191
         		190
    Figure US20210107863A2-20210415-C00192
         		191
    Figure US20210107863A2-20210415-C00193
         		192
    Figure US20210107863A2-20210415-C00194
         		193
    Figure US20210107863A2-20210415-C00195
         		194
    Figure US20210107863A2-20210415-C00196
         		195
    Figure US20210107863A2-20210415-C00197
         		196
    Figure US20210107863A2-20210415-C00198
         		197
    Figure US20210107863A2-20210415-C00199
         		198
    Figure US20210107863A2-20210415-C00200
         		199
    Figure US20210107863A2-20210415-C00201
         		200
    Figure US20210107863A2-20210415-C00202
         		201
    Figure US20210107863A2-20210415-C00203
         		202
    Figure US20210107863A2-20210415-C00204
         		203
    Figure US20210107863A2-20210415-C00205
         		204
    Figure US20210107863A2-20210415-C00206
         		205
    Figure US20210107863A2-20210415-C00207
         		206
    Figure US20210107863A2-20210415-C00208
         		207
    Figure US20210107863A2-20210415-C00209
         		208
    Figure US20210107863A2-20210415-C00210
         		209
    Figure US20210107863A2-20210415-C00211
         		210
    Figure US20210107863A2-20210415-C00212
         		211
    Figure US20210107863A2-20210415-C00213
         		212
    Figure US20210107863A2-20210415-C00214
         		213
    Figure US20210107863A2-20210415-C00215
         		214
    X = CH, R3 = Me, R4 = Me
    Figure US20210107863A2-20210415-C00216
         		215
    Figure US20210107863A2-20210415-C00217
         		216
    Figure US20210107863A2-20210415-C00218
         		217
    Figure US20210107863A2-20210415-C00219
         		218
    Figure US20210107863A2-20210415-C00220
         		219
    Figure US20210107863A2-20210415-C00221
         		220
    Figure US20210107863A2-20210415-C00222
         		221
    Figure US20210107863A2-20210415-C00223
         		222
    Figure US20210107863A2-20210415-C00224
         		223
    Figure US20210107863A2-20210415-C00225
         		224
    Figure US20210107863A2-20210415-C00226
         		225
    Figure US20210107863A2-20210415-C00227
         		226
    Figure US20210107863A2-20210415-C00228
         		227
    Figure US20210107863A2-20210415-C00229
         		228
    Figure US20210107863A2-20210415-C00230
         		229
    Figure US20210107863A2-20210415-C00231
         		230
    Figure US20210107863A2-20210415-C00232
         		231
    Figure US20210107863A2-20210415-C00233
         		232
    Figure US20210107863A2-20210415-C00234
         		233
    Figure US20210107863A2-20210415-C00235
         		234
    Figure US20210107863A2-20210415-C00236
         		235
    Figure US20210107863A2-20210415-C00237
         		236
    Figure US20210107863A2-20210415-C00238
         		237
    Figure US20210107863A2-20210415-C00239
         		238
    Figure US20210107863A2-20210415-C00240
         		239
    Figure US20210107863A2-20210415-C00241
         		240
    X = N, R3 = H, R4 = H
    Figure US20210107863A2-20210415-C00242
         		241
    Figure US20210107863A2-20210415-C00243
         		242
    Figure US20210107863A2-20210415-C00244
         		243
    Figure US20210107863A2-20210415-C00245
         		244
    Figure US20210107863A2-20210415-C00246
         		245
    Figure US20210107863A2-20210415-C00247
         		246
    Figure US20210107863A2-20210415-C00248
         		247
    Figure US20210107863A2-20210415-C00249
         		248
    Figure US20210107863A2-20210415-C00250
         		249
    Figure US20210107863A2-20210415-C00251
         		250
    Figure US20210107863A2-20210415-C00252
         		251
    Figure US20210107863A2-20210415-C00253
         		252
    Figure US20210107863A2-20210415-C00254
         		253
    Figure US20210107863A2-20210415-C00255
         		254
    Figure US20210107863A2-20210415-C00256
         		255
    Figure US20210107863A2-20210415-C00257
         		256
    Figure US20210107863A2-20210415-C00258
         		257
    Figure US20210107863A2-20210415-C00259
         		258
    Figure US20210107863A2-20210415-C00260
         		259
    Figure US20210107863A2-20210415-C00261
         		260
    Figure US20210107863A2-20210415-C00262
         		261
    Figure US20210107863A2-20210415-C00263
         		262
    Figure US20210107863A2-20210415-C00264
         		263
    Figure US20210107863A2-20210415-C00265
         		264
    Figure US20210107863A2-20210415-C00266
         		265
    X = N, R3 = H, R4 = OH
    Figure US20210107863A2-20210415-C00267
         		266
    Figure US20210107863A2-20210415-C00268
         		267
    Figure US20210107863A2-20210415-C00269
         		268
    Figure US20210107863A2-20210415-C00270
         		269
    Figure US20210107863A2-20210415-C00271
         		270
    Figure US20210107863A2-20210415-C00272
         		271
    Figure US20210107863A2-20210415-C00273
         		272
    Figure US20210107863A2-20210415-C00274
         		273
    Figure US20210107863A2-20210415-C00275
         		274
    Figure US20210107863A2-20210415-C00276
         		275
    Figure US20210107863A2-20210415-C00277
         		276
    Figure US20210107863A2-20210415-C00278
         		277
    Figure US20210107863A2-20210415-C00279
         		278
    Figure US20210107863A2-20210415-C00280
         		279
    Figure US20210107863A2-20210415-C00281
         		280
    Figure US20210107863A2-20210415-C00282
         		281
    Figure US20210107863A2-20210415-C00283
         		282
    Figure US20210107863A2-20210415-C00284
         		283
    Figure US20210107863A2-20210415-C00285
         		284
    Figure US20210107863A2-20210415-C00286
         		285
    Figure US20210107863A2-20210415-C00287
         		286
    Figure US20210107863A2-20210415-C00288
         		287
    Figure US20210107863A2-20210415-C00289
         		288
    Figure US20210107863A2-20210415-C00290
         		289
    Figure US20210107863A2-20210415-C00291
         		290
    X = N, R3 = H, R4 = Me
    Figure US20210107863A2-20210415-C00292
         		291
    Figure US20210107863A2-20210415-C00293
         		292
    Figure US20210107863A2-20210415-C00294
         		293
    Figure US20210107863A2-20210415-C00295
         		294
    Figure US20210107863A2-20210415-C00296
         		295
    Figure US20210107863A2-20210415-C00297
         		296
    Figure US20210107863A2-20210415-C00298
         		297
    Figure US20210107863A2-20210415-C00299
         		298
    Figure US20210107863A2-20210415-C00300
         		299
    Figure US20210107863A2-20210415-C00301
         		300
    Figure US20210107863A2-20210415-C00302
         		301
    Figure US20210107863A2-20210415-C00303
         		302
    Figure US20210107863A2-20210415-C00304
         		303
    Figure US20210107863A2-20210415-C00305
         		304
    Figure US20210107863A2-20210415-C00306
         		305
    Figure US20210107863A2-20210415-C00307
         		306
    Figure US20210107863A2-20210415-C00308
         		307
    Figure US20210107863A2-20210415-C00309
         		308
    Figure US20210107863A2-20210415-C00310
         		309
    Figure US20210107863A2-20210415-C00311
         		310
    Figure US20210107863A2-20210415-C00312
         		311
    Figure US20210107863A2-20210415-C00313
         		312
    Figure US20210107863A2-20210415-C00314
         		313
    Figure US20210107863A2-20210415-C00315
         		314
    Figure US20210107863A2-20210415-C00316
         		315
    X = N, R3 = Me, R4 = Me
    Figure US20210107863A2-20210415-C00317
         		316
    Figure US20210107863A2-20210415-C00318
         		317
    Figure US20210107863A2-20210415-C00319
         		318
    Figure US20210107863A2-20210415-C00320
         		319
    Figure US20210107863A2-20210415-C00321
         		320
    Figure US20210107863A2-20210415-C00322
         		321
    Figure US20210107863A2-20210415-C00323
         		322
    Figure US20210107863A2-20210415-C00324
         		323
    Figure US20210107863A2-20210415-C00325
         		324
    Figure US20210107863A2-20210415-C00326
         		325
    Figure US20210107863A2-20210415-C00327
         		326
    Figure US20210107863A2-20210415-C00328
         		327
    Figure US20210107863A2-20210415-C00329
         		328
    Figure US20210107863A2-20210415-C00330
         		329
    Figure US20210107863A2-20210415-C00331
         		330
    Figure US20210107863A2-20210415-C00332
         		331
    Figure US20210107863A2-20210415-C00333
         		332
    Figure US20210107863A2-20210415-C00334
         		333
    Figure US20210107863A2-20210415-C00335
         		334
    Figure US20210107863A2-20210415-C00336
         		335
    Figure US20210107863A2-20210415-C00337
         		336
    Figure US20210107863A2-20210415-C00338
         		337
    Figure US20210107863A2-20210415-C00339
         		338
    Figure US20210107863A2-20210415-C00340
         		339
    Figure US20210107863A2-20210415-C00341
         		340
    Figure US20210107863A2-20210415-C00342
  • Also included are isomers, e.g. enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
  • A third aspect of the present invention relates to compounds of formula III and salts and solvates thereof:
  • Figure US20210107863A2-20210415-C00343
  • wherein X, R1 and R2 are defined as in formula I, including the preferred definitions of R1 and R2.
  • In some embodiments, the following compounds shown in Table IIIa are explicitly excluded from the scope of the invention:
  • TABLE IIIa
    Compound R1 R2 X
    III-A tert-butyl H CH
    III-B tert-butyl ethyl CH
    III-C phenyl H CH
  • Specific examples of compounds falling under the scope of formula III are shown in Table IIIb. The compounds in Table IIIb are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes.
  • TABLE IIIb
    X = CH, R2 = H
    Figure US20210107863A2-20210415-C00344
         		341
    Figure US20210107863A2-20210415-C00345
         		342
    Figure US20210107863A2-20210415-C00346
         		343
    Figure US20210107863A2-20210415-C00347
         		344
    Figure US20210107863A2-20210415-C00348
         		345
    Figure US20210107863A2-20210415-C00349
         		346
    Figure US20210107863A2-20210415-C00350
         		347
    Figure US20210107863A2-20210415-C00351
         		348
    Figure US20210107863A2-20210415-C00352
         		349
    Figure US20210107863A2-20210415-C00353
         		350
    Figure US20210107863A2-20210415-C00354
         		351
    Figure US20210107863A2-20210415-C00355
         		352
    Figure US20210107863A2-20210415-C00356
         		353
    Figure US20210107863A2-20210415-C00357
         		354
    Figure US20210107863A2-20210415-C00358
         		355
    Figure US20210107863A2-20210415-C00359
         		356
    Figure US20210107863A2-20210415-C00360
         		357
    Figure US20210107863A2-20210415-C00361
         		358
    Figure US20210107863A2-20210415-C00362
         		359
    Figure US20210107863A2-20210415-C00363
         		360
    Figure US20210107863A2-20210415-C00364
         		361
    Figure US20210107863A2-20210415-C00365
         		362
    Figure US20210107863A2-20210415-C00366
         		363
    Figure US20210107863A2-20210415-C00367
         		364
    Figure US20210107863A2-20210415-C00368
         		365
    X = CH, R2 = Me
    Figure US20210107863A2-20210415-C00369
         		366
    Figure US20210107863A2-20210415-C00370
         		367
    Figure US20210107863A2-20210415-C00371
         		368
    Figure US20210107863A2-20210415-C00372
         		369
    Figure US20210107863A2-20210415-C00373
         		370
    Figure US20210107863A2-20210415-C00374
         		371
    Figure US20210107863A2-20210415-C00375
         		372
    Figure US20210107863A2-20210415-C00376
         		373
    Figure US20210107863A2-20210415-C00377
         		374
    Figure US20210107863A2-20210415-C00378
         		375
    Figure US20210107863A2-20210415-C00379
         		376
    Figure US20210107863A2-20210415-C00380
         		377
    Figure US20210107863A2-20210415-C00381
         		378
    Figure US20210107863A2-20210415-C00382
         		379
    Figure US20210107863A2-20210415-C00383
         		380
    Figure US20210107863A2-20210415-C00384
         		381
    Figure US20210107863A2-20210415-C00385
         		382
    Figure US20210107863A2-20210415-C00386
         		383
    Figure US20210107863A2-20210415-C00387
         		384
    Figure US20210107863A2-20210415-C00388
         		385
    Figure US20210107863A2-20210415-C00389
         		386
    Figure US20210107863A2-20210415-C00390
         		387
    Figure US20210107863A2-20210415-C00391
         		388
    Figure US20210107863A2-20210415-C00392
         		389
    Figure US20210107863A2-20210415-C00393
         		390
    Figure US20210107863A2-20210415-C00394
         		391
    X = CH, R2 = Et
    Figure US20210107863A2-20210415-C00395
         		392
    Figure US20210107863A2-20210415-C00396
         		393
    Figure US20210107863A2-20210415-C00397
         		394
    Figure US20210107863A2-20210415-C00398
         		395
    Figure US20210107863A2-20210415-C00399
         		396
    Figure US20210107863A2-20210415-C00400
         		397
    Figure US20210107863A2-20210415-C00401
         		398
    Figure US20210107863A2-20210415-C00402
         		399
    Figure US20210107863A2-20210415-C00403
         		400
    Figure US20210107863A2-20210415-C00404
         		401
    Figure US20210107863A2-20210415-C00405
         		402
    Figure US20210107863A2-20210415-C00406
         		403
    Figure US20210107863A2-20210415-C00407
         		404
    Figure US20210107863A2-20210415-C00408
         		405
    Figure US20210107863A2-20210415-C00409
         		406
    Figure US20210107863A2-20210415-C00410
         		407
    Figure US20210107863A2-20210415-C00411
         		408
    Figure US20210107863A2-20210415-C00412
         		409
    Figure US20210107863A2-20210415-C00413
         		410
    Figure US20210107863A2-20210415-C00414
         		411
    Figure US20210107863A2-20210415-C00415
         		412
    Figure US20210107863A2-20210415-C00416
         		413
    Figure US20210107863A2-20210415-C00417
         		414
    Figure US20210107863A2-20210415-C00418
         		415
    Figure US20210107863A2-20210415-C00419
         		416
    X = N, R2 = H
    Figure US20210107863A2-20210415-C00420
         		417
    Figure US20210107863A2-20210415-C00421
         		418
    Figure US20210107863A2-20210415-C00422
         		419
    Figure US20210107863A2-20210415-C00423
         		420
    Figure US20210107863A2-20210415-C00424
         		421
    Figure US20210107863A2-20210415-C00425
         		422
    Figure US20210107863A2-20210415-C00426
         		423
    Figure US20210107863A2-20210415-C00427
         		424
    Figure US20210107863A2-20210415-C00428
         		425
    Figure US20210107863A2-20210415-C00429
         		426
    Figure US20210107863A2-20210415-C00430
         		427
    Figure US20210107863A2-20210415-C00431
         		428
    Figure US20210107863A2-20210415-C00432
         		429
    Figure US20210107863A2-20210415-C00433
         		430
    Figure US20210107863A2-20210415-C00434
         		431
    Figure US20210107863A2-20210415-C00435
         		432
    Figure US20210107863A2-20210415-C00436
         		433
    Figure US20210107863A2-20210415-C00437
         		434
    Figure US20210107863A2-20210415-C00438
         		435
    Figure US20210107863A2-20210415-C00439
         		436
    Figure US20210107863A2-20210415-C00440
         		437
    Figure US20210107863A2-20210415-C00441
         		438
    Figure US20210107863A2-20210415-C00442
         		439
    Figure US20210107863A2-20210415-C00443
         		440
    Figure US20210107863A2-20210415-C00444
         		441
    Figure US20210107863A2-20210415-C00445
         		442
    X = N, R2 = Me
    Figure US20210107863A2-20210415-C00446
         		443
    Figure US20210107863A2-20210415-C00447
         		444
    Figure US20210107863A2-20210415-C00448
         		445
    Figure US20210107863A2-20210415-C00449
         		446
    Figure US20210107863A2-20210415-C00450
         		447
    Figure US20210107863A2-20210415-C00451
         		448
    Figure US20210107863A2-20210415-C00452
         		449
    Figure US20210107863A2-20210415-C00453
         		450
    Figure US20210107863A2-20210415-C00454
         		451
    Figure US20210107863A2-20210415-C00455
         		452
    Figure US20210107863A2-20210415-C00456
         		453
    Figure US20210107863A2-20210415-C00457
         		454
    Figure US20210107863A2-20210415-C00458
         		455
    Figure US20210107863A2-20210415-C00459
         		456
    Figure US20210107863A2-20210415-C00460
         		457
    Figure US20210107863A2-20210415-C00461
         		458
    Figure US20210107863A2-20210415-C00462
         		459
    Figure US20210107863A2-20210415-C00463
         		460
    Figure US20210107863A2-20210415-C00464
         		461
    Figure US20210107863A2-20210415-C00465
         		462
    Figure US20210107863A2-20210415-C00466
         		463
    Figure US20210107863A2-20210415-C00467
         		464
    Figure US20210107863A2-20210415-C00468
         		465
    Figure US20210107863A2-20210415-C00469
         		466
    Figure US20210107863A2-20210415-C00470
         		467
    Figure US20210107863A2-20210415-C00471
         		468
    X = N, R2 = Et
    Figure US20210107863A2-20210415-C00472
         		469
    Figure US20210107863A2-20210415-C00473
         		470
    Figure US20210107863A2-20210415-C00474
         		471
    Figure US20210107863A2-20210415-C00475
         		472
    Figure US20210107863A2-20210415-C00476
         		473
    Figure US20210107863A2-20210415-C00477
         		474
    Figure US20210107863A2-20210415-C00478
         		475
    Figure US20210107863A2-20210415-C00479
         		476
    Figure US20210107863A2-20210415-C00480
         		477
    Figure US20210107863A2-20210415-C00481
         		478
    Figure US20210107863A2-20210415-C00482
         		479
    Figure US20210107863A2-20210415-C00483
         		480
    Figure US20210107863A2-20210415-C00484
         		481
    Figure US20210107863A2-20210415-C00485
         		482
    Figure US20210107863A2-20210415-C00486
         		483
    Figure US20210107863A2-20210415-C00487
         		484
    Figure US20210107863A2-20210415-C00488
         		485
    Figure US20210107863A2-20210415-C00489
         		486
    Figure US20210107863A2-20210415-C00490
         		487
    Figure US20210107863A2-20210415-C00491
         		488
    Figure US20210107863A2-20210415-C00492
         		489
    Figure US20210107863A2-20210415-C00493
         		490
    Figure US20210107863A2-20210415-C00494
         		491
    Figure US20210107863A2-20210415-C00495
         		492
    Figure US20210107863A2-20210415-C00496
         		493
    Figure US20210107863A2-20210415-C00497
         		494
  • Also included are isomers, e.g. enantiomers or diastereomers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
  • A fourth aspect of the present invention relates to compounds of formula IV and salts and solvates thereof:
  • Figure US20210107863A2-20210415-C00498
  • wherein X and R1 are defined as in formula I, including the preferred definition of R1,
  • and R3 and R4 are defined as in formula II, including the preferred definitions of R3 and R4.
  • Specific examples of compounds falling under the scope of formula IV are shown in Table IV. The compounds in Table IV are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes.
