CN103183675A - Phosphodiesterase-4 inhibitor - Google Patents

Phosphodiesterase-4 inhibitor Download PDF

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CN103183675A
CN103183675A CN2012105812976A CN201210581297A CN103183675A CN 103183675 A CN103183675 A CN 103183675A CN 2012105812976 A CN2012105812976 A CN 2012105812976A CN 201210581297 A CN201210581297 A CN 201210581297A CN 103183675 A CN103183675 A CN 103183675A
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optionally substituted
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吴永谦
孙亮
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Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention belongs to the technical field of medicines and particularly relates to a phosphodiesterase-4 inhibitor as shown in a general formula (I) and a pharmaceutically acceptable salt, a stereoisomer or a solvent compound thereof. In the formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, R7', R8', R9', L and a ring A are as defined in the specification. The invention further relates to a preparation method for the compound, a pharmaceutical composition with the compound, and an application of the compound and the pharmaceutical composition to preparation of drugs for treating and/or preventing inflammatory diseases, disease symptoms and disease conditions characterized by or related with undesired inflammatory immune reaction and all diseases induced by or related with TNF-alpha (tumor necrosis factor-alpha) and PDE-4 (phosphodiesterase-4) hypersecretion.

Description

phosphodiesterase-4 inhibitors
Technical Field
The present invention relates to phosphodiesterase-4 inhibitors, pharmaceutically acceptable salts thereof, stereoisomers thereof or solvate compounds thereof, processes for their preparation, pharmaceutical compositions containing said compounds and the use of said compounds and pharmaceutical compositions for the preparation of a medicament for the treatment and/or prophylaxis of inflammatory diseases, disorders and conditions characterized by or associated with an undesired inflammatory immune response and all diseases induced by or associated with excessive TNF-alpha and PDE-4 secretion.
Background
Hormones are a class of compounds that affect cellular activity in different ways. In many cases, hormones act as messengers that trigger specific cellular responses and activities. However, many of the effects produced by hormones are not caused only by the specific effects of the hormone. Instead, the hormone first binds to the receptor, triggering the release of a second compound, which in turn affects cellular activity. In this case, the hormone is referred to as a first messenger, and the second compound is referred to as a second messenger. Cyclic adenylate (adenosine 3 ', 5' -cyclic monophosphate, cAMP or cyclic AMP) is considered a second messenger for hormones such as epinephrine, glucagon, calcitonin, corticotropin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyrotropin and vasopressin. Thus, cAMP mediates cellular responses to hormones, and cAMP also mediates cellular responses to various neurotransmitters.
Phosphodiesterases (PDEs) have the function of hydrolyzing intracellular second messengers, degrading intracellular cAMP, and thus terminating the biochemical role conducted by these second messengers. The PDEs family of 11 enzymes, of which the PDE4 enzyme is a specific cAMP hydrolase, is distributed primarily in airway smooth muscle cells and in inflammatory and immune cells such as lymphocytes, macrophages, neutrophils, eosinophils, basophils, monocytes, and epithelial cells, and regulates the levels of cAMP in these cells.
PDE4 inhibitors inhibit the activity of these immune and inflammatory cells and are useful in the treatment of diseases caused by inflammation, such as central nervous system diseases caused by neuronal damage due to underlying inflammation, such as asthma, Chronic Obstructive Pulmonary Disease (COPD), rheumatoid arthritis, multiple sclerosis, Alzheimer's Disease (AD), Parkinson's Disease (PD) and stroke.
Roflumilast (Roflumilast) was the first PDE4 inhibitor to be marketed. When the roflumilast is orally taken by COPD patients for more than 4 weeks, the number of neutrophils in sputum can be obviously reduced, and when the roflumilast is taken for more than 6-12 months, the lung function can be slightly improved, but acute exacerbation of the disease cannot be obviously reduced or the life quality cannot be improved, possibly because the dosage of the roflumilast is limited due to side effects of the medicine.
One concern with the use of PDE4 inhibitors is their emetic side effects, which have shown that PDE4 has 4 subtypes: PDE4A, PDE4B, PDE4C, PDE 4D; among them, PDE4B is related to anti-inflammation, PDE4D also has anti-inflammation effect, but is related to vomiting reaction of central nervous system, therefore, the PDE4B inhibitor with high selectivity can greatly reduce adverse reaction of vomiting, improve drug treatment window, thereby achieving better treatment effect.
Cilomilast (Cilomilast) is a PDE4 inhibitor that stops at phase III due to adverse emesis. Research shows that the activity of the Cilomilast (Cilomilast) on PDE4D is 10 times better than that of PDE4B, while the activity of the roflumilast on PDE4B and PDE4D is equivalent, so that the design of the PDE4 inhibitor with the activity of PDE4B equivalent to that of PDE4D can greatly reduce the side effect of emesis, improve the drug treatment window and achieve the optimal drug treatment effect.
Figure BDA00002662797200021
Disclosure of Invention
The invention provides a compound which can be used as a PDE-4 inhibitor and is shown as a formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvent compound thereof:
Figure BDA00002662797200022
wherein R is1Is hydrogen, -C (O) -Ra，-S(O)q-RaC unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, C unsubstituted or substituted by 1 to 3Q1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q2-8Alkenyl, C unsubstituted or optionally substituted with 1-3Q3-8Alkynyl, C unsubstituted or optionally substituted by 1-3Q6-14Aryl, 5-15 membered heteroaryl unsubstituted or optionally substituted with 1-3Q, or 3-15 membered heterocyclyl C unsubstituted or optionally substituted with 1-3Q1-8An alkyl group;
R2c being hydrogen, unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, or C unsubstituted or optionally substituted by 1 to 3Q3-8A cycloalkyl group;
R3，R4，R5and R6Each independently is hydrogen, halogen atom, -C (O) -Ra，-S(O)q-RaNitro, cyano, -NRaRa', C unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, or C unsubstituted or optionally substituted by 1 to 3Q1-8An alkoxy group; r7Is hydrogen, phenyl which is unsubstituted or optionally substituted by 1 to 3Q, thienyl, pyridonyl,
Figure BDA00002662797200023
Azolyl group,A diazolyl, thiazolyl, or thiadiazolyl group, a pyridyl, pyrimidinyl, indolyl, quinolinyl, or imidazolyl group unsubstituted or optionally substituted with 1 to 3Q, and their nitroxides, C unsubstituted or optionally substituted with 1 to 3Q1-8Alkyl, or C unsubstituted or optionally substituted by 1 to 3Q3-8A cycloalkyl group;
R7' absent, hydrogen, unsubstituted or optionally substituted by 1 to 3Q, phenyl, thienyl, pyridonyl,Azolyl group,
Figure BDA00002662797200032
A diazolyl, thiazolyl, or thiadiazolyl group, a pyridyl, pyrimidinyl, indolyl, quinolinyl, or imidazolyl group unsubstituted or optionally substituted with 1 to 3Q, and their nitroxides, C unsubstituted or optionally substituted with 1 to 3Q1-8Alkyl, or C unsubstituted or optionally substituted by 1 to 3Q3-8A cycloalkyl group;
and R is7' is phenyl, thienyl, pyridonyl, unsubstituted or optionally substituted by 1 to 3Q,
Figure BDA00002662797200033
Azolyl group,
Figure BDA00002662797200034
(ii) oxadiazolyl, thiazolyl or thiadiazolyl, or unsubstituted or optionally 1-3Q-substituted pyridyl, pyrimidinyl, indolyl, quinolinyl or imidazolyl and their nitroxides1Is hydrogen, -C (O) -Ra，-S(O)q-RaC unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q2-8Alkenyl, C unsubstituted or optionally substituted with 1-3Q3-8Alkynyl, C unsubstituted or optionally substituted by 1-3Q6-14Aryl, or a 3-to 15-membered heterocyclic group C which is unsubstituted or optionally substituted with 1-3Q1-8An alkyl group;
R8is hydrogen, halogen atom, nitro, cyano, = N-O-C1-8Alkyl, -O-N = C1-8Alkyl, -CH (N = NOH) -C1-8Alkyl, -NRaRa’，-C(O)-Ra，-C(O)NRaRa’，-NRaC(O)Ra’，-S(O)q-Ra，-S(O)q-NRaRa’，-NRa-S(O)q-Ra’，-C(O)ORaC unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q6-14Aryl, 5-15 membered heteroaryl unsubstituted or optionally substituted with 1-3Q, or 3-15 membered heterocyclyl C unsubstituted or optionally substituted with 1-3Q1-8An alkyl group;
R8' absence, hydrogen, halogen atom, nitro group, cyano group, = N-O-C1-8Alkyl, -O-N = C1-8Alkyl, -CH (N = NOH) -C1-8Alkyl, -NRaRa’，-C(O)-Ra，-C(O)NRaRa’，-NRaC(O)Ra’，-S(O)q-Ra，-S(O)q-NRaRa’，-NRa-S(O)q-Ra’，-C(O)ORaC unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q6-14Aryl, 5-15 membered heteroaryl unsubstituted or optionally substituted with 1-3Q, or 3-15 membered heterocyclyl C unsubstituted or optionally substituted with 1-3Q1-8An alkyl group;
R9is hydrogen, hydroxy, halogen atom, -NRbRb', or C unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
R9' absence, hydrogen, hydroxy, halogen atom, -NRbRb', or C unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
ring A is phenyl containing 1-4 5-8 membered heteroaryl groups selected from N, S, O, or 1-4 8-14 membered heterocyclic groups selected from N, S, O;
l represents-O-, -S (O)q-, 1, 1-cyclopropanyl, carbonyl, ethenyl, methylene, ethyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl;
q is selected from 0, 1 or 2;
Ra、Ra' is selected from hydrogen, C unsubstituted or optionally substituted with 1 to 3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl radical C1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q6-14Aryl, or a 3-15 membered heterocyclyl unsubstituted or optionally substituted with 1-3Q;
q is selected from hydroxyl, carboxyl, nitro, cyano, halogen atom, C1-8Alkyl radical, C3-8Cycloalkyl radical, C1-8Alkoxy, halo C1-8Alkyl, halo C1-8Alkoxy, -NRbRb’，-C(O)-Rb，-C(O)NRbRb’，-NRbC(O)Rb’，=N-O-C1-8Alkyl, -O-N = C1-8Alkyl, -S (O)q-Rb，-S(O)q-NRbRb’，-NRb-S(O)q-Rb', OR-C (O) ORbWherein R isb、Rb' independently of one another are hydrogen, C1-8Alkyl radical, C3-8Cycloalkyl, or C6-14And (4) an aryl group.
