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WO2008056176A1 - Pyrazolopyrimidines utiles comme inhibiteurs de la phosphodiestérase - Google Patents

Pyrazolopyrimidines utiles comme inhibiteurs de la phosphodiestérase Download PDF

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Publication number
WO2008056176A1
WO2008056176A1 PCT/GB2007/004306 GB2007004306W WO2008056176A1 WO 2008056176 A1 WO2008056176 A1 WO 2008056176A1 GB 2007004306 W GB2007004306 W GB 2007004306W WO 2008056176 A1 WO2008056176 A1 WO 2008056176A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
alkyl
phenyl
carboxylic acid
Prior art date
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Ceased
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PCT/GB2007/004306
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English (en)
Inventor
Simon J. Mackenzie
Lee Mitchell
Justin Kewney
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Scottish Biomedical Ltd
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Scottish Biomedical Ltd
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Filing date
Publication date
Priority claimed from GB0622367A external-priority patent/GB0622367D0/en
Priority claimed from GB0713152A external-priority patent/GB0713152D0/en
Application filed by Scottish Biomedical Ltd filed Critical Scottish Biomedical Ltd
Publication of WO2008056176A1 publication Critical patent/WO2008056176A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to materials for use as phosphodiesterase inhibitors, and to methods of treatment using phosphodiesterase inhibitors.
  • Phosphodiesterases are enzymes that play a role in the regulation of second messenger molecules, particularly cyclic nucleotides cAMP and cGMP. Specifically, PDEs regulate the localization, duration, and amplitude of cyclic nucleotide signalling within sub- cellular domains.
  • PDEs are important regulators of signal transduction mediated by second messenger molecules.
  • the balance between cAMP and cGMP in cells in patients with psychosis such as schizophrenia are dysregulated so that there is an excessive activity of the cAMP generating system which eventually leads to the pathological picture found in such conditions.
  • PDE enzymes that are present in mammals are classified into 11 families, PDEl to PDEIl. These families may be further split into subsets (e.g., PDElOA). Enzyme inhibitors are known for the vast majority of PDE families. These PDE enzyme inhibitors can prolong or enhance the effects of physiological processes mediated by cAMP or cGMP. PDE inhibitors can produce this effect by inhibiting the degradation of cAMP or cGMP by PDEs.
  • PDE inhibitors Due to their physiological effects, PDE inhibitors have been identified as new potential therapeutics in areas such as pulmonary arterial hypertension, coronary heart disease, respiratory disease, metabolic disorders, dementia, depression and schizophrenia.
  • PDEIl expression is detected in the brain in small amounts and has been linked to the treatment of diseases or conditions that affect the prostate, reproduction, the thyroid, the liver, tumours and metabolism.
  • diseases or conditions that affect the prostate, reproduction, the thyroid, the liver, tumours and metabolism.
  • potent and selective inhibitors of PDEIl there are no known potent and selective inhibitors of PDEIl.
  • a further object of the invention is to provide a PDE inhibitor compound.
  • a still further object of the invention is to provide a method of therapy using a PDE inhibitor compound.
  • the present invention addresses at least some of the aforesaid drawbacks found in the prior art by providing PDEIl inhibitor compounds.
  • the compounds of the present invention generally comprise a bicyclic unsaturated structure consisting of a six- membered heteroatom-containing ring fused to a five- membered heteroatom-containing ring.
  • the six-membered ring contains a phenyl group and an alkyl group, and the five-membered ring contains an amide which is optionally substituted with an aryl or alkyl group.
  • the aryl group generally comprises electron donating groups.
  • Xi and X 2 are independently chosen from the list comprising nitrogen and carbon atoms, and suitable H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid derivatives thereof; J 1 and J 2 are independently chosen from the list comprising nitrogen and carbon atoms; Qi and Q 2 are independently chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; Y is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; Z is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; D is chosen from the list comprising H, alkyl,
  • Xi or X 2 when Xi or X 2 is carbon, it may be further functionalised to contain a group chosen from the list comprising H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid groups.
  • Xi is carbon, more preferably CH.
  • X 2 is preferably nitrogen.
  • Ji is nitrogen.
  • J 2 is preferably carbon.
  • Qi is nitrogen and Q2 is carbon. More preferably Q2 is CH.
  • the alkyl groups can be lower alkyl C 1 -C 5 .
  • D is preferably an alkyl group, more preferably a methyl group.
  • B is preferably an aryl group, more preferably a phenyl group.
  • A can be hydrogen.
  • the alkyl group can be cyclohexane or -CH 2 ⁇ tetrahydrofuran.
  • the alkyl-aryl group can be -CH 2 -pyridine.
  • the aryl group may advantageously comprise at least one electron donating substituent group.
  • A can be a phenyl group of general structure:
  • Ei, and E 1 ' are independently chosen from the list comprising hydrogen, alkyl, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylamino, amide, -OCO- ester, and ether groups;
  • E 2 , and E 2 ' are independently chosen from the list comprising hydrogen, alkyl, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylamino, amide, -OCO- ester, and ether groups;
