WO2011103715A1 - Antagonistes de canal task - Google Patents

Antagonistes de canal task Download PDF

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Publication number
WO2011103715A1
WO2011103715A1 PCT/CN2010/070751 CN2010070751W WO2011103715A1 WO 2011103715 A1 WO2011103715 A1 WO 2011103715A1 CN 2010070751 W CN2010070751 W CN 2010070751W WO 2011103715 A1 WO2011103715 A1 WO 2011103715A1
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Prior art keywords
alkyl
oaryl
6alkyl
mmol
aryl
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PCT/CN2010/070751
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English (en)
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Craig Coburn
Jiabing Wang
Vince Santarelli
Shuangxi Hu
Mingxiang Cui
Bin Hu
Jingchao Dong
Yunfu Luo
Richard M Soll
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Merck Sharp & Dohme Corp.
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Priority to PCT/CN2010/070751 priority Critical patent/WO2011103715A1/fr
Priority to PCT/US2011/025596 priority patent/WO2011106276A1/fr
Publication of WO2011103715A1 publication Critical patent/WO2011103715A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems

Definitions

  • the invention relates generally to compounds which act as modulators, e.g., antagonists of TASK channels, particularly, TASK-1 and/or TASK-3, compositions and therapeutic uses thereof.
  • Potassium channels are membrane proteins that play an important role in many physiological processes. There are three major families of potassium channel proteins each with structural and functional distinctions characterized by the number of transmembrane domains (2, 4 or 6). The first and second families of potassium channels are the voltage-dependent potassium channels (K v ) and the inwardly rectifying potassium channel (K ir ). The members of the third family are known as the KCNK, or 3 ⁇ 4 p (Coetzee W. J. et al; New York Acad Sci. 1999 (868),
  • the TASK channels are generally referred to as TASK-1 (which is also known as (aka) KCNK3 or K 2P 3.1), TASK-2 (aka KCNK5 or K 2P 5.1), TASK-3 (aka KCNK9 or K 2P 9.1), TASK-4 (aka KCNK 17 or K 2P 17.1 or TALK-2) and TASK-5 (aka KCNK 15 or K 2P 15.1).
  • TASK-1 and TASK- 3 channels have the greatest homology within this family with a greater than 50% amino acid identity. For background discussion see Goldstein, S.A.N., et al, Nat. Rev. Neurosci.
  • the TASK channels are sensitive to extracellular pH within physiological range displaying inhibition at acidic pH and activated at alkaline pH (Duprat F., et al, EMBO I. 1997 (16), 5464-5471).
  • TASK-1 is expressed in the brain, spinal ganglia, peripheral tissues such as pancreas, placenta, uterus, lung, heart, kidney, small intestine and stomach, and have been detected in motor neurons of the locus coeruleus and hypoglossal nerve (a motor cranial nerve which is integrally involved in the maintenance of the upper respiratory pathways).
  • TASK-3 channels are primarily expressed in the cerebellum (Medhurst, A.D., et al, Mol. Brain Res. 2001 (86), 101-1 14).
  • TASK-1 channels have been shown to be involved in respiratory regulation in respiratory neurons of the brainstem, in carotid bodies and motor neurons of the hypoglossal nerve, and also in neuroepithelial cells of the lung.
  • the lowering of the pH and resultant blockage of the pH-dependent TASK-1 channels that occur from inadequate respiration (e.g., hypoxia, hindered breathing, excessive physical stress) leads to depolarization of the cells, which leads to the activation of the neurons involved in the respiratory regulation [Buckler K.J., et al, J. Physiol. 2000 (525), 135-142; Bayliss, D.A., et al, Respiration Physiology 2001 (129), 159-174).
  • Blocking TASK channels by increasing the activity of chemo sensitive neurons in conjuction with activation of the motor neurons of the hypoglossal nerve, can stimulate respiration, stabilize the upper respiratory pathways and protect the pathways from collapse and occlusion. Stabilization of the upper respiratory pathways can also help eliminate or inhibit snoring.
  • blocking TASK-1 channels can be beneficial in the treatment of respiratory disorders such as sleep apnea.