  • TABLE IV
    X = CH, R3 = H, R4 = H
    Figure US20210107863A2-20210415-C00499
         		495
    Figure US20210107863A2-20210415-C00500
         		496
    Figure US20210107863A2-20210415-C00501
         		497
    Figure US20210107863A2-20210415-C00502
         		498
    Figure US20210107863A2-20210415-C00503
         		499
    Figure US20210107863A2-20210415-C00504
         		500
    Figure US20210107863A2-20210415-C00505
         		501
    Figure US20210107863A2-20210415-C00506
         		502
    Figure US20210107863A2-20210415-C00507
         		503
    Figure US20210107863A2-20210415-C00508
         		504
    Figure US20210107863A2-20210415-C00509
         		505
    Figure US20210107863A2-20210415-C00510
         		506
    Figure US20210107863A2-20210415-C00511
         		507
    Figure US20210107863A2-20210415-C00512
         		508
    Figure US20210107863A2-20210415-C00513
         		509
    Figure US20210107863A2-20210415-C00514
         		510
    Figure US20210107863A2-20210415-C00515
         		511
    Figure US20210107863A2-20210415-C00516
         		512
    Figure US20210107863A2-20210415-C00517
         		513
    Figure US20210107863A2-20210415-C00518
         		514
    Figure US20210107863A2-20210415-C00519
         		515
    Figure US20210107863A2-20210415-C00520
         		516
    Figure US20210107863A2-20210415-C00521
         		517
    Figure US20210107863A2-20210415-C00522
         		518
    Figure US20210107863A2-20210415-C00523
         		519
    Figure US20210107863A2-20210415-C00524
         		520
    X = CH, R3 = H, R4 = OH
    Figure US20210107863A2-20210415-C00525
         		521
    Figure US20210107863A2-20210415-C00526
         		522
    Figure US20210107863A2-20210415-C00527
         		523
    Figure US20210107863A2-20210415-C00528
         		524
    Figure US20210107863A2-20210415-C00529
         		525
    Figure US20210107863A2-20210415-C00530
         		526
    Figure US20210107863A2-20210415-C00531
         		527
    Figure US20210107863A2-20210415-C00532
         		528
    Figure US20210107863A2-20210415-C00533
         		529
    Figure US20210107863A2-20210415-C00534
         		530
    Figure US20210107863A2-20210415-C00535
         		531
    Figure US20210107863A2-20210415-C00536
         		532
    Figure US20210107863A2-20210415-C00537
         		533
    Figure US20210107863A2-20210415-C00538
         		534
    Figure US20210107863A2-20210415-C00539
         		535
    Figure US20210107863A2-20210415-C00540
         		536
    Figure US20210107863A2-20210415-C00541
         		537
    Figure US20210107863A2-20210415-C00542
         		538
    Figure US20210107863A2-20210415-C00543
         		539
    Figure US20210107863A2-20210415-C00544
         		540
    Figure US20210107863A2-20210415-C00545
         		541
    Figure US20210107863A2-20210415-C00546
         		542
    Figure US20210107863A2-20210415-C00547
         		543
    Figure US20210107863A2-20210415-C00548
         		544
    Figure US20210107863A2-20210415-C00549
         		545
    Figure US20210107863A2-20210415-C00550
         		546
    X = CH, R3 = H, R4 = Me
    Figure US20210107863A2-20210415-C00551
         		547
    Figure US20210107863A2-20210415-C00552
         		548
    Figure US20210107863A2-20210415-C00553
         		549
    Figure US20210107863A2-20210415-C00554
         		550
    Figure US20210107863A2-20210415-C00555
         		551
    Figure US20210107863A2-20210415-C00556
         		552
    Figure US20210107863A2-20210415-C00557
         		553
    Figure US20210107863A2-20210415-C00558
         		554
    Figure US20210107863A2-20210415-C00559
         		555
    Figure US20210107863A2-20210415-C00560
         		556
    Figure US20210107863A2-20210415-C00561
         		557
    Figure US20210107863A2-20210415-C00562
         		558
    Figure US20210107863A2-20210415-C00563
         		559
    Figure US20210107863A2-20210415-C00564
         		560
    Figure US20210107863A2-20210415-C00565
         		561
    Figure US20210107863A2-20210415-C00566
         		562
    Figure US20210107863A2-20210415-C00567
         		563
    Figure US20210107863A2-20210415-C00568
         		564
    Figure US20210107863A2-20210415-C00569
         		565
    Figure US20210107863A2-20210415-C00570
         		566
    Figure US20210107863A2-20210415-C00571
         		567
    Figure US20210107863A2-20210415-C00572
         		568
    Figure US20210107863A2-20210415-C00573
         		569
    Figure US20210107863A2-20210415-C00574
         		570
    Figure US20210107863A2-20210415-C00575
         		571
    Figure US20210107863A2-20210415-C00576
         		572
    X = CH, R3 = Me, R4 = Me
    Figure US20210107863A2-20210415-C00577
         		573
    Figure US20210107863A2-20210415-C00578
         		574
    Figure US20210107863A2-20210415-C00579
         		575
    Figure US20210107863A2-20210415-C00580
         		576
    Figure US20210107863A2-20210415-C00581
         		577
    Figure US20210107863A2-20210415-C00582
         		578
    Figure US20210107863A2-20210415-C00583
         		579
    Figure US20210107863A2-20210415-C00584
         		580
    Figure US20210107863A2-20210415-C00585
         		581
    Figure US20210107863A2-20210415-C00586
         		582
    Figure US20210107863A2-20210415-C00587
         		583
    Figure US20210107863A2-20210415-C00588
         		584
    Figure US20210107863A2-20210415-C00589
         		585
    Figure US20210107863A2-20210415-C00590
         		586
    Figure US20210107863A2-20210415-C00591
         		587
    Figure US20210107863A2-20210415-C00592
         		588
    Figure US20210107863A2-20210415-C00593
         		589
    Figure US20210107863A2-20210415-C00594
         		590
    Figure US20210107863A2-20210415-C00595
         		591
    Figure US20210107863A2-20210415-C00596
         		592
    Figure US20210107863A2-20210415-C00597
         		593
    Figure US20210107863A2-20210415-C00598
         		594
    Figure US20210107863A2-20210415-C00599
         		595
    Figure US20210107863A2-20210415-C00600
         		596
    Figure US20210107863A2-20210415-C00601
         		597
    Figure US20210107863A2-20210415-C00602
         		598
    X = N, R3 = H, R4 = H
    Figure US20210107863A2-20210415-C00603
         		599
    Figure US20210107863A2-20210415-C00604
         		600
    Figure US20210107863A2-20210415-C00605
         		601
    Figure US20210107863A2-20210415-C00606
         		602
    Figure US20210107863A2-20210415-C00607
         		603
    Figure US20210107863A2-20210415-C00608
         		604
    Figure US20210107863A2-20210415-C00609
         		605
    Figure US20210107863A2-20210415-C00610
         		606
    Figure US20210107863A2-20210415-C00611
         		607
    Figure US20210107863A2-20210415-C00612
         		608
    Figure US20210107863A2-20210415-C00613
         		609
    Figure US20210107863A2-20210415-C00614
         		610
    Figure US20210107863A2-20210415-C00615
         		611
    Figure US20210107863A2-20210415-C00616
         		612
    Figure US20210107863A2-20210415-C00617
         		613
    Figure US20210107863A2-20210415-C00618
         		614
    Figure US20210107863A2-20210415-C00619
         		615
    Figure US20210107863A2-20210415-C00620
         		616
    Figure US20210107863A2-20210415-C00621
         		617
    Figure US20210107863A2-20210415-C00622
         		618
    Figure US20210107863A2-20210415-C00623
         		619
    Figure US20210107863A2-20210415-C00624
         		620
    Figure US20210107863A2-20210415-C00625
         		621
    Figure US20210107863A2-20210415-C00626
         		622
    Figure US20210107863A2-20210415-C00627
         		623
    Figure US20210107863A2-20210415-C00628
         		624
    X = N, R3 = H, R4 = OH
    Figure US20210107863A2-20210415-C00629
         		625
    Figure US20210107863A2-20210415-C00630
         		626
    Figure US20210107863A2-20210415-C00631
         		627
    Figure US20210107863A2-20210415-C00632
         		628
    Figure US20210107863A2-20210415-C00633
         		629
    Figure US20210107863A2-20210415-C00634
         		630
    Figure US20210107863A2-20210415-C00635
         		631
    Figure US20210107863A2-20210415-C00636
         		632
    Figure US20210107863A2-20210415-C00637
         		633
    Figure US20210107863A2-20210415-C00638
         		634
    Figure US20210107863A2-20210415-C00639
         		635
    Figure US20210107863A2-20210415-C00640
         		636
    Figure US20210107863A2-20210415-C00641
         		637
    Figure US20210107863A2-20210415-C00642
         		638
    Figure US20210107863A2-20210415-C00643
         		639
    Figure US20210107863A2-20210415-C00644
         		640
    Figure US20210107863A2-20210415-C00645
         		641
    Figure US20210107863A2-20210415-C00646
         		642
    Figure US20210107863A2-20210415-C00647
         		643
    Figure US20210107863A2-20210415-C00648
         		644
    Figure US20210107863A2-20210415-C00649
         		645
    Figure US20210107863A2-20210415-C00650
         		646
    Figure US20210107863A2-20210415-C00651
         		647
    Figure US20210107863A2-20210415-C00652
         		648
    Figure US20210107863A2-20210415-C00653
         		649
    Figure US20210107863A2-20210415-C00654
         		650
    X = N, R3 = H, R4 = Me
    Figure US20210107863A2-20210415-C00655
         		651
    Figure US20210107863A2-20210415-C00656
         		652
    Figure US20210107863A2-20210415-C00657
         		653
    Figure US20210107863A2-20210415-C00658
         		654
    Figure US20210107863A2-20210415-C00659
         		655
    Figure US20210107863A2-20210415-C00660
         		656
    Figure US20210107863A2-20210415-C00661
         		657
    Figure US20210107863A2-20210415-C00662
         		658
    Figure US20210107863A2-20210415-C00663
         		659
    Figure US20210107863A2-20210415-C00664
         		660
    Figure US20210107863A2-20210415-C00665
         		661
    Figure US20210107863A2-20210415-C00666
         		662
    Figure US20210107863A2-20210415-C00667
         		663
    Figure US20210107863A2-20210415-C00668
         		664
    Figure US20210107863A2-20210415-C00669
         		665
    Figure US20210107863A2-20210415-C00670
         		666
    Figure US20210107863A2-20210415-C00671
         		667
    Figure US20210107863A2-20210415-C00672
         		668
    Figure US20210107863A2-20210415-C00673
         		669
    Figure US20210107863A2-20210415-C00674
         		670
    Figure US20210107863A2-20210415-C00675
         		671
    Figure US20210107863A2-20210415-C00676
         		672
    Figure US20210107863A2-20210415-C00677
         		673
    Figure US20210107863A2-20210415-C00678
         		674
    Figure US20210107863A2-20210415-C00679
         		675
    Figure US20210107863A2-20210415-C00680
         		676
    X = N, R3 = Me, R4 = Me
    Figure US20210107863A2-20210415-C00681
         		677
    Figure US20210107863A2-20210415-C00682
         		678
    Figure US20210107863A2-20210415-C00683
         		679
    Figure US20210107863A2-20210415-C00684
         		680
    Figure US20210107863A2-20210415-C00685
         		681
    Figure US20210107863A2-20210415-C00686
         		682
    Figure US20210107863A2-20210415-C00687
         		683
    Figure US20210107863A2-20210415-C00688
         		684
    Figure US20210107863A2-20210415-C00689
         		685
    Figure US20210107863A2-20210415-C00690
         		686
    Figure US20210107863A2-20210415-C00691
         		687
    Figure US20210107863A2-20210415-C00692
         		688
    Figure US20210107863A2-20210415-C00693
         		689
    Figure US20210107863A2-20210415-C00694
         		690
    Figure US20210107863A2-20210415-C00695
         		691
    Figure US20210107863A2-20210415-C00696
         		692
    Figure US20210107863A2-20210415-C00697
         		693
    Figure US20210107863A2-20210415-C00698
         		694
    Figure US20210107863A2-20210415-C00699
         		695
    Figure US20210107863A2-20210415-C00700
         		696
    Figure US20210107863A2-20210415-C00701
         		697
    Figure US20210107863A2-20210415-C00702
         		698
    Figure US20210107863A2-20210415-C00703
         		699
    Figure US20210107863A2-20210415-C00704
         		700
    Figure US20210107863A2-20210415-C00705
         		701
    Figure US20210107863A2-20210415-C00706
         		702
    Figure US20210107863A2-20210415-C00707
  • Also included are isomers, e.g. enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
  • A fifth aspect of the present invention relates to compounds of formula V and salts and solvates thereof:
  • Figure US20210107863A2-20210415-C00708
  • wherein n=0-5, which comprises cyclopropyl (n=0), cyclobutyl (n=1), cyclopentyl (n=2), cyclohexyl (n=3), cycloheptyl (n=4) and cyclooctyl (n=5),
  • wherein the said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • wherein the said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups can be perhalogenated, particularly perfluorinated;
  • and wherein n is preferably 0 as constituting cyclopropyl, particularly as constituting cyclopropyl being unsubstituted;
  • R5═C1-C12 preferably C1-C6 alkyl, C2-C12 preferably C2-C6 alkenyl, C2-C12 preferably C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl,
  • wherein all alkyl, alkenyl and alkynyl residues can be linear or branched, and are perhalogenated, particularly perfluorinated,
  • and wherein all cycloalkyl and cycloalkenyl residues are perhalogenated, particularly perfluorinated;
  • or wherein all alkyl, alkenyl and alkynyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • and wherein all cycloalkyl and cycloalkenyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • wherein R5 is preferably —CF3 or —CF2CF3;
  • R6-R9 are independently from each other selected from —H, —F, —Cl, —Br, —I, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 cycloalkyl, and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • wherein R6-R8 each are preferably H, and R9 is preferably —H, —F, —Cl, or —CH3;
  • Y=a six-membered aromatic ring selected from benzene, pyridine, pyrimidine, pyridazine or pyrazine;
  • wherein the benzene ring is not substituted, or it is substituted with one to four of the substituents independently selected from R10-R13,
  • and wherein the pyridine ring is not substituted, or it is substituted at the carbon positions with one to three of the substituents independently selected from R10-R12, and wherein preferably the N-atom of the pyridine ring is in ortho-position relative to the ether bond,
  • and wherein the pyrimidine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R10-R11, and wherein preferably an N-atom of the pyrimidine ring is in ortho-position relative to the ether bond,
  • and wherein the pyridazine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R10-R11, and wherein preferably an N-atom of the pyridazine ring is in ortho-position relative to the ether bond,
  • and wherein the pyrazine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R10-R11, and wherein preferably an N-atom of the pyrazine ring is in ortho-position relative to the ether bond,
  • wherein preferably Y=benzene or pyridine being not substituted with any of the residues selected from R10-R13, or being substituted with one of the substituents selected from R10-R13 being F at the carbon atom in ortho-position relative to the ether bond;
  • R10-R13 are independently from each other selected from —F, —Cl, —Br, —I, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 cycloalkyl, and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
  • Z═O or S, and preferably Z═O;
  • R14═OR2 or NR3R4
  • wherein R2 is defined as in formula I including the preferred definition of R2 as H, methyl or ethyl;
  • wherein R3 and R4 are defined as in formula II, including the preferred definitions of R3 as H or —CH3 and R4 as H, OH or —CH3;
  • In a particularly preferred embodiment of the compounds of formula V, the present invention relates to compounds of formula Va and salts and solvates thereof:
  • Figure US20210107863A2-20210415-C00709
  • wherein n is defined as in formula V, including the preferred definition of n being n=0 as constituting cyclopropyl, particularly as constituting cyclopropyl being unsubstituted,
  • wherein Z is defined as in formula V, including the preferred definition of Z as Z═O,
  • wherein R5 is defined as in formula V, including all preferred definitions of R5,
  • R6-R9 are defined as in formula V, including all preferred definitions of R6-R9,
  • wherein R14 is defined as in formula V,
  • wherein X is N or CR13,
  • and wherein R10-R13 are independently from each other selected from —H, —F, —Cl, —Br, —I, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 cycloalkyl, and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated.
  • Specific examples of compounds falling under the scope of formula V are shown in Table V. The compounds in Table V are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes.
  • TABLE V
    Figure US20210107863A2-20210415-C00710
         		703
    Figure US20210107863A2-20210415-C00711
         		704
    Figure US20210107863A2-20210415-C00712
         		705
    Figure US20210107863A2-20210415-C00713
         		706
    Figure US20210107863A2-20210415-C00714
         		707
    Figure US20210107863A2-20210415-C00715
         		708
    Figure US20210107863A2-20210415-C00716
         		709
    Figure US20210107863A2-20210415-C00717
         		710
    Figure US20210107863A2-20210415-C00718
         		711
    Figure US20210107863A2-20210415-C00719
         		712
    Figure US20210107863A2-20210415-C00720
         		713
    Figure US20210107863A2-20210415-C00721
         		714
    Figure US20210107863A2-20210415-C00722
         		715
    Figure US20210107863A2-20210415-C00723
         		716
    Figure US20210107863A2-20210415-C00724
         		717
    Figure US20210107863A2-20210415-C00725
         		718
    Figure US20210107863A2-20210415-C00726
         		719
    Figure US20210107863A2-20210415-C00727
         		720
    Figure US20210107863A2-20210415-C00728
         		721
    Figure US20210107863A2-20210415-C00729
         		722
    Figure US20210107863A2-20210415-C00730
         		723
    Figure US20210107863A2-20210415-C00731
         		724
    Figure US20210107863A2-20210415-C00732
         		725
    Figure US20210107863A2-20210415-C00733
         		726
    Figure US20210107863A2-20210415-C00734
         		727
    Figure US20210107863A2-20210415-C00735
         		728
    Figure US20210107863A2-20210415-C00736
         		729
    Figure US20210107863A2-20210415-C00737
         		730
    Figure US20210107863A2-20210415-C00738
         		731
    Figure US20210107863A2-20210415-C00739
         		732
    Figure US20210107863A2-20210415-C00740
         		733
    Figure US20210107863A2-20210415-C00741
         		734
    Figure US20210107863A2-20210415-C00742
         		735
    Figure US20210107863A2-20210415-C00743
         		736
    Figure US20210107863A2-20210415-C00744
         		737
    Figure US20210107863A2-20210415-C00745
         		738
    Figure US20210107863A2-20210415-C00746
         		739
    Figure US20210107863A2-20210415-C00747
         		740
    Figure US20210107863A2-20210415-C00748
         		741
    Figure US20210107863A2-20210415-C00749
         		742
    Figure US20210107863A2-20210415-C00750
         		743
    Figure US20210107863A2-20210415-C00751
         		744
    Figure US20210107863A2-20210415-C00752
         		745
    Figure US20210107863A2-20210415-C00753
         		746
    Figure US20210107863A2-20210415-C00754
         		747
    Figure US20210107863A2-20210415-C00755
         		748
    Figure US20210107863A2-20210415-C00756
         		749
    Figure US20210107863A2-20210415-C00757
         		750
    Figure US20210107863A2-20210415-C00758
         		751
    Figure US20210107863A2-20210415-C00759
         		752
    Figure US20210107863A2-20210415-C00760
         		753
    Figure US20210107863A2-20210415-C00761
         		754
    Figure US20210107863A2-20210415-C00762
         		755
    Figure US20210107863A2-20210415-C00763
         		756
    Figure US20210107863A2-20210415-C00764
         		757
    Figure US20210107863A2-20210415-C00765
         		758
    Figure US20210107863A2-20210415-C00766
         		759
    Figure US20210107863A2-20210415-C00767
         		760
    Figure US20210107863A2-20210415-C00768
         		761
    Figure US20210107863A2-20210415-C00769
         		762
    Figure US20210107863A2-20210415-C00770
         		763
    Figure US20210107863A2-20210415-C00771
         		764
    Figure US20210107863A2-20210415-C00772
         		765
    Figure US20210107863A2-20210415-C00773
         		766
    Figure US20210107863A2-20210415-C00774
         		767
    Figure US20210107863A2-20210415-C00775
         		768
    Figure US20210107863A2-20210415-C00776
         		769
    Figure US20210107863A2-20210415-C00777
         		770
    Figure US20210107863A2-20210415-C00778
         		771
    Figure US20210107863A2-20210415-C00779
         		772
    Figure US20210107863A2-20210415-C00780
         		773
    Figure US20210107863A2-20210415-C00781
         		774
    Figure US20210107863A2-20210415-C00782
         		775
    Figure US20210107863A2-20210415-C00783
         		776
    Figure US20210107863A2-20210415-C00784
         		777
    Figure US20210107863A2-20210415-C00785
         		778
    Figure US20210107863A2-20210415-C00786
         		779
    Figure US20210107863A2-20210415-C00787
         		780
    Figure US20210107863A2-20210415-C00788
         		781
    Figure US20210107863A2-20210415-C00789
         		782
    Figure US20210107863A2-20210415-C00790
         		783
    Figure US20210107863A2-20210415-C00791
         		784
    Figure US20210107863A2-20210415-C00792
         		785
    Figure US20210107863A2-20210415-C00793
         		786
    Figure US20210107863A2-20210415-C00794
         		787
    Figure US20210107863A2-20210415-C00795
         		788
    Figure US20210107863A2-20210415-C00796
         		789
    Figure US20210107863A2-20210415-C00797
         		790
    Figure US20210107863A2-20210415-C00798
         		791
    Figure US20210107863A2-20210415-C00799
         		792
    Figure US20210107863A2-20210415-C00800
         		793
    Figure US20210107863A2-20210415-C00801
         		794
    Figure US20210107863A2-20210415-C00802
         		795
    Figure US20210107863A2-20210415-C00803
         		796
    Figure US20210107863A2-20210415-C00804
         		797
    Figure US20210107863A2-20210415-C00805
         		798
    Figure US20210107863A2-20210415-C00806
         		799
    Figure US20210107863A2-20210415-C00807
         		800
    Figure US20210107863A2-20210415-C00808
         		801
    Figure US20210107863A2-20210415-C00809
         		802
    Figure US20210107863A2-20210415-C00810
         		803
    Figure US20210107863A2-20210415-C00811
         		804
    Figure US20210107863A2-20210415-C00812
         		805
    Figure US20210107863A2-20210415-C00813
         		806
    Figure US20210107863A2-20210415-C00814
         		807
    Figure US20210107863A2-20210415-C00815
         		808
    Figure US20210107863A2-20210415-C00816
         		809
    Figure US20210107863A2-20210415-C00817
         		810
    Figure US20210107863A2-20210415-C00818
         		811
    Figure US20210107863A2-20210415-C00819
         		812
    Figure US20210107863A2-20210415-C00820
         		813
    Figure US20210107863A2-20210415-C00821
         		814
    Figure US20210107863A2-20210415-C00822
         		815
    Figure US20210107863A2-20210415-C00823
         		816
    Figure US20210107863A2-20210415-C00824
         		817
    Figure US20210107863A2-20210415-C00825
         		818
    Figure US20210107863A2-20210415-C00826
         		819
    Figure US20210107863A2-20210415-C00827
         		820
    Figure US20210107863A2-20210415-C00828
         		821
    Figure US20210107863A2-20210415-C00829
         		822
    Figure US20210107863A2-20210415-C00830
         		823
    Figure US20210107863A2-20210415-C00831
         		824
    Figure US20210107863A2-20210415-C00832
         		825
    Figure US20210107863A2-20210415-C00833
         		826
    Figure US20210107863A2-20210415-C00834
         		827
    Figure US20210107863A2-20210415-C00835
         		828
  • Also included are isomers, e.g. enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
    • Further Definitions
  • The term “C1-C12 alkyl” comprises all isomers of the corresponding saturated aliphatic hydrocarbon groups containing one to twelve carbon atoms; this includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methylbutyl, iso-pentyl, 2-methylbut-2-yl, 3-methylbut-2-yl, all hexyl-isomers, all heptyl-isomers, all octyl-isomers, all nonyl-isomers, all decyl-isomers, all undecyl-isomers and all dodecyl-isomers.
