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HK1090560A - Substituted p-diaminobenzene derivatives - Google Patents

Substituted p-diaminobenzene derivatives Download PDF

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Publication number
HK1090560A
HK1090560A HK06111365.8A HK06111365A HK1090560A HK 1090560 A HK1090560 A HK 1090560A HK 06111365 A HK06111365 A HK 06111365A HK 1090560 A HK1090560 A HK 1090560A
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HK
Hong Kong
Prior art keywords
amino
chloro
alk
phenyl
ylmethyl
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HK06111365.8A
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Chinese (zh)
Inventor
Nikolay Khanzhin
Mario Rottländer
Andreas RITZÉN
William Patrick Watson
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H. Lundbeck A/S
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Publication of HK1090560A publication Critical patent/HK1090560A/en

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Description

Substituted p-diaminobenzene derivatives
Technical Field
The present invention relates to novel substituted p-diaminobenzene derivatives which are potassium channel openers of the KCNQ family. The compounds are useful in the prevention, treatment and inhibition of disorders and diseases responsive to the opening of KCNQ family potassium ion channels, one such disease being epilepsy.
Background
Ion channels are cellular proteins that regulate the influx and efflux of ions into and out of cells, including potassium, calcium, chloride, and sodium. Such channels are present in all animal and human cells and affect many processes including neuronal transmission, muscle contraction, and cellular secretion.
Humans have approximately 70 genes encoding potassium channel subunits (Jentsch Nature reviews neurosciences 2000, 1, 21-30), which vary greatly in both structure and function. Neuronal potassium channels found in the brain are primarily responsible for maintaining negative resting membrane potentials and for controlling membrane repolarization following action potentials.
A subset of the potassium channel genes are the KCNQ family. Mutations in four fifths of the KCNQ gene have been shown to underlie several diseases including arrhythmia, deafness and epilepsy (JentschNature Reviews Neuroscience 2000, 1, 21-30).
The KCNQ4 gene is thought to encode the molecular association of potassium channels found in cochlear outer hair cells and vestibular organ type I hair cells, and mutations thereof may lead to the development of hereditary deafness.
KCNQ1(KvLQT1) assembles with the product of the KCN1 (smallest K (+) -channel protein) gene in the heart to form a cardiac delayed rectifier-like K (+) current. Mutations in this pathway may cause a form of hereditary long QT syndrome type 1 (LQT1) and are associated with the development of deafness (robbins pharmanzacoltlier 2001, 90, 1-19).
Genes KCNQ2 and KCNQ3 were discovered in 1988 and shown to produce variation in inherited forms of epilepsy known as benign familial neonatal convulsions (rogowski Trends in neurosciens 2000, 23, 393 398). The proteins encoded by the KCNQ2 and KCNQ3 genes are localized in the brain areas involved in the generation and spread of seizures in humans-cortex and pyramidal cells of the hippocampus (Cooper et al, Proceedi77gs National Academy of science 7zce U s A2000, 97, 4914-.
KCNQ2 and KCNQ3 are two potassium channel subunits that form an "M-current" when expressed in vitro. The M-current is a non-inactivating potassium current found in many types of neuronal cells. In each cell type, it is dominant in controlling membrane excitability as it is the only sustained current in the evoked action potential range (Marion AyanualReview Physiology 1997, 59, 483-504). Modulation of M-current has a significant effect on neuronal excitability, e.g. activation of the current will reduce neuronal excitability. Openers of these KCNQ channels or activators of M-current will reduce neuronal hyperactivity and are therefore useful in the treatment, prevention or inhibition of seizures and other diseases and conditions characterized by excessive neuronal activity, such as neuronal hyperexcitability, including convulsive conditions, epilepsy and neuropathic pain.
Retigabine (D-23129; N- (2-amino-4- (4-fluorobenzylamino) -phenyl) carbamic acid ethyl ester) and analogs thereof are disclosed in EP 554543. Retigabine is an anticonvulsant compound with broad-spectrum and potent anticonvulsant properties both in vivo and in vitro. It is effective in a series of anticonvulsant tests performed in rats and mice and after oral and intraperitoneal administration in a genetic animal model, DBA/2 mouse model, said tests comprising: electrically induced seizures, pentylenetetrazol, picrotoxin and N-methyl-D-aspartate (NMDA) induced seizures (Rostock et al, Epilepsy Research 1996, 23, 211-. In addition, retigabine is also effective in complex partial-onset tonsil excitation models. In clinical trials, retigabine has recently been shown to be effective in reducing the incidence of seizures in epileptic patients (Bialer et al, Epilepsy Research 2002, 51, 31-71).
Retigabine has been shown to activate K (+) current neurons in neuronal cells and the pharmacology of this induced current is consistent with the published pharmacological performance of the M-channel, which is currently associated with the KCNQ2/3K (+) channel heteromultimer. This suggests that activation of the KCNQ2/3 channel may be responsible for some anticonvulsant activity of this substance (Wiclenden et al, molecular Pharmacology 2000, 58, 591-600) -and that other substances that act by similar mechanisms may have similar applications.
KCNQ2 and 3 channels have also been reported to be upregulated in neuropathic pain models (Wickenden et al, Society for Neuroscience extracts 2002, 454.7), and potassium channel modulators have been hypothesized to be effective in both neuropathic pain and epilepsy (Schroder et al, Neuropharmacology 2001, 40, 888-.
Retigabine has also been shown to be beneficial in animal models of neuropathic pain (Blackbum-Munro and Jensen European Journal of Pharmacology2003, 460, 109-.
KCNQ channel mRNA is reported to be localized to the brain and other central nervous system regions associated with pain (Goldstein et al, Society for neurosciene Abstracts2003, 53.8).
In addition to its role in neuropathic pain, the expression of KCNQ 2-5 mRNA in trigeminal and dorsal root ganglia and in the tail of the trigeminal nucleus suggests that openers of these channels may also affect the sensory management of migraine pain (Goldstein et al, Society for neurosciennenecceastracts 2003, 53.8).
Recent reports demonstrated that mRNA of KCNQ3 and 5 is expressed in astrocytes and glial cells in addition to mRNA of KCNQ 2. Thus, KCNQ2, 3 and 5 channels may help to modulate synaptic activity in the CNS and contribute to the neuroprotective effects of KCNQ channel openers (Noda et al, Society for Neuroscience Abstracts2003, 53.9).
Because retigabine has been shown to prevent the expression of kainic acid-induced peripheral neurodegeneration and apoptosis markers in status epilepticus in rats, retigabine and other modulators of KCNQ may exhibit a role in protecting against the neurodegenerative aspects of the absence of epilepsy (Ebert et al, Epilepsia 2002, 43 Suppl 5, 86-95). It is associated with the process of preventing epilepsy in a patient, i.e., is anti-epileptogenic. Retigabine has also been shown to delay the progression of excitation in the hippocampus of rats, another model of epilepsy development (Tober et al, European Journal of Pharmacology 1996, 303, 163-169).
Thus, these properties of retigabine and other KCNQ modulators are suggested to prevent neuronal damage induced by neuronal overactivation and to be useful in the treatment of neurodegenerative diseases, and in the alleviation of disorders in epileptogenic patients (or as antiepileptic).
It is known to treat alcohol withdrawal syndrome clinically with anticonvulsant compounds such as benzodiazepines and chlorothiazole and other anticonvulsant compounds such as gabapentin are known to be quite effective in animal models of this syndrome (Watson et al, Neuropharmacology1997, 36, 1369-.
The mRNA of KCNQ2 and 3 subunits was found in brain regions associated with anxiety and emotional behavior such as bipolar disorder, e.g., hippocampus and amygdala (sagich et al, Journal of neuroscience 2001, 21, 4609-one 4624), retigabine was reported to be effective in several animal models of anxiety-like behavior (Hartz et al, Journal of psychopharmacology 2003, 17 suppl 3, a28, B16), and other anticonvulsant compounds used clinically in the treatment of bipolar disorder were used.
WO 200196540 discloses the use of modulators of M-current formed by expression of KCNQ2 and KCNQ3 genes for insomnia, while WO 2001092526 discloses that modulators of KCNQ5 can be used to treat sleep disorders.
WO01/022953 describes the use of retigabine for the prevention and treatment of neuropathic pain such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy and neuropathic pain associated with migraine.
WO02/049628 describes the use of retigabine for the prevention, treatment, inhibition and amelioration of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, behavioral anxiety (pefformance anxiety), post-traumatic stress disorder, acute stress response, adaptation disorder, hypochondriasis disorder, separation anxiety disorder, agoraphobia and specific phobia.
WO97/15300 describes the use of retigabine for the treatment of neurodegenerative disorders such as alzheimer's disease; huntington's chorea; sclerosis such as multiple sclerosis and amyotrophic lateral sclerosis; Creutzfeld-Jalcob disease; parkinson's disease; AIDS or rubella virus, herpes virus, Borrelia and unknown pathogen infection-induced encephalopathy; trauma-induced neurodegeneration; neuronal hyperexcitability states such as those in drug withdrawal or intoxication; use of neurodegenerative diseases of the peripheral nervous system such as polyneuropathy and polyneuritis (polyneuritides).
Thus, there is a great need for new compounds that are effective openers of KCNQ group potassium channels.
There is also a need for new compounds with improved properties relative to compounds known to be openers of KCNQ family potassium channels, such as retigabine. Improvements in one or more of the following parameters are desirable: half-life, clearance, selectivity, interaction with other drug therapies, bioavailability, potency, formulability (formulability), chemical stability, metabolic stability, membrane permeability, solubility, and therapeutic index. Improvements in this type of parameter can lead to improvements such as:
Improving the dosing regimen by reducing the number of doses required for one day,
it is easy to administer many drugs to a patient,
● the side effects are reduced, and,
● the therapeutic index is expanded by expanding the therapeutic index,
● improving tolerance or
● improve compliance.
Summary of the invention
It is an object of the present invention to provide novel compounds which are potent openers of KCNQ group potassium channels.
The compounds of the present invention are substituted aniline derivatives of the general formula I or salts thereof
Wherein Y, U, X, Z, s, q, R1、R2And R3The definition of (A) is as follows.
The invention also relates to pharmaceutical compositions comprising one or more compounds of formula I and uses thereof.
Detailed description of the invention
The invention therefore relates to substituted p-diaminobenzene derivatives of the general formula I or salts thereof
Wherein s is 0 or 1;
u is O, S, SO2、SO2NR11CO-O or CO-NR11(ii) a Wherein
R11Selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alkyl(s) (C)Alkenyl/alkynyl) group; or
R2And R11And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
q is 0 or 1;
x is CO or SO2(ii) a Provided that when X is SO2Q is 0;
z is O or S;
R1selected from hydrogen, C 1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl;
R2selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halogen, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) group, cyano group-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, NR10R10′-C1-6Alk (en/yn) yl, NR 10R10′-C3-8Cycloalkane (alkenyl) group and NR10R10′-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl;
wherein R is10And R10′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C1-6An alk (en/yn) yl group, or
R10And R10′And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
provided that when R is2Is halogen or cyano, s is 0; and
provided that when s is 1 and R2U is O or S when it is a hydrogen atom or an acyl group;
R3is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) yl, Heterocycloalkane (alkenyl) yl, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkenyl) group, C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, heterocycloalkyl (en) yl-C1-6Alk (en/yn) yl, Ar-C 1-6Alk (en/yn) yl, Ar-C3-8-cycloalk (en) yl, Ar-heteroCycloalkane (alkenyl) group, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, Ar-C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C3-8-cycloalk (en) oxy-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) oxy-C3-8Cycloalkane (alkenyl) group, C1-6-alk (en/yn) oxy-heterocycloalkyl (en) yl, Ar-oxy-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, C3-8-cycloalkane (alkene) oxy-carbonyl-C1-6Alk (en/yn) yl, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8-cycloalkane (alkenyl) yl, hydroxy-heterocycloalkane (alkenyl) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, hydroxy-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, hydroxy-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8-cycloalk (en) yl, halo-heterocycloalk (en) yl, halo-C 3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, halo-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, halo-C1-6Alk (en/yn) yl-Ar, halo-C3-8Cycloalk (en) yl-Ar, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl-Ar, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) -Ar, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) yl, cyano-heterocycloalkyl (alkenyl) yl, cyano-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) radical, cyano C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, acyl-C1-6Alk (en/yn) yl, acyl-C3-8-cycloalk (en) yl, acyl-heterocycloalk (en) yl, acyl-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) radical, acyl-C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, NR12R12′Optionally substituted NR12R12′-C1-6-alk (en/yn) yl, optionally substituted NR12R12′-C3-8-cycloalk (en) yl, optionally substituted NR12R12′-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl; wherein
R12And R12′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C 3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, Ar-heterocycloalkyl (en) yl, Ar-oxy-C1-6Alk (en/yn) yl, Ar-oxy-C3-8Cycloalkyl (alkenyl) group, Ar-oxyl C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, Ar-oxy-heterocycloalkyl (en) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C1-6An alk (en/yn) yl group, or
R12And R12′And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
provided that when R is3Is NR12R12′When q is 0;
and
y represents a group of formula XXIV, XXV, XXVI, XXVII, XXVIII, XXXXI or XXXXII:
or
Wherein
The line represents a bond linking the group represented by Y to the carbon atom;
W is O or S;
v is N, C or CH;
t is N, NH or O;
a is 0, 1, 2 or 3;
b is 0, 1, 2, 3 or 4;
c is 0 or 1;
d is 0, 1, 2 or 3;
e is 0, 1 or 2;
f is 0, 1, 2, 3, 4 or 5;
g is 0, 1, 2, 3 or 4;
h is 0, 1, 2 or 3;
j is 0, 1 or 2;
k is 0, 1, 2 or 3; and
each R5Independently selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-oxy-C1-6Alk (en/yn) yl, Ar-oxy-C3-8Cycloalkane (alkenyl) group, C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, Ar-oxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl, C1-6Alk (en/yn) oxy, C3-8Cycloalk (alk) oxy, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) oxy, C1-6-alk (en/yn) oxycarbonyl, halogen, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, -CO-NR6R6′Cyano, cyano-C1-6Alk (en/yn) yl, cyano C3-8Cycloalkyl (alkenyl) group, cyano-C3-8-cycloalk (en) yl-C 1-6Alk (en/yn) yl, NR7R7′、S-R8And SO2R8Or is or
Two adjacent R5Together with the aromatic group, form a 5-8 membered ring containing one or two heteroatoms;
R6and R6′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl and Ar;
R7and R7′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar, heterocycloalkan (en) yl-C1-6Alk (en/yn) yl, heterocycloalkan (en) yl-C3-8Cycloalkane (alkenyl) yl, Heterocycloalkane (alkenyl) yl-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, heterocycloalk (en) yl-Ar and acyl; or
R7And R7′Together with the nitrogen atom, form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms; and
R8selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, -Ar and-NR9R9′(ii) a Wherein
R9And R9′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group and C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl.
In one embodiment of the invention, the invention relates to compounds of formula I wherein s is 1.
In another embodiment of the invention, the invention relates to compounds of formula I wherein s is 0.
In another embodiment of the invention, the invention relates to compounds of formula I wherein s is 1 and U is O.
In another embodiment of the invention, the invention relates to compounds of formula I wherein S is 1 and U is S.
In another embodiment of the invention, the invention relates to wherein s is 1 and U is SO2A compound of formula (I).
In another embodiment, the invention relates to wherein s is 1 and U is SO2NR11A compound of formula (I). In this class of compounds, SO2NR11Is attached to the benzene ring of formula I, and the nitrogen atom is attached to R2The above.
In another embodiment, the inventionRelates to compounds of formula I wherein s is 1 and U is CO-O. In this class of compounds, the carbonyl group of CO-O is linked to the phenyl ring of formula I, and the oxygen atom is linked to R2The above.
In another embodiment, the invention relates to compounds wherein s is 1 and U is CO-NR11A compound of formula (I). In this class of compounds, CO-NR11Is attached to the phenyl ring of formula I, and the nitrogen atom is attached to R2The above.
In another embodiment, the invention relates to compounds wherein R is11A compound of formula I which is a hydrogen atom.
In another embodiment, the invention relates to compounds of formula I wherein X is CO.
In another embodiment, the invention relates to wherein X is SO2With the proviso that when X is SO2Q is 0.
In another embodiment, the invention relates to compounds of formula I wherein q is 0.
In another embodiment, the invention relates to compounds of formula I wherein q is 1.
In another embodiment, the invention relates to compounds of formula I wherein q is 1 and Z is O.
In another embodiment, the invention relates to compounds of formula I wherein q is 1 and Z is S.
In another embodiment, the invention relates to compounds of formula I wherein X is CO, q is 1 and Z is O.
In another embodiment, the invention relates to compounds of formula I wherein X is CO, q is 1 and Z is S.
In another embodiment, the invention relates to compounds of formula I wherein X is CO and q is 0.
In another embodiment, the invention relates to wherein X is SO2And q is 0A compound of formula I.
In another embodiment, the invention relates to compounds wherein R is1Selected from acyl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C 3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (alk) yl-C6-alk (en/yn) yl compounds of formula I.
An embodiment of the present invention relates to wherein R1Selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group and C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl groups of the general formula I.
A preferred embodiment of the present invention relates to the compounds in which R is1Selected from hydrogen and C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to R1Is C1-6Alk (en/yn) yl, typically C1-3-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is1A compound of formula I which is a hydrogen atom.
In another embodiment, the invention relates to compounds wherein R is2Selected from hydrogen, acyl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) group, cyano-C 3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, NR10R10′-C1-6-alk (en/yn) yl,NR10R10′-C3-8Cycloalkane (alkenyl) group and NR10R10′-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I; wherein
R10And R10′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C1-6An alk (en/yn) yl group, or
R10And R10′And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
provided that when s is 1 and R2When it is a hydrogen atom or an acyl group, U is O or S.
When R is2Represents NR10R10′-C1-6Alk (en/yn) yl, NR10R10′-C3-8Cycloalkane (alkenyl) yl or NR10R10′-C3-8-cycloalk (en) yl-C1-6Alkyl (alk/alkynyl) radicals through which the nitrogen atom passes1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) yl or C3-8-cycloalk (en) yl-C1-6-an alk (en/yn) yl group is attached to the remainder of the molecule.
In another embodiment, the invention relates to compounds wherein R is2Selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalkanes(alk) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halogen, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl and cyano of formula I;
provided that when R is2S is 0 when it is halogen or cyano; and
provided that when s is 1 and R2U is O or S when it is a hydrogen atom.
In another embodiment, the invention relates to compounds wherein R is2Selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkene) yl, Ar-C1-6Alk (en/yn) yl, halogen, halo-C1-6-alk (en/yn) yl and cyano of formula I;
provided that when R is2When is halogen or cyano, s is 0; and
provided that when s is 1 and R2U is O or S when it is a hydrogen atom.
In a preferred embodiment, the invention relates to compounds wherein R2Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkene) yl, Ar-C1-6-alk (en/yn) yl, halogen and cyano compounds of formula I;
provided that when R is2Is halogen or cyano, s is 0.
In another embodiment, the invention relates to compounds wherein R is2A compound of formula I which is a hydrogen atom.
In another embodiment, the invention relates to compounds wherein R is2A compound of formula I which is not a hydrogen atom.
In another embodiment, the invention relates to compounds wherein R is2Is C1-6-alkanes(alk/yn) yl, C1-3-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is2Is C3-8A cycloalk (en) yl group, typically C3-6-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is2A compound of formula I which is Ar.
In another embodiment, the invention relates to compounds wherein R is2A compound of formula I other than Ar.
In another embodiment, the invention relates to compounds wherein R is2Is Ar-C1-6Alk (en/yn) yl, typically Ar-C1-3-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is2A compound of formula I which is a halogen atom, typically a chlorine, bromine or iodine atom.
In another embodiment, the invention relates to compounds wherein R is2Is halo-C1-6Alk (en/yn) yl, typically halo-C1-3-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds of formula I wherein R2Not being halo-C1-6-alk (en/yn) yl, typically not halo-C1-3-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is2A compound of formula I which is cyano.
In another embodiment, the invention relates to compounds wherein R is10And R10′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is10And R10′Independently selected from hydrogen and C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein s is 1, U is O and R2Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkenyl) yl and halo-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein s is 1, U is O and R 2Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkene) yl, Ar-C1-6Alk (en/yn) yl and halo-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein s is 1, U is O and R2Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkyl (alkenyl) and Ar-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein S is 1, U is S and R2Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkyl (alkenyl) and Ar-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein S is 1, U is S and R2Is selected from C1-6Alk (en/yn) yl andAr-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein S is 1, U is S and R2Is selected from C3-8Cycloalkyl (alkenyl) and Ar-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein s is 0 and R2Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar, halogen, halo-C 1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl and cyano.
In another embodiment, the invention relates to wherein s is 0 and R2Is selected from C1-6Alk (en/yn) yl, Ar, halogen, halo-C1-6-alk (en/yn) yl and cyano.
In another embodiment, the invention relates to wherein s is 0 and R2Is selected from C1-6-alk (en/yn) yl, halogen and cyano.
In another embodiment, the invention relates to compounds wherein s is 1, U is CO-O and R2Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein s is 1, U is CO-O and R2Is C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein s is 1 and U is CO-NR11，R11Is a hydrogen atom and R2Is not C3-8Cycloalkane (alkene) yl, hydroxy-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalkanes(alkenyl) yl, cyano-C3-8-cycloalk (en) yl and Ar.
In another embodiment, the invention relates to wherein s is 1 and U is CO-NR 11And R2Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein s is 1 and U is CO-NR11And R2Is C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is11Is a hydrogen atom.
In another embodiment, the invention relates to compounds wherein R is3Selected from heterocycloalkyl (alkenyl) radicals, C1-6Alk (en/yn) yl heterocycloalkyl (en) yl, Ar-C1-6Alk (en/yn) yl heterocycloalkyl (en) yl, C1-6-alk (en/yn) oxy-heterocycloalkyl (en) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8-cycloalkane (alkenyl) yl, hydroxy-heterocycloalkane (alkenyl) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, hydroxy-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, hydroxy-C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, halo-C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) yl, cyano-heterocycloalkyl (alkenyl) yl, cyano-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C 1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) group, cyano-C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, acyl C1-6Alk (en/yn) yl, acyl-C3-8-cycloalk (en) yl, acyl-heterocycloalk (en) yl, acyl-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) radical, acyl-C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, NR12R12′A compound of formula I; wherein
R12And R12′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, Ar-heterocycloalkyl (en) yl, Ar-oxy-C1-6Alk (en/yn) yl, Ar-oxy-C3-8Cycloalkyl (alkenyl) group, Ar-oxyl C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, Ar-oxy-heterocycloalkyl (en) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C 3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C1-6An alk (en/yn) yl group, or
R12And R12′And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
provided that when R is3Is NR12R12′When q is 0.
When R is3Represents NR12R12′-C1-6Alk (en/yn) yl, NR12R12′-C3-8Cycloalkane (alkenyl) yl or NR12R12′-C3-8-cycloalk (en) yl-C1-6Alkyl (alk/alkynyl) yl, nitrogen atomThrough C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) yl or C3-8-cycloalk (en) yl-C6-alk (en/yn) yl is linked to the X- (Z) p group.
In another embodiment, the invention relates to compounds wherein R is3Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) group, heterocycloalkyl (alkenyl) group-C16-alk (alkenyl/alkynyl) group, heterocycloalkyl (alkenyl) group, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkenyl) group, C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C3-8-cycloalk (en) oxy-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) oxy-C 3-8Cycloalkyl (alkenyl) group, Ar-oxy-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, C3-8-cycloalkane (alkene) oxy-carbonyl-C1-6Alk (en) yl, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, halo-C1-6Alk (en/yn) yl-Ar, halo-C3-8Cycloalk (en) yl-Ar, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl-Ar, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkenyl) group-Ar, NR12R12′Optionally substituted NR12R12′-C1-6Alk (en/yn) ylOptionally substituted NR12R12′-C3-8-cycloalk (en) yl and optionally substituted HR12R12′-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, heterocycloalkan (en) yl-C1-6Alk (en/yn) yl, heterocycloalkan (en) yl, Ar-C 1-6Alk (en/yn) yl, C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, Ar-oxy-C1-6Alk (en/yn) yl, Ar-C1-6-alk (en/yn) oxy-C1-6Alk (en/yn) yl, C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl-Ar, NR12R12′Optionally substituted NR12R12′-C1-6-alk (en/yn) yl, and optionally substituted NR12R12′-C3-8-cycloalk (en) yl compounds of formula I.
In a preferred embodiment, the invention relates to compounds wherein R3Is C1-6Alk (en/yn) yl, typically C1-3-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3A compound of formula I which is Ar.
In another embodiment, the invention relates to compounds wherein R is3A compound of formula I which is a heterocycloalkyl (alkenyl) group.
In another embodiment, the invention relates to compounds wherein R is3Compounds of formula I which are not heterocycloalkyl (alkenyl) groups.
In another embodiment, the invention relates to compounds wherein R is3Is heterocycloalkyl (alkenyl) group-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Not being heterocycloalkyl (alkenyl) group-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is Ar-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is C1-6Alk (en/yn) oxy-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is not C1-6Alk (en/yn) oxy-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is Ar-oxy-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is Ar-C1-6Alk (en/yn) oxy-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is C1-6-alk (en/yn) oxy-carbonyl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to the sameIn R 3Is halo-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is halo-C1-6-alk (en/yn) yl-Ar.
In another embodiment, the invention relates to compounds wherein R is3Not being halo-C1-6-alk (en/yn) yl-Ar.
In another embodiment, the invention relates to compounds wherein R is3Is NR12R12′A compound of formula (I).
In another embodiment, the invention relates to compounds wherein R is3Is not NR12R12′A compound of formula (I).
In another embodiment, the invention relates to compounds wherein R is3Is optionally substituted NR12R12′-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is different from NR optionally substituted12R12′-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is optionally substituted NR12R12′-C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is different from NR optionally substituted12R12′-C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is optionally substituted NR12R12′-C3-8-cycloalk (en) yl-C 1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is3Is different from NR optionally substituted12R12′-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is12And R12′Independently selected from Ar-heterocycloalkyl (alkenyl) group, Ar-oxy-C1-6Alk (en/yn) yl, Ar-oxy-C3-8Cycloalkyl (alkenyl) group, Ar-oxyl C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, Ar-oxy-heterocycloalkyl (en) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C1-6An alk (en/yn) yl group, or
R12And R12′And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
a compound of formula (I).
In another embodiment, the invention relates to compounds wherein R is12And R12′Independently selected from hydrogen, C 1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is12And R12′Independently selected from hydrogen, C1-6-alk (en/yn) yl and Ar.
In another embodiment, the invention relates to compounds wherein R is12And R12′A compound of formula I in which at least one is a hydrogen atom.
In another embodiment, the invention relates to compounds wherein R is12And R12′At least one of which is C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is12And R12′A compound of formula I in which at least one is Ar.
In another embodiment, the invention relates to wherein X is CO, q is 1, Z is O and R3Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkenyl) group, ArC3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl-C3-s-cyclo-alk (en) yl, C 1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C3-8-cycloalk (en) oxy-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) oxy-C3-8Cycloalkyl (alkenyl) group, Ar-oxy-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl and halo-C1-6Alk (en/yn) yl-C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to wherein X is CO, q is 1, Z is O and R3Is selected from C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl and halo-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein X is CO, q is 1, Z is O and R3Is not C1-6Alk (en/yn) oxy-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein X is CO, q is 1, Z is O and R3Is C1-6Alk (en/yn) yl, typically C1-3-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein X is CO, q is 1, Z is S and R 3Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl and Ar-C1-6Alk (en/yn) yl-C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to wherein X is CO, q is 1, Z is S and R3Is selected from C1-6Alk (en/yn) yl and Ar-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein X is CO, q is 1, Z is S and R3Is C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein X is CO, q is 0, R3Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkanes (chain)Alkenyl) radical, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkenyl) yl, Heterocycloalkane (alkenyl) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) group, Ar-oxy-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) oxy-C 1-6Alk (en/yn) yl, C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, C3-8-cycloalkane (alkene) oxy-carbonyl-C1-6Alk (en/yn) yl, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, halo-C1-6Alk (en/yn) yl-Ar, halo-C3-8Cycloalk (en) yl-Ar, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl-Ar, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkenyl) group-Ar, NR12R12′Optionally substituted NR12R12′-C1-6-alk (en/yn) yl, and optionally substituted NR12R12′-C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to wherein X is CO, q is 0, R3Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, heterocycloalkan (en) yl, Ar-C1-6Alk (en/yn) yl, Ar-oxy-C1-6Alk (en/yn) yl, C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C 1-6Alk (en/yn) yl-Ar, NR12R12′Optionally substituted NR12R12′-C1-6-alk (en/yn) yl, and optionally substituted NR12R12′-C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to wherein X is SO2Q is 0 and R3Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl-C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to wherein X is SO2Q is 0 and R3Is selected from C1-6Alk (en/yn) yl and Ar-C1-6-alk (en/yn) yl compounds of formula I.