  • TASK-1 channesl have also been found in smooth muscle cells of mesenterial and pulmonary arteries, and are suggested to be involved in acidosis-induced pulmonary vasoconstriction
  • TASK-1 channels are responsible for programmed cell death (apoptosis) in granulose cells, and that the cell death can be preventing by blocking the TASK-3 (Patel A.J., Pflugers Arch, 2004 (448), 261-273).
  • TASK-3 Patel A.J., Pflugers Arch, 2004 (448), 261-273.
  • the TASK-3 gene has been found in several human carcinoma tissues (e.g., breast cancer, colon cancer, lung cancer), which leads to the belief that TASK-3 inhibitors may useful as an anticancer drug. See Mu D., et al, Cancer Cell 2003 (3), 297-302; and Pei, L., et al, Proc. Natl. Acad. Sci. USA 2003 (100), 7803-7807.
  • TASK-3 antagonists may also be useful for the treatment of respiratory disorders (e.g., Cheyne- Strokes respiration, disrupted central respiratory drive, muscle-related respiratory disorders, acute and chronic lung disorders with hypoxia and hypercapnia) , sleep disorders, excessive daytime sleepiness, sleep apneas, snoring, neurodegenerative disorders, cognitive impairment (e.g., dementia, Alzheimer's disease) or major depressive disorder, Parkinson's disease, Huntington's disease.
  • respiratory disorders e.g., Cheyne- Strokes respiration, disrupted central respiratory drive, muscle-related respiratory disorders, acute and chronic lung disorders with hypoxia and hypercapnia
  • sleep disorders e.g., excessive daytime sleepiness, sleep apneas, snoring
  • cognitive impairment e.g., dementia, Alzheimer's disease
  • major depressive disorder e.g., Parkinson's disease, Huntington's disease.
  • One aspect of the present invention relates to TASK-1 and/or TASK-3 antagonists and/or their pharmaceutically acceptable salts, compositions and methods for treating and preventing disorders which are caused by activation or by an activated TASK-1 and/or TASK-3, and disorders which have TASK-1 and/or TASK-3 -related damage as a secondary cause.
  • Another aspect of this invention is use of the TASK-1 and/or TASK-3 antagonists and/or their pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment or prevention of cancer disorders (e.g., breast cancer, lung cancer, colon cancer, prostate cancer), respiratory disorders (e.g., Cheyne- Strokes respiration, disrupted central respiratory drive, muscle-related respiratory disorders, acute and chronic lung disorders with hypoxia and hypercapnia) , sleep disorders, excessive daytime sleepiness, sleep apneas, snoring, neurodegenerative disorders, cognitive impairment (e.g., dementia, Alzheimer's disease) or major depressive disorder, atypical depression, Parkinson's disease, and Huntington's disease.
  • cancer disorders e.g., breast cancer, lung cancer, colon cancer, prostate cancer
  • respiratory disorders e.g., Cheyne- Strokes respiration, disrupted central respiratory drive, muscle-related respiratory disorders, acute and chronic lung disorders with hypoxia and hypercapnia
  • sleep disorders
  • the present invention relates to TASK-1 and/or TASK-3 antagonist of structural formula I or la:
  • Rl represents C 1 -6 alkylC(0)OC 1 -6alkyl, (CH2) n C 6 - 1 Oaryl, (CH2) n C5- lOheterocycle, (CH2) n C3- lOcycloalkyl, N(CH3)(CH2) n C(0)NHC 6 -l Oaryl, and N(CH3)(CH2) n C5- lOheterocycle; said cycloalkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R a ;
  • R represents H, C 1 -6 alkyl, C(0)(CH2) n C 6 - 1 Oaryl, C(0)0(CH2) n C 6 - 1 Oaryl, C(0)(CH2) n C5- lOheterocycle, (CH2)nC 6 - 1 Oaryl, SO2C 6 -IO aryl, SO2C5-IO heterocycle, C(0)NHC 6 - 1 Oaryl, C(0)C 2 - 4alkynyl, CNC 6 -1 Oaryl, (CH2) n C5-10heterocycle,or C(O)CH(CH3)N(CH3)CH2C 6 -10 aryl, said alkynyl, aryl, alkyl, and heterocycle optionally substituted with 1 to 3 groups of R a ;
  • Ra represents (CH2) n OH, (CH2) n CN, C(OH)CN, C 1 -6 alkyl, CH(OH)(CH2) n C 6 -10 aryl,
  • (CH2)nC(O)O(CH2)nC5-10 heterocyclyl halo, (CH2) n C 6 - 1 Oaryl, 0(CH2) n C 6 - 1 Oaryl, (CH 2 ) n C5- lO eterocycle, -N(CH3)CH2C(O)NHC 6 -10aryl,-NH(CH2) n C 6 -l Oaryl, -N(CH3)CH2C 6 -1 Oaryl, - NH(C 1 _6alkyl), (CH2) n S02C 1 _6alkyl, (CH2) n S02C 6 -l Oaryl, -0-, C3-IO cycloalkyl, -SC 1 -6 alkyl, CF 3 , OCF 3 , CHF2, CH2F, CF 3 OC 1 .6a.kyl, NH2, C(0)N( C 1 -6 alkyl)(CH2) n C5-l Oheter
  • R 3 , R 3 a , R 4 R4 a independently represent hydrogen or C 1 -6 alkyl; and n represents 0 to 4.