  • The term “C2-C12 alkenyl” comprises all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing two to twelve carbon atoms linked by one or more double bonds; this includes vinyl, all propenyl-isomers, all butenyl-isomers, all pentenyl-isomers, all hexenyl-isomers, all heptenyl-isomers, all octenyl-isomers, all nonenyl-isomers, all decenyl-isomers, all undecenyl-isomers and all dodecenyl-isomers.
  • The term “C2-C12 alkynyl” comprises all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing two to twelve carbon atoms linked by one or more triple bonds; this includes ethynyl, all propynyl-isomers, all butynyl-isomers, all pentynyl-isomers, all hexynyl-isomers, all heptynyl-isomers, all octynyl-isomers, all nonynyl-isomers, all decynyl-isomers, all undecynyl-isomers and all dodecynyl-isomers. The term “alkynyl” also includes compounds having one or more triple bonds and one or more double bonds.
  • The term “C3-C8 cycloalkyl” comprises the corresponding saturated hydrocarbon groups containing three to eight carbon atoms arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
  • The term “C3-C8 cycloalkenyl” comprises the corresponding unsaturated non-aromatic, anti-aromatic or aromatic hydrocarbon groups containing three to eight carbon atoms arranged in a monocyclic ring structure and linked by one or more double bonds; this includes cyclopropenyl, all cyclobutenyl-isomers, all cyclopentenyl-isomers, all cyclohexenyl-isomers, all cycloheptenyl-isomers, all cyclooctenyl-isomers.
  • The term “C4-C12 bicycloalkyl” comprises the corresponding saturated hydrocarbon groups containing four to twelve carbon atoms arranged in a bicyclic ring structure;
  • The term “C6-C12 bicycloalkenyl” comprises the corresponding unsaturated hydrocarbon groups containing six to twelve carbon atoms arranged in a bicyclic ring structure and linked by one or more double bonds;
  • The term “C5-C14 tricycloalkyl” comprises the corresponding saturated hydrocarbon groups containing five to fourteen carbon atoms arranged in a tricyclic ring structure;
  • The term “perhalogenated” relates to the exhaustive halogenation of the carbon scaffold; according residues comprise the corresponding perfluorinated, perchlorinated, perbrominated and periodinated groups. Preferably, the term “perhalogenated” relates to perfluorinated or perchlorinated groups, more preferably to perfluorinated groups.
  • The following contains definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
  • The compounds of the present invention may form salts, which are also within the scope of this invention. Reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterions (internal or inner salts) are included within the term “salt(s)” as used herein (and may be formed, for example, where the substituents comprise an acid moiety such as a carboxyl group). Also included herein are quaternary ammonium salts such as alkylammonium salts. Salts of the compounds may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
  • Exemplary basic salts (formed, for example, where the substituents comprise an acidic moiety such as a carboxyl group) include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, tert-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
  • The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science 1977, 66 (2), each of which is incorporated herein by reference in its entirety.
  • The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Furthermore, in the case of the compounds of the invention which contain an asymmetric carbon atom, the invention relates to the D form, the L form and D,L mixtures and also, where more than one asymmetric carbon atom is present, to the diastereomeric forms. Those compounds of the invention which contain asymmetric carbon atoms, and which as a rule accrue as racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use an optically active starting substance from the outset, with a corresponding optically active or diastereomeric compound then being obtained as the end product.
  • Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms.
  • Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
  • Also included are solvates and hydrates of the compounds of the invention and solvates and hydrates of their pharmaceutically acceptable salts.
  • The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, rotamers, and isotopes of the structures depicted, unless otherwise indicated.
  • In some embodiments, the compound can be provided as a prodrug. The term “prodrug”, as employed herein, denotes a compound, which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the invention, or a salt and/or solvate thereof.
  • In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof.
  • Pharmaceutical Methods
  • The compounds according to the invention have been found to have pharmacologically important properties, which can be used therapeutically. The compounds of the invention can be used alone, in combination with each other or in combination with other active compounds.
  • In certain embodiments, compounds of the present invention may be enhancers of Notch signalling.
  • The communication between cells via Notch signaling (reviewed in Kopan et al., Cell 2009, 137, 216-233; Bray, Nat. Rev. Mol. Cell Biol. 2016, 17, 722-735) is in the first step mediated by two types of transmembrane proteins: The Notch receptors being distributed within the cell membrane of the signal-receiving cell and the Notch ligands covering the membrane of the signal-sending cell. Mechanistically, Notch signaling is activated by receptor-ligand interaction, which leads to the proteolytic release of the intra cellular domain (NICD) of the membrane bound Notch receptor into the inside of the signal receiving cell. Subsequent translocation of NICD into the nucleus in turn leads to the transcriptional activation of certain and cell type specific genes. The Notch-mediated alteration of the previous gene-expression program of a cell is manifested in according cellular changes, which represent the response of the cell to a Notch signal.
  • The activation level of Notch signaling can be quantified in vitro most reliably by measuring the expression levels of Notch specific target genes. This can be accomplished by the quantification of corresponding mRNA or protein of a particular Notch target gene. Alternatively, cells can be genetically modified to carry a luciferase gene as an artificial Notch target gene, which is expressed in dependence of Notch activity. In this setting, Notch signaling levels can be quantified by measuring the luciferase-derived bioluminescence values.
  • An according Notch-reporter assay, i.e. a luciferase-based luminescence readout, was used here to quantify the ability of the claimed small molecules to augment Notch signaling in a cellular system. For this purpose, HeLa cells, obtainable from the American Type Culture Collection (ATCC) under the accession number ATCC-CCL-2, were transiently transfected for 24 hours using FuGENE® HD (Promega, #E2311) as transfection reagent with expression vectors of a membrane-tethered form of the constitutively active intracellular domain of the human Notch1 receptor (hNotch1ΔE) to activate the signaling cascade (BPS Bioscience, human analogue to Notch Pathway Reporter Kit #60509 component C), a Firefly luciferase being expressed under the control of a Notch-responsive promoter to monitor Notch signaling (BPS Bioscience, Notch Pathway Reporter Kit #60509, CSL luciferase reporter vector from component A not premixed with Renilla luciferase vector), and a Renilla luciferase being constitutively expressed in a Notch signaling independent manner to include a measure for the cell number per sample (Promega, pRL-SV40, #E2231). HeLa cells were cultivated according to the protocol of the provider in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589). The transfection was carried out in a 100 mm-culture dish (StarLab, #CC7682-3394) with cells being properly attached to the plate at a cell confluency of 80-90% in a total volume of 7 mL culture medium. Per dish to be transfected, a transfection mix was prepared by adding to 238 μL Opti-MEM (Fisherscientific, #10149832) 40 μL of the hNotch1ΔE expression vector (100 ng/μL), 80 μL of the CSL luciferase reporter vector (40 ng/μL), 4 μL of the pRL-SV40-Renilla luciferase vector (10 ng/μL), and in the last step 18.1 μL of FuGENE® HD. After addition of FuGENE® HD the transfection mix was let stand for 15 min at room temperature and hereafter equally distributed into the culture dish. Subsequently, i.e. after 24 hours of transfection, the transfected cells (10.000 cells per well) were incubated with the test-compounds at a final concentration of 10 μM (diluted from 10 mM stock-solutions in DMSO to a final DMSO concentration of 0.1% v/v) or with the empty carrier DMSO at 0.1% v/v as control for 20 hours in 96-well plates suitable for luminescence readouts (CORNING, #3610). Hereafter, the cells were lysed with 30 μL per well of Passive Lysis Buffer (Promega, #E194A, component of Dual-Luciferase® Reporter Assay System, #E1910) and the Firefly as well as Renilla luciferase values were measured with a luminescence reader with applying 15 μL per well each of the corresponding enzyme substrates needed to create the luminescence signals (Promega, Dual-Luciferase® Reporter Assay System, #E1910).
  • The suitability of the assays for monitoring Notch signaling was controlled by additionally including a generally accepted commercial Notch inhibitor, i.e. DAPT, as negative control, as well as the reported Notch enhancer resveratrol (RES) as positive control (Pinchot et al., Cancer 2011, 117, 1386-1398; Truong et al., Ann. Surg. Oncol. 2011, 18, 1506-1511; Yu et al., Mol. Cancer Ther. 2013, 12, 1276-1287). Both control compounds were likewise tested at 10 μM.
  • Per single experiment the measurement was performed in six replicates per compound. For every compound, this experiment was repeated in three or more independent replicates. The values of the Notch-reporter luciferase were normalized by division through the corresponding individual Notch-independent Renilla values in order to eliminate the impact of variation in the absolute cell-numbers in between the samples. For every individual plate, a second normalization was performed against the equally weighted arithmetic mean (here abbreviated as AVE) of the six associated Renilla-normalized DMSO-control values within a single experiment in order to obtain the relative values to a baseline level of 1.0. Two independent outlier analyses were performed according to the methods by Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12). Outliers confirmed by at least one of the methods were excluded from the calculations but not more than one value out of six per compound within a single experiment. The weighted arithmetic mean (here abbreviated as AVEw) for each compound was calculated from the double-normalized values over all independent replicates of the single experiments comprising the six replicates each. The corresponding standard deviation for the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Miffing, Taschenbuch der Mathematik, 5th edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and was combined with the Gauß′ error propagation associated with the performed calculation for the normalization. The resulting standard deviation is herein referred to as “combined standard deviation”.
  • A compound is considered as a Notch augmenting molecule, i.e. an enhancer of Notch signaling, if the weighted arithmetic mean of the luminescence values after subtraction of the corresponding combined standard deviation amounts to 1.1 or higher, in particular to 1.2 or higher, 1.3 or higher, 1.4 or higher, 1.5 or higher, 1.7 or higher, and 2.0 or higher relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all double-normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
  • According to the method described above, several molecules falling under the scope of the five compound families herein defined in formula I, formula II, formula III, formula IV and formula V have been identified as enhancers of Notch signaling. The so far identified Notch enhancers relate to the compounds listed in Table VI. The entries of Table VI are categorized by the corresponding weighted arithmetic mean of the compounds falling into the activity ranges as indicated.
  • TABLE VI
    Notch reporter assay
    Activity Range Entry Compound Specification
    AVEw ≥ 2.0 1 030
    2 186
    3 322
    1.7 ≤ AVEw < 2.0 4 003
    5 005
    6 027
    7 043
    8 045
    9 051
    10 114
    11 272
    12 284
    13 288
    14 318
    1.4 ≤ AVEw < 1.7 15 004
    16 026
    17 041
    18 050
    19 052
    20 067
    21 071
    22 072
    23 073
    24 075
    25 117
    26 120
    27 134
    28 216
    29 266
    30 269
    31 291
    32 297
    33 317
    34 336
    35 337
    36 385
    37 394
    38 395
    39 410
    40 544
    41 820
    1.5 ± 0.0 42 RES Positive control
    1.3 ≤ AVEw < 1.4 43 044
    44 066
    45 122
    46 168
    47 182
    48 184
    49 268
    50 286
    51 292
    52 319
    53 334
    54 344
    1.2 ≤ AVEw < 1.3 55 007
    56 019
    57 025
    58 091
    59 092
    60 133
    61 166
    62 195
    63 217
    64 222
    65 241
    66 242
    67 247
    68 273
    69 275
    70 316
    71 325
    72 363
    73 396
    74 784
    1.1 ≤ AVEw < 1.2 75 086
    76 118
    77 159
    78 170
    79 171
    80 189
    81 215
    82 221
    83 234
    84 267
    85 287
    86 300
    87 323
    88 343
    89 374
    90 399
    91 451
    92 644
    93 703
    94 712
    95 721
    96 730
    1.0 ± 0.0 97 DMSO Baseline control
    0.1 ± 0.0 98 DAPT Negative control
  • Several other molecules have not been identified as enhancers of Notch signaling according to the above method.
  • In the course of the evaluation of molecules falling under formula I, formula II, formula III, formula IV and formula V in further cellular assays, results indicate that compounds of said molecule families exhibit growth inhibiting properties in hyperproliferative processes. In some cases, the growth inhibiting properties correlate with Notch enhancing properties, in other cases the growth inhibiting properties do not correlate with Notch enhancing properties.
  • The biological activity of the claimed compounds can be attributed to but may not be limited to Notch signaling enhancing activity. The secondary mechanisms of the claimed compounds leading to antiproliferative effects can be used alternatively or in combination with the Notch enhancing properties in medicinal treatments, preferably in the treatment of hyperproliferative disorders including cancer and non-malignant hyperproliferative disorders.
  • The antiproliferative activities of compounds falling under formula I, formula II, formula III, formula IV and formula V were investigated on cells or cell lines originating from a disorder of the myeloid cell compartment, the neuroendocrine system, the cervix, and the mucosal epithelium, as well as from the skin epithelium. To this end, HL-60 cells, TT cells, HeLa cells, CAL-27 cells and human primary epidermal keratinocytes (HPEK) were seeded into 96-well plates suitable for fluorescence assays (CORNING #3598) at following initial cell numbers: 1000 cells per well for HL-60; 9000 cells per well for TT; 2000 cells per well for HeLa, 2000 cells per well for CAL-27, 2000 cells per well for HPEK. The cells were treated with compounds at indicated final concentrations (diluted from the 1000× stock-solutions in DMSO to a final DMSO concentration of 0.1% v/v) or with the empty carrier DMSO at 0.1% v/v as control for 5 days. At day 5 after starting the treatments the cells were subjected to the alamarBlue® Proliferation Assay (Bio-Rad Serotec GmbH, BUF012B) according to the protocol of the manufacturer. The readout was taken with a multi-well plate-reader in the fluorescence mode with applying a filter for excitation at 560 nm (band width 10 nm) and for emission at 590 nm (band width 10 nm). Resveratrol (RES) treatment was included as control for growth inhibition.
  • The assays were performed in duplicate or more replicates of independent single experiments each containing a six-fold replicate for every condition. For every individual plate, the measured fluorescence intensity values of the conditions with compound treatment were normalized against the corresponding equally weighted arithmetic mean of the fluorescence intensity values of the six DMSO treated control wells in order to obtain the relative values to a baseline level of 1.0. The statistical calculations were performed in analogy to the luciferase assay as described above. To this end, two independent outlier analyses were performed according to the methods by Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12). Outliers confirmed by at least one of the methods were excluded from the calculations but not more than one value out of six per compound within a single experiment. The weighted arithmetic mean AVEw for each compound was calculated from the normalized values over all independent replicates of the single experiments comprising the six replicates each. The corresponding standard deviation for the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Mühlig, Taschenbuch der Mathematik, 5th edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and was combined with the Gauß′ error propagation associated with the performed calculation for the normalization. The resulting standard deviation is herein referred to as “combined standard deviation”.
  • In certain embodiments, the compounds of the present invention may be growth inhibitors in hyperproliferative processes, including malignant and non-malignant hyperproliferative processes.
  • In one embodiment, several compounds of the invention were found to inhibit the growth of HL-60 cells (human acute myeloid leukemia cells) obtainable from the Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ) under the accession number ACC 3. HL-60 cells were cultivated according to the protocol of the provider in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • A compound is considered as a growth inhibitor of HL-60 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
  • According to the method described above, several molecules falling under the scope of the five compound families herein defined in formula I, formula II, formula III, formula IV and formula V have been identified as growth inhibitors of HL-60 cells. The so far identified HL-60 growth inhibitors relate to the compounds listed in Table VII. The entries of Table VII are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated.
  • TABLE VII
    Proliferation assay with HL-60 cells at 20 μM
    Activity Range Entry Compound Specification
    1.0 ± 0.0 1 DMSO Baseline control
    0.8 < AVEw ≤ 0.9 2 002
    3 030
    4 054
    5 072
    6 073
    7 075
    8 087
    9 092
    10 165
    11 245
    12 248
    13 298
    14 300
    15 316
    16 317
    17 325
    18 337
    19 374
    20 385
    21 395
    22 399
    23 427
    24 477
    25 592
    26 712
    27 723
    28 731
    29 738
    30 739
    31 740
    32 792
    33 793
    34 811
    35 812
    36 819
    0.7 < AVEw ≤ 0.8 37 041
    38 134
    39 215
    40 223
    41 322
    42 410
    43 440
    44 488
    45 581
    46 674
    47 685
    48 756
    49 785
    50 786
    51 822
    0.6 < AVEw ≤ 0.7 52 067
    53 217
    54 222
    55 334
    56 336
    57 414
    58 492
    59 700
    60 821
    61 828
    0.4 < AVEw ≤ 0.6 62 043
    63 044
    64 045
    65 066
    66 133
    67 159
    68 164
    69 167
    70 218
    71 221
    72 236
    73 238
    74 313
    75 318
    76 319
    77 320
    78 323
    79 389
    80 721
    81 722
    82 729
    83 784
    84 820
    0.4 ± 0.0 85 RES 20 μM Control
    0.2 < AVEw ≤ 0.4 86 161
    87 210
    88 211
    89 237
    90 596
    0.0 ≤ AVEw ≤ 0.2 91 166
    92 168
    93 170
    94 171
    95 182
    96 184
    97 185
    98 186
    99 216
    100 266
    101 267
    102 268
    103 269
    104 270
    105 272
    106 273
    107 275
    108 284
    109 286
    110 287
    111 288
    112 529
    113 540
    114 544
    115 633
    116 644
    117 648
    118 766
    119 767
    120 768
    121 774
    122 802
    123 803
    124 804
    125 810
  • In one embodiment, several compounds of the invention were found to inhibit the growth of CAL-27 cells (human tongue squamous cell carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ) under the accession number ACC 446. CAL-27 cells were cultivated according to the protocol of the provider (but at 5% instead of 10% CO2) in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • A compound is considered as a growth inhibitor of CAL-27 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
  • According to the method described above, several molecules falling so far under the scope of the three compound families herein defined in formula II, formula IV and formula V have been identified as growth inhibitors of CAL-27 cells. The so far identified CAL-27 growth inhibitors relate to the compounds listed in Table VIIIa and VIIIb. The entries of Table VIIIa and VIIIb are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated.
  • TABLE VIIIa
    Proliferation assay with CAL-27 cells at 20 μM
    Activity Range Entry Compound Specification
    1.0 ± 0.0 1 DMSO Baseline control
    0.9 ± 0.0 2 RES 20 μM Control
    0.8 < AVEw ≤ 0.9 3 236
    4 300
    5 596
    6 820
    7 822
    0.7 < AVEw ≤ 0.8 8 164
    9 210
    10 313
    11 774
    0.6 < AVEw ≤ 0.7 12 167
    13 238
    0.4 < AVEw ≤ 0.6 14 211
    15 237
    16 266
    0.4 ± 0.0 17 RES 40 μM Control
    0.2 < AVEw ≤ 0.4 18 166
    19 170
    20 182
    21 267
    22 287
    23 288
    24 768
    0.0 ≤ AVEw ≤ 0.2 25 168
    26 171
    27 184
    28 185
    29 186
    30 268
    31 269
    32 270
    33 272
    34 273
    35 275
    36 284
    37 286
    38 529
    39 540
    40 544
    41 633
    42 644
    43 648
    44 766
    45 767
    46 802
    47 803
    48 804
    49 810
  • TABLE VIIIb
    Proliferation assay with CAL-27 cells at 40 μM
    Activity Range Entry Compound Specification
    1.0 ± 0.0 1 DMSO Baseline control
    0.9 ± 0.0 2 RES 20 μM Control
    0.8 < AVEw ≤ 0.9 3 300
    4 334
    0.7 < AVEw ≤ 0.8 5 722
    0.6 < AVEw ≤ 0.7 6 159
    0.5 ± 0.0 7 RES 40 μM Control
    0.2 < AVEw ≤ 0.4 8 161
    9 237
    10 729
    11 768
    0.0 ≤ AVEw ≤ 0.2 12 166
    13 167
    14 210
    15 272
    16 287
  • In one embodiment, several compounds of the invention were found to inhibit the growth of TT cells (human medullary thyroid carcinoma cells) obtainable from the American Type Culture Collection (ATCC) under the accession number ATCC-CRL-1803. TT cells were cultivated according to the protocol of the provider in F-12K medium (Fisherscientific, #11580556, or ATCC, #ATCC-30-2004) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • A compound is considered as a growth inhibitor of TT cells, if—at a reference concentration of 40 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
  • According to the method described above, several molecules falling so far under the scope of the three compound families herein defined in formula II, formula IV and formula V have been identified as growth inhibitors of TT cells. The so far identified TT growth inhibitors relate to the compounds listed in Table IX. The entries of Table IX are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated.