In a preferred embodiment, the invention relates to compounds wherein R3Are Ar and q is 1.
In a preferred embodiment, the invention relates to compounds wherein R3Are Ar and q is 0.
In a preferred embodiment, the invention relates to wherein R is when q is 03A compound of formula I other than Ar.
In another embodiment, the invention relates to compounds of formula I wherein Y is of formula XXIV, XXV, XXVII, xxxxxi, or xxxxxii.
In another embodiment, the invention relates to compounds of formula I wherein Y is formula XXIV.
In another embodiment, the invention relates to compounds of formula I wherein Y is formula XXV.
In another embodiment, the invention relates to compounds of formula I wherein Y is of formula XXVII.
In another embodiment, the invention relates to compounds of formula I wherein Y is formula XXXXI.
In another embodiment, the invention relates to compounds of formula I wherein Y is formula XXXXII.
In another embodiment, the invention relates to compounds of formula I wherein W is an oxygen atom.
In another embodiment, the invention relates to compounds of formula I wherein W is a sulfur atom.
In another embodiment, the invention relates to compounds of formula I wherein V is a nitrogen atom.
In another embodiment, the invention relates to compounds of formula I wherein V is CH.
In another embodiment, the invention relates to compounds of formula I wherein T is a nitrogen atom.
In another embodiment, the invention relates to compounds of formula I wherein T is an oxygen atom.
In another embodiment, the invention relates to compounds wherein each R is5Independently selected from Ar-oxy-C 1-6Alk (en/yn) yl, Ar-oxy-C3-8Cycloalkyl (alkenyl) group, Ar-oxy-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, acyl, -CO-NR6R6′Cyano, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein each R is5Independently selected from C1-6-alkanes (chains)Ene/yne) radical, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) yl heterocycloalkyl (en) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) oxy, C3-8Cycloalk (alk) oxy, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) oxy, Ar-oxy, C1-6-alk (en/yn) oxy-carbonyl, halogen, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, NR7R7′、S-R8And SO2R8Or two adjacent R5Together with the aromatic group, form a 5-8 membered ring optionally containing one or two heteroatoms.
When R is5Represents NR7R7′-C1-6Alk (en/yn) yl, NR 7R7′-C3-8Cycloalkane (alkenyl) yl or NR7R7′-C3-8-cycloalk (en) yl-C1-6Alkyl (alk/alkynyl) radicals through which the nitrogen atom passes1- 6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) yl or C3-8-cycloalk (en) yl-C1-6-an alk (en/yn) yl group is attached to the remainder of the molecule.
In another embodiment, the invention relates to compounds wherein each R is5Independently selected from C1-6Alk (en/yn) yl, Ar, C1-6-alk (en/yn) oxy, halogen, -NR7R7′、-S-R8and-SO2R8Or two adjacent R5Together with the aromatic group, form a 5-8 membered ring optionally containing one or two heteroatoms.
In a preferred embodiment, the invention relates to compounds wherein each R is5Independently selected from C1-6Alk (en/yn) yl, Ar, C1-6Alk (en/yn) oxy, Ar-oxy, C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, C1-6-alk (en/yn) oxy-carbonyl, halogen, halo-C1-6Alk (en/yn) yl, NR7R7′、S-R8And SO2R8Or two adjacent R5Together with the aromatic group, form a 5-8 membered ring optionally containing one or two heteroatoms.
In another embodiment, the invention relates to wherein one R is5Is C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein one R is 5Is C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to wherein one R is5Is C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein one R is5A compound of formula I which is Ar.
In another embodiment, the invention relates to wherein one R is5Is Ar-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein R is absent5Is Ar-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein one R is5Is Ar-C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to wherein R is absent5A compound of formula I which is Ar-C3-s-cycloalkane (alkenyl) group.
In another embodimentThe invention relates to one of R5Is Ar-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein R is absent5Is Ar-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein one R is5Is C1-6-alk (en/yn) oxy groups of the formula I.
In another embodiment, the invention relates to wherein one R is5Is C3-8-cycloalk (alk) oxy group of formula I.
In another embodiment, the invention relates to wherein one R is5Is C3-8-cycloalk (en) yl-C1-6-alk (en/yn) oxy groups of the formula I.
In another embodiment, the invention relates to wherein one R is5A compound of formula I which is Ar-oxy.
In another embodiment, the invention relates to wherein R is absent5A compound of formula I which is Ar-oxy.
In another embodiment, the invention relates to wherein one R is5Is C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl.
In another embodiment, the invention relates to wherein R is absent5Is C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl.
In another embodiment, the invention relates to wherein one R is5Is C1-6-alk (en/yn) yl-carbonyl of formula I.
In another embodiment, the invention relates to wherein R is absent5Is C1-6Alk (en/yn) oxy-a carbonyl group.
In another embodiment, the invention relates to wherein one R is5A compound of formula I which is a halogen atom.
In another embodiment, the invention relates to wherein one R is 5Is halo-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein R is absent5Is halo-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein one R is5Is halo-C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to wherein R is absent5Is halo-C3-8-cycloalk (en) yl compounds of formula I.
In another embodiment, the invention relates to wherein one R is5Is halo-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein R is absent5Is halo-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to wherein one R is5Is NR7R7′A compound of formula (I).
In another embodiment, the invention relates to wherein R is absent5Is NR7R7′A compound of formula (I).
In another embodiment, the invention relates to wherein one R is5Is S-R8A compound of formula (I).
In another embodiment, the invention relates to wherein one R is5Is SO2R8A compound of formula (I).
In another embodiment, the invention relates to a compound wherein two adjacent R are 5Together with the aromatic group, form a 5-8 membered ring optionally containing one or two heteroatoms.
In a preferred embodiment, the invention relates to a compound in which two adjacent R are5Together form- (CH)2)n′-CH2-、-CH＝CH-(CH2)m′-、-CH2-CH＝CH-(CH2)p′，-CH＝CH-CH＝CH-、-(CH2)n′-O-、-O-(CH2)m′-O-、-CH2-O-(CH2)p′-O-、-CH2-O-CH2-O-CH2-、-(CH2)n′-S-、-S-(CH2)m′-S-、-CH2-S-(CH2)p′-S-、-CH2-S-CH2-S-CH2-、-(CH2)n′-NH-、-NH-(CH2)m′-NH-、-CH2-NH-(CH2)p′-NH-、-CH＝CH-NH-、-O-(CH2)m′-NH-、-CH2-O-(CH2)p′-NH-or-O- (CH)2)p′-NH-CH2-、-S-(CH2)m′-NH-, -N ═ CH-O-, or-N ═ CH-S-, wherein m ' is 1, 2 or 3, N ' is 2, 3 or 4 and p ' is 1 or 2.
In another embodiment, the invention relates to a compound wherein two adjacent R are5Together form-CH2-O-CH2-a compound of formula I.
In another embodiment, the invention relates to a compound wherein two adjacent R are5Together form a compound of formula I-CH-.
In another embodiment, the invention relates to compounds wherein R is7And R7′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group and C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is7And R7′Independently selected from hydrogen and C1-6-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to R7And R7′Is one of C1-6Alk (en/yn) yl, typically C1-3-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is7And R7′Are all C1-6Alk (en/yn) yl, typically C1-3-alk (en/yn) yl compounds of formula I.
In another embodiment, the invention relates to compounds wherein R is8Selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl and Ar.
In a preferred embodiment, the invention relates to compounds wherein R8Is selected from C1-6-alk (en/yn) yl and Ar.
In a preferred embodiment, the invention relates to compounds wherein R8Is C1-6-alk (en/yn) yl compounds of formula I.
In a preferred embodiment, the invention relates to compounds wherein R8A compound of formula I which is Ar.
In another embodiment, the invention relates to wherein X is SO2Q is 0 and R3Is C1-6-alk (en/yn) yl, with the proviso that R3A compound of formula I other than methyl.
In another embodiment, the invention relates to wherein q is 0, R3Is a firstRadicals and X being different from SO2A compound of formula (I).
In another embodiment, the invention relates to wherein X is SO2S is 1 and U is different from 0.
In another embodiment, the invention relates to a compound wherein s is 1, U is O and X is different from SO 2A compound of formula (I).
In another embodiment, the invention relates to wherein X is CO, q is 0 and R3Is C1- 6-alk (en/yn) yl, with the proviso that R3A compound of formula I other than methyl.
In another embodiment, the invention relates to compounds wherein s is 1, U is different from O, X is CO, q is 0 and R3A compound of formula I which is methyl.
In another embodiment, the invention relates to wherein s is 1, U is O, X is CO, q is 0 and R3Is C1-6-alk (en/yn) yl, with the proviso that R3A compound of formula I other than methyl.
The molecular weight of the compounds of the present invention may vary from compound to compound. The molecular weight of the compounds of formula I is generally higher than 200 and lower than 600, and more generally higher than 250 and lower than 550.
One aspect of the present invention relates to compounds of formula XXIX and salts thereof:
wherein f, s, q, U, X, Z, R1、R2、R3And R5Is as defined above, f, s, q, U, X, Z, R1、R2、R3、R5、R6、R6′、R7、R7′、R8、R9、R9′、R10、R10′、R11、R12And R12′Any of which accordingly has the meaning defined under formula I. Any of the embodiments to which formula I relates are also embodiments of formula XXIX.
In another embodiment, the invention relates to compounds of formula XXIX wherein f is 0.
In another embodiment, the invention relates to the substitution of one substituent R 5Substituted, e.g. in ortho-, meta-or para-position, compounds of formula XXIX.
In another embodiment, the invention relates to R being independently selected by two5Substituted, e.g. substituted in ortho-and para-positions, substituted in meta-and para-positions and substituted in ortho-and meta-positions, compounds of formula XXIX.
In another embodiment, the invention relates to R being independently selected from three5A compound of formula XXIX substituted with a substituent.
Another aspect of the invention relates to a compound of formula XXX:
wherein g, h, s, q, U, X, Z, R1、R2、R3And R5Is as defined above, g, h, s, q, U, X, Z, R1、R2、R3、R5、R6、R6′、R7、R7′、R8、R9、R9′、R10、R10′、R11、R12And R12′Any of which accordingly has the meaning defined under formula I. Any one embodiment contemplated by formula I is also an embodiment of formula XXX.
In one embodiment, the invention relates to compounds of formula XXX wherein the nitrogen atom is attached to the 1 position of the naphthyl group through a methylene group.
In another embodiment, the invention relates to compounds of formula XXX wherein the nitrogen atom is attached to the 2-position of the naphthyl group through a methylene group.
In another embodiment, the invention relates to compounds of formula XXX wherein g is 0, 1, 2 or 3, typically 0, 1 or 2.
In another embodiment, the invention relates to compounds of formula XXX wherein h is 0, 1 or 2, typically 0 or 1.
In another embodiment, the invention relates to compounds of formula XXX wherein g and h are both 0.
In another embodiment, the invention relates to the substitution of one substituent R5Substituted compounds of formula XXX, in one particular aspect thereof, g is 0 and h is 1 and in another particular aspect thereof, g is 1 and h is 0.
In another embodiment, the invention relates to R being independently selected5A compound of formula XXX substituted with substituents, in one particular aspect thereof, g is 0 and h is 2, in another particular aspect thereof, g is 1 and h is 1 and in another aspect thereof, g is 2 and h is 0.
In another embodiment, the invention relates to R being independently selected by three5A compound of formula XXX substituted with substituents, in one particular aspect thereof, g is 0 and h is 3, in another particular aspect thereof, g is 1 and h is 2, in another aspect thereof g is 2 and h is 1 and in another aspect thereof g is 3 and h is 0.
In another aspect, the invention relates to a compound of formula XXXI:
wherein a, s, q, U, W, X, Z, R 1、R2、R3And R5Is as defined above, a, s, Z, R1、R2、R3、R5、R6、R6′、R7、R7′、R8、R9、R9′、R10、R10′、R11、R12And R12′Any of which accordingly has the meaning defined under formula I. Any one embodiment to which formula I relates is also an embodiment of formula XXXI.
In one embodiment, the present invention relates to compounds of formula XXXI wherein the nitrogen atom is attached to the 2-position of the heteroaromatic group through a methylene group.
In another embodiment, the invention relates to compounds of formula XXXI wherein the nitrogen atom is attached to the 3-position of the heteroaromatic group through a methylene group.
In another embodiment, the invention relates to compounds of formula XXXI wherein a is 0, 1 or 2.
In another embodiment, the invention relates to compounds of formula XXXI wherein a is 0.
In another embodiment, the invention relates to the substitution of one substituent R5Substituted compounds of formula XXXI.
In another embodiment, the invention relates to R being independently selected by two5A compound of formula XXXI substituted with a substituent.
Another aspect of the invention relates to a compound of formula XXXII:
wherein b, c, s, q, U, W, X, Z, R1、R2、R3And R5B, c, s, q, U, W, X, Z, R are as defined above 1、R2、R3、R5、R6、R6′、R7、R7′、R8、R9、R9′、R10、R10′、R11、R12And R12′Any of which accordingly has the meaning defined under formula I. Any one embodiment to which formula I relates is also an embodiment of formula XXXII.
In one embodiment, the present invention relates to compounds of formula XXXII wherein the nitrogen atom is attached to the 2-position of the heteroaromatic group through a methylene group.
In another embodiment, the invention relates to compounds of formula XXXII wherein the nitrogen atom is attached to the 3-position of the heteroaromatic group through a methylene group.
In another embodiment, the invention relates to compounds of formula XXXII wherein b is 0, 1, 2 or 3, typically 0, 1 or 2.
In another embodiment, the invention relates to compounds of formula XXXII wherein c is 0 or 1, typically 0.
In another embodiment, the invention relates to compounds of formula XXXII wherein b and c are both 0.
In another embodiment, the invention relates to the substitution of one substituent R5Substituted compounds of formula XXXII, in one aspect thereof, b is 0 and c is 1 and in another aspect thereof, b is 1 and c is 0.
In another embodiment, the invention relates to R being independently selected by two5A compound of formula XXXII substituted with a substituent, in one aspect thereof, b is 1 and c is 1 and in another aspect thereof, b is 2 and c is 0.
In another embodiment, the invention relates to R being independently selected by three5A compound of formula XXXII substituted with a substituent, in one aspect thereof, b is 2 and c is 1 and in another aspect thereof, b is 3 and c is 0.
Another aspect of the invention relates to a compound of formula XXXIII:
wherein d, e, s, q, U, W, X, Z, R1、R2、R3And R5D, e, s, q, U, W, X, Z, R are as defined above1、R2、R3、R5、R6、R6′、R7、R7′、R8、R9、R9′、R10、R10′、R11、R12And R12′Any of which accordingly has the meaning defined under formula I. Any one embodiment to which formula I relates is also a scheme of formula XXXIII.
In one embodiment, the present invention relates to compounds of formula XXXIII wherein the nitrogen atom is attached to the 4-position of the heteroaromatic group through a methylene group.
In another embodiment, the invention relates to compounds of formula XXXIII wherein the nitrogen atom is attached to the 5-position of the heteroaromatic group through a methylene group.
In one embodiment, the present invention relates to compounds of formula XXXIII wherein the nitrogen atom is attached to the 6-position of the heteroaromatic group through a methylene group.
In another embodiment, the invention relates to compounds of formula XXXIII wherein the nitrogen atom is attached to the 7-position of the heteroaromatic group through a methylene group.
In another embodiment, the invention relates to compounds of formula XXXIII wherein d is 0, 1 or 2, typically 0 or 1.
In another embodiment, the invention relates to compounds of formula XXXIII wherein e is 0, 1 or 2.
In another embodiment, the invention relates to compounds of formula XXXIII wherein d and e are both 0.
In another embodiment, the invention relates to the substitution of one substituent R5Substituted compounds of formula XXXIII, in one particular aspect thereof, d is 0 and e is 1 and in another particular aspect thereof, d is 1 and e is 0.
In another embodiment, the invention relates to R being independently selected5A compound of formula XXXIII substituted with a substituent, in one particular aspect thereof, d is 0 and e is 2, in another particular aspect thereof, d is 1 and e is 1 and in another aspect thereof, d is 2 and e is 0.
In another embodiment, the invention relates to R being independently selected from three5A compound of formula XXXIII substituted with a substituent, in one aspect thereof, d is 1 and e is 2, in another aspect thereof, d is 2 and e is 1 and in another aspect thereof, d is 3 and e is 0.
In another aspect, the invention relates to a compound of formula XXXIII or a salt thereof:
Wherein dd, s, q, U, V, X, Z, R1、R2、R3And R5Have the meanings defined under formula I. Any one embodiment to which formula I relates is also an embodiment of formula xxxiii.
In another embodiment, the invention relates to compounds of formula XXXIII wherein V is the carbon atom to which the nitrogen atom is attached through a methylene group.
In one embodiment, the invention relates to compounds of formula xxxiii wherein the nitrogen atom is attached to the carbon atom labeled "1" through a methylene group.
In one embodiment, the invention relates to compounds of formula xxxiii wherein the nitrogen atom is attached to the carbon atom labeled "2" through a methylene group.
In another embodiment, the invention relates to compounds of formula xxxiii wherein the nitrogen atom is attached to the carbon atom labeled "3" through a methylene group.
In another embodiment, the invention relates to compounds of formula xxxiii wherein the nitrogen atom is attached to the carbon atom labeled "4" through a methylene group.
In another embodiment, the invention relates to compounds of formula XXXIII wherein dd is 0, 1 or 2, typically 0 or 1. In one aspect of the invention, dd is 0. In another aspect of the invention, dd is 0.
In another aspect, the invention relates to a compound of formula XXXXIV:
wherein aa, s, q, T, U, X, Z, R1、R2、R3And R5Have the meanings defined under formula I. Any of the embodiments contemplated by formula I are also compounds of formula XXXXIV.
In one embodiment, the present invention relates to compounds of formula XXXXIV wherein T is a nitrogen atom to which the nitrogen atom is attached through a methylene group.
In one embodiment, the invention relates to compounds of formula XXXXIV wherein the nitrogen atom is attached to the carbon atom labeled "1" through a methylene group.
In one embodiment, the present invention relates to compounds of formula XXXXIV wherein the nitrogen atom is attached to the carbon atom labeled "2" through a methylene group.
In another embodiment, the invention relates to compounds of formula XXXXIV wherein the nitrogen atom is attached to the carbon atom labeled "3" through a methylene group.
In another embodiment, the invention relates to compounds of formula XXXI wherein aa is 0, 1 or 2. In one embodiment, aa is 0. In another embodiment, formula XXXXIV is substituted with one substituent R5And (4) substituting. In another embodiment, the compound of formula XXXI is substituted with two independently selected R 5Substituted by a substituent.
In a particular embodiment, the present invention relates to substituted p-diaminobenzene derivatives of the general formula Ia or salts thereof
Wherein
s is 0 or 1;
u is O, S, SO2、SO2NR11CO-O or CO-NR11(ii) a Wherein R is11Selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C6-alk (en/yn) yl; or R2And R11Together with the nitrogen atom, form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
q is 0 or 1;
x is CO or SO2(ii) a Provided that when X is SO2Q is 0;
z is O or S;
R1selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C1-8-cyclo-alk (en) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C6-alk (en/yn) yl;
R2selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C 1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halogen, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) group, cyano-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, NR10R10′-C1-6Alk (en/yn) yl, NR10R10′-C3-8Cycloalkane (alkenyl) group and NR10R10′-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl; wherein R is10And R10′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8Cycloalk (en) yl-CI 6-alk (en/yne) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C 1-6-alk (en/yn) yl, or R10And R10′And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
provided that when R is2When is halogen or cyano, s is 0; and
provided that when s is 1 and R2When it is a hydrogen atom or an acyl group, U is O or S.
R3Is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) yl, Heterocycloalkane (alkenyl) yl, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) yl-C1-6Cycloalkane (alkenyl) group, C1-6Alk (en/yn) yl heterocycloalkyl (en), Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkyl (alkenyl) group, Ar-heterocycloalkyl (alkenyl) group, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, Ar-C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C3-8-cycloalk (en) oxy-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) oxy-C3-8Cycloalkane (alkenyl) group, C1-6-alk (en/yn) oxy-heterocycloalkyl (en) yl, Ar-oxy-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C1-6-alk (en/yn) oxy-carbonyl-C 1-6Alk (en/yn) yl, C3-8-cycloalkane (alkene) oxy-carbonyl-C1-6Alk (en/yn) yl, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8-cycloalkane (alkenyl) yl, hydroxy-heterocycloalkane (alkenyl) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, hydroxy-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, hydroxy-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8-cycloalk (en) yl, halo-heterocycloalk (en) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, halo-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, halo-C1-6Alk (en/yn) yl-Ar, halo-C3-8Cycloalk (en) yl-Ar, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl-Ar, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) -Ar, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) yl, cyano-heterocycloalkyl (alkenyl) yl, cyano-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) group, cyano-C 1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, acyl-C1-6Alk (en/yn) yl, acyl-C3-8-cycloalk (en) yl, acyl-heterocycloalk (en) yl, acyl-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) radical, acyl-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, -NR12R12′(ii) a Wherein R is12And R12′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C1-6Alk (en) enesAn/alkynyl) group, or R12And R12′And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
and
y represents a group of formula XXIV, XXV, XXVI, XXVII or XXVIII:
wherein
The line represents a bond linking the group represented by Y to the carbon atom;
W is O or S;
a is 0, 1, 2 or 3;
b is 0, 1, 2, 3 or 4;
c is 0 or 1;
d is 0, 1, 2 or 3;
e is 0, 1 or 2;
f is 0, 1, 2, 3, 4 or 5;
g is 0, 1, 2, 3 or 4;
h is 0, 1, 2 or 3; and
each R5Independently selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, acyl, C1-6Alk (en/yn) oxy, C3-8Cycloalk (alk) oxy, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) oxy, halogen, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, -CO-NR6R6′Cyano, cyano-C1-6Alk (en/yn) yl, cyano C3-8Cycloalkyl (alkenyl) group, cyano-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, NR7R7′、S-R8and-SO2R8Or two adjacent R5Together with the aromatic group, form a 5-8 membered ring containing one or two heteroatoms;
R6and R6′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl and Ar;
R7and R7′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C 1-6-alk (en/yn) yl, Ar and acyl; and
R8selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, -Ar and-NR9R9′(ii) a Wherein R is9And R9′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group and C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl.
In one embodiment, the compounds listed below, as well as salts thereof, are preferred:
{4- [ (benzofuran-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid ethyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid ethyl ester;
{ 2-methyl-4- [ (5-phenyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid ethyl ester;
[4- (4-isopropyl-benzylamino) -2-methylphenyl ] -carbamic acid ethyl ester;
[4- (4-fluoro-benzylamino) -2-methylphenyl ] -carbamic acid propyl ester;
(4- { [4- (4-chloro-benzenesulfonyl) -3-methyl-thiophen-2-ylmethyl ] -amino } -2-methylphenyl) -carbamic acid propyl ester;
{4- [ (5-methyl-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{ 2-methyl-4- [ (5-phenyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
[4- (4-isopropyl-benzylamino) -2-methylphenyl ] -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
[ 2-chloro-4- (4-isopropyl-benzylamino) -phenyl ] -carbamic acid ethyl ester;
[ 2-chloro-4- (4-fluoro-benzylamino) -phenyl ] -carbamic acid propyl ester;
2-chloro-4- { [4- (4-chloro-benzenesulfonyl) -3-methyl-thiophen-2-ylmethyl ] -amino } -phenyl) -carbamic acid propyl ester;
{4- [ (5-methyl-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{4- [ (benzofuran-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid ethyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -carbamic acid methyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -carbamic acid isopropyl ester;
{4- [ (4-fluoro-benzyl) - (methyl) amino ] -2-methoxyphenyl } -carbamic acid propyl ester;
{4- (benzo [ b ] thiophen-2-ylmethyl- (methyl) amino) -2-methoxy-phenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methoxy-phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-methoxy-phenyl } -carbamic acid propyl ester;
{ 2-methoxy-4- [ methyl- (5-methyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (4-fluorobenzyl) - (methyl) -amino ] -2-isopropoxyphenyl } -carbamic acid ethyl ester;
[4- (3-fluorobenzylamino) -2-methoxyphenyl ] -carbamic acid ethyl ester;
[4- (4-isopropylbenzylamino) -2-methoxyphenyl ] -carbamic acid ethyl ester;
{ 2-methoxy-4- [ (3-methylthiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid ethyl ester;
[4- (2, 4-difluorobenzylamino) -2-methoxyphenyl ] -carbamic acid ethyl ester;
[ 2-cyclopentyloxy-4- (4-methoxybenzylamino) -phenyl ] -carbamic acid ethyl ester;
[ 2-cyclopentyloxy-4- (3-fluoro-2-methylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
[4- (3-fluoro-2-methylbenzylamino) -2-phenylethoxyphenyl ] -carbamic acid ethyl ester;
[ 2-benzyloxy-4- (3-fluoro-2-methylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
[ 2-benzyloxy-4- (4-methylsulfanylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
{4- [ (benzo [ b ] thiophen-3-ylmethyl) -amino ] -2-cyclopentyloxyphenyl } -carbamic acid ethyl ester;
[4- (3-fluoro-2-methylbenzylamino) -2-isopropoxyphenyl ] -carbamic acid ethyl ester;
[ 2-benzyloxy-4- (3-methoxybenzylamino) -phenyl ] -carbamic acid ethyl ester;
{4- [ (benzo [1, 3] dioxol-5-ylmethyl) -amino ] -2-isopropoxyphenyl } -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
[ 2-cyano-4- (4-isopropylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (4-isopropylbenzyl) - (methyl) amino ] -2-methylphenyl } -carbamic acid propyl ester;
{ 2-methyl-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{ 2-methyl-4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
{ 2-chloro-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid ethyl ester;
{ 2-chloro-4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -phenyl } -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{ 2-chloro-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } carbamic acid ethyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (4-isopropyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ (4-isopropyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -benzoic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-cyanophenyl } -carbamic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-cyanophenyl } -carbamic acid propyl ester;
{ 2-cyano-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (4-isopropylbenzyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
[ 2-iodo-4- (4-isopropyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[4- (4-tert-butyl-benzylamino) -2-iodophenyl ] -carbamic acid propyl ester;
[ 2-iodo-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[ 2-iodo-4- (4-methylsulfanyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
{ 2-iodo-4- [4- (4-methylpiperazin-1-yl) -benzylamino ] -phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
[4- (4-tert-butyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid ethyl ester;
[4- (4-methylsulfanyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
[4- (4-isopropylbenzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
[4- (4-tert-butyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
[ 2-trifluoromethyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[4- (4-dimethylamino-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
[4- (4-methylsulfanyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid propyl ester;
[ 2-cyano-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
[ 2-bromo-4- (4-isopropylbenzylamino) -phenyl J-carbamic acid propyl ester;
[ 2-bromo-4- (4-tert-butyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[ 2-bromo-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[ 2-bromo-4- (4-methylsulfanyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
n- {4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -butyramide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl) -butyramide;
n- [4- (4-isopropylbenzylamino) -2-methoxyphenyl ] -butyramide;
n- [4- (4-tert-butyl-benzylamino) -2-methoxyphenyl ] -butyramide;
n- [ 2-methoxy-4- (4-trifluoromethyl-benzylamino) -phenyl ] -butyramide;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-furan-2-yl-phenyl } -carbamic acid propyl ester;
[ 2-furan-2-yl-4- (4-isopropylbenzylamino) -phenyl ] -carbamic acid propyl ester;
[5- (4-fluorobenzylamino) -biphenyl-2-yl ] -carbamic acid propyl ester;
{5- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -biphenyl-2-yl } -carbamic acid propyl ester;
[5- (4-isopropylbenzylamino) -biphenyl-2-yl ] -carbamic acid propyl ester;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2-phenylacetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3, 3-dimethylbutanamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl) -3-phenylpropanamide;
N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -butyramide;
pentanoic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
cyclopropanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
cyclobutanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
cyclopentanecarboxylic acid (2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
cyclohexanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2-thiophen-2-yl-acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (3-methoxy-phenyl ] -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-chloro-phenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-methoxy-phenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-fluoro-phenyl-acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3-cyclohexylpropionamide;
N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2, 2-dimethylpropionamide;
n- [ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-phenoxyacetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-phenylacetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -3, 3-dimethylbutanamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -butyramide;
pentanoic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
cyclopropanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
cyclobutanecarboxylic acid (2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] ═ phenyl } -amide;
cyclopentanecarboxylic acid (2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
cyclohexanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-thiophen-2-yl-acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (3-methoxyphenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-chlorophenyl) -acetamide;
N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-methoxyphenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-fluorophenyl) -acetamide;
2, 3-dihydro-benzo [1, 4] dioxine-6-carboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
2, 3-dihydro-benzofuran-5-carboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -3-cyclohexylpropionamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -2, 2-dimethylpropionamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -2-phenylacetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -3, 3-dimethylbutanamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -3-phenylpropanamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -butyramide;
2, 2, 2-trichloro-N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -acetamide;
cyclopropanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -amide;
Cyclobutanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl J-amide;
cyclopentanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl, -amide;
cyclohexanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl) -amide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2-thiophen-2-yl-acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } j-2- (3-methoxyphenyl) -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -malonamic acid methyl ester;
2- (4-chlorophenyl) -N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2- (4-methoxyphenyl) -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) -methyl) -amino ] -2-methylphenyl } -2- (4-fluorophenyl) -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -3-cyclohexylpropionamide;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid phenyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid benzyl ester;
(2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl) -carbamic acid isobutyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid butyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid hexyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 4-nitrobenzyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid but-3-enyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid but-2-ynyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 2, 2-dimethylpropyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl) -carbamic acid 2-chlorobenzyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 3-chloropropyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 2-benzyloxyethyl ester;
3- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -1-methyl-1-propyl-urea;
1- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3- (2-fluorophenyl) -urea;
N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2, 2, 2-trifluoroacetamide; and
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2, 2, 2-trifluoroacetamide.