The present invention preferably provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof, as defined below:
wherein R is1Is hydrogen, -C (O) -Ra，-S(O)q-RaC unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q6-14Aryl, or 5-15 membered heteroaryl unsubstituted or optionally substituted with 1-3Q;
R2is hydrogen, or C which is unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
R3，R4，R5and R6Each independently is hydrogen, halogen atom, -C (O) -Ra，-S(O)q-RaNitro, cyano, -NRaRa', C unsubstituted or substituted by 1 to 3 substituents1-8Alkyl, or C unsubstituted or optionally substituted by 1 to 3Q1-8An alkoxy group; r7Is phenyl, thienyl, pyridonyl which are unsubstituted or optionally substituted by 1 to 3Q,
Figure BDA00002662797200041
Azolyl group,
Figure BDA00002662797200042
Oxadiazolyl, thiazolyl, or thiadiazolyl, or pyridyl, pyrimidinyl, indolyl, quinolinyl, or imidazolyl and their nitroxides unsubstituted or optionally substituted with 1-3Q;
R7' absent, unsubstituted or optionally substituted by 1 to 3Q, phenyl, thienyl, pyridonyl,Azolyl, diazolyl
Figure BDA00002662797200044
(ii) an oxazolyl, thiazolyl, or thiadiazolyl group, or an unsubstituted or optionally 1-3Q-substituted pyridyl, pyrimidinyl, indolyl, quinolinyl, or imidazolyl group and nitroxides thereof;
and R is7' is phenyl, thienyl, pyridonyl, unsubstituted or optionally substituted by 1 to 3Q,Azolyl group,
Figure BDA00002662797200046
(ii) oxadiazolyl, thiazolyl or thiadiazolyl, or unsubstituted or optionally 1-3Q-substituted pyridyl, pyrimidinyl, indolyl, quinolinyl or imidazolyl and their nitroxides1Is hydrogen, -C (O) -Ra，-S(O)q-RaC unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, or C unsubstituted or optionally substituted with 1-3Q6-14An aryl group;
R8is hydrogen, a halogen atom, -NRaRa’，-C(O)-Ra，-C(O)NRaRa’，-NRaC(O)Ra’，-S(O)q-Ra，-S(O)q-NRaRa’，-NRa-S(O)q-Ra’，-C(O)ORaOr C which is unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
R8' absence, hydrogen, halogen atom, -NRaRa’，-C(O)-Ra，-C(O)NRaRa’，-NRaC(O)Ra’，-S(O)q-Ra，-S(O)q-NRaRa’，-NRa-S(O)q-Ra’，-C(O)ORaOr C which is unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
R9is hydrogen, hydroxy, halogen atom, C unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
R9' No, hydrogen, hydroxyl, halogen atom, or C unsubstituted or optionally substituted by 1 to 3 of Q1-8An alkyl group;
ring A is phenyl containing 1-4 5-8 membered heteroaryl groups selected from N, S, O, or 1-4 8-14 membered heterocyclic groups selected from N, S, O;
l is-O-, -S (O)q-, 1, 1-cyclopropanyl, carbonyl, methylene, ethyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl;
q is selected from 0, 1 or 2;
Ra、Ra' is selected from hydrogen, C unsubstituted or optionally substituted with 1 to 3Q1-8An alkyl group;
q is selected from hydroxyl, carboxyl, cyano, halogen atom, C1-8Alkyl radical, C3-8Cycloalkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, -NRbRb’，-C(O)-Rb，-C(O)NRbRb’，-NRbC(O)Rb’，-S(O)q-Rb，-S(O)q-NRbRb’，-NRb-S(O)q-Rb', OR-C (O) ORbWherein R isb、Rb' independently of one another are hydrogen or C1-8An alkyl group.
In another aspect, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof or solvate thereof,
wherein R is1Is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl;
R2is hydrogen, or methyl;
R3，R4，R5and R6Each independently is hydrogen, methyl, fluorine atom, chlorine atom, or bromine atom;
R8，R9each independently is hydrogen, methyl, fluorine atom, chlorine atom, methylsulfonyl, or 2-hydroxyisopropyl;
R7' absent;
R8’，R9' absent.
In another aspect, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof or solvate thereof,
wherein, the ring A is phenyl or 5-6-membered heteroaryl containing 1-3 selected from N, S, O;
l is-O-, -S (O)q-, 1, 1-cyclopropanyl, carbonyl, ethenyl, methylene, ethyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
In another aspect, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof or solvate thereof,
wherein, the ring A is phenyl or 5-6-membered heteroaryl containing 1-3N;
l is-O-, -S (O)q-, 1, 1-cyclopropanyl, carbonyl, ethenyl, methylene, ethyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
In another aspect, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof or solvate thereof,
wherein ring a is phenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, or pyrazinyl;
l is-O-, -S (O)q-, 1, 1-cyclopropanyl, carbonyl, ethenyl, methylene, ethyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
In another aspect, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof or solvate thereof,
wherein L is-O-, -S-, -S (O) -, -S (O)2-, 1, 1-cyclopropanyl, carbonyl, ethenyl, methylene, or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
In another aspect, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof or solvate thereof,
wherein L is-O-, -S-, -S (O) -, -S (O)2-, 1, 1-cyclopropanyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
In another aspect, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof or solvate thereof,
wherein R is7Is pyridyl or their nitroxides.
In another aspect, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof or solvate thereof,
wherein R is7Is pyridyl or their nitroxides;
ring a is phenyl, pyridyl, pyrimidinyl, or pyrazinyl;
l is-O-, -S-, -S (O) -, -S (O)2Or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
Detailed Description
Examples of the "halogen atom" in the present invention include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.
Said "C" of the present invention1-8The "alkyl group" refers to a straight or branched alkyl group derived from a hydrocarbon having 1 to 8 carbon atoms by removal of one hydrogen atom, and examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2-dimethylpentyl, 3-methylpentyl, 2-dimethylpentyl, 2-dimethylp, 3, 3-dimethylpentyl group, 2, 4-dimethylpentyl group, 3-ethylpentyl group, 2, 3-trimethylbutyl group, n-octyl group, 2-methylheptyl group, 3-methylheptyl group, 4-methylheptyl group, 2-dimethylhexyl group, 3, 3-dimethylhexyl group, 2, 4-dimethylhexyl group, 2, 5-dimethylhexyl group, 3, 4-dimethylhexyl group, 3-ethylhexyl group, 2, 3-trimethylpentyl group, 2, 4-trimethylpentyl group, 2,3, 3-trimethylpentyl group, 2,3, 4-trimethylpentyl group, 2-methyl-3-ethylpentyl group, 3-methyl-3-ethylpentyl group, 2, 3-methylpentyl group, 3-ethylpentyl group, 2,2, 2,3, 3-tetramethylbutyl, and the like.
Said "C" of the present invention1-8Alkoxy "means" C "as defined above1-8Alkyl "radicals attached to the main structure through an oxygen atom, examples include, but are not limited to, methoxy, ethoxyA group such as a phenyl group, a naphthyl group and the like.
"C" according to the invention3-8Cycloalkyl "refers to a cyclic alkyl group having 3 to 8 carbon atoms, and specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
Said "C" of the present invention2-8The alkenyl group "means a straight-chain or branched aliphatic hydrocarbon group having 2 to 8 carbon atoms and containing a carbon-carbon double bond, and examples include, but are not limited to, an ethylene group, a 1-propylene group, a 2-propylene group, a 1-methylethylene group, a 1-butylene group, a 2-butylene group, a 3-butylene group, a 1-methyl-1-propylene group, a 2-methyl-1-propylene group, a 1-methyl-2-propylene group, a 2-methyl-2-propylene group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 1-methyl-1-butylene group, a 2-methyl-1-butylene group, a 3-methyl-1-butylene group, a 1-methyl-2-butylene group, a, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-1-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenyl, 1-ethyl-1-butenylAlkenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 2-heptenyl, 5-heptenyl, 6-heptenyl, 1-methyl-1-hexenyl, 2-methyl-1-hexenyl, 3-methyl-1-hexenyl, 4-methyl-1-hexenyl, 5-methyl-1-hexenyl, 1-methyl-2-hexenyl, 2-methyl-2-hexenyl, 3-methyl-2-hexenyl, 4-methyl-2-hexenyl, 5-methyl-2-hexenyl, 1-methyl-3-hexenyl, 2-methyl-3-hexenyl, 3-methyl-3-hexenyl, 4-methyl-3-hexenyl, 5-methyl-3-hexenyl, 1-methyl-1-hexenyl, 2-methyl-3-hexenyl, 3-methyl-3-hexenyl, 4-methyl-3-hexenyl, 5-methyl-3-hexenyl, 2-methyl-hexenyl, 1-methyl-4-hexenyl, 2-methyl-4-hexenyl, 3-methyl-4-hexenyl, 4-methyl-4-hexenyl, 5-methyl-4-hexenyl, 1-methyl-5-hexenyl, 2-methyl-5-hexenyl, 3-methyl-5-hexenyl, 4-methyl-5-hexenyl, 5-methyl-5-hexenyl, 1-dimethyl-2-pentenyl, 1-dimethyl-3-pentenyl, 1-dimethyl-4-pentenyl, 1, 2-dimethyl-1-pentenyl, 2-dimethyl-3-pentenyl, 2-methyl-4-hexenyl, 5-methyl-5-hexenyl, 1-dimethyl-3-pentenyl, 3-hexenyl, 3-methyl-5-hexenyl, 2, 2-dimethyl-4-pentenyl, 3-dimethyl-1-pentenyl, 3-dimethyl-4-pentenyl, 4-dimethyl-1-pentenyl, 4-dimethyl-2-pentenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl and the like.