  • TABLE IX
    Proliferation assay with TT cells at 40 μM
    Activity Range Entry Compound Specification
    1.0 ± 0.0 1 DMSO Baseline control
    0.9 ± 0.0 2 RES 20 μM Control
    0.8 < AVEw ≤ 0.9 3 159
    4 309
    5 334
    0.8 ± 0.0 6 RES 40 μM Control
    0.7 < AVEw ≤ 0.8 7 748
    0.6 < AVEw ≤ 0.7 8 210
    0.4 < AVEw ≤ 0.6 9 161
    10 237
    0.2 < AVEw ≤ 0.4 11 166
    12 167
    13 171
    14 182
    15 186
    16 287
    17 540
    18 544
    19 644
    20 729
    0.0 ≤ AVEw ≤ 0.2 21 272
    22 284
    23 288
    24 768
  • In one embodiment, several compounds of the invention were found to inhibit the growth of HeLa cells (human cervical adenocarcinoma cells) obtainable from the American Type Culture Collection (ATCC) under the accession number ATCC-CCL-2. HeLa cells were cultivated according to the protocol of the provider in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • A compound is considered as a growth inhibitor of HeLa cells, if—at a reference concentration of 40 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
  • According to the method described above, several molecules falling so far under the scope of the compound family herein defined in formula II have been identified as growth inhibitors of HeLa cells. The so far identified HeLa growth inhibitors relate to the compounds listed in Table X. The entries of Table X are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated.
  • TABLE X
    Proliferation assay with HeLa cells at 40 μM
    Activity Range Entry Compound Specification
    1.0 ± 0.0 1 DMSO Baseline control
    0.9 ± 0.0 2 RES 20 μM Control
    0.4 <AVEw ≤ 0.6 3 166
    0.4 ± 0.0 4 RES 40 μM Control
    0.2 < AVEw ≤ 0.4 5 167
    6 287
    0.0 ≤ AVEw ≤ 0.2 7 272
  • In one embodiment, several compounds of the invention were found to inhibit the growth of human epidermal keratinocyte progenitors, (HPEKp, pooled), obtainable from CELLnTEC Advanced Cell Systems AG under the accession number HPEKp. HPEKp cells were cultivated according to the protocol of the provider in CnT-Prime epithelial culture medium (CELLnTEC, #CnT-PR, a fully defined, low calcium formulation, completely free of animal or human-derived components) without addition of further components.
  • A compound is considered as a growth inhibitor of HPEKp cells, if—at a reference concentration of 10 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
  • According to the method described above, several molecules falling so far under the scope of the four compound families herein defined in formula II, formula III, formula IV and formula V have been identified as growth inhibitors of HPEKp cells. The so far identified HPEKp growth inhibitors relate to the compounds listed in Table XI. The entries of Table XI are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated.
  • TABLE XI
    Proliferation assay with HPEKp cells at 10 μM
    Activity Range Entry Compound Specification
    1.0 ± 0.0 1 DMSO Baseline control
    0.8 < AVEw ≤ 0.9 3 140
    4 374
    5 731
    6 747
    7 749
    8 801
    0.7 < AVEw ≤ 0.8 10 312
    11 323
    12 424
    13 721
    14 819
    15 828
    0.6 < AVEw ≤ 0.7 16 086
    17 190
    18 334
    0.4 < AVEw ≤ 0.6 19 112
    20 722
    0.4 ± 0.0 21 RES 10 μM Control
    0.2 < AVEw ≤ 0.4 22 389
    23 440
    24 540
    0.0 < AVEw ≤ 0.2 25 159
    26 182
    27 185
    28 273
    29 287
    30 644
    31 810
  • Preliminary results from a single proliferation assay of six replicates per condition using cells derived from murine muscle tissue show that compounds of the invention may exhibit antiproliferative activity on muscle cells. Compounds were tested on C2C12 cells using the alamarBlue® proliferation assay in analogy to the above described method with seeding the cells at an initial number of 2000 cells per 96-well and a duration of treatment with compounds for 3 days.
  • In one embodiment, two compounds of the invention were found so far to inhibit the growth of C2C12 cells (murine myoblast cells) obtainable from the Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ) under the accession number ACC 565. C2C12 cells were cultivated according to the protocol of the provider in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • A compound is considered as a growth inhibitor of C2C12 cells, if—at a reference concentration of 40 μM—the equally weighted arithmetic mean (AVE) of the six normalized fluorescence intensity values after addition of the corresponding standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the equally weighted arithmetic mean (AVE) of the six normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding standard deviations for the tested compounds were calculated including the Gauß′ error propagation associated with the performed calculation for the normalization and amounts for the DMSO values to less than 3·10−2. Outlier analyses were performed as described above.
  • According to the method described above, molecules falling so far under the scope of the two compound families herein defined in formula II and formula V have been identified as growth inhibitors of C2C12 cells. The so far identified C2C12 growth inhibitors relate to the compounds listed in Table XII. The entries of Table XII are categorized by the corresponding equally weighted arithmetic means of the compounds falling into the activity ranges as indicated.
  • TABLE XII
    Proliferation assay with C2C12 cells at 40 μM
    Activity Range Entry Compound Specification
    1.0 ± 0.0 1 DMSO Baseline control
    0.8 < AVE ≤ 0.9 2 748
    0.3 ± 0.0 3 RES 40 μM Control
    0.2 <AVE ≤ 0.4 4 288
  • Preliminary results from a single proliferation assay of six replicates per condition using squamous cell carcinoma (SCC) cells derived from the human oral mucosa may confirm that compounds of the invention exhibit antiproliferative activity on SCC of the mucosal epithelium. Compounds were tested on BHY cells using the alamarBlue® proliferation assay in analogy to the above described method with seeding the cells at an initial number of 4000 cells per 96-well and a duration of treatment with compounds for 3 days.
  • In one embodiment, several compounds of the invention were found to inhibit the growth of BHY cells (human oral squamous cell carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ) under the accession number ACC 404. BHY cells were cultivated according to the protocol of the provider (but at 5% instead of 10% CO2) in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589).
  • A compound is considered as a growth inhibitor of BHY cells, if—at a reference concentration of 40 μM—the equally weighted arithmetic mean (AVE) of the six normalized fluorescence intensity values after addition of the corresponding standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean (AVEw) of all normalized values from the DMSO control measurements. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2. The corresponding standard deviations for the tested compounds were calculated including the Gauß′ error propagation associated with the performed calculation for the normalization. The weighted arithmetic mean (AVEw) and the combined standard deviation for RES was calculated in analogy to DMSO. Outlier analyses were performed as described above.
  • According to the method described above, molecules falling so far under the scope of the two compound families herein defined in formula II and formula IV have been identified as growth inhibitors of BHY cells. The so far identified BHY growth inhibitors relate to the compounds listed in Table XIII. The entries of Table XIII are categorized by the corresponding equally weighted arithmetic means of the compounds falling into the activity ranges as indicated.
  • TABLE XIII
    Proliferation assay with BHY cells at 40 μM
    Activity Range Entry Compound Specification
    1.0 ± 0.0 1 DMSO Baseline control
    0.6 < AVE ≤ 0.7 2 644
    0.6 ± 0.0 3 RES 40 μM Control
    0.4 < AVE ≤ 0.6 4 171
    0.2 < AVE ≤ 0.4 5 182
    6 186
    7 272
    8 284
    9 288
    10 544
    11 633
    0.0 ≤ AVE ≤ 0.2 12 540
  • In one aspect, the present invention relates to the treatment of skin, skin appendages, mucosa, mucosal appendages, cornea, and all kinds of epithelial tissue. The term “skin” relates to tissue including epidermis and dermis. The term “mucosa” relates to mucous and submucous tissues including oral mucosa, nasal mucosa, ocular mucosa, mucosa of the ear, respiratory mucosa, genital mucosa, urothelial mucosa, anal mucosa and rectal mucosa. The term “appendages” relates to tissue including hair follicles, hair, fingernails, toenails and glands including sebaceous glands, sweat glands, e.g. apocrine or eccrine sweat glands and mammary glands.
  • In one embodiment, the present invention relates to treatment of non-melanoma skin cancer and pre-cancerous lesions, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), e.g. cutaneous SCC, lung SCC, head and neck SCC, oral SCC, esophageal SCC, cervical SCC, periocular SCC, SCC of the thyroid, SCC of the penis, SCC of the vagina, SCC of the prostate, SCC of the bladder, sebaceous gland carcinoma, Merkel cell carcinoma, angiosarcoma, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, dermatofibrosarcoma, actinic keratosis (AK) or Bowen's disease (BD).
  • In a further embodiment, the present invention relates to the treatment of skin and mucosal disorders with cornification defects (keratoses) and/or abnormal keratinocyte proliferation, such as Psoriasis, Darier's disease, Lichen planus, Lupus erythematosus, Ichthyosis or Verruca vulgaris (senilis).
  • In a further embodiment, the invention relates to the treatment of skin and mucosal diseases related to and caused by viral infections, such as warts, HPV-related warts, papillomas, HPV-related papillomas, papillomatoses and HPV-related papillomatoses, e.g. Verruca (plantar warts), Verruca plana (flat warts/plane warts), Verruca filiformis (filiform warts), mosaic warts, periungual warts, subungual warts, oral warts, genital warts, fibroepithelial papilloma, intracanalicular papilloma, intraductal papilloma, inverted papilloma, basal cell papilloma, squamous papilloma, cutaneous papilloma, fibrovasular papilloma, plexus papilloma, nasal papilloma, pharyngeal papilloma, Papillomatosis cutis carcinoides, Papillomatosis cutis lymphostatica, Papillomatosis confluens et reticularis or laryngeal papillomatosis (respiratory papillomatosis), Herpes-related diseases, e.g. Herpes labialis, Herpes genitalis, Herpes zoster, Herpes corneae or Kaposi's sarcoma.
  • In a further embodiment, the invention relates to the treatment of atopic dermatitis.
  • In a further embodiment, the invention relates to the treatment of acne.
  • In a further embodiment, the invention relates to the treatment of wounds of the skin, wherein the process of wound healing is accelerated.
  • A further aspect of the present invention relates to the treatment of immune system-related disorders. The term “immune system-related” as used herein applies to a pathological condition of the hematopoietic system including the hematologic system, as well as to the intervention into proliferation, differentiation and/or activation of cell lineages of the hematopoietic system including the hematologic system in order to modulate an immune response (immune modulation).
  • Examples are diseases of the hematopoietic system including the hematologic system, such as malignancies of the myeloid lineage, e.g. chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML), including acute promyelocytic leukemia (APL); malignancies of the lymphoid lineage, e.g. B-cell acute lymphoblastic leukemia (B-ALL), pre-B-cell acute lymphoblastic leukemia (pre-B-ALL), Hodgkin lymphoma or myeloma; or acute lymphoblastic and acute myeloid mixed lineage leukemia with MLL gene translocation.
  • Furthermore, the compounds of the invention may be used in immunotherapy, alone or together with other immunotherapeutic methods or compounds, or as adjuvant for immunotherapy. The term “immunotherapy” as used herein applies to activation-immunotherapy in patients without immune deficiency or with acquired or congenital immune deficiency, and as immune recovery to enhance the functionality of the immune system in the response against pathogens or pathologically transformed endogenous cells, such as cancer cells.
  • The term “other immunotherapy methods” as used herein applies to vaccinations, antibody treatment, cytokine therapy, the use of immune checkpoint inhibitors and immune response-stimulating drugs, as well as to autologous transplantations of genetically modified or non-modified immune cells, which may be stimulated with intercellular signals, or signaling molecules, or antigens, or antibodies, i.e. adoptive immune-cell transfer.
  • Specific examples are activation of peripheral T-lymphocytes in order to amplify an immune response, particularly the stimulation of proliferation and/or cytokine production and/or secretion upon antigen recognition in order to amplify an immune response, such as the activation of B-lymphocytes in order to amplify an immune response, particularly the stimulation of proliferation and/or antibody production and/or secretion, such as the enhancement of an immune response through augmentation of the number of specific immune-cell subtypes, by regulation of differentiation and/or cell fate decision during immune-cell development, as for example to augment the number of marginal zone B-cells, or T-helper (Th) subsets in particular Th1, Th2 and regulatory T-cells; or the use as vaccine adjuvant.
  • A still further aspect of the invention relates to the treatment of muscular diseases including diseases of skeletal muscle, cardiac muscle and smooth muscle.
  • In one embodiment, the invention relates to the treatment of muscular dystrophies (MD).
  • Specific examples are Duchenne MD, Becker MD, congenital MD, Limb-Girdle MD, facioscapulohumeral MD, Emery-Dreifuss MD, distal MD, myotonic MD or oculopharyngeal MD.
  • In a further embodiment, the invention relates to the treatment of hyperproliferative disorders of the muscle, including myoblastoma, rhabdomyoma, and rhabdomyosarcoma, as well as muscle hyperplasia and muscle hypertrophy.
  • In a further embodiment, the compounds of the invention may be used for muscle regeneration after pathologic muscle degeneration or atrophy, e.g. caused by traumata, caused by muscle ischemia or caused by inflammation, in aging-related muscle-atrophy or in disease-related muscle atrophy such as myositis and fibromyositis or poliomyelitis.
  • A still further aspect relates to the treatment of disorders of the neuroendocrine system such as cancer of the neuroendocrine system, comprising neuroendocrine small cell carcinomas, neuroendocrine large cell carcinomas and carcinoid tumors, e.g. of the brain, thyroid, pancreas, gastrointestinal tract, liver, esophagus, and lung, such as neuroendocrine tumor of the pituitary gland, neuroendocrine tumor of the adrenal gland, medullary thyroid cancer (MTC), C-cell hyperplasia, anaplastic thyroid cancer (ATC), parathyroid adenoma, intrathyroidal nodules, insular carcinoma, hyalinizing trabecular neoplasm, paraganglioma, small-cell lung cancer (SCLC), lung carcinoid tumors, neuroblastoma, gastrointestinal carcinoid, Goblet-cell carcinoid, pancreatic carcinoid, gastrinoma, glucagenoma, somatostatinoma, VIPoma, insulinoma, non-functional islet cell tumor, multiple endocrine neoplasia type-1, or pulmonary carcinoid.
  • A still further aspect relates to the treatment of cancers or precancerous lesions of the brain, pancreas, liver, thyroid, genitourinary tract and endothelial tissue, including glioma, mixed glioma, glioblastoma multiforme, astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, ependymoma, anaplastic ependymoma, myxopapillary ependymoma, subependymoma, brain stem glioma, optic nerve glioma, and forebrain tumors, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma, pancreatic pseudopapillary neoplasm, pancreatic intraductal papillary-mucinous neoplasm, pancreatic mucinous cystadenocarcinoma, pancreatoblastoma and pancreatic intraepithelial neoplesia, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, papillary thyroid cancer and follicular thyroid cancer, cervical cancer and angiosarcoma.
  • As used herein, the term “treating” or “treatment” refers to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease. The term “treating” also encompasses post-treatment care.
  • In some embodiments, administration of a compound of the invention, or pharmaceutically acceptable salt thereof, is effective in preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • The compounds of the invention may be used in human and veterinary medicine, which includes the treatment of companion animals, e.g. horses, dogs, cats, rabbits, guinea pigs, birds, fishes; and livestock, e.g. cattle, poultry, pig, sheep, goat, donkey, yak and camel.
  • Pharmaceutical Compositions
  • The present invention further provides pharmaceutical compositions comprising a compound as described herein or a pharmaceutically acceptable salt thereof for use in medicine, e.g. in human or veterinary medicine. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.
  • An effective dose of the compounds according to the invention, or their salts, solvates or prodrugs thereof is used, in addition to physiologically acceptable carriers, diluents and/or adjuvants for producing a pharmaceutical composition. The dose of the active compounds can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the diseases to be treated, and similar factors. The daily dose can be given as a single dose, which is to be administered once, or be subdivided into two or more daily doses, and is as a rule 0.001-2000 mg. Particular preference is given to administering daily doses of 0.1-500 mg, e.g. 0.1-100 mg.
  • Suitable administration forms are topical or systemical including enteral, oral, rectal, and parenteral, as infusion and injection, intravenous, intra-arterial, intraperitoneal, intramuscular, intracardial, epidural, intracerebral, intracerebroventricular, intraosseous, intra-articular, intraocular, intravitreal, intrathecal, intravaginal, intracavernous, intravesical, subcutaneous, intradermal, transdermal, transmucosal, inhalative, intranasal, buccal, sublingual and intralesional preparations. Particular preference is given to using oral, parenteral, e.g. intravenous or intramuscular, intranasal preparations, e.g. dry powder or sublingual, of the compounds according to the invention. The customary galenic preparation forms, such as tablets, sugar-coated tablets, capsules, dispersible powders, granulates, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lip balms, mouthwashs, foams, pastes, tinctures, dermal patches and tapes, forms in occlusion or in combination with time release drug delivery systems, with electrophoretic dermal delivery systems including implants and devices, and with jet injectors, liposome and transfersome vesicles, vapors, sprays, syrups, juices or drops and eye drops, can be used.
  • Solid medicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminium stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gelatine, agar agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); preparations which are suitable for oral administration can comprise additional flavourings and/or sweetening agents, if desired.
  • Liquid medicinal forms can be sterilized and/or, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators. Examples of such additives are tartrate and citrate buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its non-toxic salts). High molecular weight polymers, such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.
  • Oily suspensions for parenteral or topical applications can be vegetable, synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Examples of such fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, inter alia. Silicone oils of differing viscosity, or fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, or fatty acids, such as oleic acid, are also suitable. It is furthermore possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil.
  • Suitable solvents, gelatinizing agents and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.
  • Cellulose ethers which can dissolve or swell both in water or in organic solvents, such as hydroxypropylmethyl cellulose, methyl cellulose or ethyl cellulose, or soluble starches, can be used as film-forming agents.
  • Mixtures of gelatinizing agents and film-forming agents are also perfectly possible. In this case, use is made, in particular, of ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. The following can be used as additional formulation aids: glycerol, paraffin of differing viscosity, triethanolamine, collagen, allantoin and novantisolic acid. Use of surfactants, emulsifiers or wetting agents, for example of Na lauryl sulphate, fatty alcohol ether sulphates, di-Na—N-lauryl-β-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono-/dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts can also be required for the formulation. Stabilizers, such as montmorillonites or colloidal silicic acids, for stabilizing emulsions or preventing the breakdown of active substances such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations.
  • Preparations for parenteral administration can be present in separate dose unit forms, such as ampoules or vials. Use is preferably made of solutions of the active compound, preferably aqueous solution and, in particular, isotonic solutions and also suspensions. These injection forms can be made available as ready-to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent.
  • Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilisates which are prepared before use using the suitable solvent or suspending agent.
  • Inhalable preparations can present as powders, solutions or suspensions. Preferably, inhalable preparations are in the form of powders, e.g. as a mixture of the active ingredient with a suitable formulation aid such as lactose.
  • The preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions.
  • As indicated above, the compounds of the invention may be administered as a combination therapy, as sequence therapy or as simultaneous combination therapy, with further active agents, e.g. therapeutically active compounds useful in the treatment of the above indicated disorders. These therapeutically active compounds may include but are not limited to chemotherapeutic agents such as nucleoside analogs, e.g. Cytarabin, Gemcitabine, Azathioprine, Mercaptopurine, Fluorouracil, Thioguanine, Hydroxyurea, Azacitidine, Capecitabine, Doxifluridine, and Methotrexate; such as platinum-based drugs, e.g. Cisplatin, Oxaliplatin, Carboplatin and Nedaplatin; such as anthracyclines, e.g. Doxorubicin, Epirubicin, Valrubicin, Idarubicin, Daunorubicin, Sabarubicin, Pixantrone and Mitoxantrone; such as peptide antibiotics, e.g. Actinomycin and Bleomycin; such as alkylating agents e.g. Mechlorethamine, Chlorambucil, Melphalan, Nitrosoureas, Dacarbazine, Temozolomide and Cyclophosphamide; such as antimitotic agents including taxanes and vinca alkaloids, e.g. Docetaxel, Paclitaxel, Abraxane, Cabazitaxel, Vinblastine, Vindesine, Vinorelbine and Vincristine; such as topoisomerase inhibitors, e.g. Irinotecan, Topotecan, Teniposide and Etoposide; and targeted therapeutic agents such as kinase inhibitors, regulators i.e. inhibitors and activators of signaling pathways including growth factor signaling, cytokine signaling, NF-kappaB signaling, AP1 signaling, JAK/STAT signaling, EGFR signaling, TGF-beta signaling, Notch signaling, Wnt signaling, Hedgehog signaling, hormone and nuclear receptor signaling, e.g. Erlotinib, Lapatinib, Dasatinib, Imatinib, Afatinib, Vemurafenib, Dabrafenib, Nilotinib, Cetuximab, Trametinib, Palbociclib, Cobimetinib, Cabozantinib, Pegaptanib, Crizotinib, Olaparib, Panitumumab, Cabozantinib, Ponatinib, Regorafenib, Entrectinib, Ranibizumab, Ibrutinib, Trastuzumab, Rituximab, Alemtuzumab, Gefitinib, Bevacizumab, Lenvatinib, Bosutinib, Axitinib, Pazopanib, Everolimus, Temsirolimus, Ruxolitinib, Tofacitinib, Sorafenib, Sunitinib, Aflibercept, Bortezomib, Vandetanib; Vismodegib and Sonidegib; retinoids such as retinol, tretinoin, isotretinoin, alitretinoin, bexarotene, tazarotene, acitretin, adapalene and etretinate; hormone signaling modulators including estrogen receptor modulators, androgen receptor modulators and aromatase inhibitors e.g. Raloxifene, Tamoxifen, Fulvestrant, Lasofoxifene, Toremifene, Bicalutamide, Flutamide, Anastrozole, Letrozole and Exemestane; histone deacetylase inhibitors, e.g. Vorinostat, Romidepsin, Panobinostat, Belinostat and Chidamide; and Ingenol mebutate; and other Notch enhancers not encompassed by the compounds of the present invention, e.g. Valproic acid, Resveratrol, hesperetin, chrysin, phenethyl isothiocyanate, thiocoraline, N-methylhemeanthidine chloride and Notch Signaling-activating peptides or antibodies; and immune response modulating agents e.g. Imiquimod, Ipilimumab, Atezolizumab, Ofatumumab, Rituximab, Nivolumab and Pembrolizumab; and anti-inflammatory agents including glucocorticoids and non-steroidal anti-inflammatory drugs, e.g. cortisol-based preparations, Dexamethason, Betamethason, Prednisone, Prednisolone, Methylprednisolone, Triamcinolon-hexacetonid, Mometasonfuroat, Clobetasolpropionat, acetylsalicylic acid, salicylic acid and other salicylates, Diflunisal, Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Loxoprofen, Flurbiprofen, Oxaprozin, Indomethacin, Ketorolac, Tolmetin, Diclofenac, Etodolac, Aceclofenac, Nabumetone, Sulindac, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Parecoxib, Etoricoxib and Firocoxib; and ACE inhibitors; and beta-blockers; and myostatin inhibitors; and PDE-5 inhibitors; and antihistamines. For a combination therapy, the active ingredients may be formulated as compositions containing several active ingredients in a single dose form and/or as kits containing individual active ingredients in separate dose forms. The active ingredients used in combination therapy may be co-administered or administered separately.