  • This invention also relates to compositions and methods for using the compounds disclosed herein. These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein.
  • the present invention relates to TASK-1 and/or TASK-3 antagonists and/or their pharmaceutically acceptable salts, compositions and methods for treating and preventing disorders which are caused by activation or by an activated TASK-1 and/or TASK-3, such as cancer disorders (e.g., breast cancer, lung cancer, colon cancer, prostate cancer), respiratory disorders (e.g., Cheyne- Strokes respiration, disrupted central respiratory drive, muscle-related respiratory disorders, acute and chronic lung disorders with hypoxia and hypercapnia) , sleep disorders, excessive daytime sleepiness, sleep apneas, snoring, neurodegenerative disorders, cognitive impairment (e.g., dementia, Alzheimer's disease) or major depressive disorder, Parkinson's disease, and Huntington's disease.
  • cancer disorders e.g., breast cancer, lung cancer, colon cancer, prostate cancer
  • respiratory disorders e.g., Cheyne- Strokes respiration, disrupted central respiratory drive, muscle-related respiratory disorders, acute and chronic lung
  • n in R and Rl is 0-2, preferably 0-1 and more preferably 0.
  • Rl, R, R3, R3a R4 ⁇ and R4a are as previously described.
  • Ry represents H, C 1 -6alkyl, C(0)C 1 -6alkyl, C(O)C3-l0cycloalkyl, C(0)(CH2) n C 6 - 1 Oaryl,
  • Ryl is the same as R a ; or when two Ryl are present they may combined to form a C3-10 cyclic group optionally having 1-2 heteroatoms selected from N, O, and S, said cyclic group optionally substituted with 1 to 3 groups of R a ; and R y2 is H, halo, or OH and all other variables are as described herein.
  • n in Ryl is 0-1, preferably 0.
  • Still another embodiment of the present invention is realized when R1 is and all other variables are as originally described.
  • a subembodiment of this invention is realized when Ryl is C 1 -6alkyl, C(0)OC 1 -6alkyl, C(0)C 1 -6alkyl, C3-6cycloalkyl, C(0)C3-6cycloalkyl,
  • Another subembodiment of this invention is realized when only 1 Ryl is present. Another embodiment of the present invention is realized when R 1 is and all other variables are as originally described. A subembodiment of this invention is realized when Ryl is C ⁇ .
  • R 1 is and all other variables are as originally described.
  • a subembodiment of this invention is realized when RY is C(0)C 1 _6alkyl, C(0)(CH2) n C 6 - 1 Oaryl, C(O)(CH2) n C5-10heterocycle, (CH2) n C 6 - 1 Oaryl, or
  • (CH2)nC5-10heterocycle said alkyl, aryl, cycloalkyl, and heterocycle optionally substituted with 1 to 3 groups of R a
  • Ryl is C 1 -6alkyl, CF 3 , CH2F, said alkyl optionally substitute with 1 to 3 groups of Ra.
  • Still another embodiment of the present invention is realized when Rl is and all other variables are as originally described..