"C" according to the invention3-8The alkynyl group "means a straight chain or branched alkynyl group having 3 to 8 carbon atoms and having a triple bond, and specific examples include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-methyl-1-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1-hexynyl, 2-hexynyl, 3-methyl-1-hexynyl, 3, 4-dimethyl-1 hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4 heptynyl, 5-heptynyl, 4-methyl-1-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-ethyl-1-hexynyl and the like.
Said "C" of the present invention6-14The aryl group refers to an aromatic group having 6 to 14 carbon atoms, and includes 6 to 8-membered aryl groups and 8 to 14-membered condensed ring aryl groups. The 6-to 8-membered aryl group means an all-unsaturated aryl group such as phenyl, cyclooctatetraenyl and the like. The 8-14 membered fused ring aryl group refers to a fused ring group in which two or more ring structures share two adjacent carbon atoms to form an aromatic ring in which at least one ring is unsaturated, and includes 8-14 membered unsaturated fused ring aryl groups such as naphthalene and phenanthrene, and 8-14 membered partially saturated fused ring aryl groups such as benzo C3-8Cycloalkyl, benzo C4-8Specific examples of the cycloalkenyl group include 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrahydronaphthyl and 1, 4-dihydronaphthyl.
The 5-15 membered heteroaryl group refers to an unsaturated aromatic cyclic group containing 5-15 ring atoms (wherein at least one heteroatom is contained), and comprises a 5-8 membered heteroaryl group and an 8-15 membered fused heteroaryl group, wherein the heteroatoms comprise nitrogen, oxygen, sulfur and the like, and simultaneously comprise carbon atoms, nitrogen atoms and sulfur atoms which can be oxidized.
"5-to 8-membered heteroaryl" refers to an aromatic cyclic group containing 5 to 8 ring atoms (wherein at least one heteroatom is present), and specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, and thiadiazolyl,
Figure BDA00002662797200081
Azolyl radical, isoAzolyl group,
Figure BDA00002662797200083
Oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2,3-
Figure BDA00002662797200084
Oxadiazolyl, 1,2,4-
Figure BDA00002662797200085
Oxadiazolyl, 1,2,5-
Figure BDA00002662797200086
Oxadiazolyl, 1,3,4-Oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidyl, 1, 4-dioxadienyl, 2H-1,2-
Figure BDA00002662797200088
Oxazinyl, 4H-1,2-
Figure BDA00002662797200089
Oxazinyl, 6H-1,2-
Figure BDA000026627972000810
Oxazinyl, 4H-1,3-Oxazinyl, 6H-1,3-
Figure BDA000026627972000812
Oxazinyl, 4H-1,4-
Figure BDA000026627972000813
Azinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, 1,3, 4-triazinyl, 1,2,4, 5-tetrazinyl, oxepitrienyl, thiepintrienyl, azepintrienyl, 1, 3-diazepitrienyl, azepinatetraenyl, 1, 4-dihydro-1, 4-diazacyclooctatriene, 1, 4-dioxacyclooctatriene, and the like. The "5-to 6-membered heteroaryl group" refers to an aromatic cyclic group having 5 to 6 ring atoms (at least one heteroatom contained therein), and specific examples thereof are shown in the specification of 5 to 6 ring atoms in the "5-to 8-membered heteroaryl group".
An 8-15 membered fused heteroaryl group, which is a fused heteroaryl group comprising 8 to 15 ring atoms (wherein at least one heteroatom is contained) linked by two or more cyclic structures sharing two adjacent atomsSpecific examples of unsaturated aromatic fused ring structures include, but are not limited to, benzofuranyl, benzoisoturanyl, benzothienyl, indolyl, isoindole, benzo
Figure BDA000026627972000814
Oxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinyl, isoquinolyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, phenazinyl, phenothiazinyl, benzotrifluoranyl and the like.
The term "3-15 membered heterocyclic group" as used herein means a 3-15 membered cyclic group containing one or more heteroatoms selected from N, S, O, CO, SO and/or SO2And the like. Including 3-8 membered heterocyclic groups and 6-15 membered fused heterocyclic groups. 3-8 membered heterocyclic group means a heterocyclic group containing 3 to 8 ring atoms (wherein at least one hetero atom is contained), preferably 5 to 6 membered heterocyclic group. Specific examples include, but are not limited to, 2, 5-dihydrothienyl, 4, 5-dihydropyrazolyl, 3, 4-dihydro-2H-pyranyl, 5, 6-dihydro-4H-1, 3-
Figure BDA00002662797200091
Oxazinyl, aziridinyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, 1, 4-dioxanyl, 1, 3-dithianyl, morpholinyl, piperazinyl, and the like.
The 6-15 membered fused heterocyclic group means a fused ring structure containing 6 to 15 ring atoms (wherein at least one hetero atom is contained) formed by two or more ring structures sharing two adjacent atoms to each other and connecting, preferably a 6-10 membered fused heterocyclic group such as a structure formed by a benzo 3-8 membered heterocyclic group, a structure formed by a 3-8 membered heterocyclic group and a 3-8 membered heterocyclic group, and the like, and specific examples include but are not limited to: 1, 3-dihydrobenzofuranyl, benzo [ d ]][1.3]Dioxolyl, isoindolinyl, chromanyl, 1,2,3, 4-tetrahydropyrroleAnd [3,4-c ]]Pyrrole, pyrrole,
Figure BDA00002662797200093
Cyclobutane tetrahydropyrrole, cyclopentane tetrahydropyrrole, azetidine imidazolidine radical,And the like.
The term "8-to 14-membered heterocyclic group" as used herein means a specific example in which the ring atom is 8-to 14-membered in the above example of the "3-to 15-membered heterocyclic group".
The 3-to 15-membered heterocyclic group C of the present invention1-8The alkyl group is a 3-to 15-membered heterocyclic group1-8Radicals wherein the carbon atom of the alkyl group is attached to the main structure include, but are not limited to, pyridin-4-ylmethyl, indol-5-ylethyl and the like.
The "halo C" of the present invention1-8Alkyl, halo C1-8"halo" in "alkoxy" means C1-8Alkyl radical, C1-8One or more hydrogen atoms on a carbon atom in an alkoxy group are replaced by a halogen atom, the term "halogen atom" being as described hereinbefore.
More particularly, the invention relates to compounds selected from the group consisting of:
Figure BDA00002662797200095
Figure BDA00002662797200111
Figure BDA00002662797200121
the invention also relates to a process for the preparation of a compound of formula (I) as defined above, the reaction equation being as follows, but not limited to the following process:
step 1: preparation of Compound a
Dissolving the raw material 1 in thionyl chloride, adding a proper amount of DMF (N, N-dimethylformamide), heating, after the reaction is finished, concentrating to obtain a compound a.
Step 2: preparation of Compound b
Dissolving the compound a in toluene, adding (E) -3-dimethylamino ethyl acrylate and triethylamine, heating and stirring, concentrating and purifying to obtain a compound b.
And step 3: preparation of Compound c
And dissolving the compound b in DMF, adding the raw material 2, stirring at room temperature, adding alkali, heating, stirring, extracting, and concentrating to separate out a compound c.
And 4, step 4: preparation of Compound d
Dissolving the compound c in tetrahydrofuran and methanol, adding a methanol solution of KOH, and reacting at high temperature. Adjusting pH with hydrochloric acid, filtering the solid, and drying the filter cake to obtain a compound d.
And 5: preparation of Compound e
Dissolving the compound d in dichloromethane, adding triethylamine and isopropyl chloroformate at low temperature, reacting at low temperature for a period of time, then adding the raw material 3 and triethylamine, stirring at room temperature for reaction, washing with water, and concentrating to obtain a compound e.
Step 6: preparation of Compounds of formula (I)
Dissolving the compound e and the raw material 4 in DMSO (dimethyl sulfoxide), adding a catalyst, cuprous iodide and a proper amount of alkali, carrying out microwave reaction at high temperature, extracting after the reaction is finished, and purifying and separating to obtain the compound shown in the formula (I).
In the above reaction formula, the group R1、R2、R3、R4、R5、R6、R7、R8、R9、R7’、R8’、R9', L, ring A are as defined above, and X is a halogen atom.
The pharmaceutically acceptable salt of any compound of the invention refers to a salt prepared from pharmaceutically acceptable and nontoxic alkali or acid, and comprises organic acid salt, inorganic acid salt, organic alkali salt and inorganic alkali salt. The organic acid salts include salts of formic acid, acetic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, and the like. The inorganic acid salt includes salts of hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Organic base salts include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins selected from the group consisting of betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Natural amino acid salts such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, and the like. Inorganic base salts include ammonium and salts of lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminum, iron, ketone, ferrous, manganese, manganous, and the like. Salts in solid form may exist as a solvate, e.g. as a hydrate.
The compounds of the present invention contain one or more asymmetric centers and are thus useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention have asymmetric centers that each independently produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The present invention includes all stereoisomeric forms of these compounds.
The compounds of the present invention, if they contain an olefinic double bond, include both cis-and trans-isomers, unless otherwise specified.
The compounds of the present invention may exist in tautomeric forms having different points of attachment of hydrogen through one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the invention.