In another embodiment, the compounds listed below, as well as salts thereof, are preferred:
{4- [ (benzofuran-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid ethyl ester;
(4- (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid ethyl ester;
{ 2-methyl-4- [ (5-phenyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid ethyl ester;
[4- (4-isopropyl-benzylamino) -2-methylphenyl ] -carbamic acid ethyl ester;
[4- (4-fluoro-benzylamino) -2-methylphenyl ] -carbamic acid propyl ester;
(4- { [4- (4-chloro-benzenesulfonyl) -3-methyl-thiophen-2-ylmethyl ] -amino } -2-methylphenyl) -carbamic acid propyl ester;
{4- [ (5-methyl-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{ 2-methyl-4- [ (5-phenyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
[4- (4-isopropyl-benzylamino) -2-methylphenyl ] -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
[ 2-chloro-4- (4-isopropyl-benzylamino) -phenyl ] -carbamic acid ethyl ester;
[ 2-chloro-4- (4-fluoro-benzylamino) -phenyl ] -carbamic acid propyl ester;
2-chloro-4- { [4- (4-chloro-benzenesulfonyl) -3-methyl-thiophen-2-ylmethyl ] -amino } -phenyl) -carbamic acid propyl ester;
{4- [ (5-methyl-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{4- [ (benzofuran-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid ethyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -carbamic acid methyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -carbamic acid isopropyl ester;
{4- [ (4-fluoro-benzyl) - (methyl) amino ] -2-methoxyphenyl } -carbamic acid propyl ester;
[4- [ (benzo [ b ] thiophen-2-ylmethyl- (methyl) amino) -2-methoxyphenyl ] -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methoxy-phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-methoxy-phenyl } -carbamic acid propyl ester;
{ 2-methoxy-4- [ methyl- (5-methyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (4-fluorobenzyl) - (methyl) -amino ] -2-isopropoxyphenyl } -carbamic acid ethyl ester;
[4- (3-fluorobenzylamino) -2-methoxyphenyl ] -carbamic acid ethyl ester;
[4- (4-isopropylbenzylamino) -2-methoxyphenyl ] -carbamic acid ethyl ester;
{ 2-methoxy-4- [ (3-methylthiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid ethyl ester;
[4- (2, 4-difluorobenzylamino) -2-methoxyphenyl ] -carbamic acid ethyl ester;
[ 2-cyclopentyloxy-4- (4-methoxybenzylamino) -phenyl ] -carbamic acid ethyl ester;
[ 2-cyclopentyloxy-4- (3-fluoro-2-methylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
[4- (3-fluoro-2-methylbenzylamino) -2-phenylethoxyphenyl ] -carbamic acid ethyl ester;
[ 2-benzyloxy-4- (3-fluoro-2-methylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
[ 2-benzyloxy-4- (4-methylsulfanylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
[4- [ (benzo [ b ] thiophen-3-ylmethyl) -amino ] -2-cyclopentyloxyphenyl ] -carbamic acid ethyl ester;
[4- (3-fluoro-2-methylbenzylamino) -2-isopropoxyphenyl ] -carbamic acid ethyl ester;
[ 2-benzyloxy-4- (3-methylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
[4- [ (benzo [1, 3] dioxol-5-ylmethyl) -amino ] -2-isopropoxyphenyl ] -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
[ 2-cyano-4- (4-isopropoxybenzylamino) -phenyl ] -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (4-isopropylbenzyl) - (methyl) amino ] -2-methylphenyl } -carbamic acid propyl ester;
{ 2-methyl-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{ 2-methyl-4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
{ 2-chloro-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid ethyl ester;
{ 2-chloro-4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -phenyl } -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{ 2-chloro-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (4-isopropyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ (4-isopropyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-cyanophenyl } -carbamic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-cyanophenyl } -carbamic acid propyl ester;
{ 2-cyano-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (4-isopropylbenzyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
[ 2-iodo-4- (4-isopropyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[4- (4-tert-butyl-benzylamino) -2-iodophenyl ] -carbamic acid propyl ester;
[ 2-iodo-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[ 2-iodo-4- (4-methylsulfanyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
{ 2-iodo-4- [4- (4-methylpiperazin-1-yl) -benzylamino ] -phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
[4- (4-tert-butyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid ethyl ester;
[4- (4-methylsulfanyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
[4- (4-isopropylbenzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
[4- (4-tert-butyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
[ 2-trifluoromethyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[4- (4-dimethylamino-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
[4- (4-methylsulfanyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid propyl ester;
[ 2-cyano-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
[ 2-bromo-4- (4-isopropylbenzylamino) -phenyl ] -carbamic acid propyl ester;
[ 2-bromo-4- (4-tert-butyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[ 2-bromo-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[ 2-bromo-4- (4-methylsulfanyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
N- {4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -butyramide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -butyramide;
n- [4- (4-isopropylbenzylamino) -2-methoxyphenyl ] -butyramide;
n- [4- (4-tert-butyl-benzylamino) -2-methoxyphenyl ] -butyramide;
n- [ 2-methoxy-4- (4-trifluoromethyl-benzylamino) -phenyl ] -butyramide;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-furan-2-yl-phenyl } -carbamic acid propyl ester;
[ 2-furan-2-yl-4- (4-isopropylbenzylamino) -phenyl ] -carbamic acid propyl ester;
[5- (4-fluorobenzylamino) -biphenyl-2-yl ] -carbamic acid propyl ester;
{5- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -biphenyl-2-yl } -carbamic acid propyl ester;
[5- (4-isopropylbenzylamino) -biphenyl-2-yl ] -carbamic acid propyl ester;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2-phenylacetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3, 3-dimethylbutanamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3-phenylpropanamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -butyramide;
Pentanoic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
cyclopropanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
cyclobutanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
cyclopentanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
cyclohexanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino-phenyl } -amide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2-thiophen-2-yl-acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (3-methoxy-phenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-chloro-phenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-methoxy-phenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-fluoro-phenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3-cyclohexylpropionamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2, 2-dimethylpropionamide;
N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-phenoxyacetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-phenylacetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -3, 3-dimethylbutanamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -butyramide;
pentanoic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
cyclopropanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
cyclopropanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
cyclopentanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl) -amide;
cyclohexanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-thiophen-2-yl-acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (3-methoxyphenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-chlorophenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-methoxyphenyl) -acetamide;
N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-fluorophenyl) -acetamide;
2, 3-dihydro-benzo [1, 4] dioxine-6-carboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
2, 3-dihydro-benzofuran-5-carboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] phenyl } -amide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -3-cyclohexylpropionamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -2, 2-dimethylpropionamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -2-phenylacetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -3, 3-dimethylbutanamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -3-phenylpropanamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -butyramide;
2, 2, 2-trichloro-N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -acetamide;
cyclopropanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -amide;
cyclobutanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -amide;
Cyclopentanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -amide;
cyclohexanecarboxylic acid [4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl) -amide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2-thiophen-2-yl-acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2- (3-methoxyphenyl) -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -malonamic acid methyl ester;
2- (4-chlorophenyl) -N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2- (4-methoxyphenyl) -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2- (4-fluorophenyl) -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -3-cyclohexylpropionamide;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid phenyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid benzyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid isobutyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid butyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid hexyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 4-nitrobenzyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid but-3-enyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid but-2-ynyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 2, 2-dimethylpropyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 2-chlorobenzyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 3-chloropropyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 2-benzyloxyethyl ester;
3- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -1-methyl-1-propyl-urea;
1- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3- (2-fluorophenyl) -urea;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2, 2, 2-trifluoroacetamide;
N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2, 2, 2-trifluoroacetamide;
n- {5- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -4' -dimethylamino-biphenyl-2-yl } -2- (4-fluorophenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methylamino ] -phenyl } -2- (4-chlorophenyl) -acetamide;
[4- (3-fluoro-4-trifluoromethyl-benzylamino) -2-methylphenyl ] -carbamic acid ethyl ester;
2- (4-fluorophenyl) -N- { 2-methyl-4- [ (6-p-tolyloxypyridin-3-ylmethyl) -amino ] -phenyl } -acetamide;
n- { 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -butyramide;
2- (4-fluorophenyl) -N- { 2-methyl-4- [ (6-trifluoromethylpyridin-3-ylmethyl) -amino ] -phenyl } -acetamide;
pentanoic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -amide;
3, 3-dimethyl-N- { 2-methyl-4- [ (6-p-tolyloxypyridin-3-ylmethyl) -amino ] -phenyl } -butyramide;
[ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid ethyl ester;
n- (2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-chlorophenyl) -propionamide;
[4- (4-chloro-benzylamino) -2-methylphenyl ] -carbamic acid ethyl ester;
{4- [ (6-methoxy-benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-quinolin-3-yl-phenyl } -carbamic acid ethyl ester;
{4- [ (5-dimethylamino-3-methyl-benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } 2-carbamic acid propyl ester;
3, 3-dimethyl-N- { 2-methyl-4- [ (6-trifluoromethylpyridin-3-ylmethyl) -amino ] -phenyl } -butyramide;
n- (4- { [ 6-chloro- (4-cyanophenoxy) -pyridin-3-ylmethyl ] -amino } -2-methylphenyl) -2- (4-chlorophenyl) -acetamide;
{ 2-benzyloxy-4- [ (4-fluorobenzyl) - (methyl) amino ] -phenyl } -thiocarbamic acid S-ethyl ester;
{ 2-cycloalkoxy-4- [ (4-fluorobenzyl) - (methyl) amino ] -phenyl } -thiocarbamic acid S-ethyl ester;
n- {4- [ (6-chloropyridin-3-ylmethyl) -amino ] -2-methylphenyl } -2- (4-chlorophenyl) -acetamide;
{4- [ (7-dimethylamino-benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
1- { 2-cyclopentyloxy-4- [ (4-fluorobenzyl) - (methyl) amino ] -phenyl } -3-ethyl-urea;
2-amino-4-methyl-pentanoic acid [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -amide;
{4- [ (6-methoxy-benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid ethyl ester;
2-amino-4-methyl-pentanoic acid [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl-amide;
2- (4-fluorophenyl) -N- { 2-methyl-4- [ (4-methyl-2-phenylpyrimidin-5-ylmethyl) -amino ] -phenyl } -acetamide;
3, 3-dimethyl-N- { 2-methyl-4- [ (2-phenylpyrimidin-5-ylmethyl) -amino ] -phenyl } -butyramide;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-pyridin-3-yl-phenyl } -carbamic acid ethyl ester;
1-amino-cyclopropanecarboxylic acid [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl-amide;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-pyridin-4-yl-phenyl } -carbamic acid ethyl ester;
2-piperidin-1-yl-N- [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -acetamide;
n- (4- { [5- (4-chlorophenoxy) -1, 3-dimethyl-1H-pyrazol-4-ylmethyl ] -amino } -2-methylphenyl) -2, 2-dimethylpropionamide;
2, 2-dimethyl-N- { 2-methyl-4- [ (6-phenoxypyridin-3-ylmethyl) -amino ] -phenyl } -propionamide;
n- [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -2-pyrrolidin-1-yl-acetamide;
[4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2- (6-methoxypyridin-3-yl) -phenyl ] -carbamic acid ethyl ester;
4- [ (3-methyl-4-propoxycarbonylamino-phenylamino) -methyl ] -benzoic acid methyl ester;
2-morpholin-4-yl-N- [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -acetamide;
2, 2-dimethyl-N- { 2-methyl-4- [ (3-methyl-5-phenylisoxazol-4-ylmethyl) -amino ] -phenyl } -propionamide;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-iodophenyl } -carbamic acid ethyl ester;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-iodophenyl } -2- (4-fluorophenyl) -acetamide; and
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-quinolin-5-yl-phenyl } -carbamic acid ethyl ester.
According to one embodiment, the invention relates to a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents and wherein s, q, U, X, Z, Y, R1、R2And R3A, b, c, d, e, f, g, h, s, q, U, X, Z, Y, W, R are as defined above1、R2、R3、R5、R6、R6′、R7、R7′、R8、R9、R9′、R10、R10′、R11、R12And R12′A compound of formula I or a salt thereof, any one of which has the meaning as defined under formula I, respectively. Thus, the pharmaceutical composition of the invention may comprise one or more compounds of formula I or salts thereof, such as one compound of formula I or salt thereof; or two compounds of formula I or salts thereof; or threeA compound of formula I or a salt thereof.
According to one embodiment, the invention relates to a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents and wherein f, s, q, U, X, Z, R1、R2、R3And R5Is as defined above, f, s, q, U, X, Z, R 1、R2、R3、R5、R6、R6′、R7、R7′、R8、R9、R9′、R10、R10′、R11、R12And R12′Of formula XXIX accordingly has the meaning defined under formula XXIX. Thus, the pharmaceutical composition of the invention may comprise one or more compounds of formula XXIX or a salt thereof, such as a compound of formula XXIX or a salt thereof; or two compounds of formula XXIX or a salt thereof; or three compounds of formula XXIX or salts thereof.
According to one embodiment, the invention relates to a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents and wherein g, h, s, q, U, X, Z, R1、R2、R3And R5Is as defined above, g, h, s, q, U, X, Z, R1、R2、R3、R5、R6、R6′、R7、R7′、R8、R9、R9′、R10、R10′、R11、R12And R12′A compound of formula XXX, having the meanings as defined under formula XXX, respectively. Thus, the pharmaceutical compositions of the invention may comprise one or more compounds of formula XXX or salts thereof, such as a compound of formula XXX or a salt thereof; or two compounds of formula XXX or salts thereof; or three compounds of formula XXX or salts thereof.
According to one embodiment, the invention relates to a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents and wherein a, s, q, U, W, X, Z, R1、R2、R3And R5A, s, q, U, W, X, Z, R are as defined above 1、R2、R3、R5、R6、R6′、R7、R7′、R8、R9、R9′、R10、R10′、R11、R12And R12′A compound of formula XXXI, any of which has the meaning as defined under formula XXXI, respectively. Thus, the pharmaceutical compositions of the invention may comprise one or more compounds of formula XXXI or salts thereof, such as a compound of formula XXXI or salt thereof; or two compounds of formula XXXI or salts thereof; or three compounds of formula XXXI or salts thereof.
According to one embodiment, the invention relates to a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents and wherein b, c, s, q, U, W, X, Z, R1、R2、R3And R5B, c, s, q, U, W, X, Z, R are as defined above1、R2、R3、R5、R6、R6′、R7、R7′、R8、R9、R9′、R10、R10′、R11、R12And R12′A pharmaceutical composition of formula XXXII, wherein any of (a) is accordingly defined as under formula XXXII. Thus, the pharmaceutical compositions of the invention may comprise one or more compounds of formula XXXII or salts thereof, such as a compound of formula XXXII or salt thereof; or two compounds of formula XXXII or salts thereof; or three compounds of formula XXXII or salts thereof.
According to one embodiment, the invention relates to a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents and wherein d, e, s, q, U, W, X, Z, R1、R2、R3And R5D, e, s, q, U, W, X, Z, R are as defined above 1、R2、R3、R5、R6、R6、R7、R7、R8、R9、R9′、R10、R10′、R11、R12And R12′A compound of formula XXXIII, having the meanings defined under formula XXXIII, respectively. Thus, a pharmaceutical composition of the invention may comprise one or more compounds of formula XXXIII or salts thereof, such as a compound of formula XXXIII or salt thereof; or two compounds of formula XXXIII or salts thereof; or three compounds of formula XXXIII or salts thereof.
Accordingly, the present invention provides a pharmaceutical composition for oral or parenteral administration, said pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I or XXIX or XXX or XXXI or XXXII or XXXIII or a salt thereof and one or more pharmaceutically acceptable carriers or diluents.
In one aspect, the compounds of the present invention may be administered as the only therapeutically effective compound.
In another aspect, the compounds of the invention may be administered as part of a combination therapy, i.e., the compounds of the invention may be administered in combination with other therapeutically effective compounds having, for example, anti-convulsant properties. The effects of such other anti-convulsant compounds may include, without limitation, the effects of:
● ion channels such as sodium, potassium, or calcium channels
O excitatory amino acid systems, e.g. blocking or modulating NMDA receptors
● inhibitory neurotransmitter systems, for example, enhance GABA release, or block GABA-absorption or
Membrane stabilization.
Current anti-convulsants include, without limitation, tiagabine, carbamazepine, sodium valproate, lamotrigine, gabapentin, pregabalin, ethosuximide, levetiracetam, phenytoin, topiramate, zonisamide, and members of the benzodiazepine and barbiturates classes.
In one aspect, the compounds of the invention have been found to have an effect on potassium channels of the KCNQ family, in particular the KCNQ2 subunit.
In one embodiment, the invention relates to the use of one or more compounds of the invention in a method of treatment. The condition or disorder prevented, treated or inhibited is one or more conditions or disorders responsive to an increase in the ion flow of potassium channels of the KCNQ group of potassium channels. Such disorders or conditions are preferably disorders or conditions of the central nervous system.
It is believed that the compounds of the invention are useful for increasing ion flux in voltage-dependent potassium channels in mammals such as humans.
The compounds of the invention are believed to be useful in the prevention, treatment, or inhibition of disorders or conditions that respond to an increase in the ion flux of potassium channels, such as KCNQ group potassium channels. Such disorders or conditions are preferably disorders or conditions of the central nervous system.
Accordingly, the compounds of the present invention are believed to be useful in the prevention, treatment, or inhibition of conditions or diseases such as seizure disorders, neuropathic pain and migraine headache disorders, anxiety disorders, and neurodegenerative disorders.
Accordingly, the compounds of the present invention are believed to be useful in the prevention, treatment, or inhibition of disorders or conditions such as convulsions, epilepsy, anxiety disorders, neuropathic pain, and neurodegenerative disorders.
Thus, according to a particular embodiment, the compounds of the present invention are believed to be useful in the prevention, treatment or inhibition of seizure disorders such as convulsions, epilepsy and status epilepticus.
In one embodiment, the compounds of the present invention are believed to be useful in the prevention, treatment and suppression of convulsions.
In another embodiment, the compounds of the present invention are believed to be useful in the prevention, treatment and inhibition of epilepsy, epilepsy and epileptic seizures.
In another embodiment, the compounds of the present invention are believed to be useful in the prevention, treatment and inhibition of anxiety disorders such as anxiety and panic attack related conditions and diseases, agoraphobia related panic disorder, agoraphobia unrelated panic disorder, agoraphobia without history of panic disorder, specific phobias, social phobias and other specific phobias, obsessive compulsive disorders, post-traumatic stress disorders, acute stress disorders, generalized anxiety disorders, anxiety disorders due to general medical conditions, substance-induced anxiety disorders, dissociative anxiety disorders, adaptive disorders, behavioral anxiety disorders, hypochondriac disorders, anxiety disorders due to general medical conditions, and substance-induced anxiety disorders and anxiety disorders not specifically identified.
In another embodiment, the compounds of the present invention are believed to be useful in the prevention, treatment and inhibition of neuropathic pain and migraine pain conditions such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy and neuropathic (neupathic) pain associated with migraine.
In another embodiment, the compounds of the present invention are believed to be useful in the prevention, treatment, and inhibition of neurodegenerative disorders such as alzheimer's disease; huntington's chorea; multiple sclerosis; amyotrophic lateral sclerosis; Creutzfeld-Jakob disease; parkinson's disease; AIDS or encephalopathy induced by infection with rubella virus, herpes virus, Borrelia and unknown pathogens; trauma-induced neurodegeneration; neuronal hyperexcitability states such as in drug withdrawal or intoxication; and neurodegenerative diseases of the peripheral nervous system such as polyneuropathy and polyneuritis (polyneuritides).
In another embodiment, the compounds of the present invention are believed to be useful in the prevention, treatment, and inhibition of neurodegenerative disorders such as alzheimer's disease; huntington's chorea; multiple sclerosis; amyotrophic lateral sclerosis; Creutzfeld-Jakob disease; parkinson's disease; AIDS or rubella virus, herpes virus, Borrelia and unknown pathogen infection-induced encephalopathy; and wound-induced neurodegeneration.
In another embodiment, the compounds of the invention are believed to be useful in the prevention, treatment and inhibition of states of neuronal hyperexcitability states such as drug withdrawal or intoxication.
The present invention provides compounds which exhibit an effect in one or more of the following assays:
● "relative outward flow through KCNQ2 channel"
Which is a measure of the efficacy of a compound on a target channel
● "maximal electroshock"
It is a measure of seizure induced by electrical means through non-specific CNS stimulation
● "pilocarpine-induced seizures"
Pilocarpine-induced seizures are often difficult to treat with many existing anti-seizure drugs and thus reflect a "drug-resistant seizure" model
● "Electrical seizure-threshold test" and "chemical seizure-threshold test"
These models measure the threshold at which seizures begin, and are therefore models of whether detecting these compounds will delay the onset of seizures.
'tonsil excitation'
Using this as a measure of disease progression, seizures in this model are more severe when the animals are further stimulated compared to normal animals.
According to a particular aspect of the invention, the compounds have KCNQ2 activity, with an EC of less than 15000nM, such as less than 10000nM, when measured using the "relative outward flux through KCNQ2 channel" assay described below50。
According to a particular aspect of the invention, the compounds have KCNQ2 activity, in the followingSaid "relative outward flux through KCNQ2 channel" assay having an EC of less than 2000nM, e.g., less than 1500nM50。
According to another particular aspect of the invention, the compounds have KCNQ2 activity, with an EC of less than 200nM, such as less than 150nM, as measured in the "relative outward flux through KCNQ2 channel" assay described below50。
According to another particular aspect of the invention, these compounds have an ED of less than 15mg/kg in the "maximal electroshock" test described below50。
According to another particular embodiment of the invention, these compounds have an ED of less than 5mg/kg in the "maximal electroshock" test described below50。
According to a particular aspect of the invention, these compounds have an ED of less than 5mg/kg in the "electrical seizure-threshold test" and "chemical seizure-threshold test" described below 50。
Some compounds have little or no clinical side effects. Thus, some compounds were tested in a model of the undesirable sedative, hypothermic, and ataxic effects of the compound.
Some compounds have anticonvulsant efficacy and a high therapeutic index between side effects such as impaired locomotor activity or ataxia effects such as those exhibited by behavioral measurements on rotating rods. This means that it is expected that these compounds will be well tolerated by patients, so that high doses can be used before side effects are observed. Thus, it is expected that good compliance with this treatment and allowing high dose administration allows more effective treatment of patients who would have side effects using other drugs.
Definition of
The term heteroatom refers to a nitrogen, oxygen or sulfur atom.
Halogen means fluorine, chlorine, bromine or iodine.
C1-6Alk (en/yn) yl and C1-6The expression- (alk/alkenyl/alkynyl) yl means C1-6Alkyl radical, C2-6-alkenyl or C2-6-alkynyl.
Term C1-6Alkyl refers to a branched or unbranched alkyl group having from 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
Likewise, C2-6Alkenyl and C2-6Alkynyl is each specified as such a group having from 2 to 6 carbon atoms and comprising one double bond and one triple bond, including without limitation ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
C1-3The expression alk (en/yn) yl means C1-3Alkyl radical, C2-3-alkenyl or C2-3-alkynyl.
Term C1-3Alkyl refers to a branched or unbranched alkyl group having from 1 to 3 carbon atoms, including, without limitation, methyl, ethyl, 1-propyl and 2-propyl.
Likewise, C2-3Alkenyl and C2-3Alkynyl refers to such groups having 2 to 3 carbon atoms, respectively, including one double bond and one triple bond, respectively, including without limitation ethenyl, propenyl, ethynyl and propynyl.
C3-8Cycloalkane (alkenyl) group and C3-8The expression cyclo (alk/en) yl means C3-8-cycloalkyl-or cycloalkenyl.
Term C3-8Cycloalkyl refers to a monocyclic or bicyclic carbocyclic ring having 3 to 8C-atoms, including without limitation cyclopropyl, cyclopentyl, cyclohexyl and the like.
C3-6Cycloalkane (alkenyl) group and C3-6Expression of (alk/en) ylRefers to C3-6-cycloalkyl-or cycloalkenyl.
Term C3-6Cycloalkyl refers to a monocyclic or bicyclic carbocyclic ring having 3 to 6C-atoms, including without limitation cyclopropyl, cyclopentyl, cyclohexyl and the like.
Term C3-8Cycloalkenyl refers to a monocyclic or bicyclic carbocyclic ring having 3 to 8C-atoms and comprising one double bond.
The term heterocycloalkyl (alkenyl) group refers to a monocyclic or bicyclic ring system wherein said ring is a ring formed by 5 to 8 atoms selected from carbon atoms and heteroatoms; provided that one or both of said ring-forming atoms are independently selected heteroatoms. Thus, the term heterocycloalkyl (alkenyl) group may refer to a monocyclic or bicyclic ring system wherein said ring is a ring formed by 5 to 8 atoms selected from 3 to 7 carbon atoms and 1 or 2 heteroatoms selected from N, S, or O. Examples of such ring systems are morpholine, pyrrolidine, piperidine and piperazine.
The term halo-C1-6Alk (en/yn) yl means C substituted by one or more halogen atoms1-6-alk (en/yn) yl including, but not limited to, trifluoromethyl. Likewise, halo-C3-8Cycloalkyl (alkenyl) refers to C substituted by one or more halogen atoms3-8-cycloalk (en) yl, halo-heterocycloalk (en) yl refers to heterocycloalk (en) yl substituted with one or more halogen atoms.
The term NR10R10′-C1-6Alk (en/yn) yl radicals being referred to by NR10R10′Substituted C1-6-alk (en/yn) yl; NR (nitrogen to noise ratio)12R12′-C1-6Alk (en/yn) yl radicals being referred to by NR 12R12′Substituted C1-6-alk (en/yn) yl; and NR7R7′-C1-6Alk (en/yn) yl radicals being referred to by NR7R7′Substituted C1-6-alk (en/yn) yl. 2-amino-4-methyl-pentane is an example of such a group, which is not intended to be limiting.
The term NR10R10′-C3-8Cycloalkyl (alkenyl) radicals being defined by NR10R10′Substituted C3-8-a cycloalk (en) yl group; NR (nitrogen to noise ratio)12R12′-C3-8Cycloalkyl (alkenyl) radicals being defined by NR12R12′Substituted C3-8-a cycloalk (en) yl group; and NR7R7′-C3-8Cycloalkyl (alkenyl) radicals being defined by NR7R7′Substituted C3-8-a cycloalk (en) yl group. 1-amino-cyclopropane is an example of such a group, which is not intended to be limiting.