  • R3, R3a, R and R4a are all hydrogen and all other variables are as originally described.
  • Still another embodiment of this invention is realized when R is C(0)(CH2)nC 6 - 1 Oaryl, C(O)(CH2)nC5-10heterocycle, SO2C 6 -IO aryl, or SO2C5-IO heterocycle, said aryl and heterocycle optionally substituted with 1 to 3 groups of R a .
  • a subembodiment of this invention is realized when R is C(0)(CH2)nC 6 -l Oaryl substituted with 1 to 3 groups of R a .
  • Still another embodiment of this invention is realized when R is C(0)phenyl and the R a substitution is an optionally substituted phenyl group, substituted with 1 to 3 groups of R aa .
  • Yet another subembodiment of this invention is realized when R is SO2C 6 -I Oaryl substituted with 1 to 3 groups of R a .
  • Rw and Rwa are independently selected from the group consisting of H, OC 1 -6alkyl,
  • R is pheny or pyridyl optionally substituted by 1 to 3 groups of R a .
  • a subembodiment of this invention is realized when R is optionally substituted biphenyl.
  • R3, R3a, Ryl RW and Rwa i s as previously described.
  • a subembodiment of formula III is realized when Ryl is C 1 -6alkyl, C(0)OC 1 -6alkyl, C(0)C 1 -6alkyl, C3-6cycloalkyl , C(0)C3-6cycloalkyl, said alkyl and cycloalkyl optionally substituted with 1 to 3 groups of R a .
  • Another subembodiment of formula III is realized when Ryl is C(0)OCH2CH3, C(0)CH2CH3, C(0)(CH2)2CH3, C(0)cyclopropyl, C(OH)(CH3)2, cyclopropylOH.
  • Still another subembodiment of formula III is realized when Rw and Rwa are both hydrogen.
  • any variable e.g. aryl, heterocycle, R ⁇ , R ⁇ etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • Ra is -O- and attached to a carbon it is referred to as a carbonyl group and when it is attached to a nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.
  • a nitrogen e.g., nitrogen atom on a pyridyl group
  • sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.
  • alkyl encompasses groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, alkenyl, and alkynyl and means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, and heptyl.
  • alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond.
  • alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • alkenyl is C 2 -C 6 alkenyl.
  • Preferred alkynyls are C 2 -C 6 alkynyl.
  • alkenyl “alkynyl” and other like terms include carbon chains containing at least one unsaturated C-C bond. In the case of alkenyl it has a double bond and in the case of alkynyl a triple bond is expected.
  • fluoroalkyl refers to an alkyl substituent as described herein containing at least one flurine substituent.
  • cycloalkyl refers to a saturated hydrocarbon containing one ring having a specified number of carbon atoms.
  • examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 1 -6 includes alkyls containing 6, 5, 4, 3, 2, or 1 carbon atoms
  • alkoxy as used herein, alone or in combination, includes an alkyl group connected to the oxy connecting atom.
  • alkoxy also includes alkyl ether groups, where the term
  • 'alkyl' is defined above, and 'ether' means two alkyl groups with an oxygen atom between them.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, methoxymethane (also referred to as 'dimethyl ether'), and methoxyethane (also referred to as 'ethyl methyl ether').
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, napthyl, tetrahydronapthyl, indanyl, or biphenyl.
  • heterocycle, heterocyclyl, or heterocyclic represents a stable 4- to 7-membered monocyclic or stable 8- to 1 1-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocycle or heterocyclic includes heteroaryl moieties.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,
  • dihydrobenzothiopyranyl dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl,
  • the heterocyclic group is a heteroaryl group.
  • heteroaryl refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms;
  • heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazoiyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl.
  • the heterocyclic group is fused to an aryl or heteroaryl group.
  • fused heterocycles include, without limitation, tetrahydroquinolinyl and dihydrobenzofuranyl .
  • heteroaryl represents a stable 5- to 7- membered monocyclic- or stable 9- to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole,
  • heterocycloalkyls examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
  • heteroatom means O, S or N, selected on an independent basis.
  • a moiety that is substituted is one in which one or more hydrogen atoms have been independently replaced with another chemical substituent.
  • substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2,4-fluoro-3-propylphenyl.
  • substituted n-octyls include 2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyloctyl. Included within this definition are methylenes (-CH 2 -) substituted with oxygen to form carbonyl (-CO-).
  • a moiety e.g., cycloalkyl, hydrocarbyl, aryl, alkyl, heteroaryl, heterocyclic, urea, etc.
  • substituted it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents.
  • Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(O)-), nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino,
  • Preferred substituents which are themselves not further substituted (unless expressly stated otherwise) are:
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • mammal “mammalian” or “mammals” includes humans, as well as animals, such as dogs, cats, horses, pigs and cattle.
  • phrases "effective amount” or “therapeutically effective amount” mean a concentration of TASK- 1 and/or TASK-3 receptor complex modulator sufficient to inhibit or enhance the effect of the TASK-1 and/or TASK-3 receptor complex.
  • Compounds described herein may contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers.
  • the present invention includes all such possible isomers as well as mixtures of such isomers unless specifically stated otherwise.
  • the compounds of the present invention may contain one or more asymmetric centers and may thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (iH) and deuterium (3 ⁇ 4).
  • Protium is the predominant hydrogen isotope found in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • references to the compounds of structural formula I are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or in other synthetic manipulations.
  • the compounds of the present invention may be administered in the form of a
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other
  • organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N, N -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.
  • ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N, N -dibenzylethylenediamine, diethylamine, 2-dieth
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid and the like.
  • compositions of the present invention comprise compounds of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a
  • additional therapeutic agents can include, for example, i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or antagonists, iv) sodium channel antagonists, v) MDA receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) K1 antagonists, viii) non-steroidal anti-inflammatory drugs ("NSAID”), ix) selective serotonin reuptake inhibitors ("SSRI”) and/or selective serotonin and norepinephrine reuptake inhibitors (“SS RI”), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii) valproate, xiv) neurontin (gabapentin), xv) pregabalin, and xvi) sodium channel blockers.
  • additional therapeutic agents can include, for example, i) opiate agonists or antagonists, ii)
  • compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • parenteral including subcutaneous, intramuscular, and intravenous
  • compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the instant compounds have clinical uses for the treatment of epilepsy and partial and generalized tonic seizures. They are also useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and for treating multiple sclerosis.
  • the present compounds are useful for the treatment of tachy-arrhythmias.
  • the instant compounds are useful for the treatment of neuropsychiatric disorders, including mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders, dysthymic disorders and atypical depression, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders.
  • another aspect of this invention is the use of the compounds of formula I in the manufacture of a medicament to treat diseases associated with TASK-1 and/or TASK-3 receptor complex.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats guinea pigs, or other bovine, ovine, equine, canine, feline, rodent such as mouse, species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents, such as norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (S RIs), a-adrenoreceptor antagonists, atypical anti-depressants, benzodiazepines, 5-HTi A agonists or antagonists, especially 5-HTi A partial agonists, neurokinin- 1 receptor antagonists, corticotropin releasing factor (CRF) antagonists, and pharmaceutically acceptable salts thereof.
  • SSRIs selective serotonin reuptake inhibitors
  • MAOIs monoamine oxidase inhibitors
  • RIMAs reversible inhibitors of monoamine oxidase
  • S RIs se
  • compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions and disorders, as well as to prevent other conditions and disorders associated with calcium channel activity.
  • Creams, ointments, jellies, solutions, or suspensions containing the instant compounds can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.
  • Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weight per day are useful in the treatment of neuropsychiatric disorders, or alternatively about 0.5 mg to about 7 g per patient per day.
  • neuropsychiatric disorders may be effectively treated by the administration of from about O.Olmg to about 75 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day
  • neuropsychiatric disorders may be effectively treated by the administration of from about 0.01 mg to about 125 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 5.5 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may conveniently contain from about 0.5 mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may ary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about 1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
  • the specific dose level for any particular patient will depend upon a variety of factors. Such patient-related factors include the age, body weight, general health, sex, and diet of the patient. Other factors include the time and route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the compounds of the invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • any of the usual pharmaceutical media can be employed.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used; or in the case of oral solid preparations such as powders, capsules and tablets, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be included.