The compound shown in the general formula (I), the pharmaceutically acceptable salt thereof and the stereoisomer thereof can be in the form of a solvent compound. Where the solvate compound is a hydrate, the hydration may be accomplished during the manufacturing process or may be gradual, taking advantage of the hygroscopic properties of the original anhydrous product.
Another object of the present invention is a method for the treatment of inflammatory diseases, disorders or conditions characterized by or associated with an undesired inflammatory immune response and all diseases and conditions induced by or associated with hypersecretion of TNF-alpha and PDE4, which method comprises administering to said individual a therapeutically effective amount of a compound of formula (I).
Another object of the invention is a method for treating inflammatory conditions and immune disorders in a subject in need thereof, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Preferred inflammatory conditions and immune disorders are selected from the group consisting of asthma, bronchial asthma, chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, crohn's disease, psoriasis, urticaria, adult vernal conjunctivitis, respiratory distress syndrome, rheumatoid spondylitis, osteoarthritis, gouty arthritis, uveitis, allergic conjunctivitis, inflammatory bowel disease, ulcerative colitis, eczema, atopic dermatitis and chronic inflammation. Preferred are allergic inflammatory diseases.
Further preferred are inflammatory conditions and immune disorders selected from inflammatory conditions or immune disorders of the lungs, joints, eyes, intestines, skin and heart.
Further preferred are inflammatory disorders selected from the group consisting of bronchial asthma, nephritis and allergic rhinitis.
Another object of the invention is a method of reducing inflammation in an affected organ or tissue, the method comprising delivering to the organ or tissue a therapeutically effective amount of a compound of formula (I).
A pharmaceutical composition of any of the compounds of the present invention, pharmaceutically acceptable salts thereof, stereoisomers thereof or solvates thereof, together with one or more pharmaceutically acceptable carriers and/or diluents, may be administered orally or by inhalation to a patient in need of such treatment.
When orally administered to a patient in need of such treatment, the composition can be made into conventional oral solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. The tablet is a round or special-shaped tablet solid preparation prepared by uniformly mixing and pressing the medicament and proper auxiliary materials, mainly takes an oral common tablet as a main part, and also comprises a buccal tablet, a sublingual tablet, an oral patch, a chewable tablet, a dispersible tablet, a soluble tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet, an enteric-coated tablet and the like. The capsule refers to a solid preparation prepared by filling a drug or an adjuvant into an empty capsule or sealing in a soft capsule material, and can be divided into hard capsules (generally called capsules), soft capsules (capsules), sustained-release capsules, controlled-release capsules, enteric capsules and the like according to the dissolution and release characteristics of the solid preparation. The pill refers to a spherical or spheroidal solid preparation prepared by uniformly mixing the medicament and appropriate auxiliary materials and preparing the mixture by a proper method, and comprises a dropping pill, a sugar pill, a pellet and the like. The granules refer to dry granular preparations with certain granularity prepared by the medicines and proper auxiliary materials, and can be divided into soluble granules (generally called granules), suspension granules, effervescent granules, enteric granules, sustained-release granules, controlled-release granules and the like. Oral solution means that the drug is dissolved in a suitable solvent to make into a clear liquid preparation for oral administration. Oral suspensions refer to poorly soluble solid drugs dispersed in a liquid medium to form a suspension formulation for oral administration, including dry suspensions or concentrated suspensions. Syrup refers to a concentrated aqueous solution of sucrose containing the drug.
When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. Common fillers include starch, sugar powder, calcium phosphate, calcium sulfate dihydrate, dextrin, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, and the like; common binders include sodium carboxymethylcellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methyl cellulose, ethyl cellulose, hypromellose, gelatinized starch, etc.; common disintegrants include dry starch, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, and the like; common lubricants include magnesium stearate, talc, sodium lauryl sulfate, aerosil, and the like.
Administration by inhalation to a patient in need of such treatment is by delivery of the compound of formula (I) as a pressurized aerosol. After homogenization, the compound of formula (I) is preferably micronized, for example in lactose, glucose, higher fatty acids, dioctyl sodium sulfosuccinate or most preferably in carboxymethylcellulose to bring the majority of the particles to a particle size of 5 μm or less. For inhalation formulations, the aerosol can be mixed with a propellant in the gaseous or liquid state for dispersing the active substance. An inhaler or nebulizer may be used.
The compound of the invention has the following advantages:
(1) the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof or the solvent compound thereof have better inhibitory activity and anti-inflammatory effect;
(2) the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof or the solvent compound thereof show good biological stability;
(3) the compound of the invention has simple preparation process, high medicine purity and stable quality, and is easy to carry out large-scale industrial production.
The beneficial effects of the compounds of the present invention are further illustrated below by in vitro pharmacological experiments, but this should not be understood as the only beneficial effects of the compounds of the present invention.
Experimental examples in vitro pharmacological Activity of the Compounds of the invention
And (3) testing the sample: the chemical name and the structural formula of the partial compound of the invention, which is prepared by self, are shown in the examples.
Control drug: MK-0873, made by house.
The experimental method comprises the following steps: lancet cAMP Assay:
accurately weighing the sample, adding DMSO to dissolve, mixing well, and making into 100 μ M. The above stock was then diluted to 1 μ M with DMSO and then 4-fold diluted to 0.0038 nM.
Add 2.5. mu.L of substrate to 384 well plates20nM cAMP, 50nL compound in DMSO and 2.5. mu.L PDE enzyme (PDE4B10.18nM, PDE4D30.024nM) buffer (1 XHBSS, 5mM Hepes pH 7.4,3mM MgCl20.1% BSA) was incubated at room temperature for 90min, and 5. mu.L of Alexa was added
Figure BDA00002662797200161
647-anti cAMP antibody for 30min, adding 10 μ L detection reagent for 60min, detecting its LANCE signal at 665nm, calculating inhibition rate by the following formula, and calculating IC by XLFit from inhibition rate50The value is obtained.
Inhibition rate = [ signal value (MAX) -signal value (sample) ] × 100/[ signal value (MAX) -signal value (MIN) ]
Note: MAX: blank control without enzyme; MIN: blank control without compound.
Experimental results and conclusions:
TABLE 1 IC of the Compounds of the invention against PDE-4B1, PDE-4D350Value of
Figure BDA00002662797200162
TABLE 2 IC of the Compounds of the invention against PDE-4B1, PDE-4D350Value of
Figure BDA00002662797200163
TABLE 3 IC of the Compounds of the invention on PDE-4B1, PDE-4D350Value of
Figure BDA00002662797200164
TABLE 4 IC of the Compounds of the invention on PDE-4B1, PDE-4D350Value of
Figure BDA00002662797200165
TABLE 5 IC of the Compounds of the invention against PDE-4B1, PDE-4D350Value of
Figure BDA00002662797200166
And (4) conclusion: as can be seen from tables 1-5, the inhibitory activity and anti-inflammatory action of the compounds of the present invention against PDE-4B1 and PDE-4D3 were comparable to those of the control drugs; in addition, the same compound has little difference in inhibitory activity to PDE-4B1 and PDE-4D3, and can effectively reduce the occurrence of vomiting side reaction in clinical application.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1N-cyclopropyl-4-oxo-1- (3- (pyridin-3-yloxy) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (Compound) 1) Preparation of
(1) Preparation of 2-chloro-3-pyridinecarboxylic acid chloride
Figure BDA00002662797200172
2-chloro-3-pyridinecarboxylic acid (15 g, 0.095 mol) was dissolved in thionyl chloride, DMF (N, N-dimethylformamide) (0.5 mL) was added, and the mixture was reacted at 70 ℃ for 3 hours, concentrated under reduced pressure, and cooled to precipitate a product (13 g, yield 78%).
(2) Preparation of ethyl 2- (2-chloronicotinyl) -3- (dimethylamino) acrylate
2-chloro-3-pyridinecarboxylic chloride (10g, 0.057 mol) was dissolved in toluene (200 mL), TEA (triethylamine) (10.5 g, 0.10 mol), (E) -3-dimethylaminoethylacrylate (10g,0.07mol) was added, the mixture was reacted at 90 ℃ for 3 hours, extracted with DCM (dichloromethane) and water, and then isolated and purified by silica gel column chromatography to give the product (13 g, 81% yield).
(3) Preparation of 1- (3-bromophenyl) -4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid ethyl ester
Dissolving ethyl 2- (2-chloronicotinyl) -3- (dimethylamino) acrylate (7 g, 0.025 mol) in DMF (200 mL), adding m-bromoaniline (4.2 g, 0.024 mol), stirring at room temperature for 12 hours, adding water and dichloromethane for extraction, concentrating under reduced pressure, dissolving the residue in DMF (200 mL), adding potassium carbonate (7 g, 0.05 mol), stirring at 90 ℃ for 5 hours, adding water and dichloromethane for extraction, and concentrating under reduced pressure to obtain the product (5.2 g, 56% yield).
(4) Preparation of 1- (3-bromophenyl) -4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid
Figure BDA00002662797200181
Ethyl 1- (3-bromophenyl) -4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylate (2.1 g, 5.6 mmol) was dissolved in a mixed solution of tetrahydrofuran and methanol (100 mL), and a methanol solution containing KOH (potassium hydroxide) (2.5 g, 44.6 mmol) was added to the solution to react at 70 ℃ for 4 hours. The pH value was adjusted to 5 with hydrochloric acid, filtration was carried out with suction, and the filter residue was dried under reduced pressure to give the product (1.5 g, yield 78%).