  • The compounds of the invention may be administered as antibody-drug conjugates.
  • The compounds of the invention may be administered in combination with surgery, cryotherapy, electrodessication, radiotherapy, photodynamic therapy, laser therapy, chemotherapy, targeted therapy, immunotherapy, gene therapy, antisense therapy, cell-based transplantation therapy, stem cell therapy, physical therapy and occupational therapy.
  • The compounds of the invention falling under the scope of formula I, formula II, formula III, formula IV and formula V can be synthesized in analogy to the methods described in Reinmüller et al., 2015, EPFL Thesis 6887 by a coupling step to establish the diaryl ether scaffold, which can be prepared by a method of reacting a phenol and an electron-deficient aryl halide in the presence of a base such as potassium carbonate or cesium carbonate in a non-protic organic solvent such as DMSO or DMF at room temperature or at elevated temperature or reflux, preferably at 80° C. or 100° C., with optional assistance of microwave irradiation (Li et al., Org. Lett. 2003, 5, 2169-2171);
  • or by a method of reacting a phenol and a nitroarene in the presence of a base such as potassium carbonate or cesium carbonate in a non-protic organic solvent such as DMSO or DMF at elevated temperature or reflux, with assistance of microwave irradiation (Sarkate et al., Synlett 2013, 24, 1513-1516);
  • or by a method of reacting an aryl silyl ether with an electron-deficient aryl halide in the presence of a base such as DBU and trace water in a non-protic organic solvent such as DMSO or DMF at elevated temperature or reflux (Yeom et al., Synlett 2007, 146-150);
  • or by a method of reacting a phenol with a diaryliodonium triflate or tosylate in the presence of a base such as potassium carbonate or cesium carbonate in a non-protic organic solvent such as acetonitrile at ambient or elevated temperature (Kakinuma et al., Synthesis 2013, 45, 183-184);
  • or by a method of reacting under Buchwald-Hartwig conditions a phenol with an aryl halide in the presence of a transition metal-based catalyst system such as palladium(II) acetate, an organophosphorus-based ligand such as dppf, a base such as potassium phosphate in an organic solvent such as toluene at elevated temperature or reflux (Burgos et al., Angew. Chem. Int. Ed. 2006, 45, 4321-4326);
  • or by a method of reacting under Chan-Lam conditions a phenol with an arylboronic acid or ester in the presence of air, a copper-based catalyst system such as copper(II) acetate, a base such as pyridine or triethylamine in a non-protic organic solvent such as DCM, chloroform at ambient temperature (Evans et al., Tetrahedron Letters 1998, 39, 2937-2940);
  • wherein all said methods of preparation may require a subsequent derivatisation step by standard chemical procedures known to the person skilled in the art, such as saponification, hydrolysis, esterification or amidation to obtain the corresponding carboxylic acids, esters, primary amides, secondary amides, tertiary amides, hydroxamic acids and hydroxamates.
  • For example, the corresponding carboxylic acids are synthesized by saponification of the corresponding benzoate esters, fluorobenzoate esters, nicotinate esters, or fluoronicotinate esters in the presence of potassium hydroxide or sodium hydroxide in a binary solvent mixture of water and an alcohol, preferably ethanol, or water and tetrahydrofuran at ambient or elevated temperature (Becker et al., Organikum, 22nd edition 2004 (German), pp. 488, publisher: Wiley-VCH Weinheim);
  • the esters, primary amides, secondary amides, tertiary amides, and hydroxamic acids are synthesized by in situ transformation of the corresponding benzoic acid, fluorobenzoic acid, nicotinic acid, or fluoronicotinic acid to the corresponding acid chlorides in the presence of thionyl chloride and catalytic amounts of DMF in toluene at ambient or elevated temperature, preferably at 80° C., and under inert gas atmosphere, followed by the addition of the respective nucleophile, i.e. alcohol, ammonia, secondary amine, tertiary amine, or hydroxylamine in the presence or absence of a non-nucleophilic base such as triethylamine, at ambient temperature under inert gas atmosphere (Becker et al., Organikum, 22nd edition 2004 (German), pp. 459, publisher: Wiley-VCH Weinheim).
  • The perfluoroalkylcyclopropyl moiety associated with the compounds of the invention falling under the scope of formula V is synthesized in three steps according to the procedure described in Barnes-Seeman et al., ACS Med. Chem. Lett. 2013, 4, 514-516; first, a bromoperfluoroalkenylbenzene such as 1-bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene or 1-bromo-4-(3,3,4,4,4-pentafluorobut-1-en-2-yl)benzene is obtained by a method of reacting 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one or 1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropan-1-one, respectively, in the presence of methanesulfonyl chloride and a base such as potassium fluoride in a crown ether such as 18-crown-6 in a non-protic organic solvent such as DMF at elevated temperature, preferably at 80° C.;
  • second, a bromophenylperfluoroalkyldihydropyrazole such as 3-(4-bromophenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole or 3-(4-bromophenyl)-3-(perfluoroethyl)-4,5-dihydro-3H-pyrazole is obtained by a method of reacting a bromoperfluoroalkenylbenzene such as 1-bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene or 1-bromo-4-(3,3,4,4,4-pentafluorobut-1-en-2-yl)benzene, respectively, in the presence of diazomethane in an ether such as diethyl ether or methyl tert-butyl ether at ambient temperature;
  • and third, the perfluoroalkylcyclopropylarylbromide such as 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene or 1-bromo-4-(1-(perfluoroethyl)cyclopropyl)benzene is obtained by a method of reacting 3-(4-bromophenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole or 3-(4-bromophenyl)-3-(perfluoroethyl)-4,5-dihydro-3H-pyrazole, respectively, in an organic solvent such as toluene or xylenes or a mixture thereof.
  • The obtained perfluoroalkylcyclopropylarylbromide can subsequently be converted into the corresponding phenol for one of the above said coupling reactions with an electron-deficient aryl halide, a nitroarene, a diaryliodonium triflate or tosylate by a method of reaction in the presence of a transition metal-based catalyst system such as Pd2dba3, an organophosphorus-based ligand such as 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-Bu XPhos), a base such as potassium hydroxide or sodium hydroxide in a biphasic solvent system such as water/dioxane or water/toluene at elevated temperature or reflux, preferably at 100° C., and under an inert gas atmosphere (Anderson et al., J. Am. Chem. Soc. 2006, 128, 10694-10695);
  • or by a method of reaction in the presence of a copper-based catalyst system such as CuI, a pyridyl based ligand such as 2-methylquinolin-8-ol or preferably 8-hydroxyquinoline-N-oxide, and tetrabutyl-ammonium hydroxide or preferably cesium hydroxide monohydrate in a non-protic organic solvent such as DMSO or DMF at elevated temperature or reflux, preferably at 110° C., and under an inert gas atmosphere (Paul et al., Synthesis 2010, 4268-4272; Yang et el., Org. Lett. 2011, 13, 4340-4343).
  • The compounds of the invention falling under the scope of formula I, formula II, formula III, formula IV and formula V, as well as intermediates, can be isolated by column chromatography using silica gel as stationary phase and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, or acetic acids as eluent, preferably as binary or tertiary solvent mixtures thereof;
  • or by crystallization from common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, toluene, or tert-butyl methyl ether, and mixtures thereof.
  • The compounds of the invention falling under the scope of formula I, formula II, formula III, formula IV and formula V, as well as starting materials and intermediates, can be identified by conventional methods such as nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), or thin layer chromatography (TLC).
  • Chemical Synthesis
  • The compounds of the invention falling under the scope of formula I, formula II, formula III, formula IV and formula V can be synthesized and purified by those persons skilled in the art and are preferably synthesized according to the general procedure A, or general procedure B, or general procedure C, or general procedure D, respectively, and according to the detailed synthesis procedures described herein;
  • Abbreviations
  • Ac acetyl
  • BRSM based on recovered starting material (yield)
  • Bu butyl
  • δ chemical shift in parts per million (ppm)
  • dba dibenzylideneacetone
  • DCE 1,2-dichloroethane
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • Et ethyl
  • ESI electron spray ionization
  • M mol/L
  • Me methyl
  • Ms methanesulfonyl
  • PE petroleum ether
  • TBAF tetrabutylammonium fluoride
  • THF tetrahydrofuran
  • TMS trimethylslyl
  • General Procedure A: Synthesis of Diaryl Ether Esters
  • Diaryl ether esters according to formula I, formula III, and formula V can be prepared by nucleophilic aromatic substitution, e.g. by reaction of an alkyl 4-fluorobenzoate, or an alkyl 3,4-difluorobenzoate, or an alkyl 6-chloronicotinate, or an alkyl 6-chloro-5-fluoronicotinate, with a phenol derivative (nucleophile, see Table XIV) in the presence of a base like potassium carbonate in a solvent like dimethyl sulfoxide at a temperature between 80° C. and 150° C. and in an inert atmosphere such as argon.
  • General Procedure B: Synthesis of Diaryl Ether Acids
  • Diaryl ether acids according to formula I, formula III, and formula V can be prepared by saponification, e.g. by reaction of the corresponding diaryl ether esters with an aqueous base solution like sodium hydroxide (nucleophile, see Table XIV) in a solvent like ethanol, methanol, tetrahydrofuran or a mixture thereof at a temperature between room temperature and reflux.
  • General Procedure C: Synthesis of Diaryl Ether Esters
  • Diaryl ether esters according to formula I, formula III, and formula V can be prepared by esterification via the corresponding acid chloride, e.g by reaction of a diaryl ether acid with thionyl chloride in the presence of catalytic amounts of DMF in a solvent like toluene at a temperature between 50° C. and 100° C. and in an inert atmosphere such as argon. After removal of the volatiles, the such obtained acid chloride intermediate is reacted with the alcohol corresponding to the desired ester (nucleophile, see Table XIV) in the presence of an organic base like triethylamine at a temperature between 0° C. and room temperature and in an inert atmosphere such as argon.
  • Alternatively, diaryl ether esters according to formula I, formula III, and formula V can be prepared by esterification via the corresponding acid chloride, e.g. by reaction of a diaryl ether acid with thionyl chloride in the presence of the alcohol corresponding to the desired ester (nucleophile, see Table XIV), preferably as the solvent at a temperature between 50° C. and reflux.
  • General Procedure D: Synthesis of Diaryl Ether Amides
  • Diaryl ether amides according to formula II, formula IV, and formula V can be prepared by amidation via the corresponding acid chloride, e.g by reaction of a diaryl ether acid with thionyl chloride in the presence of catalytic amounts of DMF in a solvent like toluene at a temperature between 50° C. and 100° C. and in an inert atmosphere such as argon. After removal of the volatiles, the such obtained acid chloride intermediate is reacted with the amine corresponding to the desired amide (nucleophile, see Table XIV) in a solvent like methanol, ethanol, or tetrahydrofuran at a temperature between 0° C. and room temperature and in an inert atmosphere such as argon. The presence of an organic base like triethylamine is needed if the hydrochloride salt of the amine is used.
  • TABLE XIV
    List of Synthesized compounds
    Compound ESI Ion General Nucleophile used in the
    Number m/z Type Procedure General Procedure
    002 241.17 [M − H]− B NaOH
    003 255.18 [M − H]− B NaOH
    004 269.18 [M − H]− B NaOH
    005 283.21 [M − H]− B NaOH
    019 307.28 [M − H]− B NaOH
    020 321.34 [M − H]− B NaOH
    023 243.09 [M + H]+ C methanol
    024 257.10 [M + H]+ C methanol
    025 271.11 [M + H]+ C methanol
    026 285.13 [M + H]+ C methanol
    027 299.20 [M + H]+ C methanol
    029 271.11 [M + H]+ C methanol
    030 299.20 [M + H]+ C methanol
    041 311.21 [M + H]+ C methanol
    043 323.24 [M + H]+ C methanol
    044 337.25 [M + H]+ C methanol
    045 362.32 [M + H]+ C methanol
    048 257.11 [M + H]+ A 4-methylphenol
    049 271.12 [M + H]+ A 4-ethylphenol
    050 285.15 [M + H]+ A 4-n-propylphenol
    051 299.21 [M + H]+ A 4-n-butylphenol
    052 313.26 [M + H]+ A 4-n-pentylphenol
    054 285.15 [M + H]+ A 4-isopropylphenol
    056 311.17 [M + H]+ A 4-(trifluoromethyl)phenol
    066 337.25 [M + H]+ A (±)-4-(bicyclo[2.2.1]heptan-2-yl)phenol
    (7:1 endo:exo)
    067 351.26 [M + H]+ A (±)-4-(bicyclo[2.2.2]octan-2-yl)phenol
    070 244.00 [M − H]− B NaOH
    071 258.09 [M − H]− B NaOH
    072 272.11 [M − H]− B NaOH
    073 286.16 [M − H]− B NaOH
    075 258.10 [M − H]− B NaOH
    086 308.25 [M − H]− B NaOH
    087 322.30 [M − H]− B NaOH
    091 244.07 [M + H]+ C methanol
    092 258.09 [M + H]+ C methanol
    093 272.11 [M + H]+ C methanol
    094 286.15 [M + H]+ C methanol
    095 300.19 [M + H]+ C methanol
    097 272.11 [M + H]+ C methanol
    099 300.19 [M + H]+ C methanol
    101 298.09 [M + H]+ C methanol
    110 312.19 [M + H]+ C methanol
    112 324.22 [M + H]+ C methanol
    113 338.24 [M + H]+ C methanol
    114 364.29 [M + H]+ C methanol
    117 272.12 [M + H]+ A 4-ethylphenol
    118 286.16 [M + H]+ A 4-n-propylphenol
    119 300.20 [M + H]+ A 4-n-butylphenol
    120 314.24 [M + H]+ A 4-n-pentylphenol
    122 286.16 [M + H]+ A 4-isopropylphenol
    133 338.24 [M + H]+ A (±)-4-(bicyclo[2.2.1]heptan-2-yl)phenol
    (7:1 endo:exo)
    134 352.28 [M + H]+ A (±)-4-(bicyclo[2.2.2]octan-2-yl)phenol
    138 228.10 [M + H]+ D ammonia
    139 242.10 [M + H]+ D ammonia
    140 256.12 [M + H]+ D ammonia
    141 270.11 [M + H]+ D ammonia
    142 284.16 [M + H]+ D ammonia
    144 256.12 [M + H]+ D ammonia
    145 270.12 [M + H]+ D ammonia
    146 284.16 [M + H]+ D ammonia
    157 296.20 [M + H]+ D ammonia
    159 308.22 [M + H]+ D ammonia
    160 322.26 [M + H]+ D ammonia
    161 348.27 [M + H]+ D ammonia
    164 244.07 [M + H]+ D hydroxylamine
    165 258.09 [M + H]+ D hydroxylamine
    166 272.11 [M + H]+ D hydroxylamine
    167 286.15 [M + H]+ D hydroxylamine
    168 300.19 [M + H]+ D hydroxylamine
    170 272.11 [M + H]+ D hydroxylamine
    171 300.19 [M + H]+ D hydroxylamine
    182 312.20 [M + H]+ D hydroxylamine
    184 324.22 [M + H]+ D hydroxylamine
    185 338.25 [M + H]+ D hydroxylamine
    186 364.36 [M + H]+ D hydroxylamine
    190 256.12 [M + H]+ D methylamine
    191 270.12 [M + H]+ D methylamine
    192 284.15 [M + H]+ D methylamine
    193 298.21 [M + H]+ D methylamine
    195 270.12 [M + H]+ D methylamine
    196 284.15 [M + H]+ D methylamine
    197 298.22 [M + H]+ D methylamine
    208 310.23 [M + H]+ D methylamine
    210 322.26 [M + H]+ D methylamine
    211 336.28 [M + H]+ D methylamine
    212 362.30 [M + H]+ D methylamine
    215 256.12 [M + H]+ D dimethylamine
    216 270.12 [M + H]+ D dimethylamine
    217 284.16 [M + H]+ D dimethylamine
    218 298.21 [M + H]+ D dimethylamine
    219 312.23 [M + H]+ D dimethylamine
    221 284.15 [M + H]+ D dimethylamine
    222 298.21 [M + H]+ D dimethylamine
    223 312.24 [M + H]+ D dimethylamine
    234 324.27 [M + H]+ D dimethylamine
    236 336.28 [M + H]+ D dimethylamine
    237 350.30 [M + H]+ D dimethylamine
    238 376.33 [M + H]+ D dimethylamine
    241 229.09 [M + H]+ D ammonia
    242 243.09 [M + H]+ D ammonia
    243 257.11 [M + H]+ D ammonia
    244 271.12 [M + H]+ D ammonia
    245 285.15 [M + H]+ D ammonia
    247 257.11 [M + H]+ D ammonia
    248 285.16 [M + H]+ D ammonia
    250 283.04 [M + H]+ D ammonia
    259 297.17 [M + H]+ D ammonia
    261 309.21 [M + H]+ D ammonia
    262 323.26 [M + H]+ D ammonia
    263 349.29 [M + H]+ D ammonia
    266 245.07 [M + H]+ D hydroxylamine
    267 259.09 [M + H]+ D hydroxylamine
    268 273.11 [M + H]+ D hydroxylamine
    269 287.14 [M + H]+ D hydroxylamine
    270 301.18 [M + H]+ D hydroxylamine
    272 273.12 [M + H]+ D hydroxylamine
    273 301.19 [M + H]+ D hydroxylamine
    275 299.08 [M + H]+ D hydroxylamine
    284 313.20 [M + H]+ D hydroxylamine
    286 325.21 [M + H]+ D hydroxylamine
    287 339.24 [M + H]+ D hydroxylamine
    288 365.29 [M + H]+ D hydroxylamine
    291 243.10 [M + H]+ D methylamine
    292 257.11 [M + H]+ D methylamine
    293 271.12 [M + H]+ D methylamine
    294 285.15 [M + H]+ D methylamine
    295 299.21 [M + H]+ D methylamine
    297 271.12 [M + H]+ D methylamine
    298 299.21 [M + H]+ D methylamine
    300 297.08 [M + H]+ D methylamine
    309 311.22 [M + H]+ D methylamine
    311 323.25 [M + H]+ D methylamine
    312 337.26 [M + H]+ D methylamine
    313 363.32 [M + H]+ D methylamine
    316 257.11 [M + H]+ D dimethylamine
    317 271.12 [M + H]+ D dimethylamine
    318 285.15 [M + H]+ D dimethylamine
    319 299.21 [M + H]+ D dimethylamine
    320 313.24 [M + H]+ D dimethylamine
    322 285.16 [M + H]+ D dimethylamine
    323 313.25 [M + H]+ D dimethylamine
    325 311.13 [M + H]+ D dimethylamine
    334 325.26 [M + H]+ D dimethylamine
    336 337.26 [M + H]+ D dimethylamine
    337 351.28 [M + H]+ D dimethylamine
    338 377.32 [M + H]+ D dimethylamine
    341 245.13 [M − H]− B NaOH
    342 259.15 [M − H]− B NaOH
    343 273.17 [M − H]− B NaOH
    344 287.18 [M − H]− B NaOH
    345 301.21 [M − H]− B NaOH
    347 273.15 [M − H]− B NaOH
    348 301.24 [M − H]− B NaOH
    350 299.12 [M − H]− B NaOH
    359 313.24 [M − H]− B NaOH
    363 365.39 [M − H]− B NaOH
    374 317.22 [M + H]+ C methanol
    385 329.24 [M + H]+ C methanol
    389 381.34 [M + H]+ C methanol
    392 275.09 [M + H]+ A 4-methylphenol
    393 289.13 [M + H]+ A 4-ethylphenol
    394 303.17 [M + H]+ A 4-n-propylphenol
    395 317.23 [M + H]+ A 4-n-butylphenol
    396 331.24 [M + H]+ A 4-n-pentylphenol
    398 303.19 [M + H]+ A 4-isopropylphenol
    399 331.25 [M + H]+ A 4-tert-pentylphenol
    401 329.17 [M + H]+ A 4-(trifluoromethyl)phenol
    410 343.28 [M + H]+ A 4-cyclohexylphenol
    414 395.33 [M + H]+ A 4-(1-adamantyl)phenol
    417 246.12 [M − H]− B NaOH
    423 274.15 [M − H]− B NaOH
    424 288.17 [M − H]− B NaOH
    425 304.16 [M + H]+ B NaOH
    427 300.10 [M − H]− B NaOH
    436 314.24 [M − H]− B NaOH
    440 368.29 [M + H]+ B NaOH
    451 318.21 [M + H]+ C methanol
    462 330.23 [M + H]+ C methanol
    466 382.29 [M + H]+ C methanol
    469 276.08 [M + H]+ A 4-methylphenol
    475 304.15 [M + H]+ A 4-isopropylphenol
    476 318.20 [M + H]+ A 4-tert-butylphenol
    477 332.24 [M + H]+ A 4-tert-pentylphenol
    479 330.14 [M + H]+ A 4-(trifluoromethyl)phenol
    488 344.24 [M + H]+ A 4-cyclohexylphenol
    492 396.29 [M + H]+ A 4-(1-adamantyl)phenol
    503 302.20 [M + H]+ D ammonia
    514 314.20 [M + H]+ D ammonia
    518 366.29 [M + H]+ D ammonia
    529 318.21 [M + H]+ D hydroxylamine
    540 330.23 [M + H]+ D hydroxylamine
    544 382.30 [M + H]+ D hydroxylamine
    555 316.23 [M + H]+ D methylamine
    566 328.25 [M + H]+ D methylamine
    570 380.31 [M + H]+ D methylamine
    581 330.26 [M + H]+ D dimethylamine
    592 342.28 [M + H]+ D dimethylamine
    596 394.33 [M + H]+ D dimethylamine
    607 303.19 [M + H]+ D ammonia
    618 315.21 [M + H]+ D ammonia
    622 367.36 [M + H]+ D ammonia
    633 319.21 [M + H]+ D hydroxylamine
    644 331.21 [M + H]+ D hydroxylamine
    648 383.27 [M + H]+ D hydroxylamine
    659 317.22 [M + H]+ D methylamine
    670 329.25 [M + H]+ D methylamine
    674 381.31 [M + H]+ D methylamine
    685 331.25 [M + H]+ D dimethylamine
    696 343.28 [M + H]+ D dimethylamine
    700 395.31 [M + H]+ D dimethylamine
    703 321.22 [M − H]− B NaOH
    704 371.30 [M − H]− B NaOH
    705 339.22 [M − H]− B NaOH
    711 355.21 [M − H]− B NaOH
    712 337.16 [M + H]+ C methanol
    714 353.31 [M − H]− C methanol
    721 351.20 [M + H]+ A 4-(1-(trifluoromethyl)cyclopropyl)phenol
    722 401.25 [M + H]+ A 4-(1-(perfluoroethyl)cyclopropyl)phenol
    723 369.24 [M + H]+ A 4-(1-(trifluoromethyl)cyclopropyl)phenol
    729 385.18 [M + H]+ A 2-chloro-4-(1-(trifluoromethyl)cyclo-
    propyl)phenol
    730 322.22 [M − H]− B NaOH
    731 374.19 [M + H]+ B NaOH
    732 340.21 [M − H]− B NaOH
    738 358.13 [M + H]+ B NaOH
    739 338.17 [M + H]+ C methanol
    740 388.21 [M + H]+ C methanol
    741 356.19 [M + H]+ C methanol
    747 372.15 [M + H]+ C methanol
    748 352.21 [M + H]+ A 4-(1-(trifluoromethyl)cyclopropyl)phenol
    749 402.25 [M + H]+ A 4-(1-(perfluoroethyl)cyclopropyl)phenol
    750 370.20 [M + H]+ A 4-(1-(trifluoromethyl)cyclopropyl)phenol
    756 386.17 [M + H]+ A 2-chloro-4-(1-(trifluoromethyl)cyclo-
    propyl)phenol
    757 322.18 [M + H]+ D ammonia
    759 340.18 [M + H]+ D ammonia
    766 338.17 [M + H]+ D hydroxylamine
    767 388.22 [M + H]+ D hydroxylamine
    768 356.19 [M + H]+ D hydroxylamine
    774 372.19 [M + H]+ D hydroxylamine
    775 336.20 [M + H]+ D methylamine
    777 354.19 [M + H]+ D methylamine
    784 350.21 [M + H]+ D dimethylamine
    785 400.26 [M + H]+ D dimethylamine
    786 368.22 [M + H]+ D dimethylamine
    792 384.23 [M + H]+ D dimethylamine
    793 323.17 [M + H]+ D ammonia
    794 373.21 [M + H]+ D ammonia
    795 341.17 [M + H]+ D ammonia
    801 357.14 [M + H]+ D ammonia
    802 339.17 [M + H]+ D hydroxylamine
    803 389.22 [M + H]+ D hydroxylamine
    804 357.17 [M + H]+ D hydroxylamine
    810 373.17 [M + H]+ D hydroxylamine
    811 337.18 [M + H]+ D methylamine
    812 387.23 [M + H]+ D methylamine
    813 355.20 [M + H]+ D methylamine
    819 371.17 [M + H]+ D methylamine
    820 351.21 [M + H]+ D dimethylamine
    821 401.26 [M + H]+ D dimethylamine
    822 369.21 [M + H]+ D dimethylamine
    828 385.21 [M + H]+ D dimethylamine
    • Synthesis of Representative Compounds Compound 005 4-(4-Pentylphenoxy)benzoic Acid
  • Figure US20210107863A2-20210415-C00836
  • Following general procedure B, to a solution of ethyl 4-(4-pentylphenoxy)benzoate (1.69 g, 5.4 mmol) in THF (25 mL) and MeOH (3 mL) was added 2 M aqueous NaOH (10 mL, 20 mmol) and the reaction was stirred at room temperature for 48 hours. The organic solvents were evaporated and the residue acidified with 5 M aqueous HCl to adjust a pH of 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by recrystallization from hot EtOAc to give the title compound as colorless solid (1.21 g, 79%). 1H NMR (300 MHz, CDCl3) δ 8.12-8.01 (m, 2H), 7.25-7.15 (m, 2H), 7.05-6.94 (m, 4H), 2.68-2.57 (m, 2H), 1.72-1.56 (m, 2H), 1.46-1.33 (m, 2H), 1.38-1.23 (m, 2H), 0.97-0.86 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 171.9, 163.3, 153.2, 139.7, 132.5, 130.0, 123.3, 120.4, 117.0, 35.4, 31.6, 31.4, 22.7, 14.2. HRMS (C18H19O3 −): expected: 283.1339; found: 283.1326.