  • tablets and capsules represent the most advantageous oral dosage unit form in which solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. In addition to the common dosage forms set out above, controlled release means and/or delivery devices may also be used in administering the instant compounds and compositions.
  • any convenient pharmaceutical media may be employed.
  • any convenient pharmaceutical media may be employed.
  • preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are advantageous oral dosage units whereby solid
  • tablets may be coated by standard aqueous or nonaqueous techniques
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet advantageously contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule advantageously containing from about 0.1 mg to about 500 mg of the active ingredient.
  • a tablet, cachet, or capsule conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient taken one or two tablets, cachets, or capsules, once, twice, or three times daily.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage, and thus should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, and dusting powder.
  • compositions can be in a form suitable for use in transdermal devices.
  • These formulations may be prepared, utilizing a compound represented of the invention, or
  • a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid, such as, for example, where the mixture forms unit dose suppositories.
  • suitable carriers include cocoa butter and other materials commonly used in the art.
  • the suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including anti-oxidants).
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including anti-oxidants).
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including anti-oxidants).
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including anti-oxidants).
  • preservatives including anti-oxidants
  • compositions containing a compound of the invention, or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.
  • the instant compounds can be utilized in combination with one or more therapeutically active compounds.
  • inventive compounds can be advantageously used in combination with i) opiate agonists or antagonists, ii) other calcium channel antagonists, iii) 5HT receptor agonists or antagonists, including 5-HTi A agonists or antagonists, and 5-HTi A partial agonists, iv) sodium channel antagonists, v) N-methyl-D-aspartate (NMD A) receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) neurokinin receptor 1 (NK1) antagonists, viii) non-steroidal anti-inflammatory drugs (NSAID), ix) selective serotonin reuptake inhibitors (SSRI) and/or selective serotonin and norepinephrine reuptake inhibitors (SS RI), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii)
  • MS molecular sieves
  • MsC 1 methanesulfonyl chloride
  • NaH sodium hydride
  • Na2S04 sodium sulfate
  • Pd(OH)2 palladium hydroxide, 20% on carbon
  • PE petroleum ether
  • Ph Ph
  • POCI3 phosphorous oxychloride
  • the present compounds can be prepared according to the procedures provided in the Examples.
  • the following Examples further describe, but do not limit, the scope of the invention.
  • NMR data is in the form of delta ( ⁇ ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent.
  • TMS tetramethylsilane
  • Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. Broad; etc.
  • “Ar” signifies an aromatic signal.
  • the procedures described herein for synthesizing the compounds may include one or more steps of protecting group manipulations and of purification, such as, re-crystallization, distillation, column chromatography, flash chromatography, thin-layer chromatography (TLC), radial chromatography and high-pressure chromatography (HPLC).
  • the products can be characterized using various techniques well known in the chemical arts, including proton and carbon- 13 nuclear magnetic resonance (1H and 13 C NMR), infrared and ultraviolet spectroscopy (IR and UV), X-ray crystallography, elemental analysis and HPLC and mass spectrometry (HPLC-MS).
  • Methods of protecting group manipulation, purification, structure identification and quantification are well known to one skilled in the art of chemical synthesis.
  • solvents are those which will at least partially dissolve one or all of the reactants and will not adversely interact with either the reactants or the product.
  • Suitable solvents are aromatic hydrocarbons (e.g, toluene, xylenes), halogenated solvents (e.g, methylene chloride, chloroform, carbontetrachloride, chlorobenzenes), ethers (e.g, diethyl ether,
  • nitriles e.g, acetonitrile, propionitrile
  • ketones e.g, 2-butanone, dithyl ketone, tert-butyl methyl ketone
  • alcohols e.g, methanol, ethanol,
  • Suitable bases are, generally, alkali metal hydroxides, alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, and calcium hydroxide; alkali metal hydrides and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; alkali metal amides such as lithium amide, sodium amide and potassium amide; alkali metal carbonates and alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, and cesium hydrogen carbonate; alkali metal alkoxides and alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and magnesium ethoxide; alkali metal alkyls such as methyllithium, n-butyllithium, sec-butyllithium, t- bultyllithium, phenyllithium, al
  • compounds of this invention contain one or more stereocenters that may be prepared as single enantiomers or diastereomers, or as mixtures containing two or more enantiomers or diastereomers in any proportion.