(5) Preparation of 1- (3-bromophenyl) -N-cyclopropyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide
Figure BDA00002662797200182
Dissolving 1- (3-bromophenyl) -4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid (2.0 g, 5.8 mmol) in dichloromethane (100 mL), adding triethylamine (1.2 g, 0.012 mol) and isopropyl chloride (0.85 g, 6.9 mmol) at-15 deg.C, reacting at 15 deg.C for 4 hours, concentrating under reduced pressure, dissolving the residue in DCM (100 mL), adding triethylamine (1 g, 9.9 mmol), cyclopropylamine (0.285 g, 5.0 mmol) at-5 deg.C, stirring at room temperature for 12 hours, washing with water, and concentrating under reduced pressure to obtain the product (1.5 g, 67% yield).
(6) Preparation of N-cyclopropyl-4-oxo-1- (3- (pyridin-3-yloxy) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide
Figure BDA00002662797200183
1- (3-bromophenyl) -N-cyclopropyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (200 mg, 0.52 mmol), 3-hydroxypyridine (60 mg, 0.63 mmol), ethyl 2-oxocyclopentylcarboxylate (20 mg, 0.13 mmol), cuprous iodide (40 mg, 0.21 mmol), cesium carbonate (400 mg, 1.3 mmol) were dissolved in DMSO (dimethyl sulfoxide) (20 mL) and reacted with microwave at 90 ℃ for 4 hours. Extraction with water and DCM gave the product as an isolated organic phase (21 mg, 10% yield).
The molecular formula is as follows: c23H18N4O3Molecular weight: 398.41 LC-MS: 399.2(M + H)+
1H-NMR(400MHz,CDCl3)δ：9.75(s,1H),9.01(s,1H),8.80(dd,1H),8.71(dd,1H),8.51(d,1H),8.43(d,1H),7.56(t,1H),7.48-7.42(m,2H),7.35-7.31(m,1H),7.22-7.18(m,2H),7.10-7.09(m,1H),2.99-2.97(m,1H),0.88-0.83(m,2H),0.69-0.65(m,2H).
Example 23- (3- (3- (cyclopropylcarbamoyl) -4-oxo-1, 8-naphthyridin-1 (4H) -yl) phenoxy) pyridine 1-oxide (alkylation) Nitroxides of Compound 1) preparation
Figure BDA00002662797200191
A solution of N-cyclopropyl-4-oxo-1- (3- (pyridin-3-yloxy) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide prepared in example 1 (0.6 g, 1.5 mmol) and m-chloroperoxybenzoic acid (m-CPBA) (778 mg, 4.5 mmol) in DCM (200 mL) was reacted at 40 ℃ for 3 hours. After completion of the reaction, the reaction mixture was washed with water, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation, and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol =50: 1) to obtain the product (100 mg, yield 16%).
The molecular formula is as follows: c23H18N4O4Molecular weight: 414.41 LC-MS: 415.2(M + H)+
1H-NMR(400MHz,CDCl3)δ：9.75(s,1H),9.02(s,1H),8.79(dd,1H),8.75(dd,1H),8.16(s,1H),8.02(d,1H),7.60(m,1H),7.50-7.47(m,1H),7.32-7.30(m,1H),7.28-7.23(m,2H),7.21-7.20(m,1H),7.04-7.02(m,1H),3.02-2.95(m,1H),0.88-0.84(m,2H),0.69-0.65(m,2H).
Example 3N-cyclopropyl-4-oxo-1- (3- (pyridin-3-ylsulfanyl) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (Compound) 2) Preparation of
Figure BDA00002662797200192
(1) Preparation of 3-nitrothiophenol
Figure BDA00002662797200193
1, 2-bis (3-nitrophenyl) disulfane (20 g, 65 mmol) was dissolved in tetrahydrofuran (200 mL), sodium borohydride (8 g, 211 mmol) was added dropwise at 0 deg.C, and after 10 hours of reaction at room temperature, the reaction was quenched with dilute hydrochloric acid, diluted with ethyl acetate, washed with saturated sodium chloride, the organic phase was taken, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give the product (10g, 99% yield).
(2) Preparation of 3- ((3-nitrophenyl) thio) pyridine
Figure BDA00002662797200201
Cuprous bromide (758 mg, 5.3 mmol), ethyl 2-oxocyclohexanecarboxylate (1.8 mg, 10.6 mmol) and cesium carbonate (33 g, 0.1 mol) were dissolved in dimethyl sulfoxide (100 mL) under nitrogen, and after stirring at room temperature for 0.5 hour, 3-nitrothiophenol (8 g, 52 mmol) and 3-iodopyridine (13 g, 63 mmol) were added, and the mixture was stirred at 110 ℃ for 5 hours. After completion of the reaction, it was cooled, filtered, and the dimethyl sulfoxide was removed, the residue was dissolved in ethyl acetate, washed with water, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate =3: 1) to obtain a product (7 g, yield 60%).
(3) Preparation of 3- (pyridin-3-ylthio) anilines
Figure BDA00002662797200202
3- ((3-Nitrophenyl) thio) pyridine (6 g, 26 mmol) and Pd/C (1 g) were dissolved in methanol and stirred at room temperature for 3 hours in a hydrogen system. Filtration and rotary evaporation removed the solvent to give the product (5 g, 95% yield).
(4) Preparation of 2-chloronicotinoyl chloride
Figure BDA00002662797200203
2-Chloronicotinic acid (60 g, 0.38 mol) was dissolved in thionyl chloride (400 mL) and stirred at 70 ℃ for 3 hours, and the solvent was removed by rotary evaporation to give the product (56 g, 84% yield).
(5) Preparation of ethyl 2- (2-chloronicotinyl) -3- (dimethylamino) acrylate
Figure BDA00002662797200204
Triethylamine (96 g, 0.95 mol) and ethyl 3- (dimethylamino) acrylate (81.5 g, 0.57 mmol) were added to a toluene (500 mL) solution containing 2-chloronicotinyl chloride (56 g, 0.32 mol), the mixture was stirred at 90 ℃ for 2 hours, toluene was removed by rotary evaporation, the mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate =10: 1) to obtain a product (60 g, 66% yield).
(6) Preparation of ethyl 2- (2-chloronicotinyl) -3- ((3- (pyridin-3-ylthio) phenyl) amino) acrylate
Figure BDA00002662797200211
Ethyl 2- (2-chloronicotinyl) -3- (dimethylamino) acrylate (6.6 g, 23.3 mmol) and 3- (pyridin-3-ylthio) aniline (3.9 g, 19.3 mmol) were dissolved in DMF (30 mL), the mixture was stirred at room temperature for 5 hours, potassium carbonate (5.3 g, 38.4 mmol) was added, stirred at 90 ℃ for 3 hours, diluted with ethyl acetate, washed with water, the organic layers were combined, concentrated under reduced pressure to give the crude product, which was recrystallized from ethyl acetate to give the product (5 g, 53% yield).
(7) Preparation of 4-oxo-1- (3- (pyridin-3-ylsulfanyl) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid
Figure BDA00002662797200212
Ethyl 4-oxo-1- (3- (pyridin-3-ylsulfanyl) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylate (2 g, 5 mmol) and potassium hydroxide (840 mg, 15 mmol) were dissolved in a mixed solution of ethanol and water (15 mL) and stirred at 60 ℃ for 5 hours. After cooling, the mixture was adjusted to pH 5-6 with 2N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give the product (1.7 g, 91% yield).
(8) Preparation of N-cyclopropyl-4-oxo-1- (3- (pyridin-3-ylsulfanyl) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide
Figure BDA00002662797200213
To a solution of 4-oxo-1- (3- (pyridin-3-ylsulfanyl) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid (1.7 g, 4.5 mmol) in dichloromethane at 0 ℃, triethylamine (910 mg, 9 mmol) and isobutyl chloroformate (685 mg, 5 mmol) were added, stirred at room temperature for 1 hour, cyclopropylamine (285 mg, 5 mmol) was added dropwise, stirred at room temperature for 3 hours, diluted with dichloromethane, washed with water, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (dichloromethane: methanol =20: 1) to give a product (1.5 g, yield 80%).
The molecular formula is as follows: c23H18N4O2S molecular weight: 414.48 LC-MS: 415.1(M + H)+
1H-NMR(400MHz,CDCl3)δ：9.75(s,1H),9.02(s,1H),8.79(dd,1H),8.75(dd,1H),8.16(s,1H),8.02(d,1H),7.6(d,1H),7.50-7.47(m,1H),7.32-7.30(m,1H),7.28-7.23(m,2H),7.21-7.20(m,1H),7.04-7.02(m,1H),3.02-2.95(m,1H),0.88-0.84(m,2H),0.69-0.65(m,2H).
Example 43- ((3- (3- (cyclopropylcarbamoyl-4-oxo-1, 8-naphthyridin-1 (4H) -yl) phenyl) thio) pyridine 1-oxide Preparation of (nitroxide of Compound 2)
Figure BDA00002662797200221
(1) Preparation of 3-iodopyridine 1-oxide
Figure BDA00002662797200222
3-iodopyridine (1 g, 5.0 mmol) and m-chloroperoxybenzoic acid (1.6 g, 9.3 mmol) were dissolved in dichloromethane (10 mL) and reacted overnight at room temperature. Diluted with water, extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation to give the crude product (1 g, 90% yield) which was used in the next reaction without purification.
(2) Preparation of 3- ((3-nitrophenyl) thio) pyridine 1-oxide
Figure BDA00002662797200223
Cuprous bromide (64 mg, 0.45 mmol), ethyl 2-oxocyclohexanecarboxylate (152 mg, 0.9 mmol) and cesium carbonate (2.9 g, 9 mmol) were added to dimethyl sulfoxide (20 mL) under nitrogen, and after the mixture was stirred at room temperature for 0.5 hour, 3-iodopyridine 1-oxide (1 g, 4.5 mmol) and 3-nitrothiophenol (706 mg, 4.5 mmol) were added, and the mixture was stirred at 110 ℃ for 5 hours. Cooling, filtration and removal of dimethyl sulfoxide, the residue was dissolved in ethyl acetate, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate =3: 1) to give the product (600 mg, yield 55%).