    • Compound 030 Methyl 4-(4-(tert-Pentyl)phenoxy)benzoate
  • Figure US20210107863A2-20210415-C00837
  • Following general procedure C, to a solution of 4-(4-(tert-pentyl)phenoxy)benzoic acid (122 mg, 0.43 mmol) in MeOH (2 mL) was added SOCl2 (0.1 mL, 1.4 mmol) at 0° C. and the reaction was then stirred at 80° C. in a sealed vessel for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 90% PE-EtOAc gradient to give the title compound as colorless oil (120 mg, 94%). 1H NMR (300 MHz, CDCl3) δ 8.05-7.94 (m, 2H), 7.39-7.28 (m, 2H), 7.04-6.92 (m, 4H), 3.89 (s, 3H), 1.65 (q, J=7.4 Hz, 2H), 1.30 (s, 6H), 0.71 (t, J=7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 166.8, 162.3, 153.1, 146.0, 131.8, 127.6, 124.3, 119.7, 117.2, 52.1, 37.8, 37.1, 28.7, 9.3. HRMS (C19H23O3 +): expected: 299.1642; found: 299.1640.
    • Compound 044 (±)-Methyl 4-(4-(bicyclo[2.2.2]octan-2-yl)phenoxy)benzoate
  • Figure US20210107863A2-20210415-C00838
  • Following general procedure C, to a solution of (±)-4-(4-(Bicyclo[2.2.2]octan-2-yl)phenoxy)benzoic acid (30.3 mg, 0.1 mmol) in toluene (1 mL) was added one drop of DMF followed by SOCl2 (0.02 mL, 0.3 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. A solution of NEt3 (0.2 mL, 1.4 mmol) in MeOH (1 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 85% PE-EtOAc gradient to give the title compound as colorless oil (29.3 mg, 93%). 1H NMR (300 MHz, CDCl3) δ 8.05-7.94 (m, 2H), 7.35-7.21 (m, 2H), 7.06-6.91 (m, 4H), 3.89 (s, 3H), 3.11-2.94 (m, 1H), 2.01 (dddd, J=12.9, 10.6, 3.9, 1.9 Hz, 1H), 1.85-1.45 (m, 10H), 1.43-1.23 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 166.8, 162.3, 153.3, 143.1, 131.8, 129.3, 124.3, 120.0, 117.1, 52.1, 41.4, 32.6, 31.2, 27.6, 26.1, 25.4, 24.9, 20.6. HRMS (C22H25O3 +): expected: 337.1798; found: 337.1778.
    • Compound 051 Ethyl 4-(4-butylphenoxy)benzoate
  • Figure US20210107863A2-20210415-C00839
  • Following general procedure A, to 4-butylphenol (1.75 mL, 11.4 mmol) and K2CO3 (1.89 g, 13.7 mmol) in DMSO (18 mL) was added ethyl 4-fluorobenzoate (1.35 mL, 9.2 mmol) and the reaction was then stirred at 120° C. for 3 days in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed first with 1 M aqueous NaOH (1×) then washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 70% PE-DCM gradient to give the title compound as colorless oil (1.72 g, 63%). 1H NMR (300 MHz, CDCl3) δ 8.05-7.94 (m, 2H), 7.24-7.13 (m, 2H), 7.02-6.91 (m, 4H), 4.36 (q, J=7.1 Hz, 2H), 2.67-2.56 (m, 2H), 1.69-1.53 (m, 2H), 1.47-1.23 (m, 5H), 0.95 (t, J=7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 166.3, 162.3, 153.5, 139.4, 131.7, 130.0, 124.7, 120.1, 117.1, 60.9, 35.1, 33.8, 22.5, 14.5, 14.1. HRMS (C19H23O3 +): expected: 299.1642; found: 299.1642.
    • Compound 071 6-(4-Propylphenoxy)nicotinic Acid
  • Figure US20210107863A2-20210415-C00840
  • Following general procedure B, to a solution of ethyl 6-(4-propylphenoxy)nicotinate (2.11 g, 7.4 mmol) in EtOH (15 mL) was added 2 M aqueous NaOH (10 mL, 20 mmol) and the reaction was stirred at room temperature for 48 hours. The reaction was acidified with 5 M aqueous HCl to adjust a pH of 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by recrystallization from hot EtOAc to give the title compound as colorless solid (1.26 g, 66%). 1H NMR (300 MHz, CDCl3) δ 11.01 (br, s, 1H), 8.92 (dd, J=2.4, 0.7 Hz, 1H), 8.31 (dd, J=8.7, 2.4 Hz, 1H), 7.28-7.18 (m, 2H), 7.12-7.02 (m, 2H), 6.94 (dd, J=8.7, 0.7 Hz, 1H), 2.61 (dd, J=8.7, 6.7 Hz, 2H), 1.76-1.58 (m, 2H), 0.97 (t, J=7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.5, 167.4, 151.4, 151.2, 141.2, 140.2, 129.9, 121.3, 120.3, 110.9, 37.6, 24.6, 14.0. HRMS (C15H14NO3 −): expected: 256.0979; found: 256.0979.
    • Compound 114 Methyl 6-(4-(adamantan-1-yl)phenoxy)nicotinate
  • Figure US20210107863A2-20210415-C00841
  • Following general procedure C, to a solution of 6-(4-(adamantan-1-yl)phenoxy)nicotinic acid (170 mg, 0.49 mmol) in MeOH (2 mL) was added SOCl2 (0.1 mL, 1.37 mmol) at room temperature and the reaction was then stirred at 80° C. in a sealed vessel for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 90% PE-EtOAc gradient to give the title compound as colorless solid (47 mg, 27%). 1H NMR (300 MHz, CDCl3) δ 8.84 (dd, J=2.4, 0.7 Hz, 1H), 8.25 (dd, J=8.6, 2.4 Hz, 1H), 7.46-7.35 (m, 2H), 7.15-7.04 (m, 2H), 6.90 (dd, J=8.6, 0.7 Hz, 1H), 3.91 (s, 3H), 2.11 (p, J=3.0 Hz, 4H), 1.93 (d, J=2.9 Hz, 6H), 1.87-1.68 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 166.7, 165.6, 150.9, 150.5, 148.4, 140.5, 126.3, 121.0, 120.7, 110.7, 52.2, 43.3, 36.8, 36.0, 29.0. HRMS (C23H26NO3 +): expected: 364.1907; found: 364.1900.
    • Compound 117 Ethyl 6-(4-Ethylphenoxy)nicotinate
  • Figure US20210107863A2-20210415-C00842
  • Following general procedure A, to 4-ethylphenol (1.36 g, 11.1 mmol) and K2CO3 (1.89 g, 13.7 mmol) in DMSO (18 mL) was added ethyl 6-chloronicotinate (1.65 mL, 10.9 mmol) and the reaction was then stirred at 80° C. for 48 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed first with 1 M aqueous NaOH (1×) then washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 60% PE-MeOH gradient to give the title compound as colorless oil (1.78 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.83 (dd, J=2.4, 0.7 Hz, 1H), 8.25 (dd, J=8.6, 2.4 Hz, 1H), 7.28-7.20 (m, 2H), 7.11-7.00 (m, 2H), 6.90 (dd, J=8.7, 0.8 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 2.68 (q, J=7.6 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 166.8, 165.2, 151.3, 150.5, 141.4, 140.6, 129.3, 121.4, 121.3, 110.7, 61.2, 28.4, 15.6, 14.4. HRMS (C16H18NO3 +): expected: 272.1281; found: 272.1271.
    • Compound 159 (±)-4-(4-(Bicyclo[2.2.1]heptan-2-yl)phenoxy)benzamide, Mixture of Endo and Exo
  • Figure US20210107863A2-20210415-C00843
  • Following general procedure D, to a solution of (±)-4-(4-(bicyclo[2.2.1]heptan-2-yl)phenoxy)benzoic acid (50.2 mg, 0.16 mmol) in toluene (0.8 mL) was added one drop of DMF followed by SOCl2 (0.04 mL, 0.55 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. 2 M ammonia in MeOH (0.6 mL, 1.3 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 10% PE-EtOAc gradient to give the title compound as colorless solid (46.6 mg, 93%, 6:1 mixture endo:exo). 1H NMR (300 MHz, CDCl3, mixture of rotamers 0.3:1, and diastereoisomers 6:1) δ 7.82-7.72 (m, 2H), 7.26-7.13 (m, 2H), 7.08-6.91 (m, 4H), 6.05 (s, 2H), 3.20 (major diastereomer, tt, J=14.0, 4.8 Hz, 0.85H), 2.79-2.70 (minor diastereomer, m, 0.15H), 2.46-2.29 (major diastereomer, m, 1.7H), 2.28-2.14 (minor diastereomer, m, 0.3H), 2.12-1.10 (m, 8H). 13C NMR (75 MHz, CDCl3, mixture of rotamers 0.3:1, and diastereoisomers 6:1) δ 169.0, 161.5, 161.4, 153.5, 153.3, 144.1, 140.1, 139.9, 129.8, 129.7, 129.5, 128.6, 127.5, 127.4, 119.9, 119.7, 119.6, 117.6, 117.5, 117.4, 50.3, 46.9, 46.6, 45.6, 43.6, 43.1, 42.7, 42.4, 42.2, 42.1, 41.6, 41.1, 40.7, 39.4, 37.7, 37.7, 37.0, 36.7, 36.4, 36.2, 34.6, 30.7, 30.3, 29.0, 24.7, 24.6, 23.0. HRMS (C20H22NO2 +): expected: 308.1645; found: 308.1624.
    • Compound 186 4-(4-(Adamantan-1-yl)phenoxy)-N-hydroxybenzamide
  • Figure US20210107863A2-20210415-C00844
  • Following general procedure D, to a solution of 4-(4-(adamantan-1-yl)phenoxy)benzoic acid (200 mg, 0.57 mmol) in toluene (2 mL) was added two drops of DMF followed by SOCl2 (0.1 mL, 1.37 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. Hydroxylamine hydrochloride (208 mg, 3 mmol) in a solution of NEt3 (1.0 mL, 7.2 mmol) and MeOH (2 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed first with 1 M aqueous HCl (1×) then washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 30% PE-EtOAc gradient to give the title compound as colorless solid (176 mg, 84%). 1H NMR (300 MHz, CDCl3/DMSO-d6) δ 11.10 (s, 1H), 8.87 (s, 1H), 7.80-7.69 (m, 2H), 7.37-7.26 (m, 2H), 6.98-6.86 (m, 4H), 2.09-2.01 (m, 4H), 1.85 (d, J=2.8 Hz, 6H), 1.81-1.63 (m, 6H). 13C NMR (75 MHz, CDCl3/DMSO-d6) δ 163.8, 159.7, 152.9, 146.7, 128.6, 126.7, 126.0, 118.9, 116.7, 42.6, 36.1, 35.3, 28.2. HRMS (C23H24NO3 −): expected: 362.1761; found: 362.1672.
    • Compound 195 4-(4-Isopropylphenoxy)-N-methylbenzamide
  • Figure US20210107863A2-20210415-C00845
  • Following general procedure D, to a solution of 4-(4-isopropylphenoxy)benzoic acid (177 mg, 0.7 mmol) in toluene (2.5 mL) was added two drops of DMF followed by SOCl2 (0.15 mL, 2.1 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. 33 wt % methylamine in EtOH (2 mL, 16 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 40% PE-EtOAc gradient to give the title compound as colorless solid (178 mg, 94%). 1H NMR (300 MHz, CDCl3) δ 7.78-7.67 (m, 2H), 7.27-7.16 (m, 2H), 7.01-6.90 (m, 4H), 6.31 (s, 1H), 2.98 (d, J=4.6 Hz, 3H), 2.90 (hept, J=6.9 Hz, 1H), 1.26 (d, J=6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 167.8, 160.8, 153.8, 145.1, 128.8, 128.8, 127.9, 119.8, 117.5, 33.6, 26.9, 24.2. HRMS (C17H18NO2 −): expected: 268.1343; found: 268.1384.
    • Compound 222 4-(4-(tert-Butyl)phenoxy)-N,N-dimethylbenzamide
  • Figure US20210107863A2-20210415-C00846
  • Following general procedure D, to a solution of 4-(4-(tert-butyl)phenoxy)benzoic acid (154 mg, 0.57 mmol) in toluene (2.5 mL) was added two drops of DMF followed by SOCl2 (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. 2 M dimethylamine in THF (2.5 mL, 5 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 40% PE-EtOAc gradient to give the title compound as colorless oil (166 mg, 98%). 1H NMR (300 MHz, CDCl3) δ 7.44-7.31 (m, 4H), 7.03-6.91 (m, 4H), 3.06 (s, 6H), 1.33 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 171.4, 159.1, 153.9, 147.0, 130.6, 129.2, 126.8, 119.2, 117.8, 39.9 (br), 35.6 (br), 34.5, 31.6. HRMS (C19H24NO2+): expected: 298.1802; found: 298.1820.
    • Compound 241 6-(p-Tolyloxy)nicotinamide
  • Figure US20210107863A2-20210415-C00847
  • Following general procedure D, to a solution of 6-(p-tolyloxy)nicotinic acid (148 mg, 0.66 mmol) in toluene (2.5 mL) was added two drops of DMF followed by SOCl2 (0.12 mL, 1.6 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. 2 M ammonia in MeOH (3 mL, 1.3 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 20% PE-EtOAc gradient to give the title compound as colorless solid (104 mg, 70%). 1H NMR (300 MHz, CDCl3/DMSO-d6, mixture of rotamers 0.3:1) δ 8.89 (d, J=2.5 Hz, 0.25H, minor rotamer), 8.65 (d, J=2.4 Hz, 0.75H, major rotamer), 8.25 (dt, J=8.6, 2.9 Hz, 1H), 7.96 (br, s, 1H), 7.49 (d, J=8.4 Hz, 0.25H, minor rotamer), 7.27 (br, s, 1H), 7.21 (d, J=8.2 Hz, 2H), 7.06-6.97 (m, 2H), 6.93 (d, J=8.6 Hz, 0.75H, major rotamer), 2.35 (s, 3H). 13C NMR (75 MHz, CDCl3/DMSO-d6, mixture of rotamers 0.3:1) δ 166.6, 165.9 (minor rotamer), 165.4 (major rotamer), 153.3 (minor rotamer), 151.5 (major rotamer), 149.7 (minor rotamer), 148.0 (major rotamer), 139.5 (major rotamer), 138.9 (minor rotamer), 134.4, 130.3, 129.3 (minor rotamer), 125.2 (major rotamer), 124.1 (minor rotamer), 121.4, 110.5 (major rotamer), 20.9. HRMS (C13H13N2O2 +): expected: 229.0972; found: 229.0978.
    • Compound 275 N-Hydroxy-6-(4-(trifluoromethyl)phenoxy)nicotinamide
  • Figure US20210107863A2-20210415-C00848
  • Following general procedure D, to a solution of 6-(4-(trifluoromethyl)phenoxy)nicotinic acid (62.9 mg, 0.22 mmol) in toluene (1.5 mL) was added two drops of DMF followed by SOCl2 (0.06 mL, 0.82 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. Hydroxylamine hydrochloride (94 mg, 1.35 mmol) in a solution of NEt3 (0.5 mL, 3.6 mmol) and MeOH (1 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 40% PE-EtOAc (+0.2% AcOH) gradient to give the title compound as colorless solid (42.7 mg, 65%). 1H NMR (300 MHz, CDCl3/DMSO-d6) δ 11.29 (s, 1H), 9.07 (s, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.19 (dd, J=8.6, 2.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.5 Hz, 1H). 13C NMR (75 MHz, CDCl3/DMSO-d6) δ 163.6, 161.9, 156.2 (d, J=1.5 Hz), 146.4, 138.8, 126.6 (q, J=3.8 Hz), 125.6 (q, J=32.4 Hz), 124.2, 123.8 (q, J=273.0 Hz), 121.5, 111.1. HRMS (C13H8F3N2O3 −): expected: 297.0492; found: 297.0597.