  • the compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail.
  • the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
  • the synthesis of the compounds in this invention can be synthesized using one of the methods described in schemes A or B.
  • Cyclocondensation of an appropriately substituted keto ester 1 using formamidine and a base catalyst such as sodium methoxide can provide bicyclic structure 2 which can subsequently be deprotected using catalytic hydrogenation to afford amine 3.
  • Amine 3 can then be coupled using an appropriately substituted carboxylic acid and an amide coupling agent to give intermediate pyrazinone 4 which can be converted the the corresponding chloropyrimidine 5.
  • the penultimate compounds 5 can then be heated with a cyclic amine in the presence of an acid scavenger to afford the final compounds 6 which could be functionalized further depending on the structure of the target.
  • Scheme B represents an alternative procedure for the synthesis of the claimed compounds and begins with the bicyclic pyrazinone 2 from scheme A above.
  • Chloropyrimidine formation can be effected by the action of an electrophilic halogenating agent such as phosphorous oxychloride to afford intermediate 3.
  • Nucleophilic aromatic substitution with an appropriately substituted cyclic amine can provide intermediate 4 which can then be deprotected using hydrogenating conditions.
  • the resulting amine can then be functionalized using a variety of acylating or sulfonylating agents to provide the desired targets 6.
  • Example 7 cyclopropyl(l- ⁇ 6-[(4'-fluorobiphenyl-4-yl)carbonyl]-5,6,7,8- tetra- hydropyrido[4,3- d]pyrimidin-4-yl ⁇ piperidin-4-yl)methanone
  • Example 8 l- ⁇ l-[6-(biphenyl-4-ylcarbonyl)-5,6,7,8- tetrahydropyrido[4,3-d]- pyrimidin-4- yl]piperidin-4-yl ⁇ propan-1-one
  • the TASK-3 antagonist assay was designed to determine the inhibition of compounds on the human TASK-3 current.
  • the human TASK-3/pENTR221 clone was ordered from Invitrogen (Cat #IOH45737, accession #NM_016601) and was subcloned into the pcCNA5/FRT/TO vector (Invitrogen #V6520-20). The clone was transfected with Lipofectamine 2000 reagent into TRex- Flp-In-CHO cells.
  • TASK-3 Antagonist Assay was developed using the IonWorks®QuattroTM system from Molecular Devices (Sunnyvale, CA). In this electrophysiology platform cells are sealed on a Population Patch PlateTM (PPC) technology.
  • PPC Population Patch PlateTM
  • Electical access is obtained using the Nystatin (Sigma, #N6261). Currents are recorded using a 200ms depolarization to +50 mV followed by a 200 ms ramp from -110 - +70 mV for both the pre- and post-compound recordings.
  • the compounds of formula I have an IC 50 activity of 100 ⁇ or less for the TASK receptor. Many of the compounds of formula I have an IC 50 of less than 200 nM. For example, the compounds below have IC 50 ⁇ 3000nM in the "TASK-3 antagonist assay". In particular,

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Abstract

Cette invention concerne des antagonistes de TASK-1 et/ou TASK-3 et/ou leurs sels pharmaceutiquement acceptables, des compositions et des procédés de traitement et de prévention de troubles qui sont provoqués par l'activation de TASK-1 et/ou TASK-3 ou par un TASK-1 et/ou TASK-3 activé(s), et de troubles ayant des lésions liées à TASK-1 et/ou TASK-3 comme cause secondaire.