(3) Preparation of 3- ((3-aminophenyl) thio) pyridine 1-oxide
Figure BDA00002662797200224
3- ((3-Nitrophenyl) thio) pyridine 1-oxide (600 mg, 2.4 mmol) and Pd/C (100 mg) were dissolved in tetrahydrofuran (20 mL) and reacted in a hydrogen system at room temperature for 3 hours. After the reaction was complete, filtration and rotary evaporation to remove the solvent gave the product (500 mg, 95% yield).
(4) Preparation of 3- ((3- (3- (ethoxyformyl) -4-oxo-1, 8-naphthyridin-1 (4H) -yl) phenyl) thio) pyridine 1-oxide
Figure BDA00002662797200231
Ethyl 2- (2-chloronicotinyl) -3- (dimethylamino) acrylate (340 mg, 1.2 mmol) and 3- ((3-aminophenyl) thio) pyridine 1-oxide (220 mg,1.0 mmol) were dissolved in DMF (10 mL) and reacted at room temperature for 3 hours, followed by addition of potassium carbonate (276 mg, 2 mmol) and reaction at 90 ℃ for 3 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate, washed with water, combined, concentrated under reduced pressure to give a crude product, which was recrystallized from ethyl acetate to give 460 mg.
(5) Preparation of 3- ((3- (3-carboxy-4-oxo-1, 8-naphthyridin-1 (4H) -yl) phenyl) thio) pyridine 1-oxide
Figure BDA00002662797200232
3- ((3- (3- (ethoxyformyl) -4-oxo-1, 8-naphthyridin-1 (4H) -yl) phenyl) thio) pyridine 1-oxide (470 mg, 1.1 mmol) and potassium hydroxide (185 mg, 3.3 mmol) were dissolved in a mixed solution of ethanol and water (7 mL) and stirred at 60 ℃ for 5 hours. And cooling, adjusting the pH value of the mixed solution to 5-6 by using 2N hydrochloric acid, and extracting by using dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation to give the product (300 mg, 70% yield).
(6) Preparation of 3- ((3- (3- (cyclopropylcarbamoyl-4-oxo-1, 8-naphthyridin-1 (4H) -yl) phenyl) thio) pyridine 1-oxide
To a solution of 3- ((3- (3-carboxy-4-oxo-1, 8-naphthyridin-1 (4H) -yl) phenyl) thio) pyridine 1-oxide (210 mg, 0.54 mg) in dichloromethane (10 mL) was added triethylamine (109 mg,1.08 mmol) and neopentyl chloroformate (89 mg,0.59 mmol), 2 hours later aminocyclopropane (34 mg,0.59 mmol) was added, and the reaction was continued at room temperature for 2 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the residue was isolated and purified by silica gel column chromatography (dichloromethane: methanol =20: 1) to give a product (200 mg, yield 86%)
The molecular formula is as follows: c23H18N4O3S molecular weight: 430.48 LC-MS: 431.2(M + H)+
1H-NMR(400MHz,CDCl3)δ：9.75(s,1H),9.02(s,1H),8.78~8.81(m,2H),8.20(s,1H),8.04~8.06(m,1H),7.59~7.64(m,3H),7.27~7.49(m,2H),7.21~7.22(m,2H),2.97~3.00(m,1H),0.76~0.89(m,2H),0.67~0.69(m,2H).
Example 5N-cyclopropyl-4-oxo-1- (3- (pyridin-3-ylsulfinyl) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (acylation) Preparation of Compound 3)
Figure BDA00002662797200241
N-cyclopropyl-4-oxo-1- (3- (pyridin-3-ylsulfanyl) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (100 mg, 0.24 mmol) prepared in example 3 was dissolved in a mixed solution of dichloromethane and water, and potassium hydrogen peroxymonosulfate complex salt 2KHSO was added5·KHSO4·K2SO4(Oxone) (223 g, 0.36 mmol), stirring at room temperature for 5 hours, separating the organic layer, washing with saturated sodium chloride water, anhydrous Na2SO4Dried and then isolated and purified by silica gel column chromatography (dichloromethane: methanol =20: 1) to obtain a product (50 mg).
The molecular formula is as follows: c23H18N4O3S molecular weight: 430.48 LC-MS: 431.1(M + H)+
1H-NMR(400MHz,CDCl3)δ：9.72(s,1H),8.97(s,1H),8.90(s,1H),8.79(m,1H),8.75(m,1H),8.65(m,1H),8.04(d,1H),7.84-7.71(m,3H),7.57-7.46(m,3H),3.00-2.96(m,1H),0.89-0.84(m,2H),0.69-0.65(m,2H).
Example 6N-cyclopropyl-4-oxo-1- (3- (pyridin-3-ylsulfonyl) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (Compound No.) Preparation of object 4)
Figure BDA00002662797200242
To a mixed solution of N-cyclopropyl-4-oxo-1- (3- (pyridin-3-ylsulfanyl) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-propenoic acid ethyl ester (100 mg, 0.24 mmol) prepared in example 3 dissolved in dichloromethane and water was added 2KHSO5·KHSO4·K2SO4(Oxone) (223 mg, 0.36 mmol), stirred at room temperature for 5 hours, the organic layer was separated, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and then isolated and purified by silica gel column chromatography (dichloromethane: methanol =20: 1) to give a product (50 mg).
The molecular formula is as follows: c23H18N4O4S molecular weight: 446.48 LC-MS: 447.2(M + H)+
1H-NMR(400MHz,CDCl3)δ：9.70(s,1H),9.20(s,1H),8.96(s,1H),8.80~8.86(m,2H),8.64~8.66(m,1H),8.65(d,1H),8.25(d,1H),8.10~8.15(m,1H),7.68~7.79(m,2H),7.49~7.53(m,2H),2.98~2.99(m,1H),0.84~0.89(m,2H),0.67~0.70(m,2H).
Example 73- ((3- (3- (cyclopropylcarbamoyl-4-oxo-1, 8-naphthyridin-1 (4H) -yl) phenyl) sulfonyl) pyridine 1-oxide Preparation of (nitroxide of Compound 4)
Figure BDA00002662797200251
N-cyclopropyl-4-oxo-1- (3- (pyridin-3-ylsulfonyl) phenyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (300 mg, 0.67 mmol) prepared in example 6 and m-chloroperoxybenzoic acid (m-CPBA) (407 mg, 2 mmol) were dissolved in dichloromethane (20 mL), and the mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane, washed with water, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation, and the residue was isolated and purified by silica gel column chromatography (dichloromethane: methanol =20: 1) to obtain a product (50 mg, yield 16%).
The molecular formula is as follows: c23H18N4O5S molecular weight: 462.48 LC-MS: 463.1(M + H)+
1H-NMR(400MHz,CDCl3)δ：9.74(s,1H),8.98(s,1H),8.83(d,1H),8.71~8.72(m,2H),8.31(d,1H),8.11~8.13(m,2H),7.81~7.85(m,1H),7.74~7.77(m,2H),7.44~7.54(m,2H),2.97~3.00(m,1H),0.85~0.90(m,2H),0.66~0.70(m,2H).
Example 8N-cyclopropyl-4-oxo-1- (2- (pyridin-3-ylethynyl) pyrimidin-4-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide Preparation of (Compound 6)
Figure BDA00002662797200261
(1) Preparation of 1- (2-chloropyrimidin-4-yl) -4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid ethyl ester
Ethyl 4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylate (10.9 g, 0.05 mol) was dissolved in DMF (100 mL) and after 30 minutes of reaction, sodium hydride (2.4 g, 0.1 mol) was added in portions and 2, 4-dichloropyrimidine was added after 2 hours. The reaction was stirred overnight, water (3 mL quench the reaction mixture was extracted with DCM (200 mL × 3) and brine (200 mL), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate =2: 1-dichloromethane: methanol =20: 1) to give the product as a solid (1.35 g, 8.3% yield).
(2) Preparation of 1- (2-iodopyrimidin-4-yl) -4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid ethyl ester
Figure BDA00002662797200263
Ethyl 1- (2-chloropyrimidin-4-yl) -4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylate (2.2 g, 6.65 mmol) was dissolved in 40% hydroiodic acid (10 mL) and the reaction was stirred at room temperature overnight. After completion of the reaction, pH 9-10 was adjusted with aqueous ammonia, then extracted three times with DCM (100 mL. times.3), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give the product as a solid (1.2 g, 43% yield).
(3) Preparation of ethyl 4-oxo-1- (2- (pyridin-3-ylethynyl) pyrimidin-4-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylate
Figure BDA00002662797200271
Ethyl 1- (2-iodopyrimidin-4-yl) -4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylate (1.2 g, 2.84 mmol), 3-ethynylpyridine (0.35 g, 3.41 mmol), cuprous iodide (0.16 g, 0.85 mmol), Pd (pph)3)2Cl2([ 1,1' -bis (diphenylphosphino) ferrocene)]Palladium dichloride) (0.6 g, 0.85 mmol) and TEA (0.72 g, 7.1 mmol) were dissolved in DMF (10 mL) and stirred at room temperature overnight. The mixture was extracted with DCM, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and chromatographed on silica gel column (II)Methyl chloride methanol =100:1 to 25: 1) was isolated and purified to obtain a solid product (0.5 g, yield 44%).
(4) Preparation of 4-oxo-1- (2- (pyridin-3-ylethynyl) pyrimidin-4-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid
Figure BDA00002662797200272
LiOH (lithium hydroxide) (0.84 g, 0.02 mol) was dissolved in methanol (5 mL) solution, ethyl 4-oxo-1- (2- (pyridin-3-ylethynyl) pyrimidin-4-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylate (0.6 g, 1.5 mmol) was added, and the reaction was stirred at room temperature overnight. The pH is adjusted to be approximately equal to 3-4 by 10 percent hydrochloric acid aqueous solution. The mixture was extracted with DCM and concentrated under reduced pressure to give the solid product (0.54 g, 97% yield).