  • E 3 is chosen from the list comprising hydrogen, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylamino, amide, -OCO- ester, and ether groups; wherein the group situated para to Ei or Ei' is not halogen when Ei or Ei' is alkoxy.
  • the remaining substituents are preferably hydrogen.
  • alkyl is -CH 2 CH 3 .
  • the halogen is chlorine.
  • alkoxy is methoxy
  • Ei and E 2 , or Ei' and E 2 ' can be taken together to form -CHCHCHCH-, so-forming a naphthalene group.
  • a preferred compound according to the invention is shown as IA (7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2- carboxylic acid benzo [ 1, 3] dioxol-5-ylamide) :
  • the compounds described are useful in the inhibition of phosphodiesterases and particularly PDEIl.
  • Expression of PDEIl is detected in the brain and has been linked to, amongst other things, major depressive disorder (MDD).
  • MDD major depressive disorder
  • a fourth aspect of the invention there is provided a method of inhibiting phosphodiesterase using a compound of formula I, as described herein.
  • a fifth aspect of the invention there is provided a method of selectively inhibiting phosphodiesterase 11 using a compound of formula I, as described herein.
  • a compound of formula I as described herein, in combination with a pharmaceutical carrier or excipient for use in therapy or as a medicament.
  • a compound of formula I as described in herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a psychiatric disorder in a mammal.
  • the mammal may be a human.
  • the compound is useful in the therapeutic and/or prophylactic treatment of further conditions including psychiatric disorders such as schizophrenia, major depressive disorder, dementia, depression, bi-polar disorder, or psychotic disorder.
  • psychiatric disorders such as schizophrenia, major depressive disorder, dementia, depression, bi-polar disorder, or psychotic disorder.
  • a compound of formula I as described in herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of circulatory disease or disorder.
  • the circulatory disease or disorder can be a cardiovascular disease or hypertension.
  • the conditions described may affect the prostate.
  • the disorder described may affect the thyroid, liver or brain.
  • the compound may be one or more of the compounds of formula IA, IB, IC, ID, IE, IF, IH, IJ, IK, or IL, as described herein.
  • the compound is of formula IA, IB or IC, most preferably of formula IA.
  • Figure 1 is a synthetic scheme showing how compounds IA, IB, and IC can be prepared.
  • Figure 2 is a graph that illustrates the relative amount of PDEIlA present in brain tissue taken from Schizophrenics.
  • Compound IL is sourced from Interchim, 211 Bis, Avenue Kennedy, BP1140, 03103 Montiucon Cedex, France.
  • the compounds are 7-Methyl-5-phenyl-pyrazolo [ 1 , 5-a] pyrimidine-2-carboxylic acid amide derivatives, and are useful in the inhibition of phosphodiesterases, and in particular PDEIl.
  • Xi and X 2 are independently chosen from the list comprising nitrogen and carbon atoms, and suitable H, alkyl, and aryl derivatives thereof;
  • Ji and J 2 are independently chosen from the list comprising nitrogen and carbon atoms;
  • Qi and Q 2 are independently chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof;
  • Y is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof;
  • Z is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof;
  • D is chosen from the list comprising H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sul
  • a compound that inhibits PDEIl selectively over other phosphodiesterases said compound containing a six-membered heterocycle and a five-membered heterocycle fused to form an indole-type structure.
  • the five-membered ring contains an amide substituent which can be linked to a substituted phenyl.
  • the six-membered ring contains a phenyl substituent and an alkyl substituent.
  • Examples of compounds with the properties described above that act as PDEIl inhibitors are 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a]pyrimidine-2-carboxylic acid benzo [ 1, 3] dioxol-5-ylamide (IA), 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a]pyrimidine-2-carboxylic acid (3-hydroxy- phenyl) -amide (IB), and 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a]pyrimidine-2-carboxylic acid (4-hydroxy- phenyl) -amide (IC).
  • a compound that inhibits PDEIl selectively over other phosphodiesterases said compound containing a six-membered heterocycle and a five-membered heterocycle fused to form an indole-type structure.
  • the five- membered ring contains an amide substituent.
  • the amide substituent can be linked to an alkyl group which may contain heteroatoms, an aryl group, or an alkyl-aryl group.
  • the six-membered ring contains a phenyl substituent and an alkyl substituent.
  • Examples of compounds with the properties described above that act as PDEIl inhibitors are 7-Methyl-5-phenyl- pyrazolo [ 1 , 5-a] pyrimidine-2-carboxylic acid amide (ID), 7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid cyclohexylamide (IE) , 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (3-chloro- phenyl) -amide (IF), 7-Methyl-5-phenyl- pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (tetrahydro- furan-2-ylmethyl) -amide (IG), 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (pyridine-3- ylmethyl) -amide (
  • the phosphodiesterase assay is performed using recombinant human PDE enzymes expressed in a baculoviral system.
  • the recombinant PDE enzymes were tested for their similarity to PDE enzymes taken from human tissue using know inhibitor standards where available.