PCT/CN2010/070751 2010-02-25 2010-02-25 Antagonistes de canal task WO2011103715A1 (fr)

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CN105601639A (zh) * 2014-11-19 2016-05-25 上海合全药物研发有限公司 一种6-叔丁氧羰基八氢-2H-吡喃[3,2-c]并吡啶-8-羧酸的合成方法
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US10392376B2 (en) 2017-07-13 2019-08-27 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of ATR kinase
US10421765B2 (en) 2017-05-26 2019-09-24 Board Of Regents, The University Of Texas System Tetrahydropyrido[4,3-d]pyrimidine inhibitors of ATR kinase
US10800774B2 (en) 2017-08-17 2020-10-13 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of ATR kinase
US10894052B2 (en) 2018-03-16 2021-01-19 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of ATR kinase
CN112694436A (zh) * 2020-12-30 2021-04-23 济南周行医药科技有限公司 一种槟榔碱的合成方法
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US11839663B2 (en) 2019-09-30 2023-12-12 Janssen Pharmaceutica Nv Radiolabelled MGL pet ligands
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US9499536B2 (en) 2010-07-06 2016-11-22 Novartis Ag Tetrahydro-pyrido-pyrimidine derivatives
US11225478B2 (en) 2013-03-14 2022-01-18 Janssen Pharmaceutica Nv P2X7 modulators
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JP2016516771A (ja) * 2013-04-12 2016-06-09 イーライ リリー アンド カンパニー ジヒドロピリドピリミジン化合物
JP2017528474A (ja) * 2014-09-12 2017-09-28 ヤンセン ファーマシューティカ エヌ．ベー． Ｐ２ｘ７調節因子
CN105503890A (zh) * 2014-09-23 2016-04-20 天津药明康德新药开发有限公司 一种5-叔丁氧羰基八氢呋喃[3,2-c]并吡啶-7-羧酸的合成方法
CN105669687A (zh) * 2014-11-19 2016-06-15 上海合全药业股份有限公司 一种4-叔丁氧羰基-六氢-2H-呋喃[3,2-b]并吡咯-6-羧酸的合成方法
CN105601639A (zh) * 2014-11-19 2016-05-25 上海合全药物研发有限公司 一种6-叔丁氧羰基八氢-2H-吡喃[3,2-c]并吡啶-8-羧酸的合成方法
KR20170134443A (ko) * 2015-03-02 2017-12-06 암젠 인크 비시클릭 케톤 술폰아마이드 화합물
JP2018510858A (ja) * 2015-03-02 2018-04-19 アムジエン・インコーポレーテツド 二環式ケトンスルホンアミド化合物
KR102649836B1 (ko) 2015-03-02 2024-03-22 암젠 인크 비시클릭 케톤 술폰아마이드 화합물
CN108290887A (zh) * 2015-12-10 2018-07-17 拜耳制药股份公司 用于治疗睡眠相关的呼吸病症的作为task-1和task-2通道阻断剂的2-苯基-3-(哌嗪子基甲基)咪唑并[1,2-a]吡啶衍生物
US10421765B2 (en) 2017-05-26 2019-09-24 Board Of Regents, The University Of Texas System Tetrahydropyrido[4,3-d]pyrimidine inhibitors of ATR kinase
US10745420B2 (en) 2017-05-26 2020-08-18 Board Of Regents, The University Of Texas System Tetrahydropyrido[4,3-d]pyrimidine inhibitors of ATR kinase
EP3630116A4 (fr) * 2017-05-26 2021-03-24 Board of Regents, The University of Texas System Inhibiteurs de la kinase atr à base de tétrahydropyrido[4,3-d]pyrimidine
US10392376B2 (en) 2017-07-13 2019-08-27 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of ATR kinase
US11434233B2 (en) 2017-07-13 2022-09-06 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of ATR kinase
US10800769B2 (en) 2017-07-13 2020-10-13 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of ATR kinase
US10800774B2 (en) 2017-08-17 2020-10-13 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of ATR kinase
US10894052B2 (en) 2018-03-16 2021-01-19 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of ATR kinase
US11597728B2 (en) 2018-09-28 2023-03-07 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
US11820766B2 (en) 2018-09-28 2023-11-21 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
US11993601B2 (en) 2018-09-28 2024-05-28 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
US11839663B2 (en) 2019-09-30 2023-12-12 Janssen Pharmaceutica Nv Radiolabelled MGL pet ligands
US11891387B2 (en) 2020-03-26 2024-02-06 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
CN112694436B (zh) * 2020-12-30 2022-07-08 济南周行医药科技有限公司 一种槟榔碱的合成方法
CN112694436A (zh) * 2020-12-30 2021-04-23 济南周行医药科技有限公司 一种槟榔碱的合成方法

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