(5) Preparation of N-cyclopropyl-4-oxo-1- (2- (pyridin-3-ylethynyl) pyrimidin-4-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide
Figure BDA00002662797200273
4-oxo-1- (2- (pyridin-3-ylethynyl) pyrimidin-4-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid (0.54 g, 1.46 mmol) was dissolved in DCM (5 mL), tert-butyl chloroformate (0.2 g, 1.46 mmol) and TEA (0.18 g, 1.76 mmol) were added, and the mixture was stirred at room temperature for 3 hours and used in the next reaction without purification.
Cyclopropylamine (0.17 g, 2.92 mmol) was added to the reaction mixture, the mixture was stirred at room temperature overnight, the reaction mixture was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure in vacuo, and subjected to silica gel column chromatography (dichloromethane: methanol =100:1 to 30: 1) to isolate and purify the product (0.12 g, yield 20%).
The molecular formula is as follows: c23H16N6O2Molecular weight:408.41 LC-MS：409.2(M+H)+
1H-NMR(400MHz,CDCl3)δ：8.99(s,1H),8.60(s,1H),8.56(s,1H),8.44(s,1H),8.42(s,1H),8.36(s,1H),7.93(s,1H),7.40(s,1H),7.27(s,1H),7.17(s,1H),3.12(s,1H),1.02-0.92(m,5H)
example 93- ((4- (3- (cyclopropylcarbamoyl) -4-oxo-1, 8-naphthyridin-1 (4H) -yl) pyrimidin-2-yl) ethynyl) pyridine 1- Preparation of oxide (nitroxide of Compound 6)
Figure BDA00002662797200281
N-cyclopropyl-4-oxo-1- (2- (pyridin-3-ylethynyl) pyrimidin-4-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide prepared in example 8 (0.15 g, 0.367 mmol) and m-CPBA (0.127 g, 0.735 mmol) were dissolved in DCM (5 mL) and stirred at RT overnight. The reaction mixture was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated and purified by silica gel column chromatography (dichloromethane: methanol =100:1 to 20: 1) to obtain a product (0.06 g).
The molecular formula is as follows: c23H16N6O3Molecular weight: 424.41 LC-MS: 425.2(M + H)+
1H-NMR(400MHz,CDCl3)δ：8.99(s,1H),8.59(s,1H),8.56(s,1H),8.44(s,1H),8.34(s,1H),8.22(s,1H),7.50(s,1H),7.29(s,1H),7.20(s,1H),7.17(s,1H),3.15(s,1H),1.14-0.74(m,5H).
With reference to the above preparation method, the following compounds can also be prepared:
Figure BDA00002662797200282
Figure BDA00002662797200301

Claims (13)

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof:
Figure FDA00002662797100011
wherein R is1Is hydrogen, -C (O) -Ra，-S(O)q-RaC unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl unsubstituted or substituted by 1 to 3QSubstituted C1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q2-8Alkenyl, C unsubstituted or optionally substituted with 1-3Q3-8Alkynyl, C unsubstituted or optionally substituted by 1-3Q6-14Aryl, 5-15 membered heteroaryl unsubstituted or optionally substituted with 1-3Q, or 3-15 membered heterocyclyl C unsubstituted or optionally substituted with 1-3Q1-8An alkyl group;
R2c being hydrogen, unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, or C unsubstituted or optionally substituted by 1 to 3Q3-8A cycloalkyl group;
R3，R4，R5and R6Each independently is hydrogen, halogen atom, -C (O) -Ra，-S(O)q-RaNitro, cyano, -NRaRa', C unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, or C unsubstituted or optionally substituted by 1 to 3Q1-8An alkoxy group;
R7is hydrogen, phenyl which is unsubstituted or optionally substituted by 1 to 3Q, thienyl, pyridonyl,Azolyl group,
Figure FDA00002662797100013
A diazolyl, thiazolyl, or thiadiazolyl group, a pyridyl, pyrimidinyl, indolyl, quinolinyl, or imidazolyl group unsubstituted or optionally substituted with 1 to 3Q, and their nitroxides, C unsubstituted or optionally substituted with 1 to 3Q1-8Alkyl, or C unsubstituted or optionally substituted by 1 to 3Q3-8A cycloalkyl group;
R7' absent, hydrogen, unsubstituted or optionally substituted by 1 to 3Q, phenyl, thienyl, pyridonyl,
Figure FDA00002662797100014
Azolyl group,
Figure FDA00002662797100015
A diazolyl, thiazolyl, or thiadiazolyl group, a pyridyl, pyrimidinyl, indolyl, quinolinyl, or imidazolyl group unsubstituted or optionally substituted with 1 to 3Q, and their nitroxides, C unsubstituted or optionally substituted with 1 to 3Q1-8Alkyl, or C unsubstituted or optionally substituted by 1 to 3Q3-8A cycloalkyl group;
and R is7' is phenyl, thienyl, pyridonyl, unsubstituted or optionally substituted by 1 to 3Q,
Figure FDA00002662797100016
Azolyl group,
Figure FDA00002662797100017
(ii) oxadiazolyl, thiazolyl or thiadiazolyl, or unsubstituted or optionally 1-3Q-substituted pyridyl, pyrimidinyl, indolyl, quinolinyl or imidazolyl and their nitroxides1Is hydrogen, -C (O) -Ra，-S(O)q-RaC unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q2-8Alkenyl, C unsubstituted or optionally substituted with 1-3Q3-8Alkynyl, C unsubstituted or optionally substituted by 1-3Q6-14Aryl, or a 3-to 15-membered heterocyclic group C which is unsubstituted or optionally substituted with 1-3Q1-8An alkyl group;
R8is hydrogen, halogen atom, nitro, cyano, = N-O-C1-8Alkyl, -O-N = C1-8Alkyl, -CH (N = NOH) -C1-8Alkyl, -NRaRa’，-C(O)-Ra，-C(O)NRaRa’，-NRaC(O)Ra’，-S(O)q-Ra，-S(O)q-NRaRa’，-NRa-S(O)q-Ra’，-C(O)ORaGroup of (A) not covered byC substituted or optionally substituted with 1-3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q6-14Aryl, 5-15 membered heteroaryl unsubstituted or optionally substituted with 1-3Q, or 3-15 membered heterocyclyl C unsubstituted or optionally substituted with 1-3Q1-8An alkyl group;
R8' absence, hydrogen, halogen atom, nitro group, cyano group, = N-O-C1-8Alkyl, -O-N = C1-8Alkyl, -CH (N = NOH) -C1-8Alkyl, -NRaRa’，-C(O)-Ra，-C(O)NRaRa’，-NRaC(O)Ra’，-S(O)q-Ra，-S(O)q-NRaRa’，-NRa-S(O)q-Ra’，-C(O)ORaC unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q6-14Aryl, 5-15 membered heteroaryl unsubstituted or optionally substituted with 1-3Q, or 3-15 membered heterocyclyl C unsubstituted or optionally substituted with 1-3Q1-8An alkyl group;
R9is hydrogen, hydroxy, halogen atom, -NRbRb', or C unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
R9' absence, hydrogen, hydroxy, halogen atom, -NRbRb', or C unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
ring A is phenyl containing 1-4 5-8 membered heteroaryl groups selected from N, S, O, or 1-4 8-14 membered heterocyclic groups selected from N, S, O;
l represents-O-, -S (O)q-, 1, 1-cyclopropanyl, carbonyl, ethenyl, methylene, ethyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl;
q is selected from 0, 1 or 2;
Ra、Ra' is selected from hydrogen, C unsubstituted or optionally substituted with 1 to 3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl radical C1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q6-14Aryl, or a 3-15 membered heterocyclyl unsubstituted or optionally substituted with 1-3Q;
q is selected from hydroxyl, carboxyl, nitro, cyano, halogen atom, C1-8Alkyl radical, C3-8Cycloalkyl radical, C1-8Alkoxy, halo C1-8Alkyl, halo C1-8Alkoxy, -NRbRb’，-C(O)-Rb，-C(O)NRbRb’，-NRbC(O)Rb’，=N-O-C1-8Alkyl, -O-N = C1-8Alkyl, -S (O)q-Rb，-S(O)q-NRbRb’，-NRb-S(O)q-Rb', OR-C (O) ORbWherein R isb、Rb' independently of one another are hydrogen, C1-8Alkyl radical, C3-8Cycloalkyl, or C6-14And (4) an aryl group.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof:
wherein R is1Is hydrogen, -C (O) -Ra，-S(O)q-RaC unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, C unsubstituted or optionally substituted by 1 to 3Q6-14Aryl, or 5-15 membered heteroaryl unsubstituted or optionally substituted with 1-3Q;
R2is hydrogen, or C which is unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
R3，R4，R5and R6Each of which is independently hydrogen, or a salt thereof,halogen atom, -C (O) -Ra，-S(O)q-RaNitro, cyano, -NRaRa', C unsubstituted or substituted by 1 to 3 substituents1-8Alkyl, or C unsubstituted or optionally substituted by 1 to 3Q1-8An alkoxy group;
R7is phenyl, thienyl, pyridonyl which are unsubstituted or optionally substituted by 1 to 3Q,Azolyl group,Oxadiazolyl, thiazolyl, or thiadiazolyl, or pyridyl, pyrimidinyl, indolyl, quinolinyl, or imidazolyl and their nitroxides unsubstituted or optionally substituted with 1-3Q;
R7' absent, unsubstituted or optionally substituted by 1 to 3Q, phenyl, thienyl, pyridonyl,
Figure FDA00002662797100033
Azolyl group,
Figure FDA00002662797100034
(ii) an oxazolyl, thiazolyl, or thiadiazolyl group, or an unsubstituted or optionally 1-3Q-substituted pyridyl, pyrimidinyl, indolyl, quinolinyl, or imidazolyl group and nitroxides thereof;
and R is7' is phenyl, thienyl, pyridonyl, unsubstituted or optionally substituted by 1 to 3Q,Azolyl group,(ii) oxadiazolyl, thiazolyl or thiadiazolyl, or unsubstituted or optionally 1-3Q-substituted pyridyl, pyrimidinyl, indolyl, quinolinyl or imidazolyl and their nitroxides1Is hydrogen, -C (O) -Ra，-S(O)q-RaC unsubstituted or optionally substituted by 1 to 3Q1-8Alkyl, C unsubstituted or optionally substituted by 1 to 3Q1-8Alkoxy, C unsubstituted or optionally substituted by 1 to 3Q3-8Cycloalkyl, or C unsubstituted or optionally substituted with 1-3Q6-14An aryl group;
R8is hydrogen, a halogen atom, -NRaRa’，-C(O)-Ra，-C(O)NRaRa’，-NRaC(O)Ra’，-S(O)q-Ra，-S(O)q-NRaRa’，-NRa-S(O)q-Ra’，-C(O)ORaOr C which is unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
R8' absence, hydrogen, halogen atom, -NRaRa’，-C(O)-Ra，-C(O)NRaRa’，-NRaC(O)Ra’，-S(O)q-Ra，-S(O)q-NRaRa’，-NRa-S(O)q-Ra’，-C(O)ORaOr C which is unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
R9is hydrogen, hydroxy, halogen atom, C unsubstituted or optionally substituted by 1 to 3Q1-8An alkyl group;
R9' No, hydrogen, hydroxyl, halogen atom, or C unsubstituted or optionally substituted by 1 to 3 of Q1-8An alkyl group;
ring A is phenyl containing 1-4 5-8 membered heteroaryl groups selected from N, S, O, or 1-4 8-14 membered heterocyclic groups selected from N, S, O;
l is-O-, -S (O)q-, 1, 1-cyclopropanyl, carbonyl, methylene, ethyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl;
q is selected from 0, 1 or 2;
Ra、Ra' is selected from hydrogen, C unsubstituted or optionally substituted with 1 to 3Q1-8An alkyl group;
q is selected from hydroxyl, carboxyl, cyano, halogen atom, C1-8Alkyl radical, C3-8Cycloalkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, -NRbRb’，-C(O)-Rb，-C(O)NRbRb’，-NRbC(O)Rb’，-S(O)q-Rb，-S(O)q-NRbRb’，-NRb-S(O)q-Rb', OR-C (O) ORbWherein R isb、Rb' independently of one another are hydrogen or C1-8An alkyl group.