    • Compound 284 6-(4-Cyclohexylphenoxy)-N-hydroxynicotinamide
  • Figure US20210107863A2-20210415-C00849
  • Following general procedure D, to a solution of 6-(4-cyclohexylphenoxy)nicotinic acid (150 mg, 0.5 mmol) in toluene (2 mL) was added two drops of DMF followed by SOCl2 (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. Hydroxylamine hydrochloride (208 mg, 3 mmol) in a solution of NEt3 (1.0 mL, 7.2 mmol) and MeOH (2 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 95% PE-EtOAc gradient to give the title compound as colorless solid (150 mg, 95%). 1H NMR (300 MHz, CDCl3/DMSO-d6) δ 11.27 (s, 1H), 9.05 (s, 1H), 8.54 (s, 1H), 8.20-8.06 (m, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz, 2H), 6.95 (d, J=8.6 Hz, 1H), 1.86 (d, J=8.3 Hz, 4H), 1.74 (d, J=12.6 Hz, 1H), 1.43 (q, J=11.3, 10.1 Hz, 4H), 1.35-1.16 (m, 2H). 13C NMR (75 MHz, CDCl3/DMSO-d6) δ 163.4, 160.9, 149.8, 145.2, 142.8, 137.1, 126.2, 122.0, 119.5, 109.0, 41.9, 32.7, 25.0, 24.2. HRMS (C18H21N2O3 +): expected: 313.1547; found: 313.1622.
    • Compound 297 6-(4-Isopropylphenoxy)-N-methylnicotinamide
  • Figure US20210107863A2-20210415-C00850
  • Following general procedure D, to a solution of 6-(4-isopropylphenoxy)nicotinic acid (151 mg, 0.6 mmol) in toluene (2.5 mL) was added two drops of DMF followed by SOCl2 (0.1 mL, 1.5 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. 33 wt % methylamine in EtOH (2.5 mL, 20 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 20% PE-EtOAc gradient to give the title compound as colorless solid (150 mg, 96%). 1H NMR (300 MHz, CDCl3) δ 8.55 (dd, J=2.5, 0.7 Hz, 1H), 8.11 (dd, J=8.6, 2.5 Hz, 1H), 7.32-7.21 (m, 2H), 7.11-7.00 (m, 2H), 6.90 (dd, J=8.6, 0.7 Hz, 1H), 6.47 (d, J=5.3 Hz, 1H), 2.98 (d, J=4.7 Hz, 3H), 2.94 (hept, J=7.0 Hz, 1H), 1.27 (d, J=6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 166.1, 165.8, 151.4, 146.6, 145.9, 139.0, 127.8, 125.3, 121.1, 111.0, 33.7, 26.9, 24.1. HRMS (C16H19N2O2 +): expected: 271.1441; found: 271.1491.
    • Compound 322 6-(4-Isopropylphenoxy)-N,N-dimethylnicotinamide
  • Figure US20210107863A2-20210415-C00851
  • Following general procedure D, to a solution of 6-(4-isopropylphenoxy)nicotinic acid (156 mg, 0.6 mmol) in toluene (2.5 mL) was added two drops of DMF followed by SOCl2 (0.1 mL, 1.5 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. 2 M dimethylamine in THF (2.5 mL, 5.4 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 30% PE-EtOAc gradient to give the title compound as colorless oil (169 mg, 98%). 1H NMR (300 MHz, CDCl3) δ 8.28 (dd, J=2.4, 0.8 Hz, 1H), 7.79 (dd, J=8.5, 2.4 Hz, 1H), 7.31-7.20 (m, 2H), 7.11-7.00 (m, 2H), 6.91 (dd, J=8.5, 0.7 Hz, 1H), 3.07 (s, 6H), 2.92 (hept, J=7.0 Hz, 1H), 1.26 (dd, J=6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 168.9, 164.5, 151.4, 146.8, 145.6, 139.2, 127.7, 126.6, 121.0, 111.0, 39.7 (br), 35.6 (br), 33.6, 24.1. HRMS (C17H21N2O2 +): expected: 285.1598; found: 285.1643.
    • Compound 344 4-(4-(Butylphenoxy)-3-fluorobenzoic Acid
  • Figure US20210107863A2-20210415-C00852
  • Following general procedure B, to a solution of ethyl 4-(4-butylphenoxy)-3-fluorobenzoate (1.42 g, 4.5 mmol) in EtOH (9 mL) was added 2 M aqueous NaOH (5 mL, 10 mmol) and the reaction was stirred at room temperature overnight. 1 M aqueous HCl was added to adjust a pH of 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by recrystallization from hot EtOAc to give the title compound as colorless solid (0.56 g, 43%). 1H NMR (300 MHz, CDCl3) δ 11.18 (br, s, 1H), 7.91 (dd, J=11.0, 2.0 Hz, 1H), 7.82 (ddd, J=8.6, 2.0, 1.1 Hz, 1H), 7.26-7.15 (m, 2H), 7.04-6.88 (m, 3H), 2.68-2.57 (m, 2H), 1.70-1.54 (m, 2H), 1.47-1.23 (m, 2H), 0.95 (t, J=7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 171.0 (d, J=2.5 Hz), 153.3, 152.9 (d, J=249.5 Hz), 150.8 (d, J=11.0 Hz), 139.7, 130.1, 127.3 (d, J=3.5 Hz), 124.3 (d, J=6.5 Hz), 119.4, 118.9 (d, J=19.9 Hz), 118.6 (d, J=1.4 Hz), 35.1, 33.8, 22.5, 14.1. HRMS (C17H16FO3 −): expected: 287.1089; found: 287.1062.
    • Compound 395 Ethyl 4-(4-butylphenoxy)-3-fluorobenzoate
  • Figure US20210107863A2-20210415-C00853
  • Following general procedure A, to 4-butylphenol (1.75 mL, 11.4 mmol) and K2CO3 (1.90 g, 13.8 mmol) in DMSO (18 mL) was added ethyl 3,4-difluorobenzoate (1.37 mL, 9 mmol) and the reaction was then stirred at 80° C. for 24 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed first with 1 M aqueous NaOH (1×) then washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 80% PE-DCM gradient to give the title compound as colorless oil (1.80 g, 63%). 1H NMR (300 MHz, CDCl3) δ 7.84 (dd, J=11.2, 2.0 Hz, 1H), 7.75 (ddd, J=8.5, 2.0, 1.2 Hz, 1H), 7.23-7.12 (m, 2H), 7.01-6.88 (m, 3H), 4.37 (q, J=7.1 Hz, 2H), 2.67-2.55 (m, 2H), 1.68-1.52 (m, 2H), 1.46-1.23 (m, 5H), 0.94 (t, J=7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.4 (d, J=2.6 Hz), 153.7, 153.0 (d, J=249.0 Hz), 149.5 (d, J=11.2 Hz), 139.3, 129.9, 126.4 (d, J=3.5 Hz), 126.0 (d, J=6.3 Hz), 119.0, 119.0 (d, J=1.4 Hz), 118.3 (d, J=19.9 Hz), 61.3, 35.1, 33.8, 22.5, 14.4, 14.1. HRMS (C19H22FO3 +): expected: 317.1548; found: 317.1549.
    • Compound 451 Methyl 5-fluoro-6-(4-(tert-pentyl)phenoxy)nicotinate
  • Figure US20210107863A2-20210415-C00854
  • Following general procedure C, to a solution of 5-fluoro-6-(4-(tert-pentyl)phenoxy)nicotinic acid (100 mg, 0.33 mmol) in MeOH (2 mL) was added SOCl2 (0.1 mL, 1.4 mmol) at 0° C. and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 90% PE-EtOAc gradient to give the title compound as colorless solid (30 mg, 29%). 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=1.9 Hz, 1H), 8.02 (dd, J=10.0, 1.9 Hz, 1H), 7.43-7.31 (m, 2H), 7.17-7.04 (m, 2H), 3.92 (s, 3H), 1.66 (q, J=7.4 Hz, 2H), 1.31 (s, 6H), 0.72 (t, J=7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 164.8 (d, J=1.6 Hz), 155.7 (d, J=11.1 Hz), 150.4, 147.1 (d, J=261.8 Hz), 146.9, 144.4 (d, J=6.1 Hz), 127.4, 125.0 (d, J=17.0 Hz), 122.1 (d, J=1.7 Hz), 120.7, 52.6, 37.9, 37.1, 28.6, 9.3. HRMS (C18H21FNO3 +): expected: 318.1500; found: 318.1555.
    • Compound 544 4-(4-(Adamantan-1-yl)phenoxy)-3-fluoro-N-hydroxybenzamide
  • Figure US20210107863A2-20210415-C00855
  • Following general procedure D, to a solution of 4-(4-(adamantan-1-yl)phenoxy)-3-fluorobenzoic acid (110 mg, 0.3 mmol) in toluene (2 mL) was added two drops of DMF followed by SOCl2 (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. NEt3 (0.7 mL, 5.1 mmol) and hydroxylamine hydrochloride (148 mg, 2.1 mmol) in MeOH (1.5 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography twice, eluting first with a 100% to 40% PE-EtOAc gradient and then with a 100% to 97% DCM-MeOH gradient to give the title compound as colorless solid (60 mg, 52%). 1H NMR (300 MHz, CDCl3/DMSO-d6) δ 11.23 (s, 1H), 9.00 (s, 1H), 7.68 (dd, J=11.6, 2.0 Hz, 1H), 7.57 (ddd, J=8.5, 2.1, 1.1 Hz, 1H), 7.37-7.25 (m, 2H), 6.97 (t, J=8.4 Hz, 1H), 6.96-6.86 (m, 2H), 2.12-1.97 (m, 4H), 1.84 (d, J=2.9 Hz, 6H), 1.80-1.63 (m, 6H). 13C NMR (75 MHz, CDCl3/DMSO-d6) δ 162.4, 153.2, 152.4 (d, J=247.5 Hz), 146.6, 146.3 (d, J=11.1 Hz), 128.4 (d, J=5.7 Hz), 126.0, 123.5, 119.5, 117.4, 115.5 (d, J=19.6 Hz), 42.6, 36.1, 35.3, 28.2. HRMS (C23H23FNO3 −): expected: 380.1667; found: 380.1541.
    • Compound 644 6-(4-Cyclohexylphenoxy)-5-fluoro-N-hydroxynicotinamide
  • Figure US20210107863A2-20210415-C00856
  • Following general procedure D, to a solution of 6-(4-cyclohexylphenoxy)-5-fluoronicotinic acid (120 mg, 0.4 mmol) in toluene (2.5 mL) was added two drops of DMF followed by SOCl2 (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. Hydroxylamine hydrochloride (208 mg, 3 mmol) in a solution of NEt3 (1.0 mL, 7.2 mmol) and MeOH (2 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 30% PE-EtOAc gradient to give the title compound as colorless solid (110 mg, 88%). 1H NMR (300 MHz, CDCl3/DMSO-d6) δ 11.32 (s, 1H), 9.12 (s, 1H), 8.28 (d, J=1.9 Hz, 1H), 8.06-7.94 (m, 1H), 7.26-7.15 (m, 2H), 7.08-6.97 (m, 2H), 1.88-1.75 (m, 4H), 1.75-1.64 (m, 1H), 1.48-1.31 (m, 4H), 1.31-1.13 (m, 2H). 13C NMR (75 MHz, CDCl3/DMSO-d6) δ 161.0, 153.2 (d, J=11.3 Hz), 150.4, 146.3 (d, J=259.6 Hz), 144.4, 140.6, 127.4, 124.5, 123.1 (d, J=16.7 Hz), 120.7, 43.2, 34.0, 26.2, 25.5. HRMS (C18H18FN2O3 −): expected: 329.1307; found: 329.1279.
    • Compound 703 4-(4-(1-(Trifluoromethyl)cyclopropyl)phenoxy)benzoic Acid
  • Figure US20210107863A2-20210415-C00857
  • Following general procedure B, to a solution of ethyl 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate (0.86 g, 2.5 mmol) in EtOH (20 mL) was added 2 M aqueous NaOH (10 mL, 20 mmol) and the reaction was stirred at room temperature overnight. 1 M aqueous HCl was added to adjust a pH of 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 75% PE-EtOAc (+0.2% AcOH) gradient to give the title compound as slightly yellow solid (0.75 g, 95%). 1H NMR (300 MHz, CDCl3) δ 11.15 (br, s, 1H), 8.15-8.04 (m, 2H), 7.54-7.43 (m, 2H), 7.09-6.98 (m, 4H), 1.38 (dd, J=6.7, 5.1 Hz, 2H), 1.07-1.01 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 171.8, 162.3, 155.7, 133.2, 132.6, 132.5, 126.5 (q, J=273.4 Hz), 124.0, 119.9, 117.8, 27.8 (q, J=33.7 Hz), 10.0 (q, J=2.4 Hz). HRMS (C17H12F3O3 −): expected: 321.0744; found: 321.0712.
    • Compound 712 Methyl 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate
  • Figure US20210107863A2-20210415-C00858
  • Following general procedure C, to a solution of 4-(4-(1-(Trifluoromethyl)cyclopropyl)phenoxy)benzoic acid (112 mg, 0.35 mmol) in toluene (2 mL) was added two drops of DMF followed by SOCl2 (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. A solution of NEt3 (0.6 mL, 4.4 mmol) in MeOH (1.2 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 85% PE-EtOAc gradient to give the title compound as colorless oil (176 mg, 93%). 1H NMR (300 MHz, CDCl3) δ 8.07-7.96 (m, 2H), 7.52-7.41 (m, 2H), 7.07-6.95 (m, 4H), 3.90 (s, 3H), 1.41-1.31 (m, 2H), 1.09-0.97 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 166.7, 161.4, 156.0, 133.1, 132.2, 131.9, 126.4 (q, J=273.0 Hz), 125.0, 119.7, 117.9, 52.2, 27.8 (q, J=33.6 Hz), 10.0 (q, J=2.5 Hz). HRMS (C18H16F3O3 +): expected: 337.1046; found: 337.1036.
    • Compound 729 Ethyl 4-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-benzoate
  • Figure US20210107863A2-20210415-C00859
  • Following general procedure A, to 2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenol (245 mg, 1.5 mmol) and K2CO3 (220 mg, 1.6 mmol) in DMSO (2 mL) was added ethyl 4-fluorobenzoate (0.15 mL, 1.1 mmol) and the reaction was then stirred at 120° C. for 2 days in an argon atmosphere. K2CO3 (220 mg, 1.6 mmol) was added and the reaction was then stirred at 150° C. for 9 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 70% PE-DCM gradient to give the title compound as yellow oil (100 mg, 18%). 1H NMR (300 MHz, CDCl3) 8.08-7.97 (m, 2H), 7.58 (d, J=2.1 Hz, 1H), 7.41-7.27 (m, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.03-6.88 (m, 2H), 4.36 (q, J=7.1 Hz, 2H), 1.44-1.33 (m, 5H), 1.11-1.00 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 166.0, 160.7, 151.3, 133.9, 133.8, 131.7, 131.1, 126.2, 126.0 (q, J=273.4 Hz), 125.5, 121.6, 116.8, 60.9, 27.6 (q, J=33.1 Hz), 14.4, 10.0 (q, J=2.3 Hz). HRMS (C19H17C1F3O3 +): expected: 385.0813; found: 385.0796.
    • Compound 730 6-(4-(1-(Trifluoromethyl)cyclopropyl)phenoxy)nicotinic Acid
  • Figure US20210107863A2-20210415-C00860
  • Following general procedure B, to a solution of ethyl 6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinate (1.47 g, 4.2 mmol) in EtOH (20 mL) was added 2 M aqueous NaOH (10 mL, 20 mmol) and the reaction was stirred at room temperature overnight. 1 M aqueous HCl was added to adjust a pH of 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 75% PE-EtOAc (+0.2% AcOH) gradient to give the title compound as colorless solid (1.21 g, 90%). 1H NMR (300 MHz, CDCl3/DMSO-d6) δ 12.16 (s, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.30 (dd, J=8.6, 2.3 Hz, 1H), 7.51 (dd, J=8.1, 1.6 Hz, 2H), 7.19-7.08 (m, 2H), 6.97 (d, J=8.6 Hz, 1H), 1.41-1.30 (m, 2H), 1.18-1.02 (m, 2H). 13C NMR (75 MHz, CDCl3/DMSO-d6) δ 166.1, 165.3, 152.9, 149.8, 140.5, 132.2, 132.2, 125.9 (q, J=273.1 Hz), 121.8, 120.7, 110.5, 27.1 (q, J=33.5 Hz), 9.3 (q, J=2.4 Hz). HRMS (C16H13F3NO3 +): expected: 324.0842; found: 324.0847.
    • Compound 749 Ethyl 6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinate
  • Figure US20210107863A2-20210415-C00861
  • Following general procedure A, to 4-(1-(perfluoroethyl)cyclopropyl)phenol (330 mg, 1.3 mmol) and K2CO3 (305 mg, 2.2 mmol) in DMSO (2.7 mL) was added ethyl 6-chloronicotinate (0.2 mL, 1.3 mmol) and the reaction was then stirred at 80° C. for 3 days in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed first with 1 M aqueous NaOH (1×) then washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 90% PE-EtOAc gradient to give the title compound as yellow oil (445 mg, 88%). 1H NMR (300 MHz, CDCl3) δ 8.83 (dd, J=2.4, 0.7 Hz, 1H), 8.28 (dd, J=8.6, 2.4 Hz, 1H), 7.48 (d, J=8.6 Hz, 2H), 7.14-7.07 (m, 2H), 6.93 (dd, J=8.6, 0.7 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.43-1.34 (m, 5H), 1.12-1.04 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 166.14, 165.10, 153.39, 150.44, 140.84, 133.21, 133.12, 121.86, 121.20, 111.12, 61.31, 25.88 (t, J=23.9 Hz), 14.42, 10.02 (t, J=4.0 Hz). The two multiplets of the CF2 (tq) and the CF3 (qt) are too weak to be resolved. HRMS (C19H17F5NO3 +): expected: 402.1123; found: 402.1124.
    • Compound 784 N,N-Dimethyl-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-benzamide
  • Figure US20210107863A2-20210415-C00862
  • Following general procedure D, to a solution of 4-(4-(1-(Trifluoromethyl)cyclopropyl)phenoxy)benzoic acid (101 mg, 0.3 mmol) in toluene (2 mL) was added two drops of DMF followed by SOCl2 (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. 2 M dimethylamine in THF (1.2 mL, 2.5 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 15% PE-EtOAc gradient to give the title compound as colorless oil (110 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 7.48-7.37 (m, 4H), 7.06-6.92 (m, 4H), 3.06 (d, J=9.8 Hz, 6H), 1.39-1.28 (m, 2H), 1.07-0.95 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 171.2, 158.2, 156.7, 133.0, 131.6, 131.4, 129.3, 126.5 (q, J=272.1 Hz), 119.0, 118.6, 39.8 (br), 35.6 (br), 27.7 (q, J=33.7 Hz), 10.0 (q, J=2.5 Hz). HRMS (C19H19F3NO2 +): expected: 350.1363; found: 350.1351.
    • Compound 820 N,N-Dimethyl-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-nicotinamide
  • Figure US20210107863A2-20210415-C00863
  • Following general procedure D, to a solution of 6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy) nicotinic acid (162 mg, 0.5 mmol) in toluene (2 mL) was added two drops of DMF followed by SOCl2 (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. 2 M dimethylamine in THF (2.5 mL, 5 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 30% PE-EtOAc gradient to give the title compound as colorless solid (172 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 8.28 (dd, J=2.4, 0.8 Hz, 1H), 7.82 (dd, J=8.5, 2.4 Hz, 1H), 7.54-7.44 (m, 2H), 7.16-7.06 (m, 2H), 6.96 (dd, J=8.5, 0.8 Hz, 1H), 3.18-2.96 (m, 6H), 1.40-1.29 (m, 2H), 1.10-0.98 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 168.8, 163.9, 153.5, 146.7, 139.3, 132.7, 132.7, 127.1, 126.3 (q, J=274.0 Hz), 121.0, 111.4, 39.7 (br), 35.63 (br), 27.7 (q, J=33.6 Hz), 9.8 (q, J=2.5 Hz). HRMS (C18H18F3N2O2 +): expected: 351.1315; found: 351.1293.
    • Synthesis of Intermediates (±)-4-(Bicyclo[2.2.1]heptan-2-yl)phenol, Mixture of Endo and Exo
  • Figure US20210107863A2-20210415-C00864
  • To a solution of 4-acetoxystyrene (3 mL, 20 mmol) in dicyclopentadiene (3 mL, 22 mmol) was added hydroquinone (10 mg, 0.1 mmol). The reaction vessel was purged with argon and sealed. The reaction mixture was stirred at 160° C. for 24 h. The reaction mixture was filtered through silica and washed with DCM. The solution was concentrated in vacuo and used in the next step without further purification.