The term NR10R10′-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl radicals being referred to by NR10R10′Substituted C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl; NR (nitrogen to noise ratio)12R12′-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl radicals being referred to by NR12R12′Substituted C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl; and NR7R7′-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl radicals being referred to by NR7R7′Substituted C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl.
When NR is12R12′-C1-6Alk (en/yn) yl, NR12R12′-C3-8Cycloalkane (alkenyl) yl radical, NR12R12′-C3-8-cycloalk (en) yl-C1-6When any of the alk (en/yn) yl groups is optionally substituted, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C 3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl optionally substituted by one or more substituents independently selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl or Ar.
The term acyl as used herein refers to formyl, C1-6Alk (en/yn) ylcarbonyl, C3-8Cycloalkyl (alkenyl) carbonyl, Ar-C1-6Alk (en/yn) ylcarbonyl or C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl-carbonyl, wherein C1-6Alk (en/yn) yl, C3-8Cycloalkyl (alkenyl) and Ar are as defined above.
When two substituents form together with the nitrogen atom a 5-to 8-membered saturated or unsaturated ring optionally containing one further heteroatom, then a monocyclic ring system is formed of 5 to 8 atoms, one or both of said atoms being a heteroatom selected from N, S, or S. Examples of such ring systems are pyrrolidine, piperidine, piperazine, morpholine, pyrrole, oxazolidine, thiazolidine, imidazolidine, azetidine, beta-lactam, tetrazole and pyrazole.
When two adjacent substituents and the aromatic group to which they are attached together form a 5-8 membered ring optionally containing one or two additional heteroatoms, then the ring is formed from 5-8 atoms selected from 3-8 carbon atoms and 0-2 heteroatoms selected from N, S, or O and. Such two adjacent substituents may together form: - (CH) 2)-CH2-、-CH＝CH-(CH2)m″-、-CH2-CH＝CH-(CH2)p″、-CH＝CH-CH＝CH-、-(CH2)n″-O-、-O-(CH2)m″-O-、-CH2-O-(CH2)p″-O-、-CH2-O-CH2-O-CH2-、-(CH2)n″-S-、-S-(CH2)m″-S-、-CH2-S-(CH2)p″-S-、-CH2-S-CH2-S-CH2-、-(CH2)n″-NH-、-NH-(CH2)m″-NH-、-CH2-NH-(CH2)n″-NH-、-CH＝CH-NH-、-O-(CH2)m″-NH-、-CH2-O-(CH2)p′-NH-or-O- (CH)2)p″-NH-CH2-、-S-(CH2)m″-NH-, -N ═ CH-NH-, -N-CH-O-, or-N-CH-S-, wherein m "is 1, 2 or 3, N" is 2, 3 or 4 and p "is 1 or 2.
The term Ar refers to an optionally substituted aromatic system of 5 to 10 carbon atoms in which 0, 1, 2, 3 or 4 carbon atoms may be replaced by a heteroatom independently selected from N, S, or O. Examples of such Ar groups are optionally substituted phenyl, optionally substituted naphthyl (naptyl), optionally substituted quinoline, optionally substituted indole, optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted thiophene, optionally substituted furan, optionally substituted thiazole and optionally substituted oxazole. Such optionally substituted Ar groups may be substituted with one or more substituents independently selected from hydroxy, halogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) oxy, C3-8-alk (en/yn) oxy, acyl, nitro, cyano, -CO-NH-C1-6-alk (en/yn) yl, -CO-N (C)1-6Alk (en/yn) yl)2、-NH2、-NH-C1-6Alk (en/yn) yl, N (C)1-6Alk (en/yn) yl)2、S-C1-6-alk (en/yn) yl, -SO 2N(C1-6Alk (en/yn) yl)2and-SO2NH-C1-6Alk (en/yn) yl, SO2-C1-6Alk (en/yn) yl and SO2O-C1-6-alk (en/yn) yl; or two adjacent substituents may form together with the aromatic group a 5-8 membered ring optionally containing one or two heteroatoms and which may be saturated or unsaturated.
Term C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkenyl) group, C1-6Alk (en/yn) yl heterocycloalkyl (en), Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkyl (alkenyl) group, Ar-heterocycloalkyl (alkenyl) group, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, Ar-C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, C1-6Alk (en/yn) oxy, C2-6-alkenyloxy, C2-6-alkynyloxy, C3-8Cycloalk (alk) oxy, C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C3-8-cycloalk (en) oxy-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) oxy-C3-8Cycloalkane (alkenyl) group, C1-6-alk (en/yn) oxy-heterocycloalkyl (en) yl, Ar oxy-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) ylcarbonyl, C 3-8Alk (en) ylcarbonyl, Ar-carbonyl, Ar-C1-6Alk (en) ylcarbonyl, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) ylcarbonyl, -CO-C1-6Alk (en/yn) yl, S-C1-6Alk (en/yn) yl, SO2-C1-6Alk (en/yn) yl and SO2O-C1-6Alk (en/yn) yl, C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, C3-8-cycloalkane (alkene) oxy-carbonyl-C1-6Alk (en/yn) yl, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, acyl-C1-6Alk (en/yn) yl, acyl-C3-8Alk (en) yl, acyl-heterocycloalkyl (en) yl, acyl-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) radical, acyl-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8-cycloalkane (alkenyl) yl, hydroxy-heterocycloalkane (alkenyl) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6-cycloalkanes(alk/yn) yl, hydroxy-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, hydroxy-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8-cycloalk (en) yl, halo-heterocycloalk (en) yl, halo-C3-8-cycloalk (en) yl-C 1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, halo-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, halo-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, halo-C1-6Alk (en/yn) yl-Ar, halo-C3-8Cycloalk (en) yl-Ar, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl-Ar, halo-C1-6Alk (en/yn) yl-C3-8-cycloalk (en) yl-Ar, halo-heterocycloalk (en) yl-Ar, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) yl, cyano-heterocycloalkyl (alkenyl) yl, cyano-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) group, cyano-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl and the like refer to wherein C1-6Alk (en/yn) yl, C2-6-alkenyl, C2-6-alkynyl, C3-8Cycloalkyl (alkenyl) group, heterocycloalkyl (alkenyl) group, Ar, cyano, halo-C1-6Alk (en/yn) yl, halo-C3-8-cyanoalk (en) yl, halo-heterocycloalkalk (en) yl and acyl groups as defined above.
The salts of the present invention are preferably pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts.
The pharmaceutically acceptable salts of the present invention are preferably acid addition salts. The acid addition salts of the present invention are preferably pharmaceutically acceptable salts of the compounds of the present invention with non-toxic acids. Acid addition salts include salts of inorganic acids as well as organic acids.
Typical examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric, and nitric acids, and the like. Such acid addition salts may be formed by methods well known to those skilled in the art. Additional examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in j.pharm.sci.1977, 66, 2, which is incorporated herein by reference.
Typical examples of suitable organic acids include acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, gluconic acid, furoic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, di-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, itaconic acid, benzenesulfonic acid, p-toluenesulfonic acid, theophylline acetic acid, and 8-halotheophyllines, such as 8-bromotheophylline and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in j.pharm.sci.1977, 66, 2, which is incorporated herein by reference.
Examples of metal salts include lithium, sodium, potassium, magnesium salts, and the like.
Examples of ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts, and the like.
In the case of pharmaceutically acceptable acid addition salts, there are also hydrates which the compounds of the invention are able to form.
The compounds of the present invention may have one or more asymmetric centers and, when isolated, any optical isomer, pure or partially purified optical isomer, or racemic mixture thereof is included within the scope of the present invention.
Furthermore, geometric isomers may be formed when a double bond or a fully or partially saturated ring system is present in the molecule. In isolation, any geometric isomer, pure or partially purified geometric isomer or mixtures thereof are included within the scope of the present invention. Likewise, molecules with rotationally constrained bonds may form geometric isomers. Which are also included in the scope of the present invention.
Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and any tautomeric form which these compounds can form is also included within the scope of the present invention.
The compounds of the present invention may exist in unsolvated forms as well as solvated forms with solvents such as water, ethanol, and the like. The solvated forms are generally considered equivalent to unsolvated forms for the purposes of the present invention.
Some of the compounds of the present invention contain a chiral center and such compounds exist in isomeric (i.e., enantiomeric) forms. The present invention includes all such isomers and any mixtures thereof including racemic mixtures.
The resolution of the racemic form can be carried out in a known manner, for example by separation of the diastereomeric salts thereof with an optically active acid and treatment with a base to liberate the optically active amine compound. Another method for resolving racemates into optical enantiomers is based on chromatography using optically active matrices. For example, fractional crystallization of the d-or 1- (tartrate, mandelate or camphorsulfonate) salt may also be used to resolve racemic compounds of the present invention into their optical isomers. The compounds of the invention may also be resolved by formation of diastereomeric derivatives.
Additional methods of resolving optical isomers may be used as known to those skilled in the art. Such methods include those discussed by j.jaques, a.collet and s.wilen in "Enantiomers, Racemates, and resolution (enertiomers, Racemates, and Resolutiohs)", John Wiley and Sons, new york (1981).
These optically active compounds can also be prepared from optically active starting materials.
The invention also includes prodrugs of the compounds of the invention which, upon administration, undergo chemical transformation by metabolic processes and then become pharmacologically active substances. Such prodrugs are generally functional derivatives of compounds of formula I, XXIX, XXX, XXXI, XXXII or XXXIII which can be readily converted in vivo into compounds of formula I, XXIX, XXX, XXXI, XXXII or XXXIII. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "prodrug Design (Design of produgs)", h.
The invention also includes active metabolites of the compounds of the invention.
Whenever, in reference to compounds of formula I, XXIX, XXX, XXXI, XXXII or XXXIII, the terms epilepsy (epilesys and epilepsies) are included in international league Against epilesys: clinical correction protocol and electroencephalography Classification of seizures (clinical for reviewed clinical and electronopharmagraphic Classification of diseases), communication on Classification and timing of the International League agaimnst epiilepsy 198122: 489-: epilepsy and epilepsy Classification correction scheme (Propusal for review Classification of epileptics and epileptic syndromes), Commission on Classification and Terminology of the International League age of Epilepsy. Epilepsia193930 (4): 389-399 is called any one of epilepsy, epilepsy and epileptic seizures.
Whenever reference is made to compounds of formula I, XXIX, XXX, XXXI, XXXII or XXXIII, the term anxiety disorder includes the diagnostic and statistical manuals (diagnostic and statistical manual of analytical disorders) referred to as panic attack, agoraphobia, panic disorder associated with agoraphobia, panic disorder not associated with agoraphobia, agoraphobia without history of panic disorder, specific phobias, social phobias, obsessive-compulsive disorders, post-traumatic stress disorders, acute stress disorders, generalized anxiety disorders, anxiety disorders due to general medical conditions, substance-induced anxiety disorders, dissociative anxiety disorders, adaptive disorders and american psychiatric Association disorders, 4 th edition, 1994: 110-, 393-, 444-and 623-627-defined conditions and diseases of anxiety disorders not specified.
Pharmaceutical composition
The compounds of the invention are generally used in the form of their free bases or pharmaceutically acceptable salts. Typical examples thereof are as described above.
If desired, the pharmaceutical compositions of the invention may comprise a compound of formula I and further pharmacologically active substances such as those mentioned above.
The compounds of the present invention may be administered alone or in combination with a pharmaceutically acceptable carrier or excipient in single or multiple doses. May be prepared according to conventional techniques such as those described in Remington: the pharmaceutical compositions of the present invention are formulated using conventional techniques disclosed in the science and Practice of Pharmacy, 19 Edition, Gennaro, ed., mack publishing co., Easton, PA, 1995, using pharmaceutically acceptable carriers or diluents and any other known adjuvants and excipients.
These pharmaceutical compositions may be prepared for administration by any suitable route, such as by oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes, with oral routes being preferred. It will be appreciated that the preferred route will depend upon the general condition and age of the individual being treated, the nature of the condition being treated and the active ingredient selected.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they may be prepared with coatings such as enteric coatings or they may be prepared by methods well known in the art to provide controlled, e.g. sustained or prolonged, release of the active ingredient.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous or non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use. Injectable depot formulations are also contemplated as being within the scope of the invention.
Other suitable forms of administration include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants and the like.
The pharmaceutical compositions of the invention or those prepared according to the invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups and the like, or parenterally in the form of injectable solutions. For the preparation of such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carrier, diluent, excipient or other additive commonly used in the art may be used.
A typical oral dose is a dose of about 0.001 to about 100mg/kg body weight administered in one or more doses, such as 1 to 3 doses, per day, preferably about 0.01 to about 50mg/kg body weight per day, and more preferably about 0.05 to about 10mg/kg body weight per day. The precise dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the individual being treated, the nature and severity of the condition being treated and any co-existing disease being treated and other factors which will be apparent to those skilled in the art.
The formulations may be presented in unit dosage form by methods well known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day, such as 1 to 3 times per day, may comprise 0.05 to about 1000mg, preferably about 0.1 to about 500mg, and more preferably about 0.5mg to about 200 mg.
For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typical doses are about half of those used for oral administration.
The compounds of the invention are generally used in the form of the free substances or their pharmaceutically acceptable salts. One example is a base addition salt of a compound having the utility of the free acid. When the compounds of the invention comprise a free acid, such salts may be prepared in conventional manner by treating a solution or suspension of the free acid of the compounds of the invention with a stoichiometric amount of a pharmaceutically acceptable base. Typical examples are as described above.
For parenteral administration, solutions of the novel compounds of the invention in sterile aqueous solutions, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be used. If necessary, such aqueous solutions can be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed can be readily obtained using standard techniques known to those skilled in the art.
Injectable solutions may be prepared by dissolving the active ingredient and possible additives in a portion of the injectable solvent, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling it in suitable ampoules or vials. Any suitable additive commonly used in the art may be added, such as isotonic agents, preservatives, antioxidants, and the like.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, agar, pectin, acacia, stearic acid and lower alkyl ethers of cellulose, corn starch, potato starch, talc (talcum), magnesium stearate, gelatin, lactose, gums and the like.
Any other auxiliary or additive commonly used for such purposes may be used, such as colorants, flavors, preservatives, and the like, provided that it is compatible with the active ingredient.
Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyethylene oxide and water. Likewise, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
The pharmaceutical compositions formed by combining the novel compounds of the present invention and a pharmaceutically acceptable carrier can then be readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods well known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include one or more suitable excipients. In addition, the preparations which can be obtained orally can also be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, oil-in-water or water-in-oil liquid emulsions.
If a solid carrier is used for oral administration, the preparation may be in the form of tablets, which are placed in a hard gelatin capsule in powder form, or pellets, or it may be in the form of lozenges or pastilles.
The amount of the solid carrier can vary over a wide range, but is generally from about 25mg to about 1 g.
If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or nonaqueous liquid suspension or solution.
If desired, the pharmaceutical compositions of the invention may comprise compounds of the formula I, XXIX, XXX, XXXII or XXXIII and further pharmacologically active substances such as those disclosed above.
Typical examples of formulations of the present invention are as follows:
1) tablets containing 5.0mg (calculated as free base) of a compound of the invention:
5.0mg of a compound of formula I, XXIX, XXX, XXXI, XXXII or XXXIII
Lactose 60mg
Corn starch 30mg
Hydroxypropyl cellulose 2.4mg
Microcrystalline cellulose 19.2mg
Type A croscarmellose sodium 2.4mg
Magnesium stearate 0.84mg
2) Tablets containing 0.5mg (calculated as free base) of a compound of the invention:
0.5mg of a compound of formula I, XXIX, XXX, XXXI, XXXII or XXXIII
Lactose 46.9mg
Corn starch 23.5mg
Povidone 1.8mg
Microcrystalline cellulose 14.4mg
Type A croscarmellose sodium 1.8mg
Magnesium stearate 0.63mg
3) A syrup comprising per ml:
25mg of a compound of formula I, XXIX, XXX, XXXI, XXXII or XXXIII
Sorbitol 500mg
Hydroxypropyl cellulose 15mg
Glycerol 50mg
Nipagin methyl ester 1mg
Propyl p-hydroxybenzoate 0.1mg
0.005mL of ethanol
0.05mg of flavoring agent
Saccharin sodium 0.5mg
Water to 1mL
4) An injectable solution comprising per ml:
0.5mg of a compound of formula I, XXIX, XXX, XXXI, XXXII or XXXIII
Sorbitol 5.1mg
Acetic acid 0.05mg
Saccharin sodium 0.5mg
Water to 1mL
Preparation of the Compounds of the invention
Wherein a, b, c, d, e, f, g, h, s, q, U, W, X, Z, R1、R2、R3、R5、R6、R6′、R7、R7′、R8、R9、R9′、R10、R10′、R11、R12And R 12′The compounds of the general formula I according to the invention as defined under formula I can be prepared by the methods described below and as shown in the scheme.
The substituted 4-nitroanilines of the formulae IX or XI are commercially available, described in the literature or can be prepared according to methods known to the person skilled in the art. s is 0 and R2Compounds of the formula IX or XI which are substituted aryl or substituted heteroaryl as defined above, such as furyl, thienyl, phenyl, pyridyl, may be represented in particular by R2Corresponding compounds being I or Br using state of the art chemistryCross-linking-coupling reactions known to the skilled worker, such as Suzuki coupling, Stille coupling or other transition metal-catalyzed cross-linking-coupling reactions [ D.W.Knight, "coupling reactions between sp2 carbon centers", Comprehensive organic Synthesis, 3 rd edition, page 481, 520 th edition, Pergamon Press 1991]To prepare the compound. Alternatively, 4-nitroanilines of the formulae IX or XI can be prepared from the corresponding 2-substituted anilines in protected or unprotected form by nitration, as is known to the skilled worker, by means of the methods known to the skilled chemist [ R.Behnisch, "aromatic Nitro-Verbindungen", Methoden der Organische Chemie/(Houben-Weyl), p.255, v.E16d, Thieme: 1992 ]To prepare the compound. This method is particularly useful where U is S, SO2Or SO2NR11A compound of formula IX or XI. Compounds of the formulae IX or XI in which U is S can also be converted by oxidation into compounds in which U is SO according to methods known to the skilled chemist2By using 3-chloroperoxybenzoic acid or NaIO4In the presence of RuCl as catalyst3In the case of (3), oxidation is carried out.
The compounds of the formula XI can also be prepared from compounds of the formula IX by reacting the compounds of the formula XI with the compounds of the formula IX to form R3-(Z)qSuitable electrophiles of the group X, such as, without limitation, alkyl, aryl, or heteroaryl chloroformates or carbamoyl chlorides, carbonic anhydrides, acid fluorides, acid chlorides, acid bromides, acid iodides, active esters, active carbonic acids with activating reagents such as carbodiimides, sulfonyl chlorides, or isocyanates in suitable solvents such as acetonitrile, tetrahydrofuran, 1, 2-dichloroethane, or dichloromethane, with or without the addition of bases such as magnesium oxide, potassium carbonate, sodium hydride, trialkylamines, purified sodium-or potassium, sodium or potassium carbonate, sodium or potassium bicarbonate, or pyridine, at suitable temperatures such as room temperature or reflux, obtained by conventional heating or under minimal radiation, reactions well known to some of the skilled chemists.
In addition, for R2In another variation, the compounds of formula (I) wherein R is a hydrogen atom, may be prepared by methods well known to those skilled in the art2Is methyl, U is oxygen, and s is1, such as by treatment with boron tribromide in a suitable solvent, such as dichloromethane, at a suitable temperature, such as 0 ℃ or room temperature. The phenol obtained is then converted into a compound of the formula XI in which U is oxygen and s is 1, by methods known to the skilled chemist. The method comprises the following steps: (a) reacting an electrophile, such as alkyl chloride, alkyl bromide, alkyl iodide, benzyl chloride, carbonic acid bromide, or carbonic anhydride, in the presence of a suitable base, such as potassium carbonate, in a suitable solvent, such as tetrahydrofuran, N-dimethylformamide, or 1, 2-dichloroethane, at a suitable temperature, such as room temperature or reflux temperature; (b) alkyl, benzyl, or heteroarylalkyl alcohols are reacted under conditions known as the Mitsunobu reaction (o. mitsunobusynthesis 1981, 1).
The nitro group in the compound of formula XI can be reduced with a suitable reducing agent such as zinc or iron powder in the presence of an acid such as acetic acid or aqueous hydrochloric acid, or hydrogen or ammonium formate in the presence of a suitable hydrogenation catalyst such as palladium on activated carbon in a suitable solvent such as methanol, ethanol, or tetrahydrofuran at a suitable temperature or under ultrasonic irradiation to give the aniline of formula XII. Alternatively, tin (II) chloride or sodium dithionite may be used as a reducing agent under conditions well known to those of skill in the art.
The resulting aniline of formula XII is subjected to a reductive alkylation reaction well known to those skilled in the art using an aldehyde of formula YCHO, wherein Y is as defined above, in a suitable solvent such as methanol, ethanol, xylene, tetrahydrofuran, acetonitrile, or mixtures thereof at a suitable temperature to form an imine intermediate, which is reduced in situ or isolated by evaporation of the solvent or crystallization. Reducing it to form R wherein R is reduced with a reducing agent such as sodium borohydride or sodium cyanoborohydride in a suitable solvent such as ethanol, methanol or acetonitrile, with or without the addition of a catalytic amount of an acid such as acetic acid, at a suitable temperature1The compounds of the invention of formula I are hydrogen.
For R1In a variation of (a), the resulting compound wherein R is optionally subjected to a second reductive alkylation process with a suitable aldehyde and a reducing agent such as sodium cyanoborohydride as described above1The compounds of formula I which are hydrogen are further derivatized. This process may be carried out in situ after the first reductive alkylation reaction with an aldehyde of the general formula YCHO. Alternatively, it may be prepared by using a compound of formula R wherein LG is a suitable leaving group such as iodide, bromide, or sulfonate 1-electrophilic substitution of suitable electrophiles of LG to introduce R under conditions well known to the chemist in the art1。
For R3Z and X further variants, the compounds of the invention of the general formula I can be obtained in an alternative way: can be prepared by using a suitable Protecting Group (PG)1) [ Protective Groups in Organic Synthesis (Protective Synthesis), 3 rd edition, T.W.Greene, P.G.M.Wuts, Wiley Interscience 1999]Such as the trifluoroacetyl group, which is known to those skilled in the art as a TFA group, is prepared by protecting the aniline nitrogen of a substituted 4-nitroaniline of formula IX by reacting a protecting group-forming reagent such as trifluoroacetic anhydride in a suitable solvent such as 1, 2-dichloroethane at a suitable temperature.
The anilines of the general formula XIV can be obtained by nitro reduction as described above, which is well known to the person skilled in the art. This is then reductively alkylated with an aldehyde of formula YCHO as described above, to give the compound of formula XV.
Subjecting the compound of formula XV to a second reductive alkylation step as described above to obtain PG thereof1A compound of formula XVI which is TFA. The TFA group can then be removed by methods well known to those skilled in the art, such as hydrolysis with aqueous potassium carbonate in a suitable solvent such as methanol at a suitable temperature, to provide the compound of formula XVII.
Wherein R is1Compounds of the invention which are not hydrogen are prepared from anilines of the general formula XVII by the use ofTo R3-(Z)qSuitable electrophiles of the group X, such as alkyl, aryl or heteroaryl chloroformates or carbamoyl chlorides, acid bromides, acid iodides, sulfonyl chlorides, isocyanates, carbonic anhydrides, activated carbonic anhydrides, and activators such as carbodiimides or others known to those of skill in the art, are reacted in a suitable solvent such as acetonitrile, tetrahydrofuran, 1, 2-dichloroethane, or dichloromethane at a suitable temperature such as room temperature or reflux temperature with or without the addition of a base such as magnesium oxide, potassium carbonate, trialkylamines, or pyridine, or obtained by other methods as described above.
For R in the formula1For the compounds of the invention of the general formula I which are hydrogen, suitable Protecting Groups (PG) known to the skilled chemist are used2) [ protecting group in organic Synthesis, 3 rd edition, T.W.Greene, P.G.M.Wuts, Wiley Interscience 1999]Protecting the compound of formula XV to give a compound of formula XVIII. Wherein PG2Compounds of the general formula XVIII, which are tert-butylcarbonyl groups referred to as Boc groups by the person skilled in the art, can be reacted in particular with suitable reagents for forming protective groups, such as tert-butylcarbonic anhydride, in suitable solvents, such as acetonitrile, and at suitable temperatures, such as +80 ℃ to give PG therein 2Is Boc and is of general formula XVIII. The TFA protecting group (PG1) is then removed as described above to provide the compound of formula XIX, which is then used to form R as described above3-(Z)qDerivatizing it with a suitable electrophile of-X to give a compound of general formula XX.
Alternatively, compounds of formula XIX can be prepared from 4-nitroaniline using a three-step process as follows: reductive alkylation of a compound of formula XXXIV as described above will give a compound of formula XXXV which may then be protected with for example di-tert-butyl dicarbonate and dimethylaminopyridine in a suitable solvent such as tetrahydrofuran to give a compound of formula XXXVI which may then be protected with a suitable reducing agent such as Na as described above2S2O4Reducing it to a compound of formula XIX。
Finally, PG may be passed by methods well known to those of skill in the art2To obtain a compound of formula XX wherein R1The compounds of the invention of formula I are hydrogen. In particular, the Boc protecting group can be cleaved by methods known to those of skill in the art, such as deprotection with a suitable acid, e.g., trifluoroacetic acid, in the absence or presence of a solvent, e.g., dichloromethane or toluene, at a suitable temperature.
Alternatively, the compounds of formula I may be prepared by the following route:
wherein R is2Compounds of formula XXI, where U and s are as defined above, are commercially available or may be prepared by methods known to those of skill in the art. These methods include the reaction of 5-fluoro-2-nitrophenol under Mitsunobu-, alkylation-or acylation conditions as described above for the synthesis of compounds of formula XI from phenol. With Y-CH2-NH-R1Nucleophilic aromatic substitution of amines of the type-a reaction well known to those skilled in the art-gives compounds of the general formula XXII. Alternatively, compounds of formula XXII may be prepared by reductive alkylation of 4-nitroanilines of formula XXXIV as described above. Compounds of formula XXIII can be prepared by reduction of the nitro group under the conditions described above for the synthesis of compounds of formula XII. Formation of R from a compound of formula XXIII with a compound of formula XI as described above3-(Z)qThe reaction with a suitable electrophile of-X gives the compounds of the invention of the general formula I.
Or, s is 0 and R2Compounds of the formula I which are substituted aryl or substituted heteroaryl as defined above, such as furyl, thienyl, phenyl, pyridyl may be substituted by corresponding R 2The compounds that are I or Br are prepared by the above-described cross-linking-coupling reaction.
Examples
Analysis of LC-MS data (LC-MS ═ LC/MS) was obtained on a PE Sciex API 150EX instrument equipped with an APPI (atmospheric pressure photoionization) ion source and Shimadzu LC-8A/SLC-10A LC system. Column: 30X4.6mm Waters Symmetry C18 column with particle size of 3.5 μm; solvent system: a ═ water/trifluoroacetic acid (100: 0.05) and B ═ water/acetonitrile/trifluoroacetic acid (5: 95: 0.03); the method comprises the following steps: elution was performed with a linear gradient from 90% A to 100% B over 4 min at a flow rate of 2 mL/min. LC/MS-TOF (time-of-flight) data were obtained on a micro (micro) LCT 4-channel MUX equipped with a Waters 2488/Sedex 754 detection system. Column: a 30X4.6mm Waters Symmetry C18 column, for example, 3.5 μm; solvent system: a ═ water/trifluoroacetic acid (100: 0.05) and B ═ water/acetonitrile/trifluoroacetic acid (5: 95: 0.03); the method comprises the following steps: elution was performed with a linear gradient from 90% A to 100% B over 4 min at a flow rate of 2 mL/min. The measured separated ion value (M/z, where M is the molecular ion mass and z is the charge) is assigned as the molecular weight (M) of the optionally added or subtracted fragment consisting of the most abundant isotope. In the presence of [ M +3 ]+Or [ M +2 ]]+In the example of the assignment, the reported M/z value corresponds to the highest peak selected from a number of molecular ion peaks with different isotopic compositions and the molecular weight M is calculated based on the most abundant isotopic distribution. Purity was determined by integration of UV (254nm) and ELSD traces. Retention Time (RT) is expressed in minutes.