3. The compound of claim 2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof:
wherein R is1Is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl;
R2is hydrogen, or methyl;
R3，R4，R5and R6Each independently is hydrogen, methyl, fluorine atom, chlorine atom, or bromine atom;
R8，R9each independently is hydrogen, methyl, fluorine atom, chlorine atom, methylsulfonyl, or 2-hydroxyisopropyl;
R7' absent;
R8’，R9' absent.
4. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof:
wherein,
ring A is phenyl or 5-6 membered heteroaryl containing 1-3 members selected from N, S, O;
l is-O-, -S (O)q-, 1, 1-cyclopropanyl, carbonyl, ethenyl, methylene, ethyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
5. The compound of claim 4, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof:
wherein,
ring A is phenyl or 5-6 membered heteroaryl containing 1-3 selected from N;
l is-O-, -S (O)q-, 1, 1-cyclopropanyl, carbonyl, ethenyl, methylene, ethyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
6. The compound of claim 5, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof:
wherein,
ring a is phenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, or pyrazinyl;
l is-O-, -S (O)q-, 1, 1-cyclopropanyl, carbonyl, ethenyl, methylene, ethyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
7. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof:
wherein,
l is-O-, -S-, -S (O) -, -S (O)2-, 1, 1-cyclopropanyl, carbonyl, ethenyl, methylene, or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
8. The compound of claim 7, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof:
wherein,
l is-O-, -S-, -S (O) -, -S (O)2-, 1, 1-cyclopropanyl, or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
9. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof:
wherein R is7Is pyridyl or their nitroxides.
10. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof:
wherein,
R7is pyridyl or their nitroxides;
ring a is phenyl, pyridyl, pyrimidinyl, or pyrazinyl;
l is-O-, -S-, -S (O) -, -S (O)2Or ethynyl, and when L is ethynyl, ring a cannot be phenyl.
11. The compound of claim 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof:
Figure FDA00002662797100051
Figure FDA00002662797100061
12. a pharmaceutical composition of a compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof according to any one of claims 1 to 11, in any pharmaceutically acceptable dosage form, together with one or more pharmaceutically acceptable carriers and/or diluents.
13. Use of a compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, for the manufacture of a medicament for the treatment of inflammatory diseases, disorders and conditions characterised by or associated with an unwanted inflammatory immune response and all diseases induced by or associated with excessive TNF-a and PDE-4 secretion.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9034900B2 (en) 2013-10-18 2015-05-19 Quanticel Pharmaceuticals, Inc. Bromodomain inhibitors
CN105588886A (en) * 2014-11-18 2016-05-18 重庆医药工业研究院有限责任公司 Method for assaying impurities in apremilast and preparations thereof through liquid chromatography
WO2017184491A1 (en) 2016-04-19 2017-10-26 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
WO2017184462A1 (en) 2016-04-18 2017-10-26 Celgene Quanticel Research, Inc. Therapeutic compounds
CN109336810A (en) * 2018-11-02 2019-02-15 浙江星月药物科技股份有限公司 A kind of preparation method of haloperidid class nitrogen oxides
CN109937202A (en) * 2016-11-02 2019-06-25 詹森药业有限公司 [1,2,4] triazol [1,5-A] pyrimidine compound as PDE2 inhibitor
CN110092788A (en) * 2014-04-23 2019-08-06 达特神经科学(开曼)有限公司 Substituted [1,2,4] triazol [1,5-a] pyrimidin-7-yl compound as PDE2 inhibitor
EP3831383A1 (en) 2015-04-15 2021-06-09 Celgene Quanticel Research, Inc. Bromodomain inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1239478A (en) * 1997-08-06 1999-12-22 三得利株式会社 1-aryl-1,8-naphthylidin-4-one derivative as type IV phosphodiesterase inhibitor
CN1256693A (en) * 1998-01-29 2000-06-14 三得利株式会社 1-cycloalkyl-1,8-naphthyridin-4-one derivatives with phosphodiesterase IV inhibitory activity
CN1639161A (en) * 2001-08-29 2005-07-13 麦克弗罗斯特(加拿大)公司 Alkyne-aryl phosphodiesterase-4 inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1239478A (en) * 1997-08-06 1999-12-22 三得利株式会社 1-aryl-1,8-naphthylidin-4-one derivative as type IV phosphodiesterase inhibitor
CN1256693A (en) * 1998-01-29 2000-06-14 三得利株式会社 1-cycloalkyl-1,8-naphthyridin-4-one derivatives with phosphodiesterase IV inhibitory activity
CN1639161A (en) * 2001-08-29 2005-07-13 麦克弗罗斯特(加拿大)公司 Alkyne-aryl phosphodiesterase-4 inhibitors

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3290407A1 (en) 2013-10-18 2018-03-07 Celgene Quanticel Research, Inc Bromodomain inhibitors
US10941160B2 (en) 2013-10-18 2021-03-09 Celgene Quanticel Research, Inc. Bromodomain inhibitors
EP3640241A1 (en) 2013-10-18 2020-04-22 Celgene Quanticel Research, Inc. Bromodomain inhibitors
US9598372B2 (en) 2013-10-18 2017-03-21 Celgene Quanticel Research, Inc. Bromodomain inhibitors
US11884680B2 (en) 2013-10-18 2024-01-30 Celgene Quanticel Research, Inc. Bromodomain inhibitors
EP4134364A2 (en) 2013-10-18 2023-02-15 Celgene Quanticel Research, Inc. Bromodomain inhibitors
US9115114B2 (en) 2013-10-18 2015-08-25 Quanticel Pharmaceuticals, Inc. Bromodomain inhibitors
US10023592B2 (en) 2013-10-18 2018-07-17 Celgene Quanticel Research, Inc. Bromodomain inhibitors
US10562915B2 (en) 2013-10-18 2020-02-18 Celgene Quanticel Research, Inc. Bromodomain inhibitors
US9034900B2 (en) 2013-10-18 2015-05-19 Quanticel Pharmaceuticals, Inc. Bromodomain inhibitors
CN110092788B (en) * 2014-04-23 2022-02-25 达特神经科学(开曼)有限公司 Substituted [1,2,4] triazolo [1,5-a ] pyrimidin-7-yl compounds as PDE2 inhibitors
CN110092788A (en) * 2014-04-23 2019-08-06 达特神经科学(开曼)有限公司 Substituted [1,2,4] triazol [1,5-a] pyrimidin-7-yl compound as PDE2 inhibitor
CN105588886B (en) * 2014-11-18 2020-01-31 重庆医药工业研究院有限责任公司 method for determining impurities in apremilast and its preparation by liquid chromatography
CN105588886A (en) * 2014-11-18 2016-05-18 重庆医药工业研究院有限责任公司 Method for assaying impurities in apremilast and preparations thereof through liquid chromatography
EP3831383A1 (en) 2015-04-15 2021-06-09 Celgene Quanticel Research, Inc. Bromodomain inhibitors
WO2017184462A1 (en) 2016-04-18 2017-10-26 Celgene Quanticel Research, Inc. Therapeutic compounds
EP4011876A1 (en) 2016-04-19 2022-06-15 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
WO2017184491A1 (en) 2016-04-19 2017-10-26 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
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