  • Table 1 shows the IC 5O values in ⁇ M for compounds IA and IB as inhibitors of PDEIlAl with reference to a selection of other phosphodiesterases. The remaining compounds were tested for efficacy with respect to PDEIlAl only. It is clear from the IC 50 studies that the compounds of the present invention are inhibitors of PDEIl.
  • mice are placed in one of four sound attenuated chambers (Medical Associates Prol, Vermont USA) equipped with an acoustic audio generator containing a platform fitted with a transducer amplifier that detects the motion of the animal. High frequency speakers deliver the startle stimulus and prepulse acoustic stimuli. Data acquisition and analysis was performed using Startle Reflex software, for example MEDPRO from Medical Associates Vermont USA. In certain . experiments the mice were pre-dosed with PCP which has been shown to produce schizophrenic-like symptoms in humans and also to worsen the psychotic state in schizophrenics .
  • mice The general activity of treated and untreated mice was determined using the open field activity (OFA) apparatus (such as model MED-OFA-MS, Medical Associates Vermont USA comprising 27.9 cm x 27.9 cm test environment with three 16 beam I/R arrays , 48 channel control, with computer software to record and analyse the data) .
  • OFA open field activity
  • Pre-pulse inhibition is an operational measure of sensorimotor gating, a phenomenon by which the brain shields the effect of subsequent stimuli while still processing another to protect against stimulus overflow or sensory inundation.
  • Schizophrenics have markedly reduced prepulse inhibition that can be redressed with antipsychotic drugs.
  • Compound IB like the known anti- psychotic clozapine, reverses the effect of phenylcyclidine on prepulse inhibition in mice.
  • the open field test is an index of simple information- processing and activity by the animal over time that occurs as an animal becomes acclimated to its environment. Faster habituation indicates greater information-processing.
  • Compound IB (unlike clozapine) had no effect upon open filed activity ruling out that the observed reversal of PCP-inhibition of PPI by the compound was due to sedation or an effect on the compounds on animal locomotion.
  • the present invention • * demonstrates compounds that act as PDEIl inhibitors. .-, relief> Furthermore, the compounds of the present invention vsf' selectively inhibit PDEIl over other phosphodiesterases. •,.;?
  • cDNA was synthesised using 5 ⁇ g of total RNA extracted from four control brains and four human schizophrenic brains. Regions known to be associated with schizophrenia were sampled from both the control and disease brains. Approximately 0.2 ⁇ g RNA equivalent in real time PCR analysis was used to determine the relative amounts of PDEIlA transcript in the samples. Duplicates were used for each sample. PDEIlA primers with a FAM labelled probe were used to determine the PDEIlA transcript levels. Ribosomal RNA control primers and VIC labelled probes were included in the reaction to control for quantitative errors between samples.
  • PDEIlA transcript in human schizophrenic brains was found to be around 3.5 fold higher than the transcript in the control brains. This result was found to be significant (p > 0.05) using the student T-test. Therefore, it is clear that PDEIlA transcript increases in human schizophrenic brain, possibly signifying increased PDEIlA activity in these individuals. Use of a PDEIlA specific or selective inhibitor may therefore prove therapeutic for psychiatric disorders and in particular schizophrenia.
  • the compounds described herein show inhibition of phosphodieterases, and selective inhibition of phoshpodiesterase 11. Therefore, the compounds may be used in combination with a pharmaceutical carrier or excipient for use in therapy or as a medicament.
  • the compounds are likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a psychiatric disorder in a mammal.
  • the psychiatric disorder could be schizophrenia, major depressive disorder, dementia, depression, bi-polar disorder, or psychotic disorder.
  • the compounds described are likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of circulatory disease or disorder, and in particular a cardiovascular disease or hypertension.
  • the compounds described are likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a benign or malignant neoplastic condition, and in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a condition manifested in the reproductive function of a mammal.
  • the compounds are likely to be of use when these conditions affect the prostate.
  • the compounds described are also likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a condition affecting the metabolism of a mammal, and in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a disorder in an organ or tissue.
  • the compounds are likely to be of use when these disorders affect the thyroid, liver or brain.
  • the compounds of the present invention show an inhibitory effect on phosphodiesterases, and in particular PDEIl, they may have application as new potential therapeutics in areas such as pulmonary arterial hypertension, coronary heart disease, metabolic disorders, dementia, depression and schizophrenia.
  • PDEIl is known to exist in the brain in small amounts and has been linked to the treatment of diseases or conditions that affect the prostate, reproduction, the thyroid, the liver, tumours and the metabolism. Therefore the compounds of the present invention may provide useful medicaments or therapeutics for use in the treatment of diseases affecting the prostate, reproduction, the thyroid, the liver, tumours and the metabolism, or the brain. The compounds of the present invention may also be useful as medicaments or therapeutics for use in the treatment of pulmonary arterial hypertension, coronary heart disease, dementia, depression bi-polar disorder and psychotic disorders such as schizophrenia.