Preparation of LC-MS-purification was performed on the same PE Sciex API 150EX instrument. Column: 50X20mm YMC ODS-A, particle size 5 μm; the method comprises the following steps: elution was performed with a linear gradient from 80% A to 100% B over 7 min at a flow rate of 22.7 mL/min. Fractional collection was performed with split MS detection.
1H NMR spectra were recorded at 500.13MHz or 250.13MHz, on a Bruker Avance DRX500 or Bruker AC 250 instrument, respectively. Deuterated chloroform (99.8% D) or dimethylsulfoxide (99.8% D) was used as solvent. TMS was used as an internal reference standard. The chemical shift values are expressed in ppm-value units. The multiplicity of NMR signals is carried out by the following abbreviationsRepresents: s ═ singlet, d ═ doublet, t ═ triplet, q ═ quartet, qui ═ quintet, h ═ hexamet, dd ═ doublet, dt ═ doublet, dq ═ quartet, tt ═ triplet, m ═ multiplet and br.s ═ broad singlet, br.d ═ broad doublet, br.t ═ broad triplet.
Preparation of intermediates
N- (p-fluorobenzyl) -methylamine was synthesized according to the method described in g.m.singer and a.w.andrewsj.med.chem.1983, 26, 309. 2-iodo-4-nitroaniline was prepared according to the methods described in J.J.Pak, T.J.R.Weakly, and M.MHaley J.Amer.chem.Soc.19999121, 8182.
Preparation of intermediates of formula XI
(2-chloro-4-nitrophenyl) -carbamic acid ethyl ester.
A suspension of MgO (2.0g), 2-chloro-4-nitroaniline (3.768g, 21.83mmol) and ethyl chloroformate (5mL) in acetonitrile (25mL) was heated to reflux temperature for 4 hours, then more ethyl chloroformate (4mL) was added. Heating was continued until complete conversion (20 h) and the reaction mixture was then quenched with SiO2Plug filtration with ethyl acetate as eluent. Evaporation in vacuo (50 ℃) gave 5.8g (100% yield) of the crude title compound, which was used in the next step without further purification. LC/MS (M/z)245([ M + H)]+)；RT＝2.95，(UV，ELSD)96％，98.5％。1H NMR(DMSO-d6)：1.27(t，3H)，4.19(q，2H)，8.06(d，1H)，8.19(dd，1H)，8.30(d，1H)，9.49(s，NH)。
The following compounds were prepared analogously using the appropriate chloroformate:
(2-chloro-4-nitrophenyl) -carbamic acid propyl ester.
Instead, propyl chloroformate and tetrahydrofuran were used. The title compound was crystallized by adding propyl ether to the crude product and isolated by filtration. Yield 3.3g (62%), colorless solid NMR (DMSO-d) 6)：0.94(t，3H)，1.67(m，2H)，4.10(t，2H)，8.06(d，1H)，8.20(dd，1H)，8.31(d，1H)，9.52(s，NH)。
(4-Nitrophenyl) -carbamic acid propyl ester.
The reaction was carried out in acetone as a solvent at room temperature. The product was used in the next step without purification.
(4-Nitrophenyl) -carbamic acid ethyl ester.
The reaction was carried out in acetone as a solvent at room temperature. The product was used in the next step without purification.
(2-methoxy-4-nitrophenyl) -carbamic acid methyl ester.
The reaction was carried out in acetone as a solvent at room temperature. The product was used in the next step without purification.
(2-methoxy-4-nitrophenyl) -carbamic acid isopropyl ester.
The reaction was carried out in acetone as a solvent at room temperature. The product was used in the next step without purification.
(2-methoxy-4-nitrophenyl) -carbamic acid propyl ester.
The reaction was carried out in acetone as a solvent at room temperature. The product was used in the next step without purification.
(2-methoxy-4-nitrophenyl) -carbamic acid 4-fluorophenyl ester.
The reaction was carried out in acetone as a solvent at room temperature. The product was used in the next step without purification.
(2-methyl-4-nitrophenyl) -carbamic acid ethyl ester.
The crude product was used in the next step without further purification.
LC/MS(m/z)207.9([M-16]+)；RT＝2.69，(UV，ELSD)75％，99.7％。
(2-methyl-4-nitrophenyl) -carbamic acid propyl ester.
The crude product was used in the next step without further purification.
LC/MS(m/z)223.1([M-15]+)；RT＝2.97，(UV，ELSD)62％，99.7％。
(2-bromo-4-nitrophenyl) -carbamic acid propyl ester.
The crude product was crystallized from ethyl acetate-hexane.1H NMR(DMSO-d6)：0.94(t，3H)，1.66(m，2H)，4.10(t，2H)，7.97(d，1H)，8.23(dd，1H)，8.44(d，1H)，9.28(br.s，NH)。
(2-iodo-4-nitrophenyl) -carbamic acid propyl ester.
The crude product was purified by crystallization from ethyl acetate-hexane. Light yellow needles.1H NMR(DMSO-d6)：0.94(t，3H)，1.66(m，2H)，4.09(t，2H)，7.79(d，1H)，8.24(dd，1H)，8.60(d，1H)，9.07(br.s，NH)。LC/MS(m/z)335.0([M-O]+)；RT＝3.40，(UV，ELSD)99％，100％。
(4-nitro-2-cyanophenyl) -carbamic acid propyl ester.
Alternatively sodium hydride is used as the base, followed by the addition of propyl chloroformate at room temperature. With saturated aqueous sodium bicarbonate (NaHCO)3) The crude product contaminated with the diacylated product was treated in methanol for 16 h and purified by flash column chromatography.1H NMR(CDCl3)：1.01(t，3H)，1.76(m，2H)，4.22(t，2H)，7.47(br.s，1H，NH)，8.43(dd，1H)，8.47(d，1H)，8.57(d，1H)。
The following compounds were prepared analogously:
(4-nitro-2-cyanophenyl) -carbamic acid ethyl ester.
1H NMR(DMSO-d6)：1.28(t，3H)，4.21(q，2H)，7.88(d，1H)，8.47(dd，1H)，8.68(d，1H)，10.34(s，1H，NH)。LC/MS(m/z)220.1([M+H]+)，RT＝2.46，(UV，ELSD)97％，98％。
(2-trifluoromethyl-4-nitrophenyl) -carbamic acid propyl ester.
1H NMR(CDCl3)：1.00(t，3H)，1.75(m，2H)，4.20(t，2H)，7.26(br.s，1H，NH)，8.41(dd，1H)，8.50(d，1H)，8.57(d，1H)。
(2-trifluoromethyl-4-nitrophenyl) -carbamic acid ethyl ester.
1H NMR(CDCl3)：1.37(t，3H)，4.31(q，2H)，7.25(br.s，1H，NH)，8.41(dd，1H)，8.50(d，1H)，8.57(d，1H)。
N- (2-methoxy-4-nitrophenyl) -butyramide.
To an ice-cold (ice/water bath) solution of 2-methoxy-4-nitroaniline (4.00g, 23.8mmol) in acetonitrile (40mL) and triethylamine (5mL) was added butyryl chloride (2.66g, 25 mmol). After 30 minutes, the resulting suspension was poured into saturated sodium bicarbonate (NaHCO) 3) Aqueous solution (300 mL). After sonicating it for 10 minutes, the title compound was isolated by filtration as a tan solid, washed with water and dried in vacuo. The yield was 5.34g, 94%. LC/MS (M/z)238.9([ M + H)]+)；RT＝2.69，(UV，ELSD)98％，99％。1HNMR(DMSO-d6)：0.91(t，3H)，1.60(m，2H)，2.47(t，2H)，3.98(s，3H，OMe)，7.79(s，1H)，7.88(dd，1H)，8.39(d，1H)，9.50(s，1H，NH)。
The following compounds were prepared analogously using the appropriate acid chloride:
n- (2-methoxy-4-nitrophenyl) -3, 4-dichlorobenzamide.
LC/MS(m/z)313.0([M+H-NO]+；RT＝3.72，(UV，ELSD)99％，100％。
1H NMR(DMSO-d6)：4.0(s，3H，OMe)，7.82(d，1H)，7.88(d，11I)，7.93(m，2H)，8.17(d，1H)，8.20(s，1H)，10.01(s，1H，NH)。
3, 3-dimethyl-N- (-N2 ethyl-4-nitrophenyl) -butyramide.
To a solution of 2-methyl-4-nitroaniline (5g, 32.9mmol) in acetonitrile (75mL) was added tert-butylacetyl chloride (5.3g, 1.2 equiv.). The resulting mixture was dispensed into 15Smith Process vials and sealed. Each vial was heated and stirred under microwave irradiation at 150 ℃ for 10 minutes. The combined mixture was evaporated in vacuo to give 9.27g of a solid (100%), which was used in the next step without further purification.
LC/MS(m/z)251.1([M+H]+)；RT＝3.01，(UV，ELSD)89％，99.6％。1HNMR(DMSO-d6)：1.05(s，9H)，2.33(s，2H)，2.36(s，3H)，7.91(d，1H)，8.05(dd，1H)，8.12(d，1H)，9.41(s，1H，NH)。
The following compounds have been prepared analogously:
2, 2-dimethyl-N- (2-methyl-4-nitrophenyl) -propionamide.
LC/MS(m/z)237.1([M+H]+)；RT＝2.72，(UV，ELSD)96.7％，98.6％。1H NMR(DMSO-d6)：1.26(s，9H)，2.31(s，3H)，7.61(d，1H)，8.05(dd，1H)，8.14(d，1H)，9.06(s，1H，NH)。
2- (4-fluorophenyl) -N- (2-methyl-4-nitrophenyl) -acetamide.
LC/MS(m/z)288.9([M+H]+)；RT＝2.90，(UV，ELSD)99.6％，99.4％。1H NMR(DMSO-d6)：2.34(s，3H)，3.79(s，2H)，7.18(t，2H)，7.39(dd，2H)，7.91(d，1H)，8.06(dd，1H)，8.13(d，1H)，9.72(s，1H，NH)。
2- (4-fluorophenyl) -N- (2-iodo-4-nitrophenyl) -acetamide.
The product was washed with ice cold acetonitrile.1H NMR(DMSO-d6)：3.81(s，2H)，7.16-7.19(m，2H)，7.41-7.44(m，2H)，7.87(d，1H)，8.23(dd，1H)，8.62(d，1H)，9.66(bs，1H)。
(2-iodo-4-nitrophenyl) -carbamic acid ethyl ester.
The product was purified by flash column chromatography (silica, heptane/ethyl acetate).1HNMR(DMSO-d6)：1.27(t，3H)，4.18(q，2H)，7.80(d，1H)，8.24(dd，1H)，8.60(d，1H)，9.05(s，1H)。
(2- (furan-2-yl) -4-nitrophenyl) -carbamic acid propyl ester.
Propyl (2-iodo-4-nitrophenyl) -carbamate (30mg, 0.086mmol), 0.9M potassium carbonate (K)2CO3) A mixture of aqueous solution (0.285mL, 0.257mmol), palladium (II) acetate (5mg) and 2-furanboronic acid (48mg, 0.428mmol) in acetone (2mL) was heated to +125 ℃ for 3 minutes under microwave irradiation in the sealed vial. The resulting reaction mixture was evaporated and the title compound was purified with SiO2Flash column chromatography (5g, heptane-ethyl acetate gradient elution). The yield was 21mg, 84%.1H NMR(CDCl3): 1.00(t, 3H), 1.75(m, 2H), 4.18(t, 2H), 6.62(dd, 1H, furan), 6.79(d, 1H, furan), 7.64(d, 1H, furan), 8.16(dd, 1H), 8.36(br.s, 1H, NH), 8.39(d, 1H), 8.48(d, 1H). LC/MS (M/z)261.0([ M + H)]+)；RT＝1.57。
The following compounds were prepared analogously with the appropriate boronic acids:
(2-phenyl-4-nitrophenyl) -carbamic acid propyl ester.
The mixture was used in the next step without purification.
(2-methoxy-4-nitrophenyl) -carbamic acid ethyl ester
2-methoxy-4-nitrophenylamine (5.0g) was dissolved in anhydrous dioxane (30mL) and N, N-diisopropylethylamine (7.8mL) was added thereto at 0 ℃. Ethyl chloroformate (4.25mL) in dioxane (35mL) was added dropwise thereto, and the resulting mixture was allowed to warm to room temperature and stirred overnight. Water (200mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3X 150 mL). The combined organic phases were washed with water (2X 200mL) and brine (200mL), dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was recrystallized from ethanol to give the title compound as a colorless solid (4.45g, 62%).
1H NMR(DMSO-d6)：1.26(t，3H)，3.94(s，3H)，4.18(q，2H)，7.78(d，1H)，7.90(dd，1H)，8.09(d，1H)，8.99(s，1H)。
(2-hydroxy-4-nitrophenyl) -carbamic acid ethyl ester
(2-methoxy-4-nitrophenyl) -carbamic acid ethyl ester (2.15g) was dispersed in 1, 2-dichloroethane (20mL) and cooled to 0 ℃. To this was added dropwise boron tribromide (2.0mL) in 1, 2-dichloroethane (10 mL). The reaction mixture was stirred at 0 ℃ for 10 minutes and at room temperature for 30 minutes. The mixture was cooled again to 0 ℃ and water (10mL) was carefully added. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate and aqueous hydrochloric acid (5M). The resulting mixture was extracted with ethyl acetate (3X 100 mL). The combined organic phases were washed with water (2 × 100mL) and brine (100mL), dried over magnesium sulfate, filtered, and evaporated in vacuo to give the title compound as a brown solid (1.96g, 97%).
1H NM；R(DMSO-d6)：1.25(t，3H)，4.17(q，2H)，7.64(d，1H)，7.74(dd，1H)，8.01(d，1H)，8.69(s，1H)，10.96(br.s，1H)。
(2-cyclopentyloxy-4-nitrophenyl) -carbamic acid ethyl ester
Cyclopentanol (7.24mL, 376mM in anhydrous tetrahydrofuran) was added to triphenylphosphine (1.44g, polystyrene linkage, 1.89mMol/g) under argon, then a solution of (2-hydroxy-4-nitrophenyl) -carbamic acid ethyl ester (25.6mL, 62mM in anhydrous tetrahydrofuran) and diethyl azodicarboxylate (7.24mL, 376mM in anhydrous tetrahydrofuran) were added thereto. The reaction mixture was shaken overnight at room temperature. The resin was filtered off and washed with Tetrahydrofuran (THF) (35mL) and methanol (35 mL). The combined organic phases were evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel, heptane/ethyl acetate, gradient elution) to give the title compound as a light yellow solid (294mg, 64%).
1H IVMR(DMSO-d6)：1.27(t，3H)，1.59(m，2H)，1.76(m，2H)，1.87(m，2H)，1.94(m，2H)，4.19(q，2H)，5.01(h，1H)，7.72(d，1H)，7.86(dd，1H)，8.11(d，1H)，8.82(s，1H)。
The following compounds were prepared in a similar manner:
(4-Nitro-2-phenylethoxyphenyl) -carbamic acid ethyl ester
1H NMR(DMSO-d6)：1.28(t，3H)，3.15(t，2H)，4.19(q，2H)，4.38(t，2H)，7.23(t，1H)，7.32(t，2H)，7.36(d，2H)，7.80(d，1H)，7.88(dd，1H)，8.08(d，1H)，8.66(s，1H)。
(2-benzyloxy-4-nitrophenyl) -carbamic acid ethyl ester
1H NMR(DMSO-d6)：1.26(t，3H)，4.18(q，2H)，5.33(s，2H)，7.35(t，1H)，7.41(t，2H)，7.55(d，2H)，7.86(d，1H)，7.89(dd，1H)，8.06(d，1H)，8.95(s，1H)。
(2-isopropoxy-4-nitrophenyl) -carbamic acid ethyl ester
1H NMR(DMSO-d6)：1.27(t，3H)，1.33(d，6H)，4.19(q，2H)，4.84(h，1H)，7.78(d，1H)，7.86(dd，1H)，8.12(d，1H)，8.77(s，1H)。
Preparation of intermediates of the formula XII
(4-amino-2-methoxyphenyl) -carbamic acid ethyl ester
(2-methoxy-4-nitrophenyl) -carbamic acid ethyl ester (2.20g) was dissolved in ethanol (220 mL). Aqueous hydrochloric acid (26mL, 6M) and iron powder (4.74g) were added thereto, and the mixture was stirred at 65 ℃ for 15 minutes. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 × 200 mL). The organic phase was washed with water (2 × 100mL) and brine (100mL), dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was dissolved in ethanol (100mL) and the above procedure was repeated with aqueous hydrochloric acid (26mL, 6M) and iron powder (3.7g) to give the title compound (1.80g, 93%) as a dark oil.
1H NMR(DMSO-d6)：1.19(t，3H)，3.67(s，3H)，4.01(q，2H)，4.97(s，2H)，6.08(dd，1H)，6.23(d，1H)，6.97(br.s，1H)，7.92(br.s，1H)。
(4-amino-2-iodophenyl) -carbamic acid ethyl ester.
1H NMR(CDCl3)：1.31(t，3H)，3.58(br.s，2H)，4.21(q，2H)，6.52(br.s，1H)，6.67(dd，1H)，7.12(d，1H)，7.60(br.d，1H)。
The following compounds were prepared analogously:
n- (4-amino-2-iodophenyl) -2- (4-fluorophenyl) -acetamide.
1H NMR(DMSO-d6)：3.59(br.s，2H)，3.73(s，2H)，6.65(dd，1H)，7.05(d，1H)，7.09-7.12(m，3H)，7.34-7.37(m，2H)，7.82(d，1H)。
(4-amino-2-chlorophenyl) -carbamic acid ethyl ester.
To an ice-cold (ice/water bath) (2-chloro-4-nitrophenyl) -urethane (5.8g, 21.8mmol) solution of crude, vigorously stirred, in Tetrahydrofuran (THF) (100mL) and acetic acid (12mL) was added zinc powder (20g) in small portions while maintaining the temperature below 40 ℃. The mixture was slowly warmed to room temperatureAfter completion of the reaction (1 hour), SiO was used2(20g) It was filtered through a plug using ethyl acetate as eluent. The resulting solution was evaporated in vacuo and the crude yellow solid residue (4.9g) was purified by recrystallization from Tetrahydrofuran (THF)/heptane to give 3.00g of the title compound as a pale yellow solid in 56% yield. LC/MS (M/z)214, 216 (M)+)；RT＝1.18，(UV，ELSD)86％，97％。1H NMR(DMSO-d6)：1.18(br.t，3H)，4.02(q，2H)，5.29(s，2H，NH2)，6.45(dd，1H)，6.61(d，1H)，6.98(br.d，1H)，8.52(br.s，NHCO)。
The following compounds were prepared analogously:
(4-amino-2-chlorophenyl) -carbamic acid propyl ester.
The yield was 84.6% (2.44g, colorless solid). LC/MS (M/z)228.1 (M)+)；RT＝1.53，(UV，ELSD)97.3％，99％。
(4-aminophenyl) -carbamic acid propyl ester.
By SiO2Flash column chromatography (heptane-ethyl acetate gradient elution). A dark purple crystalline solid was obtained in a yield of 3.066g, 63.3%. LC/MS (M/z)195([ M + H)]+)；RT＝1.18，(UV，ELSD)87％，98.3％。
(4-aminophenyl) -carbamic acid ethyl ester.
LC/MS (in/z) 180.8([ M + H)]+)；RT＝0.48，(UV，ELSD)71％，97％。
(4-amino-2-methoxyphenyl) -carbamic acid methyl ester.
LC/MS(m/z)197.0([M+H]+)；RT＝0.49，(UV，ELSD)71％，98％。
(4-amino-2-methoxyphenyl) -carbamic acid ethyl ester.
LC/MS(m/z)210.9([M+H]+)；RT＝0.98，(UV，ELSD)69％，97％。
(4-amino-2-methoxyphenyl) -carbamic acid isopropyl ester.
LC/MS(m/z)224.0(M+)；RT＝1.33，(UV，ELSD)63％，99％。
(4-amino-2-methoxyphenyl) -carbamic acid propyl ester.
LC/MS(m/z)224.9([M+H]+)；RT＝1.36，(UV，ELSD)70％，98％。
(4-amino-2-methoxyphenyl) -carbamic acid 4-fluorophenyl ester.
LC/MS(m/z)277.0([M+H]+)；RT＝1.64，(UV，ELSD)44％，93％。
(4-amino-2-methylphenyl) -carbamic acid propyl ester.
LC/MS(m/z)208.1(M+)；RT＝1.16，(UV，ELSD)95％，100％。1HNMR(CDCl3)：0.96(t，3H)，1.68(m，2H)，2.17(s，3H，Me)，3.59(br.s，2H，NH2)，4.09(t，2H)，6.14(br.s，1H，ArH)，6.51(m，2H)，7.32(br.s，1H，NH)。
(4-amino-2-methylphenyl) -carbamic acid ethyl ester.
1H NMR(CDCl3)：1.28(t，3H)，2.16(s，3H，Me)，3.62(br.s，2H，NH2)，4.19(q，2H)，6.16(br.s，1H，ArH)，6.5(m，2H)，7.31(br.s，1H，NH).LC/MS(m/z)195.1([M+H]+)；RT＝0.75，(UV，ELSD)70％，95％。
(4-amino-2-trifluoromethylphenyl) -carbamic acid ethyl ester.
1H NMR(CDCl3)：1.30(t，3H)，3.77(br.s，2H，NH2)，4.20(q，2H)，6.52(br.s，1H，ArH)，6.82(dd，1H)，6.87(unres.d，1H)，7.65(br.s，1H，NH).).LC/MS(m/z)248.1(M+)；RT＝1.65，(UV，ELSD)94％，90％。
(4-amino-2-trifluoromethylphenyl) -carbamic acid propyl ester.
1H NMR(CDCl3)：0.96(t，3H)，1.69(m，2H)，3.76(br.s，2H，NH2)，4.11(t，2H)，6.51(br.s，1H，ArH)，6.81(dd，1H)，6.87(d，1H)，7.61(br.s，1H，NH).LC/MS(m/z)261.9(M+)；RT＝2.06，(UV，ELSD)92％，98％。
(4-amino-2-cyanophenyl) -carbamic acid ethyl ester.
1H NMR(DMSO-d6)：1.21(t，3H)，4.07(q，2H)，5.49(br.s，2H，NH2)，6.81(m，2H，ArH)，7.04(d，1H)，9.09(br.s，1H，NH)。LC/MS(m/z)204.9(M+)；RT 1.05，(UV，ELSD)98％，99％。
(4-amino-2-cyanophenyl) -carbamic acid propyl ester.
1H NMR(CDCl3)：0.98(t，3H)，1.71(m，2H)，3.72(br.s，2H，NH2)，4.13(t，2H)，6.81(br.s，ArH)，6.82(d，1H)，6.89(dd，1H)，7.83(br.s，1H，NH)。LC/MS(m/z)220.1([M+H]+)；RT＝1.52，(UV，ELSD)98％，100％。
N- (4-amino-2-methoxyphenyl) -butanamide.
LC/MS(m/z)208.9([M+H]+)；RT＝0.77，(UV，ELSD)81％，95％。1HNMR(DMSO-d6): 0.89(t, 3H), 1.56(m, 2H), 2.22(t, 2H), 3.4 (very broad singlet, NH)2)，3.69(s，3H，OMe)，6.08(dd，1H)，6.25(d，1H)，7.27(d，1H)，8.62(s，1H，NH)。
N- (4-amino-2-methoxyphenyl) -3, 4-dichlorobenzamide.
LC/MS(m/z)311.2(M+)；RT＝1.93，(UV，ELSD)100％，100％。1HNMR(DMSO-d6)：3.70(s，3H，OMe)，5.12(br.s，2H，NH2)，6.15(dd，1H)，6.30(d，1H)，7.09(d，1H)，7.77(d，1H)，7.91(dd，1H)，8.17(d，1H)，9.46(s，1H，NH)。
N- (4-amino-2-methylphenyl) -3, 3-dimethylbutanamide.
LC/MS(m/z)221.1([M+H]+)；RT＝1.22，(UV，ELSD)53.7％，92.3％。1H NMR(DMSO-d6)：1.02(s，9H)，2.02(s，3H)，2.11(s，2H)，4.89(br.s，2H，NH2)，6.33(dd，1H)，6.38(d，1H)，6.82(d，1H)，8.83(s，1H，NH)。
N- (4-amino-2-methylphenyl) -2- (4-fluorophenyl) -acetamide.
LC/MS(m/z)259.1([M+H]+)；RT＝1.36，(UV，ELSD)48.1％，91.4％。1H NMR(DMSO-d6)：1.95(s，3H)，3.56(s，2H)，4.88(br.s，2H，NH2)，6.31(dd，1H)，6.38(d，1H)，6.83(d，1H)，7.14(t，2H)，7.35(dd，2H)，9.16(s，1H，NH)。
N- (4-amino-2-methylphenyl) -2, 2-dimethylpropionamide.
LC/MS(m/z)206.9([M+H]+)；RT＝0.59，(UV，ELSD)93％，95％。1HNMR(DMSO-d6)：1.19(s，9H)，1.98(s，2H)，4.87(br.s，2H，NH2)，6.33(dd，1H)，6.39(d，1H)，6.71(d，1H)，8.55(s，1H，NH)。
[ 4-amino-2- (furan-2-yl) -phenyl ] -carbamic acid propyl ester.
IH NMR(CDCl3)：0.96(t，3H)，1.68(m，2H)，3.65(br.s，2H，NH2) 4.10(t, 2H), 6.50(dd, 1H, furan), 6.58(d, 1H, furan), 6.66(dd, 1H), 6.91(br.s (non-resolved d), 1H), 7.26(br.s, ArH), 7.52(d, 1H), 7.72(br.s, 1H, NH) LC/MS (M/z)261.0([ M + H, NH) ([ M/z) ([ M + H ] 261.0) ]+)；RT＝1.57。
(2-phenyl-4-aminophenyl) -carbamic acid propyl ester.
LC/MS(m/z)271.1([M+H]+)；RT＝1.75，(UV，ELSD)57％，99％。
(4-amino-2-bromophenyl) -carbamic acid propyl ester.
A suspension of iron powder (20g, excess) and (2-bromo-4-nitrophenyl) -propyl carbamate (2.183g, 7.20mmol) in ethanol (80mL) and 6M aqueous hydrochloric acid (20mL) was sonicated at room temperature for 10 minutes. The mixture was slowly poured into saturated sodium bicarbonate (NaHCO)3) In the aqueous solution, it was filtered and extracted with ethyl acetate. The combined organic solution is treated with a solution comprising NaHCO3Washed 3 times with sodium sulfate (Na)2SO4) was dried and evaporated in vacuo to give 1.67g of the title compound as a pale yellow oil which solidified. The yield thereof was found to be 85%. LC/MS (M/z)271.9, 273.8 (M)+)；RT＝1.30，(UV，ELSD)99％，100％。1HNMR(DMSO-d6): 0.90(br.s (unresolved t), 3H), 1.59(br.s (unresolved m), 2H), 3.94(t, 2H), 5.31(s, 2H, NH)2) 6.50(dd, 1H), 6.80 (unresolved d, 1H), 6.96(br.d, 1H), 8.51(br.s, NHCO).
The following compounds were prepared analogously:
(4-amino-2-iodophenyl) -carbamic acid propyl ester.
1H NMR(CDCl3)：0.97(t，3H)，1.69(m，2H)，3.59(br.s，2H，NH2)，4.11(t，2H)，6.53(br.s，1H，ArH)，6.66(dd，1H)，7.11(d，1H)，7.61(br.s，1H，NH)。LC/MS(m/z)320.7([M+H]+)；RT＝1.71，(UV，ELSD)98％，99％。
Synthesis of intermediates of formulae XIII to XXIII:
n- (4-amino-2-chlorophenyl) -2, 2, 2-trifluoroacetamide.