  • The resulting oil was dissolved in EtOAc (40 mL). Under an argon atmosphere, palladium on charcoal (5% Pd, 0.2 g, 0.1 mmol) was added and the reaction vessel was flushed with H2. The reaction was stirred strongly for 22 h at room temperature. The reaction mixture was then purged back with argon, filtered through celite, washed with EtOAc, and concentrated in vacuo. The crude mixture was then filtered on silica (PE/EtOAc), concentrated in vacuo and used in the next step without further purification.
  • The resulting oil was dissolved in EtOH (40 mL), and 2 M aqueous NaOH (20 mL, 40 mmol) was added. The reaction mixture was stirred for 17 h at room temperature. The reaction was quenched with 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 0% PE-DCM gradient. Recrystallization in hot PE afforded the title compound as white needles (1.5 g, 40% over three steps, 7:1 mixture endo:exo)
    • (±)-4-(Bicyclo[2.2.2]octan-2-yl)phenol
  • Figure US20210107863A2-20210415-C00865
  • To a solution of 4-acetoxystyrene (3 mL, 20 mmol) in cyclohexadiene (2.1 mL, 22 mmol) was added hydroquinone (10 mg, 0.1 mmol). The reaction vessel was purged with argon and sealed. The reaction mixture was stirred at 160° C. for 24 h. The reaction mixture was filtered through silica and washed with DCM. The solution was concentrated in vacuo and used in the next step without further purification.
  • The resulting oil was dissolved in EtOAc (40 mL). Under an argon atmosphere, palladium on charcoal (5% Pd, 0.2 g, 0.1 mmol) was added and the reaction vessel was flushed with H2. The reaction was stirred strongly for 22 h. The reaction mixture was then purged back with argon, filtered through celite, washed with EtOAc, and concentrated in vacuo. The crude mixture was then filtered on silica (PE/DCM), concentrated in vacuo and used in the next step without further purification.
  • The resulting oil was dissolved in EtOH (40 mL), and 2 M aqueous NaOH (20 mL, 40 mmol) was added. The reaction mixture was stirred for 17 h at room temperature. The reaction was quenched with 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 0% PE-DCM gradient. Recrystallization in hot PE afforded the title compound as white needles (0.6 g, 15% over three steps)
    • 4-(1-(Trifluoromethyl)cyclopropyl)phenol
  • Figure US20210107863A2-20210415-C00866
  • Following a procedure from Anderson, K. W. et al., J. Am. Chem. Soc., 2006, 128 (33), 10694-10695, to a solution of KOH (2.6 g, 46.3 mmol), Pd2dba3 (278 mg, 0.30 mmol), and di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphate (510 mg, 1.20 mmol) in degassed 1,4-dioxane (7.5 mL) and water (7.5 mL) under argon was added 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene (3.98 g, 15.0 mmol). The reaction vessel was then sealed and immerged in a pre-heated oil bath at 100° C. The reaction was stirred for 4-10 h. The reaction was quenched with 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 90% PE-EtOAc gradient to give the title compound as a yellow oil (3.0 g, 99%).
    • 2-Chloro-4-(1-(trifluoromethyl)cyclopropyl)phenol
  • Figure US20210107863A2-20210415-C00867
  • To a solution of 4-(1-(trifluoromethyl)cyclopropyl)phenol (1.03 g, 5.1 mmol) in DCE (25 mL) under argon at 0° C. were added N-chlorosuccinimide (737 mg, 5.52 mmol) and aluminium trichloride (740 mg, 5.55 mmol). The reaction mixture was stirred at 0° C. for 3 h, before being quenched with water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 80% PE-EtOAc gradient to give the title compound as a yellow oil (380 mg, 31%).
    • 6-Chloro-5-fluoronicotinic Acid
  • Figure US20210107863A2-20210415-C00868
  • To a solution of 2-chloro-3-fluoro-5-methylpyridine (512 mg, 3.52 mmol) in pyridine (2.5 mL) and water (2.5 mL) was added one portion of potassium permanganate (1.1 g, 6.9 mmol). The reaction mixture was heated to 100° C. Two more equal portion of potassium permanganate (for a total of 3.3 g, 20.7 mmol) were added after respectively 1 h and 2 h of stirring at 100° C. When needed, the solid accumulated in the condenser were washed down with water and pyridine. After another 1 h of stirring at 100° C., the reaction mixture was cooled down to room temperature. The reaction mixture was quenched with saturated aqueous Na2S2O3 and stirred 30 minutes. The mixture was filtered, then acidified to pH 2 with HCl 5 M. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 90% to 70% PE-EtOAc gradient to give the title compound as a white solid (300 mg, 49%).
    • 6-Chloro-5-fluoronicotinic Acid Ethyl Ester
  • Figure US20210107863A2-20210415-C00869
  • To a solution of 6-chloro-5-fluoronicotinic acid (5.1 g, 29.1 mmol) in EtOH (150 mL) at 0° C. was added SOCl2 (4.5 mL, 61.7 mmol). The mixture was heated at reflux for 4 h. The reaction mixture was allowed to cool down to room temperature, and the reaction was quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 80% PE-EtOAc gradient to give the title compound as a white solid (5.28 mg, 89%).
    • 1-(4-Bromophenyl)-N-cyclohexylethan-1-imine
  • Figure US20210107863A2-20210415-C00870
  • Following a procedure from Mercadante, M. A., et al., Chemical Science, 2014, 5, 3983-3994, to a solution of 4′-bromoacetophenone (10.0 g, 50.2 mmol) and p-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol) in toluene (70 mL) was added cyclohexylamine (6.1 mL, 53.5 mmol) and the mixture was stirred at reflux with a Dean-Stark for 21 h. The reaction mixture was allowed to cool down to room temperature and PE was added (100 mL). The p-toluenesulfonic acid precipitated and could be filtered off. The solid was washed with PE (2×). The filtrate was concentrate in vacuo to afford crude product that was recrystallized from hot PE to give the title compound as slightly yellow flakes (12.4 g, 88%).
    • (Iodomethyl)dimethylphenylsilane
  • Figure US20210107863A2-20210415-C00871
  • Following a procedure from Mercadante, M. A., et al., Chemical Science, 2014, 5, 3983-3994, to a solution of (chloromethyl)dimethylphenylsilane (4.9 mL, 27 mmol) in acetone (30 mL) was added sodium iodide (7.1 g, 47.3 mmol). The reaction mixture was then stirred at reflux for 19 h. The mixture was concentrated in vacuo, filtered over celite, and the solid washed with PE (60 mL). The solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 70% PE-DCM gradient to give the title compound as a yellow oil (7.1 g, 95%).
    • 1-(4-Bromophenyl)-3-(dimethyl(phenyl)silyl)propan-1-one
  • Figure US20210107863A2-20210415-C00872
  • Following a procedure from Mercadante, M. A., et al., Chemical Science, 2014, 5, 3983-3994, to a solution of 1-(4-bromophenyl)-N-cyclohexylethan-1-imine (5.6 g, 20 mmol) in THF (10 mL) at 0° C. was slowly added freshly prepared LDA in THF (approximatively 1.5 M, 15 mL, 22 mmol) dropwise. The mixture was stirred 1 h at 0° C. before adding (iodomethyl)dimethylphenylsilane (6.1 g, 22 mmol). The reaction was stirred for another 1 h at 0° C. before quenching with a buffer aqueous solution of sodium acetate (29.5 g, 360 mmol), acetic acid (10.3 mL, 180 mmol) in water (11 mL). The mixture was stirred for 15 minutes before being diluted with water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 95% PE-EtOAc gradient to give the title compound as a yellow solid (5.24 g, 75%).
    • Trimethyl(perfluoroethyl)silane
  • Figure US20210107863A2-20210415-C00873
  • A solution of n-BuLi (2.3 M in cyclohexane, 9 mL, 20.7 mmol) in THF (40 mL) was stirred at −90° C. (Acetone/N2). The system was purged with an atmosphere of pentafluoroethane and the system was kept between −78° C. and −90° C. for 1 h, then slowly warmed to −65° C. and stirred for another 0.5 h. A solution of TMSCl (2.55 mL, 20 mmol) in THF (5 mL) was added and the mixture was allowed to warm-up slowly in the acetone bath and stirred for 15 h at room temperature. The solution was then distilled to obtain the title compound as a solution in THF (65 mL).
    • 4-(1-(Perfluoroethyl)cyclopropyl)phenol
  • Figure US20210107863A2-20210415-C00874
  • Following a procedure from Mercadante, M. A., et al., Chemical Science, 2014, 5, 3983-3994, to the solution of trimethyl(perfluoroethyl)silane in THF previously obtained (60 mL) at 0° C. was added 1-(4-bromophenyl)-3-(dimethyl(phenyl)silyl)propan-1-one (4.9 g, 14.2 mmol). The mixture was stirred for 10 minutes and TBAF (1 M solution in THF, 0.14 mL, 0.14 mmol) was added and the reaction mixture was stirred at room temperature for 7.5 h. The reaction mixture was cooled down to 0° C., water (1.4 mL) and TBAF (1 M solution in THF, 1.4 mL, 1.4 mmol) were added and the reaction mixture was stirred at room temperature for 14 h. The reaction was quenched with water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 95% PE-EtOAc gradient to give 3-(4-bromophenyl)-5-(dimethyl(phenyl)silyl)-1,1,1,2,2-pentafluoropentan-3-ol as a mixture with the starting 1-(4-bromophenyl)-3-(dimethyl(phenyl)silyl)propan-1-one (4.9 g, 1:1 ratio by NMR) due to similar polarity.
  • To a solution of the previous alcohol/ketone mixture (4.5 g, containing approximatively 5.5 mmol of 3-(4-bromophenyl)-5-(dimethyl(phenyl)silyl)-1,1,1,2,2-pentafluoropentan-3-ol) in THF (25 mL) at 0° C. was added NaH (60 wt % in oil, 565 mg, 14.1 mmol). The mixture was stirred at room temperature for 45 minutes. The reaction was cooled down to 0° C. and MSCl (0.9 mL, 11.6 mmol) was added dropwise. After stirring at room temperature for 2 h, the reaction mixture was cooled down to 0° C. and quenched with water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with water, saturated aqueous NaHCO3, brine (1×), dried over Na2SO4, filtered and concentrated in vacuo.
  • To the resulting oil at 0° C. was added a mixture of pyridine (0.9 mL, 11.2 mmol) and 1,1,1,3,3,3-Hexafluoropropan-2-ol (8 mL). The flask was sealed and the reaction mixture was stirred for 12.5 h. The reaction was quenched with water. The aqueous layer was extracted with PE (3×). The combined organics were washed with aqueous HCl 1 M, water, saturated aqueous NaHCO3 and brine (1×), dried over Na2SO4, filtered and concentrated in vacuo (water bath at 25° C., no lower than 200 mbar, the desired product is volatile). The residue was purified by silica gel flash chromatography eluting with 100% PE to give 1-bromo-4-(1-(perfluoroethyl)cyclopropyl)benzene. As it is a highly volatile product, the PE was not fully removed and the product was directly subjected to the next step. By further eluting the column with 9:1 PE/EtOAc, 1.7 g of the starting 1-(4-bromophenyl)-3-(dimethyl(phenyl)silyl)propan-1-one was recovered.
  • Following a procedure from Anderson, K. W. et al., J. Am. Chem. Soc., 2006, 128 (33), 10694-10695, to a solution of KOH (900 m16.0 mmol), Pd2dba3 (93 mg, 0.10 mmol), and di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphate (170 mg, 0.40 mmol) in degassed 1,4-dioxane (2 mL) and water (2 mL) under argon was added 1-bromo-4-(1-(perfluoro ethyl)cyclopropyl)benzene (obtained in the previous step) in 1,4-dioxane (0.5 mL) and water (0.5 mL). The reaction vessel was then sealed and immerged in a pre-heated oil bath at 100° C. The reaction was stirred for 4-10 h. The reaction was quenched with 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 90% PE-EtOAc gradient to give the title compound as a yellow oil (1.04 g, 29% over 4 steps, 44% BRSM).
  • The compounds listed in Table XIV have been identified by TLC using pre-coated silica TLC sheets and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, or acetic acids as eluent, preferably as binary or tertiary solvent mixtures thereof, UV light at a wavelength of 254 or 366 nm, and/or common staining solutions such as phosphomolybdic acid, potassium permanganate, or ninhydrin.
  • The compounds listed in Table XIV have furthermore been identified by mass spectrometry using formic acid in the mobile phase for detection of positive ions, while no additive was used for negative ions. Ammonium Carbonate was used if the molecule was difficult to ionize. Representative compounds have also been identified by nuclear magnetic resonance spectroscopy. Chemical shifts (δ) were reported in parts per million (ppm) relative to residual solvent peaks rounded to the nearest 0.01 ppm for proton and 0.1 ppm for carbon (ref.: CHCl3 [1H: 7.26 ppm, 13C: 77.2 ppm], DMSO [1H: 2.50 ppm, 13C: 39.5 ppm]). Coupling constants (J) were reported in Hz to the nearest 0.1 Hz. Peak multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), hept (heptet), m (multiplet), and br (broad).

Claims (22)

1. A compound for use in the treatment of immune system-related disorders such as disorders of the hematopoietic system including the hematologic system, such as malignancies of the myeloid lineage, malignant and non-malignant disorders of the skin and mucosa, such as squamous and basal cell carcinoma, actinic keratosis, and hyperproliferative disorders of the skin and mucosa, e.g. cornification disorders, malignant and non-malignant disorders of the muscle, including hyperproliferative disorders of the muscle, such as muscle hyperplasia and muscle hypertrophy, disorders of the neuroendocrine system, such as medullary thyroid cancer, and hyperproliferative disorders of the genitourinary tract, e.g. cervical cancer,
wherein the compound is selected from
(i) a compound of formula I,
Figure US20210107863A2-20210415-C00875
wherein X is CH or N,
R1═C1-C12 preferably C1-C6 alkyl, C2-C12 preferably C2-C6 alkenyl, C2-C12 preferably C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C4-C12 bicycloalkyl, C6-C12 bicycloalkenyl, C5-C14 tricycloalkyl,
wherein all alkyl, alkenyl and alkynyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues can be perhalogenated, particularly perfluorinated;
and wherein R1 is preferably selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, tert-butyl, tert-pentyl, 3-pentyl, —CF3, —CF2CF3, —(CF2)2CF3, —(CF2)3CF3, —CH(CF3)2, —CF(CF3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, and 9-methylbicyclo[3.3.1]nonyl;
R2═H, C1-C6 alkyl, C3-C6 cycloalkyl,
wherein all alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
wherein all cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
wherein all alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated;
and wherein R2 is preferably selected from H, methyl and ethyl,
or a salt or solvate thereof,
(ii) a compound of formula II,
Figure US20210107863A2-20210415-C00876
wherein X and R1 are defined as in formula I, including the preferred definition of R1,
R3═H, C1-C6 alkyl, or C3-C6 cycloalkyl,
wherein all alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
wherein all cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
wherein all alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated;
and wherein R3 is preferably H or methyl;
R4═H, C1-C6 alkyl, C3-C6 cycloalkyl, OH or OC1-C6 alkyl,
wherein all alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
wherein all cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
wherein all alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated;
and wherein R4 is preferably H, OH or methyl,
or a salt or solvate thereof,
(iii) a compound of formula III,
Figure US20210107863A2-20210415-C00877
wherein X, R1 and R2 are defined as in formula I, including the preferred definitions of R1 and R2,
or a salt or solvate thereof,
(iv) a compound of formula IV,
Figure US20210107863A2-20210415-C00878
wherein X and R1 are defined as in formula I, including the preferred definition of R1,
and R3 and R4 are defined as in formula II, including the preferred definitions of R3 and R4,
or a salt or solvate thereof,
(v) a compound of formula V,
Figure US20210107863A2-20210415-C00879
wherein n=0-5, which comprises cyclopropyl (n=0), cyclobutyl (n=1), cyclopentyl (n=2), cyclohexyl (n=3), cycloheptyl (n=4) and cyclooctyl (n=5),
wherein the said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
wherein the said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups can be perhalogenated, particularly perfluorinated;
and wherein n is preferably 0 as constituting cyclopropyl, particularly as constituting cyclopropyl being unsubstituted;
R5═C1-C12 preferably C1-C6 alkyl, C2-C12 preferably C2-C6 alkenyl, C2-C12 preferably C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl,
wherein all alkyl, alkenyl and alkynyl residues can be linear or branched, and are perhalogenated, particularly perfluorinated,
and wherein all cycloalkyl and cycloalkenyl residues are perhalogenated, particularly perfluorinated;
or wherein all alkyl, alkenyl and alkynyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
and wherein all cycloalkyl and cycloalkenyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
wherein R5 is preferably —CF3 or —CF2CF3;
R6-R9 are independently from each other selected from —H, —F, —Cl, —Br, —I, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 cycloalkyl, and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
wherein R6-R8 each are preferably H, and R9 is preferably —H, —F, —Cl, or —CH3;
Y=a six-membered aromatic ring selected from benzene, pyridine, pyrimidine, pyridazine or pyrazine;
wherein the benzene ring is not substituted, or it is substituted with one to four of the substituents independently selected from R10-R13,
and wherein the pyridine ring is not substituted, or it is substituted at the carbon positions with one to three of the substituents independently selected from R10-R12, and wherein preferably the N-atom of the pyridine ring is in ortho-position relative to the ether bond,
and wherein the pyrimidine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R10-R11, and wherein preferably an N-atom of the pyrimidine ring is in ortho-position relative to the ether bond,
and wherein the pyridazine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R10-R11, and wherein preferably an N-atom of the pyridazine ring is in ortho-position relative to the ether bond,
and wherein the pyrazine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R10-R11, and wherein preferably an N-atom of the pyrazine ring is in ortho-position relative to the ether bond,
wherein preferably Y=benzene or pyridine being not substituted with any of the residues selected from R10-R13, or being substituted with one of the substituents selected from R10-R13 being —F at the carbon atom in ortho-position relative to the ether bond;
R10-R13 are independently from each other selected from —F, —Cl, —Br, —I, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 cycloalkyl, and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from —F, —Cl, —Br, —I; and C1-C3 alkyl such as —CH3 optionally halogenated or perhalogenated, particularly perfluorinated such as —CF3; and OC1-C3 alkyl optionally halogenated or perhalogenated, particularly perfluorinated;
Z═O or S, and preferably Z═O;
R14═OR2 or NR3R4
wherein R2 is defined as in formula I including the preferred definition of R2 as H, methyl or ethyl;
wherein R3 and R4 are defined as in formula II, including the preferred definitions of R3 as H or —CH3 and R4 as H, OH or —CH3,
or a salt or solvate thereof.
2. A compound of formula I as defined in claim 1 or a salt or solvate thereof, with the proviso that compounds listed in Table Ia are excluded.
3. The compound of claim 2 as shown in Table Ib, or a salt or solvate thereof.
4. A compound of formula II as defined in claim 1 or a salt or solvate thereof, with the proviso that compounds listed in Table IIa are excluded.
5. The compound of claim 4 as shown in Table IIb, or a salt or solvate thereof.
6. A compound of formula III as defined in claim 1 or a salt or solvate thereof, with the proviso that compounds listed in Table IIIc are excluded.
7. The compound of claim 6 as shown in Table IIIb, or a salt or solvate thereof.
8. A compound of formula IV as defined in claim 1 or a salt or solvate thereof.
9. The compound of claim 8 as shown in Table IV, or a salt or solvate thereof.
10. A compound of formula V as defined in claim 1 or a salt or solvate thereof.
11. The compound of claim 10 as shown in Table V, or a salt or solvate thereof.
12. The compound of any one of claims 2-11 for use in medicine, e.g. in human medicine or veterinary medicine.
13. The compound of any one of claims 2-11 for use in the treatment of disorders associated with, accompanied by and/or caused by dysfunctional Notch signaling.
14. The compound of any one of claims 2-11 for use as an enhancer of Notch signaling.
15. The compound of any one of claims 2-11 for use in the treatment of hyperproliferative disorders, including malignant and non-malignant hyperproliferative disorders.
16. The compound of any one of claims 2-11 for use in the treatment of disorders of the skin, mucosa, skin and mucosal appendages, cornea, and epithelial tissues, including non-melanoma skin cancer and precancerous lesions, skin and/or mucosal disorders with cornification defects and/or abnormal keratinocyte proliferation, skin and/or mucosal diseases associated with, accompanied by and/or caused by viral infections, atopic dermatitis and acne and in the promotion of wound healing of the skin and mucosa.
17. The compound of any one of claims 2-11 for use in immune system-related therapeutic applications including the treatment of disorders of the hematopoietic system including the hematologic system, immunotherapy or as a vaccine adjuvant.
18. The compound of any one of claims 2-11 for use in the treatment of muscular diseases including muscular dystrophies, or in muscle regeneration, or in hyperproliferative disorders of the muscle.
19. The compound of any one of claims 2-11 for use in the treatment of disorders of the neuroendocrine system including small cell carcinomas, large cell carcinomas and carcinoid tumors.
20. The compound of any one of claims 2-11 for use in the treatment of cancers or precancerous lesions of the brain, pancreas, liver, thyroid, genitourinary tract and endothelial tissue.
21. A method of treating a hyperproliferative disorder comprising administering a subject in need thereof, particularly a human subject, a therapeutically effective amount of a compound according to any one of claims 2-11.
22. A method of treating a disorder associated with, accompanied by and/or caused by dysfunctional Notch signaling, comprising administering a subject in need thereof, particularly a human subject, a therapeutically effective amount of a compound according to any one of claims 2-11.
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