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Abstract

Composés utilisables en tant qu'inhibiteurs de la phosphodiestérase et, en particulier, inhibant la PDE 11. Ces composés peuvent être utilisés à des fins thérapeutiques ou sous la forme d'un médicament dans le traitement de la schizophrénie par exemple.
PCT/GB2007/004306 2006-11-10 2007-11-12 Pyrazolopyrimidines utiles comme inhibiteurs de la phosphodiestérase Ceased WO2008056176A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0622367.1 2006-11-10
GB0622367A GB0622367D0 (en) 2006-11-10 2006-11-10 Phosphodiesterase inhibitors
GB0713152A GB0713152D0 (en) 2007-07-06 2007-07-06 Phosphodlesterase inhibitors
GB0713152.7 2007-07-06

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Cited By (22)

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US9120788B2 (en) 2013-02-19 2015-09-01 Pfizer Inc. Azabenzimidazole compounds
US9493450B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493442B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9573954B2 (en) 2012-11-16 2017-02-21 University Health Network Pyrazolopyrimidine compounds
US9598421B2 (en) 2014-08-06 2017-03-21 Pfizer Inc. Imidazopyridazine compounds
EP3061754A4 (fr) * 2013-10-23 2017-03-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US10131669B2 (en) 2014-07-24 2018-11-20 Pfizer Inc. Pyrazolopyrimidine compounds
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
US10329255B2 (en) 2015-08-12 2019-06-25 Incyte Corporation Salts of an LSD1 inhibitor
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US11161850B2 (en) 2018-07-05 2021-11-02 Incyte Corporation Fused pyrazine derivatives as A2A / A2B inhibitors
US11168089B2 (en) 2018-05-18 2021-11-09 Incyte Corporation Fused pyrimidine derivatives as A2A / A2B inhibitors
WO2022084741A1 (fr) * 2020-10-23 2022-04-28 Ildong Pharmaceutical Co., Ltd. Composés modulateurs de cftr, compositions et utilisations associées
US11390624B2 (en) 2019-01-29 2022-07-19 Incyte Corporation Pyrazolopyridines and triazolopyridines as A2A / A2B inhibitors
US11673894B2 (en) 2018-02-27 2023-06-13 Incyte Corporation Imidazopyrimidines and triazolopyrimidines as A2A / A2B inhibitors

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US10167289B2 (en) 2012-11-16 2019-01-01 University Health Network Pyrazolopyrimidine compounds
US10106545B2 (en) 2012-11-16 2018-10-23 University Health Network Pyrazolopyrimidine compounds
US10570143B2 (en) 2012-11-16 2020-02-25 University Health Network Pyrazolopyrimidine compounds
US9573954B2 (en) 2012-11-16 2017-02-21 University Health Network Pyrazolopyrimidine compounds
US9657025B2 (en) 2012-11-16 2017-05-23 University Health Network Pyrazolopyrimidine compounds
US9815832B2 (en) 2013-02-19 2017-11-14 Pfizer Inc. Azabenzimidazole compounds
US9120788B2 (en) 2013-02-19 2015-09-01 Pfizer Inc. Azabenzimidazole compounds
EP3061754A4 (fr) * 2013-10-23 2017-03-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique
US10717737B2 (en) 2014-02-13 2020-07-21 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US11155532B2 (en) 2014-02-13 2021-10-26 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
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US11247992B2 (en) 2014-02-13 2022-02-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
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US10138249B2 (en) 2014-07-10 2018-11-27 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US10125133B2 (en) 2014-07-10 2018-11-13 Incyte Corporation Substituted [1,2,4]triazolo[1,5-a]pyridines and substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
US10968221B2 (en) 2014-07-10 2021-04-06 Incyte Corporation Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
US10112950B2 (en) 2014-07-10 2018-10-30 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
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US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
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