To a suspension of 4-nitro-2-chloroaniline (17.2g, 0.1mol) in 1, 2-dichloroethane (100mL) was added trifluoroacetic anhydride (16mL, 0.113 mol). After 5 minutes, the resulting yellow solution was evaporated in vacuo. The obtained yellow N- (R) ((R)) The solid 4-nitro-2-chlorophenyl) -2, 2, 2-trifluoroacetamide is reduced with Zn powder in Tetrahydrofuran (THF) -acetic acid. The resulting crude product was treated with 2M hydrochloric acid (150mL) and diethyl ether. The resulting white precipitate was filtered off to give 14.7g of the title compound as the hydrochloride salt. The aqueous solution was taken up with saturated sodium bicarbonate (NaHCO)3) Aqueous neutralization and filtration gave 4.58g of the title compound as a pale gray solid in pure form. 1H NB (DMSO-d)6)：5.54(br.s，2H，NH2)，6.53(dd，1H)，6.70(d，1H)，7.02(d，1H)，10.79(br.s，1H9 NHCO)。LC/MS(m/z)239.8([M+H]+)；RT＝1.67，(UV)100％。
N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2, 2, 2-trifluoroacetamide.
A solution of N- (4-amino-2-chlorophenyl) -2, 2, 2-trifluoroacetamide (4.567g, 19.14mmol) and 5-chloro-thiophene-2-carbaldehyde (3.97g, 27.1mmol) in absolute ethanol (50mL) was heated to reflux for 15 min and evaporated in vacuo (0.1mbar, 30 min) at 70 ℃. The crude imine in crystalline solid form was dissolved in methanol and then sodium cyanoborohydride (NaBH) in methanol (50mL) and acetic acid (9mL) was added portionwise3CN). The resulting reaction mixture was stirred at room temperature for 60 minutes and evaporated in vacuo to a small volume. After quenching the concentrated solution with water and filtration after 30 minutes 6.98g (yield 99%) of the title compound are obtained in the form of a brown-yellow solid. 1H NMR(DMSO-d6)：4.43(d，2H)，6.63(dd，1H)，6.77(d，1H)，6.79(t，1H，NH)，6.94(d，1H)，6.97(d，1H)，7.10(d，1H)，10.85(br.s，1H，NHCO)。LC/MS(m/z)367.9(M+)；RT＝3.36，(UV，ELSD)99％，100％。
N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2, 2, 2-trifluoroacetamide.
To N { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -was added under stirring over 30 minutes]-phenyl } -2, 2, 2-trifluoroacetamide (3.28g, 8.88mmol), 37% aqueous formaldehyde (5mL), and acetic acid (3mL)) To the mixture of (1) was added dropwise sodium cyanoborohydride (NaBH) in methanol (10mL)3CN) (1.1 g). The reaction mixture was allowed to stand at room temperature for 2 hours and poured into water. After the oil solidified, it was filtered off, washed with water and dried in vacuo to give 3.26g of a pale yellow-brown solid. The yield thereof was found to be 95%.1HNMR(DMSO-d6)：2.97(s，3H，NMe)，4.72(s，2H)，6.82(m，1H)，6.91(m，2H)，6.97(d，1H)，7.21(d，1H)，10.92(br.s，1H，NHCO)。LC/MS(m/z)382.0(M+)；RT＝3.66，(UV，ELSD)85％，98％。
(5-chloro-thiophen-2-ylmethyl) - [ 3-chloro-4- (2, 2, 2-trifluoro-acetylamino) -phenyl ] -carbamic acid tert-butyl ester.
Reacting N- (2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino]A mixture of-phenyl } -2, 2, 2-trifluoroacetamide (2.219g, 6.01mmol), di-tert-butyl dicarbonate (2g), and acetonitrile (3mL) was heated to +80 ℃ until the reaction was complete (36 h). During this time, an additional amount of di-tert-butyl dicarbonate (2X 1.5g) was added. The resulting reaction mixture was evaporated in vacuo (80 ℃, 0.1mbar) to give the crude title compound, which was used in the next step without further purification. 1H NMR(DMSO-d6)：1.44(s，9H)，4.94(s，2H)，6.81(d，1H)，6.93(d，1H)，7.25(dd，1H)，7.43(d，1H)，7.50(d，1H)，11.24(br.s，1H，NHCO)。LC/MS(m/z)366.9([M-Boc]+)；RT＝3.99，(UV，ELSD)87％，96％。
2-chloro-N (4) - (5-chloro-thiophen-2-ylmethyl) -N (4) -methyl-benzene-1, 4-diamine.
To N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino]To a solution of-phenyl } -2, 2, 2-trifluoroacetamide (3.118g) in methanol (MeOH) (50mL) was added potassium carbonate (K)2CO3) (6.4g) solution in water (25mL) and the reaction mixture was stirred at room temperature until the reaction was complete (24 h). The resulting reaction mixture was extracted with ethyl acetate and saturated sodium bicarbonate (NaHCO)3) The aqueous solution was washed and evaporated to give 2.26g of a dark brown oil. Will be provided withIt was used in the next step without further purification.1H NMR(DMSO-d6)：2.71(s，3H，NMe)，4.47(s，2H)，4.71(br.s，2H，NH2)，6.67-6.75(m，3H)，6.82(d，1H)，6.93(d，1H)。LC/MS(m/z)288.0([M+H]+)；RT＝2.07，(UV，ELSD)85％，98％。
The following compounds were prepared analogously:
(4-amino-3-chlorophenyl) - (5-chloro-thiophen-2-ylmethyl) -carbamic acid tert-butyl ester.
IH NMR(DMSO-d6): 1.39(br.s, 9H, t-Bu), 4.74(s, 2H), 5.35(br.s, 2H, NH)2)，6.67-6.74(m，2H)，6.77(br.d，1H)，6.90(d，1H)，6.97(d，1H)。LC/MS(m/z)271.9([M-Boc]+)；RT＝3.73，(UV，ELSD)77％，97％。
4-fluoro-2-isopropoxy-1-nitrobenzene
5-fluoro-2-nitrophenol (48g) was dissolved in anhydrous Tetrahydrofuran (THF) (300 mL). Triphenylphosphine (88g) and 2-propanol (47mL) were added to the solution, and the resulting mixture was cooled to 0 ℃. Diisopropyl azoformate (66mL) was added dropwise thereto. The resulting mixture was warmed to room temperature and stirred overnight. The solvent was evaporated under vacuum and the resulting mixture was filtered over silica (elution with heptane/ethyl acetate 1: 1). The solvent was evaporated in vacuo and the resulting mixture was recrystallized from heptane/ethyl acetate (1: 1). The organic phase was separated from the crystalline solid by filtration, the solvent was evaporated in vacuo and the remaining product was purified by flash column chromatography (silica gel, heptane/ethyl acetate 9: 1) to give the title compound as a colourless oil (47.2g, 78%). 1H NMR(DMSO-d6)：1.30(d，6H)，4.85(h，1H)，6.93(m，1H)，7.34(dd，1H)，7.96(dd，1H)。
The following compounds were prepared analogously:
2-cyclopentyloxy-4-fluoro-1-nitrobenzene.
1H NMR(DMSO-d6)：1.57-1.78(m，6H)，1.86-1.94(m，2H)，6.90-6.97(m，1H)，7.27-7.32(m，1H)，7.98(dd，1H)。
2-benzyloxy-4-fluoro-1-nitrobenzene.
1H NMR(DMSO-d6)：5.33(s，2H)，6.96-7.04(m，1H)，7.32-7.49(m，6H)，8.04(dd，1H)。
(4-Fluorobenzyl) - (3-isopropoxy-4-nitrophenyl) - (methyl) -amine
4-fluoro-2-isopropoxy-1-nitrobenzene (1.0g) was dissolved in anhydrous dimethyl sulfoxide (25 mL). To this were added potassium carbonate (1.4g) and (4-fluorobenzyl) - (methyl) -amine (0.84 g). The resulting mixture was heated to 90 ℃ overnight. After cooling to room temperature, water (75mL) was added thereto, and the resulting mixture was extracted with ethyl acetate (3X 75 mL). The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound as a slightly yellow solid (1.6g, 100%). LC-MS (M/z)319.1([ M + H)]+)；RT＝3.43，(UV，ELSID)85％，96％。1H NMR(DMSO-d6)：1.21(d，6H)，3.18(s，3H)，4.71(m，1H)，4.73(s，2H)，6.26(d，1H)，6.41(dd，1H)，7.17(m，2H)，7.25(m，2H)，7.84(d，1H)，
The following compounds were prepared analogously:
(3-benzyloxy-4-nitrophenyl) (4-fluorobenzyl) methylamine.
LC-MS(m/z)320.9([M+H-NO2]+)；RT＝3.54，(UV，ELSD)96％，100％。
(3-cyclopentyloxy-4-nitrophenyl) (4-fluorobenzyl) methylamine.
LC-MS(m/z)299.2([M+H-NO2]+)RT＝3.64，(UV，ELSD)96％，100％。
4- (4-fluorobenzyl) - (methyl) -amino-2-isopropoxy aniline
(4-Fluorobenzyl) - (3-isopropoxy-4-nitrophenyl) - (methyl) -amine (1.60g) was dissolved in methanol (50 mL). Ammonium formate (1.91g) and palladium (10%, on charcoal, 0.21g) and the mixture was stirred at room temperature for 1.5 hours, the reaction mixture was filtered and the solvent was evaporated in vacuo. The residue was dissolved in a small amount of methanol and concentrated aqueous sodium hydroxide (2mL) was added thereto. The resulting mixture was filtered through a silica gel column (using ethyl acetate as eluent) and the resulting solution was evaporated in vacuo to give the crude title compound as a dark oil (0.76g), which was used directly in the next step. LC-MS (M/z)288.9([ M + H) ]+)；RT＝1.91，(UV，ELSD)80％，72％，
(5-chloro-thiophen-2-ylmethyl) - (methyl) - (3-methyl-4-nitrophenyl) -amine
5-chloro-thiophene-2-carbaldehyde (1.61g, 11.0mmol), 3-methyl-4-nitroaniline (1.52g, 10.0mmol), and Amberlite IRC-84(100mg, H)+Form) the suspension in o-xylene (40mL) was heated under nitrogen at 140 ℃ for 5 hours. After cooling to room temperature, the resin was removed by filtration and the volatiles were evaporated. The residue was dissolved in acetonitrile (40mL) and all of sodium cyanoborohydride (1.26g, 20.0mmol) was added thereto at once, then acetic acid (1mL) was added thereto in portions over 15 minutes, then a formaldehyde solution (37% aqueous solution, 2.23mL, 30.0mmol) was added thereto and the mixture was stirred for another 30 minutes. The volatiles were evaporated and the residue partitioned between saturated aqueous sodium bicarbonate (100mL) and ethyl acetate (100mL) and the aqueous phase extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, the solvent was evaporated, and the residue was analyzed by NMR. Incomplete N-methylation requires that the reductive amination step be repeated three times (using formaldehyde solution, 7.4mL, 100mmol, and sodium cyanoborohydride, 2.07g, 33mmol) before complete conversion is obtained. After this time, the crude product was purified using a FlashMaster system (silica, elution with heptane/ethyl acetate mixture) to afford the title compound as a yellow oil (1.85g, 62%). 1H NMR(CDCl3)：2.64(s，3H)，3.11(s，3H)，4.66(s，3H)，6.52(d，1H)，6.60(dd，1H)，6.69(d，1H)，6.77(d，1H)，8.10(d，1H)。
N- (4) - (5-chloro-thiophen-2-ylmethyl) -2, N (4) -dimethyl-benzene-1, 4-diamine
To a suspension of (5-chloro-thiophen-2-ylmethyl) - (methyl) - (3-methyl-4-nitrophenyl) -amine (1.85g, 6.23mmol) and iron powder (2.09g, 37.4mmol) in ethanol (60mL) was added 6N HCl (12.5mL, 75mmol), and the mixture was stirred vigorously at +60 ℃ for 50 minutes. It was then poured into saturated aqueous sodium bicarbonate (200mL) to which was added sufficient sodium carbonate to obtain a pH of > 10. The resulting mixture was extracted with ethyl acetate (200mL, then 2X 100mL), the extracts were dried over sodium sulfate and the volatiles were evaporated. The residue was purified using a FlashMaster system (silica, elution with a heptane/ethyl acetate mixture) to give the title compound as a brown oil (1.51g, 91%).1H NMR(CDCl3)：2.16(s，3H)，2.79(s，3H)，3.32(br.s，2H)，4.39(s，3H)，6.58-6.65(m，4H)，6.72(d，1H)。
Synthesis of intermediates of formula XXXV, XXXVI, and XIX from XXXIV:
(3-methyl-4-nitrophenyl) - (4-trifluoromethylbenzyl) -amine
4-Trifluoromethylbenzaldehyde (8191L, 6.00mmol), 3-methyl-4-nitroaniline (609mg, 4.00mmol), and Amberlite IRC-84(200mg, H)+Form) the suspension in o-xylene (4mL) was heated under nitrogen at 140 ℃ for 6 hours. Then, it was cooled to room temperature, diluted with ethyl acetate (5mL), dried over sodium sulfate, filtered, and the volatiles were evaporated. The residue was dissolved in acetonitrile (20mL) and all of sodium cyanoborohydride (503mg, 8.00mmol) was added thereto in one portion, followed by addition of acetic acid (1mL) in portions over 15 minutes. After an additional 30 minutes, the solvent was evaporated and the residue partitioned between ethyl acetate (50mL), brine (25mL), and 10% aqueous potassium carbonate (25 mL). Sulfur is used for the organic layer The sodium salt was dried, the solvent evaporated and the residue purified on a FlashMaster system (silica, eluting with a heptane/ethyl acetate mixture) to give the title compound as a yellow powder (1.02g, 82%).1HNMR(CDCl3)：2.59(s，3H)，4.50(d，2H)，4.76(br.t，1H)，6.40(d，1H)，6.43(dd，1H)，7.45(d，2H)，7.63(d，2H)，8.05(d，1H)。
(3-methyl-4-nitrophenyl) - (4-trifluoromethylbenzyl) -carbamic acid tert-butyl ester
A solution of (3-methyl-4-nitrophenyl) - (4-trifluoromethylbenzyl) -amine (1.02g, 3.29mmol), di-tert-butyl dicarbonate (1.08g, 4.93mmol), dimethylaminopyridine (201mg, 1.64mmol), and triethylamine (687. mu.L, 4.93mmol) in acetonitrile (20mL) was stirred in an open flask at room temperature for 18 hours (to remove carbon dioxide). The volatiles were evaporated and the residue was dissolved in ethyl acetate (50 mL). This solution was washed with saturated aqueous ammonium chloride (2 × 50mL), dried over sodium sulfate, the volatiles were evaporated and the residue was purified on a FlashMaster system (silica, elution with an alkane/ethyl acetate mixture) to give the title compound as a pale yellow viscous oil (1.17g, 86%) which remained with traces of heptane.
1H NMR(CDCl3)：1.44(s，9H)，2.58(s，3H)，4.95(s，2H)，7.16(dd，1H)，7.21(d，1H)，7.34(d，2H)，7.60(d，2H)，7.96(d，1H)。
(4-amino-3-methylphenyl) - (4-trifluoromethylbenzyl) -carbamic acid tert-butyl ester
Mixing Na2S2O4A solution of (3.00g, 17.2mmol) in water (20mL) was added to a solution of (3-methyl-4-nitrophenyl) - (4-trifluoromethylbenzyl) -carbamic acid tert-butyl ester (1.41g, 3.44mmol) in tetrahydrofuran (20mL) and the resulting mixture was stirred at +55 ℃ for 20 h. After cooling to room temperature, the aqueous phase was saturated with potassium carbonate, the organic layer was separated and the aqueous layer was washed with ethyl acetate (2X 20 m)L) extracting. The combined organic layers were dried over sodium sulfate, the solvent was evaporated and the residue was purified on a FlashMaster system (silica, elution with heptane/ethyl acetate mixture) to give the title compound as a white solid (1.09g, 83%).
1H NMR(CDCl3)：1.41(s，9H)，2.10(s，3H)，3.59(br.s，2H)，4.78(s，2H)，6.56(d，1H)，6.76(br.s，2H)，7.36(d，2H)，7.55(d，2H)。
Compounds of the invention
Example 1
1a {4- [ (benzofuran-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester.
A mixture of 0.1M (4-amino-2-methylphenyl) -carbamic acid propyl ester (0.35mL, 0.035mmol) in Tetrahydrofuran (THF) and 0.1M solution of benzofuran-2-carbaldehyde (0.35mL) in Tetrahydrofuran (THF) was held at 55 deg.C for 60 minutes. Volatiles were removed under vacuum. To the resulting residue was added 0.2M sodium cyanoborohydride (NaBH) in methanol 3CN) (0.5mL) and acetic acid (0.03 mL). After sonicating it for 60 minutes, the reaction mixture was evaporated in vacuo and the title compound was isolated by preparative LC/MS to give 5.1mg of a colorless solid. The yield thereof was found to be 43%. LC/MS (M/z)339.2([ M + H)]+)；RT＝2.92，(UV，ELSD)94％，94％。
1b {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid ethyl ester.
LC/MS(m/z)323.9(M+)；RT＝2.67，(UV，ELSD)94％，100％。
1c {4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid ethyl ester.
LC/MS(m/z)340.0(M+)；RT＝2.87，(UV，ELSD)91％，100％。
1d { 2-methyl-4- [ (5-phenyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid ethyl ester.
LC/MS(m/z)365.3([M-H]+)；RT＝2.89，(UV，ELSD)97％，99％。
1e [4- (4-isopropyl-benzylamino) -2-methylphenyl ] -carbamic acid ethyl ester.
LC/MS(m/z)326.0(M+)；RT＝2.50，(UV，ELSD)84％，98％。
1f [4- (4-fluoro-benzylamino) -2-methylphenyl ] -carbamic acid propyl ester.
LC/MS(m/z)317.1([M+H]+)；RT＝2.32，(UV，ELSD)82％，96％。
1g (4- { [4- (4-chloro-benzenesulfonyl) -3-methyl-thiophen-2-ylmethyl ] -amino } -2-methylphenyl) -carbamic acid propyl ester.
LC/MS(m/z)493.0([M+H]+)；RT＝3.18，(UV，ELSD)91％，97％。
1h {4- [ (5-methyl-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester.
LC/MS(m/z)317.1([M-H]+)；RT＝2.41，(UV，ELSD)76％，93％。
1i {4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester.
LC/MS(m/z)382.0(M+)；RT＝2.96，(UV，ELSD)70％，87％。
1j {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester.
LC/MS(m/z)338.2(M+)；RT＝2.92，(UV，ELSD)85％，84％。
1k {4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester.
LC/MS(m/z)355.1([M+H]+)；RT＝3.08，(UV，ELSD)93％，97％。
11{ 2-methyl-4- [ (5-phenyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)379.3([M-H]+)；RT＝3.08，(UV，ELSD)91％，95％。
1m [4- (4-isopropyl-benzylamino) -2-methylphenyl ] -carbamic acid propyl ester.
LC/MS(m/z)341.2([M+H]+)；RT＝2.71，(UV，ELSD)73％，96％。
1o {4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester.
LC/MS(m/z)389.0([M+H]+)；RT＝3.24，(UV，ELSD)98％，99％。
1p {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester.
LC/MS(m/z)345.0([M+H]+)；RT＝3.21，(UV，ELSD)99％，100％。
1q {4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester.
LC/MS(m/z)361.0([M+H]+)；RT＝3.28，(UV，ELSD)95％，100％。
Ir [ 2-chloro-4- (4-isopropyl-benzylamino) -phenyl ] -carbamic acid ethyl ester.
LC/MS(m/z)346.0(M+)；RT＝3.48，(UV，ELSD)95％，100％。
1s [ 2-chloro-4- (4-fluoro-benzylamino) -phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)337.1([M+H]+)；RT＝3.20，(UV，ELSD)97％，99％。
1t 2-chloro-4- { [4- (4-chloro-benzenesulfonyl) -3-methyl-thiophen-2-ylmethyl ] -amino } -phenyl) -carbamic acid propyl ester.
LC/MS(m/z)514.2([M+H]+)；RT＝3.52，(UV，ELSD)94％，99％。
1u {4- [ (5-methyl-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester.
LC/MS(m/z)337.0([M-1]+)；RT＝3.27，(UV，ELSD)94％，100％。
1v {4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester.
LC/MS(m/z)403.9([M+H]+)；RT＝3.45，(UV，ELSD)99％，99％。
1w { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)356.9([M-H]+)；RT＝3.43，(UV，ELSD)98％，95％。
1x {4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester.
LC/MS(m/z)372.9([M-H]+)；RT＝3.49，(UV，ELSD)93％，99％。
1y {4- [ (benzofuran-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester.
LC/MS(m/z)357.1([M-H]+)；RT＝3.37，(UV，ELSD)95％，98％。
1z {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid ethyl ester.
LC/MS(m/z)335.0(M+)；RT＝2.91，(UV，ELSD)99％，100％。
1aa {4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -carbamic acid methyl ester.
LC/MS(m/z)341.1(M；RT＝2.62，(UV，ELSD)96％，100％。
1ab {4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -carbamic acid isopropyl ester.
LC/MS(m/z)400.0(M+)；RT＝2.93，(UV，ELSD)96％，100％。
1ac {4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)367.9(M+)；RT＝2.66，(UV，ELSD)87.0％，95.0％。
1ad {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)324.0(M+)；RT＝2.60，(UV，ELSD)88.2％，96.5％。
1ae [ 2-cyano-4- (4-isopropylbenzylamino) -phenyl J-carbamic acid ethyl ester.
LC/MS(m/z)337.0(M+)；RT＝3.25，(UV，ELSD)90.8％，99.6％。
1af [ 2-iodo-4- (4-isopropyl-benzylamino) -phenyl 7-carbamic acid propyl ester.
LC/MS(m/z)452.0(M+)；RT＝3.72，(UV，ELSD)88.0％，97.7％。
1ag [4- (4-tert-butyl-benzylamino) -2-iodophenyl ] -carbamic acid propyl ester.
LC/MS(m/z)465.9([M-1]+)；RT＝3.85，(UV，ELSD)86.6％，96.6％。
1ah [ 2-iodo-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)479.0([M+H]+)；RT＝3.54，(UV，ELSD)97.7％，99.8％。
1ai [ 2-iodo-4- (4-methylsulfanyl-benzylamino) -phenyl ] -carbamic acid propyl ester.
LC/MS(Z)454.8([M-1]+)RT＝3.38，(UV，ELSD)98.0％，99.8％。
1aj { 2-iodo-4- [4- (4-methylpiperazin-1-yl) -benzylamino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)508.9([M+H]+)；RT＝1.90，(UV，ELSD)62.0％，79.2％。
1ak {4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester.
LC/MS(m/z)421.9(M+)；RT＝3.27，(IJV，ELSD)98.7％，98.5％。
1al {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester.
LC/MS(m/z)378.0(M+)；RT＝3.25，(UV，ELSD)97.7％，99.5％。
1am [4- (4-tert-butyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid ethyl ester.
LC/MS(m/z)394.2(M+)；RT＝3.70，(UV，ELSD)90.2％，97.9％。
1an [4- (4-methylsulfanyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid ethyl ester.
LC/MS(m/z)384.1(M+)；RT＝3.22，(UV，ELSD)84.4％，94.6％。
1ao {4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester.
LC/MS(m/z)438.1([M+H]+)；RT＝3.47，(UV，ELSD)98.9％，99.9％。
1ap [4- (4-isopropylbenzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)393.3([M-1]+)；RT＝3.60，(UV，ELSD)71.3％，74.1％。
1q [4- (4-tert-butyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)408.3(M+)；RT＝3.89，(UV，ELSD)91.1％，98.6％。
1ar [ 2-trifluoromethyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)421.1([M+H]+)；RT＝3.52，(UV，ELSD)99.2％，99.8％。
1as [4- (4-dimethylamino-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)394.3([M-1]+)；RT＝2.02，(UV，ELSD)63.4％，100.0％。
1at [4- (4-methylsulfanyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)398.1(M+)；RT＝3.40，(UV，ELSD)92.5％，98.1％。
1au {4- [ (4-bromo-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid propyl ester.
LC/MS(m/z)394.0([M+H]+)；RT＝3.15，(UV，ELSD)97.5％，89.8％。
1av {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid propyl ester.
LC/MS(m/z)348.9(M+)；RT＝3.11，(UV，ELSD)99.7％，96.3％。
1aw [ 2-cyano-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)378.3([M+H]+)；RT＝3.25，(UV，ELSD)99.6％，99.7％。
1ax { 2-bromo-4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)447.9([M+H]+)；RT＝3.48，(UV，ELSD)99.3％，99.3％。
1ay { 2-bromo-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)402.9([M+H]+)；RT＝3.47，(UV，ELSD)95.7％，99.6％。
1az [ 2-bromo-4- (4-isopropylbenzylamino) -phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)406.1([M+H]+)；RT＝3.72，(UV，ELSD)80.2％，93.9％。
1ba [ 2-bromo-4- (4-tert-butyl-benzylamino) -phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)418.2(M+)；RT＝3.86，(UV，ELSD)87.2％，96.8％。
1bb [ 2-bromo-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)431.0([M+H]+)；RT＝3.55，(UV，ELSD)95.9％，99.8％。
1bc [ 2-bromo-4- (4-methylsulfanyl-benzylamino) -phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)409.0([M+H]+)；RT＝3.36，(UV，ELSD)98.4％，99.7％。
1bd N- {4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -butyramide.
LC/MS(m/z)382.0(M+)；RT＝2.66，(UV，ELSD)95.9％，99.3％。
1be N- {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -butyramide.
LC/MS(m/z)339.2([M+H]+)；RT＝2.61，(UV，ELSD)96.4％，98.4％。
1bf N- [4- (4-isopropylbenzylamino) -2-methoxyphenyl ] -butyramide.
LC/MS(m/z)341.1([M+H]+)；RT＝2.49，(UV，ELSD)91.1％，100.0％。
1bg N- [4- (4-tert-butyl-benzylamino) -2-methoxyphenyl ] -butyramide.
LC/MS(m/z)355.2([M+H]+)；RT＝2.65，(UV，ELSD)97.0％，100.0％。
1bh N- [ 2-methoxy-4- (4-trifluoromethyl-benzylamino) -phenyl ] -butyramide.
LC/MS(m/z)367.2([M+H]+)；RT＝2.79，(UV，ELSD)93.9％，96.6％。
1bi {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-furan-2-yl-phenyl } -carbamic acid propyl ester.
LC/MS(m/z)390.1(M+)；RT＝3.38，(UV，ELSD)92.9％，99.8％。
1bj [ 2-furan-2-yl-4- (4-isopropylbenzylamino) -phenyl ] -carbamic acid propyl ester.
LC/MS(m/z)393.2([M+H]+)；RT＝3.41，(UV，ELSD)89.9％，100.0％。
1bk [5- (4-fluorobenzylamino) -biphenyl-2-yl ] -carbamic acid propyl ester.
LC/MS(m/z)379.3([M+H]+)；RT＝3.06，(UV，ELSD)83.7％，99.7％。
1bl {5- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -biphenyl-2-yl } -carbamic acid propyl ester.
LC/MS(m/z)400.0(M+)；RT＝3.48，(UV，ELSD)89.8％，98.7％。
1bm [5- (4-isopropylbenzylamino) -biphenyl-2-yl ] -carbamic acid propyl ester.
LC/MS(m/z)403.2([M+H]+)；RT＝3.37，(UV，ELSD)73.8％，98.7％。
1zz N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2, 2, 2-trifluoroacetamide.
Data for this compound is reported above in the synthesis of intermediates of formulas XIII-XXIII.
Example 2
2a {4- [ (4-fluoro-benzyl) - (methyl) amino ] -2-methoxyphenyl } -carbamic acid propyl ester.
A mixture of (4-amino-2-methoxyphenyl) -carbamic acid propyl ester (0.3mL, 0.1M in Tetrahydrofuran (THF)) and 4-fluorobenzaldehyde (0.3mL, 0.1M in Tetrahydrofuran (THF)) was heated to 50 deg.C for 60 minutes and evaporated in vacuo. To the resulting residue was added sodium cyanoborohydride (NaBH) 3CN) (0.6mL, 0.2M in methanol) and acetic acid (0.03 mL). The reaction mixture was kept at room temperature for 30 minutes, and then formaldehyde (0.03mL, 37% aqueous solution) and acetic acid (0.03mL) were added thereto. After 30 minutes, the reaction mixture was evaporated in vacuo. The title compound was isolated by preparative LC/MS affording 4.3mg of a colorless solid in 41% yield.1H NMR(1∶4DMSO-H6/DMSO-D6)：8.04(br.s，NH)，7.25(m，2H)，7.13(m，3H)，6.36(s，1H)，6.24(d，1H)，4.53(s，2H，CH2)，3.93(t，2H)，3.70(s，3H，OMe)，2.97(s，NMe)，1.57(m，2H)，0.89(t，3H)。LC/MS(m/z)347.2([M+H]+)；RT＝2.32，(UV，ELSD)96％，100％。
The following compounds were prepared analogously from the appropriate anilines and aldehydes:
2b [4- (benzo [ b ] thiophen-2-ylmethyl- (methyl) amino) -2-methoxy-phenyl ] -carbamic acid propyl ester
1H NMR(1∶4DMSO-H6/DMSO-D6)：8.07(br.s，NH)，7.86(d，1H)，7.76(d，1H)，7.30(m，4H)，6.49(s，1H)，6.36(d，1H)，4.83(s，2H，CH2)，3.94(t，2H)，3.75(s，3H，OMe)，2.98(s，NMe)，1.58(m，2H)，0.89(t，3H))。LC/MS(m/z)385.0([M+H]+)；RT＝3.25，(UV，ELSD)99％，100％。
2c {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methoxy-phenyl } -carbamic acid propyl ester.
LC/MS(m/z)367.9(M+)；RT＝3.07，(UV，ELSD)99％，100％。
2d {4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-methoxy-phenyl } -carbamic acid propyl ester.
LC/MS(m/z)412.1(M+)；RT＝3.12，(UV，ELSD)99％，100％。
2e { 2-methoxy-4- [ methyl- (5-methyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)348.0(M+)；RT＝2.46，(UV，ELSD)95％，100％。
2f {4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -carbamic acid propyl ester.
LC/MS(m/z)398.0([M+2]+)；RT＝3.10，(UV，ELSD)97.0％，98.1％。
2g {4- [ (4-isopropylbenzyl) - (methyl) amino ] -2-methylphenyl } -carbamic acid propyl ester.
LC/MS(m/z)355.2([M+H]+)；RT＝2.70，(UV，ELSD)85.4％，99.5％。
2h { 2-methyl-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)380.3(M+)；RT＝3.18，(UV，ELSD)95.2％，98.5％。
2i { 2-methyl-4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)358.0(M+)；RT＝2.42，(UV，ELSD)97.9％，99.0％。
2j {4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid ethyl ester.
LC/MS(m/z)374.9([M+H]+)；RT＝3.92，(UV，ELSD)97.8％，100.0％。
2k { 2-chloro-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid ethyl ester.
LC/MS(m/z)387.3([M+H]+)；RT＝3.59，(UV，ELSD)99.9％，100.0％。
2l { 2-chloro-4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -phenyl } -carbamic acid ethyl ester.
LC/MS(m/z)363.1([M-1]+)；RT＝3.36，(UV，ELSD)92.1％，99.6％。
2m {4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid propyl ester.
LC/MS(m/z)418.1([M+H]+)；RT＝3.80，(UV，ELSD)99.3％，100.0％。
2n { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)374.0([M+H]+)；RT＝3.77，(UV，ELSD)99.6％，99.9％。
2o {4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid propyl ester.
LC/MS(m/z)389.2([M+H]+)；RT＝4.09，(UV，ELSD)99.6％，99.9％。
2p { 2-chloro-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)401.1([M+H]+)；RT＝3.81，(UV，ELSD)99.8％，100.0％。
2q {4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester.
LC/MS(m/z)435.9([M-1]+)；RT＝3.56，(UV，ELSD)99.4％，100.0％。
2r {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } carbamic acid ethyl ester.
LC/MS(m/z)392.3(M+)；RT＝3.56，(UV，ELSD)99.0％，100.0％。
2s {4 (4-isopropyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester.
LC/MS(m/z)395.3([M+H]+)；RT＝3.85，(UV，ELSD)99.0％，100.0％。
2t {4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester.
LC/MS(m/z)409.2([M+H]+)；RT＝3.98，(UV，ELSD)97.9％，99.8％。
2u {4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester.
LC/MS(m/z)421.2([M+H]+)；RT＝3.59，(UV，ELSD)92.9％，98.5％。
2v {4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester.
LC/MS(m/z)397.0([M-1]+)；RT＝3.48，(UV，ELSD)99.4％，99.9％。
2w {4- [ (5-bromo-thiophen-2-ylmethyl) -methyl-amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester.
LC/MS(m/z)449.9([M-1]+)；RT＝3.76，(UV，ELSD)99.5％，100.0％。
2x {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester.
LC/MS(m/z)405.9(M+)；RT＝3.73，(UV，ELSD)98.4％，100.0％。
2y {4- [ (4-isopropyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester.
LC/MS(m/z)409.2([M+H]+)；RT＝4.04，(UV，ELSD)99.3％，99.9％。
2z {4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester.
LC/MS(m/z)423.1([M+H]+)；RT＝4.29，(UV，ELSD)98.9％，99.7％。
2aa {4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester.
LC/MS(m/z)435.3([M+H]+)；RT＝3.77，(UV，ELSD)99.7％，99.9％。
2ab {4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester.
LC/MS(m/z)412.0(M+)；RT＝3.67，(UV，ELSD)99.3％，99.8％。
2ac {4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-cyanophenyl } -carbamic acid propyl ester.
LC/MS(m/z)407.0(M+)；RT＝3.39，(UV，ELSD)97.7％，99.6％。
2ad {4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-cyanophenyl } -carbamic acid propyl ester.
LC/MS(m/z)380.3([M+H]+)；RT＝3.83，(UV，ELSD)99.4％，99.9％。
2ae { 2-cyano-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)392.3([M+H]+)；RT＝3.44，(UV，ELSD)98.9％，99.9％。
2af { 2-bromo-4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)462.1([M+H]+)；RT＝3.84，(UV，ELSD)98.2％，99.9％。
2ag { 2-bromo-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino]-phenyl } -carbamic acid propyl ester. LC/MS (M/z)418.1([ M + H)]+)；RT＝3.83，(UV，ELSD)99.3％，100.0％。
2ah { 2-bromo-4- [ (4-isopropylbenzyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)420.2([M+H]+)；RT＝4.04，(UV，ELSD)98.8％，99.7％。
2ai { 2-bromo-4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)432.1(M+)；RT＝4.15，(UV，ELSD)99.3％，100.0％。
2aj { 2-bromo-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester.
LC/MS(m/z)447.0([M+H]+)；RT＝3.84，(UV，ELSD)98.4％，99.9％。
2zz N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2, 2, 2-trifluoroacetamide.
Data for this compound is reported above in the synthesis of intermediates of formulas XIII-XXIII.
Example 3
3a {4- [ (4-Fluorobenzyl) - (methyl) -amino ] -2-isopropoxyphenyl } -carbamic acid ethyl ester
4- (4-Fluorobenzyl) - (methyl) -amino-2-isopropoxyaniline (0.29g) was dissolved in anhydrous dioxane (3 mL). N, N-diisopropylethylamine (0.27mL) and ethyl chloroformate (0.15mL) were added thereto and the reaction mixture was stirred at room temperature overnight. Water (5mL) was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate (3X 10 mL). The organic phase was dried over sodium sulfate and filtered. Mixing the solventEvaporation in vacuo and purification of the crude product by flash column chromatography (silica gel, gradient elution with heptane/ethyl acetate 19: 1, 1% triethylamine). The solvent was evaporated in vacuo to give the title compound as a colourless oil (0.20g, 55%). LC-MS (M/z)361.3([ M + H) ]+)；RT＝2.58，(UV，ELSD)90％，98％。
Example 4
4a [4- (3-Fluorobenzylamino) -2-methoxyphenyl J-carbamic acid ethyl ester
A solution of 3-fluorobenzaldehyde in dry methanol (84. mu.L, 476mM) was added to a solution of (4-amino-2-methoxyphenyl) -carbamic acid ethyl ester (84. mu.L, 0.476M in dry methanol). The resulting mixture was heated to 40 ℃ for 30 minutes. The solvent was evaporated in vacuo and the remaining material was dissolved in 1, 2-dichloroethane (1 mL). Sodium triacetoxyborohydride (20mg) was added thereto and the resulting mixture was kept at room temperature for 2 hours, and sonication was performed for 10 minutes in each of the two periods. The reaction mixture was filtered through silica gel (500mg) and the column was washed with 1, 2-dichloroethane (3 mL). The solvent was evaporated in vacuo to give the title compound (5.7mg, 45%).
LC-MS(m/z)318.1(M+)；RT＝2.33，(UV，ELSD)93％，100％。
The following compounds were prepared in a similar manner:
4b [4- (4-Isopropylbenzylamino) -2-methoxyphenyl ] -carbamic acid ethyl ester
LC-MS(m/z)341.3([M-1]+)；RT＝2.51，(UV，ELSD)86％，100％。
4c { 2-methoxy-4- [ (3-methylthiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid ethyl ester
LC-MS(m/z)319.9(M+)；RT＝2.10，(UV，ELSD)79％，99％。
4d [4- (2, 4-difluorobenzylamino) -2-methoxyphenyl ] -carbamic acid ethyl ester
LC-MS(m/z)337.2([M+H]+)；RT＝2.44，(UV，ELSD)93％，100％。
Example 5
5a [ 2-cyclopentyloxy-4- (4-methoxybenzylamino) -phenyl ] carbamic acid ethyl ester
(2-Cyclopentyloxy-4-nitrophenyl) -carbamic acid ethyl ester (294mg) was dissolved in ethanol (26 mL). Zinc particles (1.63g) and aqueous hydrochloric acid (5.0mL, 2M) were added to it. The resulting mixture was sonicated at room temperature for 6.5 hours and then allowed to stand at room temperature overnight. Saturated aqueous sodium bicarbonate (100mL) was added and the mixture was extracted with ethyl acetate (2X 100 mL). The organic phase was washed with water (100mL) and brine (100mL), dried over magnesium sulfate, and evaporated in vacuo. The resulting oil was dissolved in methanol (1.82mL) and an aliquot of this solution (40. mu.L) was mixed with 4-methoxybenzaldehyde (40. mu.L, 0.466M in methanol). The resulting mixture was heated to 40 ℃ for 20 minutes. The solvent was evaporated in vacuo and the remaining material was dissolved in 1, 2-dichloroethane (1 mL). Sodium triacetoxyborohydride (20mg) was added thereto and the resulting mixture was left at room temperature for 2 hours, and sonication was carried out for 10 minutes in each of the two periods. The reaction mixture was filtered through silica gel (500mg), and the column was washed with 1, 2-dichloroethane (3 mL). The solvent was evaporated in vacuo to give the title compound (6.0mg, 84% from aldehyde).
LC-MS(m/z)384.1(M+)；RT＝2.40，(UV，ELSD)76％，96％。
The following compounds were prepared in a similar manner:
5b [ 2-Cyclopentyloxy-4- (3-fluoro-2-methylbenzylamino) -phenyl ] -carbamic acid ethyl ester
The product was purified by preparative LC-MS.
LC-MS(m/z)386.2(M+)；RT＝3.22，(UV，ELSD)80％，91％。
5c [4- (3-fluoro-2-methylbenzylamino) -2-phenylethoxyphenyl ] -carbamic acid ethyl ester
The product was purified by preparative LC-MS.
LC-MS(in/z)422.3(M+)；RT＝3.38，(UV，ELSD)84％，91％。
5d [ 2-benzyloxy-4- (3-fluoro-2-methylbenzylamino) -phenyl ] -carbamic acid ethyl ester
The product was purified by preparative LC-MS.
LC-MS(m/z)409.2([M+H]+)；RT＝3.30，(UV，ELSD)80％，89％。
5e [ 2-benzyloxy-4- (4-methylsulfanylbenzylamino) -phenyl ] -carbamic acid ethyl ester
LC-MS(m/z)422.1(M+)；RT＝2.92，(UV，ELSD)83％，89％。
5f {4- [ (benzo [ b ] thiophen-3-ylmethyl) -amino ] -2-cyclopentyloxyphenyl } -carbamic acid ethyl ester
The product was purified by preparative LC-MS.
LC-MS(m/z)411.1([M+H]+)；RT＝3.12，(UV，ELSD)79％，85％。
5g of [4- (3-fluoro-2-methylbenzylamino) -2-isopropoxyphenyl ] -carbamic acid ethyl ester
The product was purified by preparative LC-MS.
LC-MS(m/z)361.2([M+H]+)；RT＝2.95，(UV，ELSD)77％，86％。
5h [ 2-benzyloxy-4- (3-methoxybenzylamino) -phenyl ] -carbamic acid ethyl ester
LC-MS(m/z)407.3([M+H]+)RT＝2.81，(UV，ELSD)76％，87％。
5i {4- [ (benzo [1, 3] dioxol-5-ylmethyl) -amino ] -2-isopropoxyphenyl } -carbamic acid ethyl ester
LC-MS(m/z)372.1(M+)；RT＝2.24，(UV，ELSD)76％，86％。
Example 6
6o N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3-cyclohexylpropionamide.
The method A comprises the following steps: to a mixture of 2-chloro-N (4) - (5-chloro-thiophen-2-ylmethyl) -N (4) -methyl-benzene-1, 4-diamine (14mg) and triethylamine (0.04mL) in acetonitrile (1mL) was added 3-cyclohexyl-propionyl (proionyl) chloride (0.03 mL). The volatiles were evaporated in vacuo and the title compound was isolated by preparative LC-MS.
The method B comprises the following steps: to a compound of 2-chloro-N (4) - (5-chloro-thiophen-2-ylmethyl) -N (4) -methyl-benzene-1, 4-diamine (470mg, 1.64mmol) and sodium bicarbonate in acetonitrile (40mL) was added 3-cyclohexyl-propionyl (proionyl) chloride (372mg, 2.13 mmol). After 1 hour, the reaction mixture was quenched with water (100mL) and ice. The title compound was isolated by filtration as a grey-brown solid. The yield was 0.422g, 60%.
LC/MS(m/z)425.4([M+H]+)；RT＝4.09，(UV，ELSD)97％，100％。1HNMR(DMSO-d6)：0.87(m，2H)，1.05-1.29(m，4H)，1.47(q，2H)，1.56-1.76(m，5H)，2.29(t，2H)，2.91(s，3H)，4.67(s，2H)，6.76(dd，1H)，6.83(d，1H)，6.88(d，1H)，6.96(d，1H)，7.27(d，1H)。
By method A from the corresponding aniline and the appropriate acid chloride, chloroformate, carbamoyl chloride, isocyanate, or di-tert-butyl dicarbonate (Boc)2O) the following compounds were prepared similarly. Triethylamine is used as base in the case of acid chlorides. Pyridine is used as a base in the case of chloroformates and carbamoyl chlorides. In the case of isocyanate and Boc2O no base was used. In the case of (4-amino-3-chlorophenyl) - (5-chloro-thiophen-2-ylmethyl) -carbamic acid tert-butyl ester as aniline, the residue is, after evaporation, dissolved in a 1: 1 mixture of trifluoroacetic acid and dichloromethane with 2% anisoleTreated for 1 hour and evaporated again and then treated with preparative LC-MS:
6a N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2-phenylacetamide.
LC/MS(m/z)406.2([M+2]+)；RT＝3.58，(UV，ELSD)95.5％，100.0％。
6b N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3, 3-dimethylbutanamide.
LC/MS(m/z)384.1(M+)；RT＝3.72，(UV，ELSD)98.3％，100.0％。
6c N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3-phenylpropanamide.
LC/MS(m/z)418.1(M+)；RT＝3.66，(UV，ELSD)98.8％，100.0％。
6d N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -butyramide.
LC/MS(m/z)356.1(M+)；RT＝3.32，(UV，ELSD)99.4％，100.0％。
6e pentanoic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl 7-amide.
LC/MS(m/z)371.1(M+H]+)；RT＝3.55，(UV，ELSD)98.3％，100.0％。
6f Cyclopropanecarboxylic acid { 2-chloro-4- [ (5- (chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide.
LC/MS(m/z)355.0([M+H]+)；RT＝3.23，(UV，ELSD)98.6％，100.0％。
6g cyclobutanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide.
LC/MS(m/z)368.1(M+)；RT＝3.46，(UV，ELSD)93.4％，98.5％。
6h Cyclopentanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide.
LC/MS(m/z)382.0(M+)；RT＝3.65，(UV，ELSD)95.2％，99.2％。
6i Cyclohexanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide.
LC/MS(m/z)396.1(M+)；RT＝3.83，(UV，ELSD)97.3％，99.8％。
6j N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2-thiophen-2-yl-acetamide.
LC/MS(m/z)412.0([M+2]+)；RT＝3.54，(UV，ELSD)79.3％，96.4％。
6k N- (2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (3-methoxyphenyl) -acetamide.
LC/MS(m/z)435.0([M+H]+)；RT＝3.54，(UV，ELSD)90.9％，100.0％。
6l N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-chloro-phenyl) -acetamide.
LC/MS(m/z)438.0(M+)；RT＝3.78，(UV，ELSD)98.9％，100.0％。
6m N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-methoxy-phenyl) -acetamide.
LC/MS(m/z)436.0([M+2]+)；RT＝3.53，(UV，ELSD)92.0％，99.4％。
6n N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-fluoro-phenyl) -acetamide.
LC/MS(m/z)421.9(M+)；RT＝3.58，(UV，ELSD)92.2％，100.0％。
6p N- (2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2, 2-dimethylpropionamide.
LC/MS(m/z)357.0([M+H]+)；RT＝3.34，(UV，ELSD)96.4％，99.5％。
6q N- { 2-chloro-5- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-phenoxyacetamide.
LC/MS(m/z)406.9([M+H]+)；RT＝3.54，(UV，ELSD)93.9％，100.0％。
6r N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-phenylacetamide.
LC/MS(m/z)391.1([M+H]+)；RT＝3.29，(UV，ELSD)98.0％，100.0％。
6s N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -3, 3-dimethylbutanamide.
LC/MS(m/z)371.1([M+H]+)；RT＝3.40，(UV，ELSD)94.1％，98.1％。
6t N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -butyramide.
LC/MS(m/z)343.0([M+H]+)；RT＝3.01，(UV，ELSD)77.8％，88.9％。
6u pentanoic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide.
LC/MS(m/z)357.1([M+H]+)；RT＝3.24，(UV，ELSD)95.7％，100.0％。
6v Cyclopropanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide.
LC/MS(m/z)340.8(M+)；RT＝2.93，(UV，ELSD)97.6％，100.0％。
6w cyclobutanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl ] -amide.
LC/MS(m/z)355.0([M+H]+)；RT＝3.15，(UV，ELSD)95.1％，100.0％。
6x Cyclopentanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide.
LC/MS(m/z)368.8([M+H]+)；RT＝3.34，UV，ELSD)99.0％，100.0％。
6y cyclohexane carboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide.
LC/MS(m/z)384.0([M+2]+}；RT＝3.50，(UV，ELSD)98.2％，100.0％。
6z N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-thiophen-2-yl-acetamide.
LC/MS(m/z)397.0([M+H]+)；RT＝3.24(UV，ELSD)94.8％，100.0％。
6aa N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (3-methoxyphenyl) -acetamide.
LC/MS(m/z)420.9([M+H]+)；RT＝3.26，(UV，ELSD)64.6％，99.8％。
6ab N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-chlorophenyl) -acetamide.
LC/MS(m/z)425.0([M+H]+)；RT＝3.50，(UV，ELSD)98.9％，100.0％。
6ac N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-methoxyphenyl) -acetamide.
LC/MS(m/z)421.2([M+H]+)；RT＝3.24，(UV，ELSD)95.3％，99.6％。
6ad N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-fluorophenyl) -acetamide.
LC/MS(m/z)409.0([M+H]+)；RT＝3.31，(UV，ELSD)97.2％，100.0％。
6ae 2, 3-dihydro-benzo [1, 4] dioxine-6-carboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino J-phenyl) -amide.
LC/MS(m/z)434.9([M+H]+)；RT＝3.21，(UV，ELSD)92.7％，100.0％。
6af 2, 3-dihydro-benzofuran-5-carboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide.
LC/MS(m/z)419.3([M+H]+)；RT＝3.26，(UV，ELSD)81.6％，94.8％。
6ag N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -3-cyclohexylpropionamide.
LC/MS(m/z)411.1([M+H]+)；RT＝3.89，(UV，ELSD)95.3％，99.5％。
6ah N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -2, 2-dimethylpropionamide.
LC/MS(m/z)350.1(M+)；RT＝2.98，(UV，ELSD)91.8％，99.1％。
6ai N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methylamino ] -2-methyl-phenyl } -2-phenylacetamide.
LC/MS(m/z)384.1(M；RT＝3.04，(UV，ELSD)95.8％，100.0％。
6aj N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -3, 3-dimethylbutanamide.
LC/MS(m/z)364.1(M+)；RT＝3.10，(UV，ELSD)93.0％，99.7％。
6ak N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -3-phenylpropanamide.
LC/MS(rn/z)399.1([M+H]+)；RT＝3.12，(UV，ELSD)98.2％，99.9％。
6al N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -butyramide.
LC/MS(m/z)337.3([M+H]+)；RT＝2.68，(UV，ELSD)92.5％，99.7％。
6am 2, 2, 2-trichloro-N- (4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -acetamide.
LC/MS(m/z)411.9([M+H]+)；RT＝3.65，(UV，ELSD)97.3％，100.0％。
6an cyclopropanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl) -amide.
LC/MS(m/z)335.1([M+H]+)；RT＝2.58，(UV，ELSD)86.4％，97.8％。
6ao cyclobutanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -amide.
LC/MS(m/z)348.0(M+)；RT＝2.79，(UV，ELSD)95.4％，100.0％。
6ap cyclopentanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -amide.
LC/MS(m/z)363.2([M+H]+)；RT＝2.99，(UV，ELSD)97.7％，99.9％。
6aq Cyclohexanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -amide.
LC/MS(m/z)377.1([M+H]+)；RT＝3.16，(UV，ELSD)88.0％，97.5％。
6ar N- (4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2-thiophen-2-yl-acetamide.
LC/MS(m/z)390.0(M+)；RT＝3.02，(UV，ELSD)97.2％，99.9％。
6as N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2- (3-methoxyphenyl) -acetamide.
LC/MS(m/z)416.0([M+2]+)；RT＝3.03，(UV，ELSD)92.9％，100.0％。
6at N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -malonamic acid methyl ester.
LC/MS(m/z)366.1(M+)；RT＝2.53，(UV，ELSD)94.5％，100.0％。
6au 2- (4-chlorophenyl) -N- {4- [ (5-chloro-thiophen-2-ylmethyl- (methyl) amino ] -2-methylphenyl } -acetamide.
LC/MS(m/z)418.1(M+)；RT＝3.31，(UV，ELSD)97.3％，99.9％。
6av N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2- (4-methoxyphenyl) -acetamide.
LC/MS(m/z)415.2([M+H]+)；RT＝2.99，(UV，ELSD)87.8％，98.1％。
6aw N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2- (4-fluorophenyl) -acetamide.
LC/MS(m/z)403.2([M+H]+)；RT＝3.10，(UV，ELSD)94.5％，99.9％。
6ax N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -3-cyclohexylpropionamide.
LC/MS(m/z)405.1([M+H]+)；RT＝3.61，(UV，ELSD)92.6％，98.9％。
6ba { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid phenyl ester.
LC/MS(m/z)406.2(M+)；RT＝3.78，(UV，ELSD)96.3％，99.4％。
6bb { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid benzyl ester.
LC/MS(m/z)422.1([M+2]+)；RT＝3.91，(UV，ELSD)92.7％，99.3％。
6bc { 2-chloro-4 [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid isobutyl ester.
LC/MS(m/z)388.1([M+2]+)；RT＝3.99，(UV，ELSD)99.0％，100.0％。
6bd { 2-chloro-4 [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid butyl ester.
LC/MS(m/z)386.0(M+)；RT＝4.03，(UV，ELSD)97.1％，99.9％。
6be { 2-chloro-4 [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid hexyl ester.
LC/MS(m/z)415.9([M+2]+)；RT＝4.44，(UV，ELSD)91.7％，98.9％。
6bf 2-chloro-4- (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl) -carbamic acid 4-nitrobenzyl ester.
LC/MS(m/z)465.0(M+)；RT＝3.80，(UV，ELSD)91.7％，97.9％。
6bg { 2-chloro-4 [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid but-3-enyl ester.
LC/MS(m/z)383.9(M+)；RT＝3.82，(UV，ELSD)93.9％，99.6％。
6bh { 2-chloro-4 [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid but-2-ynyl ester.
LC/MS(m/z)384.0([M+2]+)；RT＝3.61，(UV，ELSD)76.3％，99.0％。
6bi { 2-chloro-4 [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 2, 2-dimethylpropyl ester.
LC/MS(m/z)399.9(M+)；RT＝4.11，(UV，ELSD)98.8％，99.6％。
6bj { 2-chloro-4 [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 2-chlorobenzyl ester.
LC/MS(m/z)453.9(M+)；RT＝4.12，(UV，ELSD)97.5％，99.8％。
6bk { 2-chloro-4 [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 3-chloropropyl ester.
LC/MS(m/z)407.9([M+2]+)；RT＝3.72，(UV，ELSD)88.7％，97.5％。
6bl { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 2-benzyloxyethyl ester.
LC/MS(m/z)464.0(M+)；RT＝3.86，(UV，ELSD)89.1％，98.7％。
6bm 3- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -1-methyl-1-propyl-urea.
LC/MS(m/z)388.1([M+3]+)；RT＝3.38，(UV，ELSD)86.0％，99.5％。
6bo 1- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3- (2-fluorophenyl) -urea.
LC/MS(m/z)425.0([M+2]+)；RT＝3.65，(UV，ELSD)94.9％，99.9％。
Example 7
7a N- (4- { [5- (4-chlorophenoxy) -1, 3-dimethyl-1H-pyrazol-4-ylmethyl ] -amino } -2-methylphenyl) -2, 2-dimethylpropanamide.
A mixture of N- (4-amino-2-methylphenyl) -2, 2-dimethylpropionamide (300mg, 1.45mmol) and 5- (4-chlorophenoxy) -1, 3-dimethyl-1H-pyrazole-4-carbaldehyde (360mg, 1.45mmol) in acetonitrile (4mL) was heated and stirred under microwave irradiation at 170 ℃ for 20 minutes. Mixing the obtained reactionTo a solution of sodium cyanoborohydride (0.36g) in methanol was carefully added acetic acid (1 mL). After 60 minutes, it was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the organic layer was evaporated. By SiO2The title compound was isolated by flash column chromatography eluting with heptane-ethyl acetate and then precipitated from ethyl acetate with heptane. The yield was 112mg, 18%. LC/MS-TOF (m/z) 441; RT 2.34, (UV, ELSD) 98%, 100%. 1H NMR(DMSO-d6)：1.18(s，9H)，1.96(s，3H)，2.15(s，3H)，3.47(s，3H)，3.75(d，2H)，5.4(t，1H，NH)，6.29(dd，1H)，6.33(d，1H)，6.24(d，1H)，6.99(d，2H)，7.41(d，2H)，8.58(s，1H，NH)。
The following compounds were prepared analogously from the corresponding anilines and aldehydes:
7b 2, 2-dimethyl-N- { 2-methyl-4- [ (6-phenoxypyridin-3-ylmethyl) -amino ] -phenyl } -propionamide.
LC/MS-TOF(m/z)390；RT＝2.54，(L1V，ELSD)90％，100％。
7c 2, 2-dimethyl-N- { 2-methyl-4- [ (3-methyl-5-phenylisoxazol-4-ylmethyl) -amino ] -phenyl } -propionamide.
LC/MS-TOF(m/z)378；RT＝2.82，(UV，ELSD)97％，100％。1HNMR(DMSO-d6)：1.19(s，9H)，1.96(s，3H)，2.3(s，3H)，4.11(d，2H)，5.85(t，1H，NH)，6.42(overlappingm，2H)，6.79(d，1H)，7.55(m，3H)，7.72(d，2H)，8.61(s，1H，NH)。
7d 2- (4-fluorophenyl) -N- { 2-methyl-4- [ (6-trifluoromethylpyridin-3-ylmethyl) -amino ] -phenyl } -acetamide.
LC/MS-TOF(m/z)418.4([M+H]+)；RT＝2.75，(UV，ELSD)99％，100％。1H NMR(DMSO-d6)：1.98(s，3H)，3.54(s，2H)，4.39(d，2H)，6.28(t，1H，NH)，6.36(dd，1H)，6.43(d，1H)，6.91(d，1H)，7.14(t，2H)，7.35(dd，2H)，7.85(d，1H)，7.99(dd，1H)，8.74(d，1H)，9.21(s，1H，NH)。
7e 3, 3-dimethyl-N- { 2-methyl-4- [ (6-trifluoromethylpyridin-3-ylmethyl) -amino ] -phenyl } -butyramide.
LC/MS-TOF(m/z)380.5([M+H]+)；RT＝2.75，(UV，ELSD)97％，99％。
7f 2- (4-fluorophenyl) -N- { 2-methyl-4- [ (6-p-tolyloxypyridin-3-ylmethyl) -amino ] -phenyl) -acetamide.
LC/MS(m/z)456.2([M+H]+)；RT＝2.79，(UV，ELSD)82.5％，99.8％。
7g 3, 3-dimethyl-N- { 2-methyl-4- [ (6-p-tolyloxypyridin-3-ylmethyl) -amino ] -phenyl } -butyramide.
LC/MS(m/z)418.3([M+H]+)；RT＝2.75，(UV，ELSD)62％，93％。
7h N- (4- { [6- (4-cyanophenoxy) -pyridin-3-ylmethyl ] -amino } -2-methylphenyl) -2- (4-fluorophenyl) -acetamide.
LC/MS(m/z)467.2([M+H]+)；RT＝2.65，(UV，ELSD)72％，96％。
7i N- {4- [ (6-Chloropyridin-3-ylmethyl) -amino ] -2-methylphenyl } -2- (4-fluorophenyl) -acetamide.
LC/MS(m/z)384.1([M+H)+)；RT＝2.46，(UV，ELSD)87％，99％。
7j 2- (4-fluorophenyl) -N- { 2-methyl-4- [ (4-methyl-2-phenylpyrimidin-5-ylmethyl) -amino ] -phenyl } -acetamide.
LC/MS(m/z)441.4([M+H]+)；RT＝2.97，(UV，ELSD)90％，100％。
7k 3, 3-dimethyl-N- { 2-methyl-4- [ (2-phenylpyrimidin-5-ylmethyl) -amino ] -phenyl } -butyramide.
LC/MS-TOF(m/z)389.6([M+H]+)；RT＝2.83，(UV，ELSD)89％，95％。
Example 8
8a {4- [ (5-dimethylamino-3-methyl-benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester
A solution of (4-amino-2-methylphenyl) -carbamic acid propyl ester (21mg, 0.10mmol) and 5-dimethylamino-3-methyl-benzo [ b ] thiophene-2-carbaldehyde (26mg, 0.12mmol) in acetonitrile (0.5mL) was heated at 170 ℃ for 2 minutes using a Personal Chemistry Smith synthesizer microwave apparatus. After cooling to room temperature, a solution of sodium cyanoborohydride (25mg, 0.40mmol) in methanol (0.1mL) was added, followed by acetic acid (50. mu.L) and the mixture was stirred for 30 minutes. It was partitioned between saturated aqueous sodium bicarbonate (10mL) and ethyl acetate (10mL) and the organic layer was dried over sodium sulfate and evaporated. Preparation LC-MS provided the title compound (32mg, 77% yield).
LC/MS-TOF(m/z)412.4([M+H]+)；RT＝2.02，(UV，ELSD)81％，97％。
The following compounds were prepared analogously from the appropriate anilines and aldehydes:
8b [4- (3-fluoro-4-trifluoromethyl-benzylamino) -2-methylphenyl ] -carbamic acid ethyl ester
LC/MS(m/z)371.2([M+H]+)；RT＝3.10，(UV，ELSD)83％，96％。
8c [4- (4-chloro-benzylamino) -2-methylphenyl ] -carbamic acid ethyl ester
LC/MS(m/z)319.0([M+H]+)；RT＝2.57，(UV，ELSD)79％，95％。
8d {4- [ (6 ═ methoxy-benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester
LC/MS-TOF(m/z)384.4(M+)；RT＝3.07，(UV，ELSD)97％，94％。
8e {4- [ (7-dimethylamino-benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester
LC/MS-TOF(m/z)398.4([M+H]+)；RT＝2.64，(UV，ELSD)97％，100％。
8f {4- [ (6-methoxy-benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid ethyl ester
LC/MS-TOF(m/z)370.4(M+)；RT＝2.79，(LW，ELSD)98％，99％。
8g of 4- [ (3-methyl-4-propoxycarbonylamino-phenylamino) -methyl ] -benzoic acid methyl ester
LC/MS(m/z)356.1(NI)；RT＝2.52，(UV，ELSD)80％，100％。
Example 9
9a N- [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -butyramide
To a solution of (4-amino-3-methylphenyl) - (4-trifluoromethyl-benzyl) -carbamic acid tert-butyl ester (500mg, 1.31mmol) in anhydrous tetrahydrofuran (10mL) at 0 deg.C was added pyridine (159. mu.L, 1.97mmol), to which was then added butyryl chloride (164. mu.L, 1.58mmol) dropwise. After 5 minutes, the reaction mixture was allowed to warm to room temperature and stirring was continued for 1 hour. The reaction mixture was then diluted with ethyl acetate, washed with 2N HCl, and aqueous sodium bicarbonate (twice), and brine, and then dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was dissolved in a 1: 1 mixture of dichloromethane and trifluoroacetic acid. After 30 minutes, the mixture was evaporated to dryness at room temperature, the residue was dissolved in ethyl acetate (10mL), the solution was washed twice with saturated aqueous sodium bicarbonate solution, twice with water and then dried over sodium sulfate. The solvent was evaporated and the residue was recrystallized from ethyl acetate: heptane to give the title compound (226mg, 49%) as a colorless solid.
1H NMR(DMSO-d6)：0.90(t，3H)，1.58(sextet，2H)，2.01(s，3H)，2.19(t，2H)，4.35(d，2H)，6.24(t，1H)，6.32(dd，1H)，6.41(d，1H)，6.87(d，1H)，7.55(d，2H)，7.67(d，2H)，8.91(s，1H).LC/MS(m/z)350.2(M+)；RT＝2.77，(UV，ELSD)95％，100％。
The following compounds were prepared analogously:
9b [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid ethyl ester
Yield: 254mg (55%).
LC/MS(m/z)353.2([M+H]+)；RT＝2.93，(W1，ELSD)97％，100％。
1H NMR(DMSO-d6)：1.19(br.s，3H)，2.03(s，3H)，4.02(q，2H)，4.35(s，2H)，6.29(br.s，1H)，6.33(dd，1H)，6.41(d，1H)，6.86(br.d，1H)，7.55(d，2H)，7.67(d，2H)，8.39(br.s，1H)。
Example 10
10a N- [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -2-piperidin-1-yl-acetamide
To a solution of (4-amino-3-methylphenyl) - (4-trifluoromethyl-benzyl) -carbamic acid tert-butyl ester (15.2mg, 40. mu. mol) in DMF (100. mu.L) was added a solution of O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 27.4mg, 72. mu. mol) in DMF (100. mu.L) to which was then added i-PR2NEt (25. mu.L, 144. mu. mol) and piperidin-1-yl-acetic acid (8.6mg, 60. mu. mol). The resulting mixture was shaken at room temperature for 3 hours, after which it was diluted with ethyl acetate (10mL), washed with a saturated aqueous ammonium chloride solution (2 × 10mL), dried over sodium sulfate, and evaporated. The residue was purified on a FlashMaster system (silica, elution with heptane/ethyl acetate mixture) to give [ 3-methyl-4- (2-piperidin-1-yl-acetylamino) -phenyl as a white solid]- (4-trifluoromethylbenzyl) -carbamic acid tert-butyl ester (10.7mg, 53%). It was dissolved in methylene chloride (2) 00 μ L) and trifluoroacetic acid (200 μ L), and the solution was left at room temperature for 30 minutes, after which the volatile materials were evaporated off and the residue was dried under vacuum at 0.1mmHg and +40 ℃ for 1 hour. The trifluoroacetic acid addition salt of the title compound was obtained in quantitative yield as a yellow semi-solid.
LC/MS-TOF(m/z)406.4([M+H]+)；RT＝2.02，(UV，ELSD)99％，98％。
The following compounds were prepared analogously from aniline and carboxylic acid:
10b N- [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -2-pyrrolidin-1-yl-acetamide
LC/MS-TOF(m/z)392.3([M+H]+)，RT＝2.04，(UV，ELSD)98％，99％。
10c N- [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -2-morpholin-4-yl-acetamide
LC/MS-TOF(m/z)408.3([M+H]+)；RT＝1.98，(UV，ELSD)99％，100％。
10d (S) -2-amino-4-methyl-pentanoic acid [ 2-methyl-4- (4-trifluoromethylbenzylamino) -phenyl ] -amide
LC/MS-TOF(m/z)394([M+H]+)；RT＝2.12，(UV，ELSD)75％，73％。
10e (R) -2-amino-4-methyl-pentanoic acid [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -amide
LC/MS-TOF(m/z)394([M+H]+)；RT＝2.29，(UV，ELSD)89％，100％。
10f 1-amino-cyclopropanecarboxylic acid [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -amide
LC/MS-TOF(m/z)365；RT＝1.98，(UV，ELSD)94％，89％。
Example 11 pentanoic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -amide
To a solution of N (4) - (5-chloro-thiophen-2-ylmethyl) -2, N (4) -dimethyl-benzene-1, 4-diamine (54mg, 0.20mmol) and triethylamine (84L, 0.60mmol) in anhydrous tetrahydrofuran (1mL) was added valeryl chloride (36, L, 0.30mmol) and the mixture was stirred at room temperature for 1 hour, after which it was partitioned between saturated aqueous sodium bicarbonate (5mL) and ethyl acetate (5 mL). The organic layer was dried over sodium sulfate, the volatiles were evaporated and the residue was purified on a FlashMaster system (silica, elution with heptane/ethyl acetate mixture) to give the title compound as a white solid (61mg, 86%).
LC/MS(m/z)351.3([M+H]+)；RT＝3.06，(UV，ELSD)100％，99％。
Example 12
12a { 2-benzyloxy-4- [ (4-fluorobenzyl) - (methyl) amino ] -phenyl } -thiocarbamic acid S-ethyl ester
(3-benzyloxy-4-nitrophenyl) (4-fluorobenzyl) methylamine (50mg) was dissolved in tetrahydrofuran (2 mL). Acetic acid (0.1mL) and zinc powder (200mg) were added thereto and the resulting mixture was sonicated for 1 hour. Additional zinc dust (100mg) was added to it and sonication continued for 1 hour. The reaction mixture was filtered over silica (500mg) and evaporated to dryness. 1, 2-dichloroethane (1mL) was added thereto, followed by diphosgene (0.03 mL). The reaction mixture was left at room temperature for 15 minutes and then heated to 80 ℃ for 3 hours. After cooling to room temperature, triethylamine (0.12mL) was added thereto. An aliquot (one quarter) of the resulting mixture was mixed with thioethanol (0.026mL) and the resulting mixture was shaken overnight at room temperature. The mixture was evaporated to dryness, dissolved in dimethyl sulfoxide (0.2mL) and treated with preparative LC-MS to give 7.6mg of the title compound. Yield: 52 percent.
LC-MS(m/z)425.2([M+H]+)；RT＝3.35，(UV，ELSD)95％，99％。
The following compounds were prepared analogously from the appropriate nitro compounds and nucleophiles:
12b { 2-cyclopentyloxy-4- [ (4-fluorobenzyl) - (methyl) amino ] -phenyl } -thiocarbamic acid S-ethyl ester
LC-MS(m/z)403.1([M+H]+)；RT＝3.30，(UV，ELSD)99％，100％。
12c 1- { 2-cyclopentyloxy-4- [ (4-fluorobenzyl) - (methyl) amino ] -phenyl } -3-ethyl-urea
Ethylamine was used instead of thioethanol.
LC-MS(m/z)386.2([M+H]+)；RT＝2.08，(UV，ELS9)97％，100％。
Example 13
13a N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-chlorophenyl) -acetamide
2-chloro-N (4) - (5-chloro-thiophen-2-ylmethyl) -N (4) -methyl-benzene-1, 4-diamine (100mg) was added to a solution of 4-chlorophenylacetyl chloride (69mg) in anhydrous acetonitrile (2mL) in a rubber-covered glass vial. The reaction mixture was heated to 150 ℃ for 15 minutes in a microwave apparatus. The reaction mixture was poured into saturated aqueous sodium bicarbonate (5mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with water (5mL) and brine (5mL), dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash column chromatography (eluting with a heptane/ethyl acetate gradient) to yield 25.2mg of the title compound. Yield: 16 percent.
LC-MS(m/z)441.2([M+2]+)；RT＝3.83，(UV，ELSD)91％，99％。
The following compound (2-phenylpropionyl chloride was prepared by heating 2-phenylpropionic acid in thionyl chloride followed by evaporation) was prepared analogously:
13b N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-chlorophenyl) -propionamide
LC-MS(m/z)453.0(M+)；RT＝4.01，(UV，ELSD)91％，99％。
Example 14
14a {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-iodophenyl } -carbamic acid ethyl ester.
(4-amino-2-iodophenyl) -carbamic acid ethyl ester (2.3g) and 5-chloro-thiophene-2-carbaldehyde (1.15g) were dissolved in methanol (8mL) and heated in a sealed glass tube at 130 ℃ for 3 minutes with microwave radiation. After cooling to room temperature, a solution of sodium cyanoborohydride (4.7g) in methanol (10mL) was added thereto and the resulting mixture was heated to 130 ℃ for 5 minutes under microwave irradiation in a sealed glass tube. After cooling to room temperature, the mixture was poured into water (50mL) and extracted with ethyl acetate (50 mL). The aqueous phase was extracted with ethyl acetate (50mL) and the combined organic phases were washed with water (twice 80 mL) and brine (twice 80 mL). The organic phase was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The resulting oil was purified by flash column chromatography (silica gel, eluting with a heptane/ethyl acetate gradient). The resulting product was lyophilized from dioxane/water to give the title compound as an orange solid (2g, 63%).
1H NMR(CDCl3)：1.31(t，3H)，4.02(b，1H)，4.21(q，2H)，4.35(d，2H)，6.53(b，1H)，6.63(dd，1H)，6.75(s，2H)，7.06(d，1H)，7.63(bs，1H)。
The following compounds were prepared analogously:
14b N- {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-iodophenyl } -2- (4-fluorophenyl) -acetamide.
1H NMR(CDCl3)：3.72(s，2H)，4.01(b9 1H)，4.35(d，2H)，6.62(dd，1H)，6.75(s，2H)，7.00(d，1H)，7.09-7.12(m，3H)，7.35(dd，2H)，7.85(d，1H)。
Example 15
N- {5- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -4' -dimethylamino-biphenyl-2-yl } -2- (4-fluorophenyl) -acetamide.
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-iodophenyl } -carbamic acid ethyl ester (270mg), 4-dimethylaminophenylboronic acid (445mg), and palladium (II) acetate (about 10mg) were suspended in acetone (5 mL). Potassium carbonate (0.54mL, 5M aqueous solution) was added thereto and the mixture was heated in a sealed glass tube in a microwave synthesizer at 125 ℃ for 10 minutes. After cooling to room temperature, the organic phase was separated off, evaporated onto silica gel and treated three times with flash column chromatography (eluting with a heptane/ethyl acetate gradient). The resulting solid was recrystallized three times from acetonitrile to give 38mg of the title compound as a colorless solid. The combined mother liquors were evaporated on silica gel and treated with flash column chromatography. The resulting product was recrystallized from methanol to give a second yield (12mg), which was combined with the first yield to give a total of 50mg (19%) of the title compound.
1H NMR(DMSO-d6)：2.91(s，6H)，3.44(s，2H)，4.39(d，2H)，6.32(t，1H)，6.51(dd，2H)，6.61(d，2H)，6.93(dd，2H)，7.02-7.04(m，3H)，7.07-7.10(m，2H)，7.22-7.23(m，2H)，9.01(s，1H)。
LC-MS(m/z)494.2(M+)；RT＝2.50，(UV，ELSD)95％，99％。
Example 16
16a {4- [ (5-chloro-thiophen-2-ylmethyl) -amino j-2-quinolin-3-yl-phenyl } -carbamic acid ethyl ester
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-iodophenyl } -carbamic acid ethyl ester (15mg), 3-quinolineboronic acid (29.7mg), palladium (II) acetate (ca. 1mg), potassium carbonate (0.035mL, 5M in water), and acetone (2mL) were mixed and heated in a sealed tube in a microwave synthesizer at 125 ℃ for 10 minutes, the reaction mixture was extracted with ethyl acetate (4mL), the organic phase was washed with water (2X 2mL) and brine (2X 2mL), dried over magnesium sulfate, and filtered. The solvent was removed under vacuum and the crude product was purified by preparative LC-MS. The collected fractions were evaporated in vacuo, redissolved in ethyl acetate (5mL) and the organic phase washed with saturated aqueous sodium bicarbonate (3mL), water (3mL) and brine (2 × 2 mL). The organic phase was dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the title compound (5mg, 33%).
LC-MS(m/z)438.0([M+H]+)；RT＝2.32，(UV，ELSD)89％，100％。
The following compounds were prepared analogously:
16b {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-pyridin-3-yl-phenyl } -carbamic acid ethyl ester
LC-MS(m/z)388.2([M+H]+)；RT＝2.01，(UV，ELSD)97％，100％。
16c {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-pyridin-4-yl-phenyl } -carbamic acid ethyl ester
LC-MS(m/z)388.1([M+H]+)；RT＝1.95，(UV，ELSD)98％，100％。
16d [4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2- (6-methoxypyridin-3-yl) -phenyl ] -carbamic acid ethyl ester
LC-MS(m/z)418.3([M+H]+)；RT＝2.37，(UV，ELSD)79％，100％。
16e {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-quinolin-5-yl-phenyl } -carbamic acid ethyl ester
LC-MS(m/z)430.8([M+H]+)；RT＝2.13，(UV，ELSD)79％，99％。
In vitro and in vivo assays
The compounds of the invention have been tested and show effects in one or more of the following models.
Relative outward flow through KCNQ2 channel
It illustrates a KCNQ2 screening protocol for the evaluation of the compounds of the invention. This assay measures the relative outward flow through the KCNQ2 channel and was performed according to the method described by Tang et al (Tang W. et al, J.Biomol. Screen 77.2001, 6, 325-331) for the hERG potassium channel with the following modifications.
On the day of the experiment, a sufficient number of CHO cells stably expressing the voltage-gated KCNQ2 channel were plated at a density sufficient to generate a single-fusion layer. The cells were inoculated with 1. mu. Ci/ml on day before the test86Rb]Load overnight. On the day of the experiment, the cells were washed with HBSS-containing buffer. The cells were pre-incubated with the drug for 30 minutes and stimulated with sub-maximal concentration of 15mM KCl in the further continuous presence of the drug for 30 minutes 86Rb+An outward flow rate. After a suitable period of incubation, the supernatant was removed and counted in a liquid scintillation counter (Tricarb). Cells were lysed with 2mM NaOH and paired86Rb+The number is counted. Calculating the relative outward flow ((CPM)Supernatant fluid/(CPMSupernatant fluid+CPMCells))CCompound (I)/(CPMSupernatant fluid/(CPMSupernatant fluid+CPMCells))15nM KCl)*100-100。
The compounds of the invention have an EC of less than 20000nM50EC of which50In most cases less than 2000nM and in many cases less than 200 nM. Accordingly, the compounds of the present invention are believed to be useful in the treatment of diseases associated with the KCNQ family of potassium channels.
Electrophysiology patch clamp recordings.
Voltage-activated KCNQ2 current from mammalian CHO cells was recorded in a whole-cell patch-clamp configuration using conventional patch-clamp recording techniques (Hamill OP et al, Pflgers Arch 1981; 391: 85-100). Subjecting cells having stably expressed voltage-activated KCNQ2 channel to CO2In incubators in normalGrowth was performed under cell culture conditions and electrophysiological recordings were made using them 1-7 days after plating. KCNQ2 potassium channel was activated by stepwise increasing the voltage from a membrane holding potential of-100 mV to-40 mV in 5-20mV increments (or with a ramp protocol) to +80mV (Tatulian L et al, J Neuroscience 2001; 21 (15): 5535-. The electrophysiological effects induced by these compounds were evaluated on the basis of various parameters of the voltage-activated KCNQ2 current. In particular, the effect thereof on the activation threshold of this current and on the maximum current induced was studied.
Some of the compounds of the invention have been studied in such assays. This left shift in activation threshold or the induced increase in maximum potassium current is thought to reduce activity in neuronal networks, making these compounds useful in diseases with increased neuronal activity such as epilepsy.
Maximal electric shock
This experiment was performed using corneal electrodes in a group of male mice, in which a square wave current of 26mA was administered for 0.4 seconds to induce convulsions characterized by tonic extension of hind limbs (Wlaz et al, Epilepsy Research 1998, 30, 219-229).
Pilocarpine-induced seizures
Pilocarpine-induced seizures were induced by intraperitoneal injection of pilocarpine (250mg/kg) into male mice, and observed for seizure activity leading to loss of posture within 30 minutes (Starr et al, Pharmacology bioclaemistny and Behavior 1993, 45, 321-325)
Electric seizure threshold test
A variation of this reciprocal method (up-and-down method) (Kimball et al, Radiation Research 1957, 1-12) was used to determine the median threshold for inducing hindlimb tonic extension in response to corneal electroconvulsive shock in male mice. The first mouse in each group was electrically shocked at 14mA (0.4s, 50Hz) and observed for seizure activity. If a seizure was observed, the current of the next mouse was decreased by 1mA, but if no seizure was observed, the current thereof was increased by 1 mA. This procedure was repeated for 15 mice in the treatment group.
Chemical seizure threshold test
The dose threshold of pentylenetetrazole required to induce clonic convulsions was determined by timed infusion of pentylenetetrazole (5mg/ml, rate 0.5 ml/min) into the lateral tail vein of each group of male mice (Nutt et al, J Pharmacy and Pharmacology, 1986, 38, 697-698).
Tonsil excitation
The rats were operated with tripolar electrodes implanted in their dorsolateral tonsils. After surgery, the animals were allowed to recover and then groups of rats received various doses of the test compound or matrix of the drug. The animals were stimulated starting after a discharge threshold of +25 μ Α per day within 3-5 weeks, and the severity of each cause of seizures, duration of seizures, and duration of electricity after discharge were noted. (racine. electroanalysis and chromatography neurology 1972, 32, 281-.
Side effects
Central nervous system side effects were measured by measuring the time the mice remained on the rotarod device (Capacio et al, Drug and Chemical biology 1992, 15, 177-; or by measuring their locomotor activity by counting the number of infrared beams passing through the test cage ((Watson et al, Neuropharmacology 1997, 36, 1369-.
Pharmacokinetics
The pharmacokinetic properties of the compounds were determined by i.v. and p.o. administration to Spraque Dawley rats, after which blood samples were taken within 20 hours. Plasma concentrations were determined by LC/MS/MS.

Claims (36)

1. Substituted p-diaminobenzene derivatives of the general formula I or salts thereof
Wherein
s is 0 or 1;
u is O, S, SO2、SONR11CO-O or CONR11(ii) a Wherein
R11Selected from hydrogen, C1-6Alk (en/yn) yl, C3-8-cycloalkanes(alkenyl) yl, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl; or
R2And R11And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
q is 0 or 1;
x is CO or SO2(ii) a Provided that when X is SO2Q is 0;
z is O or S;
R1selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl;
R2selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C 3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halogen, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) group, cyano-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl、NR10R10′-C1-6Alk (en/yn) yl, NR10R10′-C3-8Cycloalkane (alkenyl) group and NR10R10′-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl; wherein
R10And R10′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C1-6An alk (en/yn) yl group, or
R10And R10′And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
Provided that R is2When is halogen or cyano, s is 0; and
provided that when s is 1 and R2U is O or S when it is a hydrogen atom or an acyl group;
R3is selected from C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) yl, Heterocycloalkane (alkenyl) yl, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkenyl) group, C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, heterocycloalkyl (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkyl (alkenyl) group, Ar-heterocycloalkyl (alkenyl) group, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, Ar-C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C3-8-cycloalk (en) oxy-C1-6Alk (en/yn) yl, C1-6Alk (en/yn) oxy-C3-8Cycloalkane (alkenyl) group, C1-6-alk (en/yn) oxy-heterocycloalkyl (en) yl, Ar-oxy-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C1-6-alk (en/yn) oxy-carbonyl-C1-6Alk (en/yn) yl, C3-8-cycloalkane (alkene) oxy-carbonyl-C1-6Alk (en/yn) yl, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) oxy-carbonyl-C 1-6Alk (en/yn) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8-cycloalkane (alkenyl) yl, hydroxy-heterocycloalkane (alkenyl) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, hydroxy-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, hydroxy-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8-cycloalk (en) yl, halo-heterocycloalk (en) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkane (alkene) yl, halo-C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, halo-C1-6Alk (en/yn) yl-Ar, halo-C3-8-Cycloalk (en) yl Ar, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl-Ar, halo-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) -Ar, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) yl, cyano-heterocycloalkyl (alkenyl) yl, cyano-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) group, cyano-C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, acyl-C1-6Alk (en/yn) yl, acyl-C3-8-cycloalk (en) yl, acyl-heterocycloalk (en) yl, acyl-C 3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl-C1-6Alk (en/yn) yl-C3-8Cycloalkyl (alkenyl) radical, acyl-C1-6Alk (en/yn) yl-heterocycloalkyl (en) yl, NR12R12′Optionally substituted NR12R12′-C1-6-alk (en/yn) yl, optionally substituted NR12R12′-C3-8-cycloalk (en) yl, optionally substituted NR12R12′-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl; wherein
R12And R12′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, Ar-heterocycloalkyl (en) yl, Ar-oxy-C1-6Alk (en/yn) yl, Ar-oxy-C3-8Cycloalkyl (alkenyl) group, Ar-oxyl C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, Ar-oxy-heterocycloalkyl (en) yl, hydroxy-C1-6Alk (en/yn) yl, hydroxy-C3-8Cycloalkane (alkene) yl, hydroxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) and cyano-C3-8-cycloalk (en) yl-C 1-6An alk (en/yn) yl group, or
R12And R12′And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms;
and
y represents a group of formula XXIV, XXV, XXVI, XXVII, XXVIII, XXXI or XXXXXII:
or
Wherein
The line represents a bond linking the group represented by Y to the carbon atom;
w is O or S;
v is N, C or CH;
t is N, NH or O;
a is 0, 1, 2 or 3;
b is 0, 1, 2, 3 or 4;
c is 0 or 1;
d is 0, 1, 2 or 3;
e is 0, 1 or 2;
f is 0, 1, 2, 3, 4 or 5;
g is 0, 1, 2, 3 or 4;
h is 0, 1, 2 or 3;
j is 0, 1 or 2;
k is 0, 1, 2 or 3; and
each R5Independently selected from a C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) yl, Ar-C3-8Cycloalkane (alkene) yl, Ar-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar-oxy-C1-6Alk (en/yn) yl, Ar-oxy-C3-8Cycloalkane (alkenyl) group, C1-6-alk (en/yn) yl-heterocycloalkyl (en) yl, Ar-oxy-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, acyl, C1-6Alk (en/yn) oxy, C3-8Cycloalk (alk) oxy, C 3-8-cycloalk (en) yl-C1-6Alk (en/yn) oxy, C1-6-alk (en/yn) oxy-carbonyl, halogen, halo-C1-6Alk (en/yn) yl, halo-C3-8Cycloalkane (alkene) yl, halo-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, -CO-NR6R6′Cyano, cyano-C1-6Alk (en/yn) yl, cyano-C3-8Cycloalkyl (alkenyl) group, cyano-C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, NR7R7′、S-R8And SO2R8Or is or
Two adjacent R5Together with the aromatic group, form a 5-8 membered ring containing one or two heteroatoms;
R6and R6′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl and Ar;
R7and R7′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8Cycloalk (en) yl-C1-6Alk (en/yn) yl, Ar, heterocycloalkan (en) yl-C1-6Alk (en/yn) yl, heterocycloalkan (en) yl-C3-8Cycloalkane (alkenyl) yl, Heterocycloalkane (alkenyl) yl-C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, heterocycloalk (en) yl-Ar and acyl; or
R7And R7′And the nitrogen atom to which it is attached form a 5-to 8-membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms; and
R8Selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl, -Ar and-NR9R9′(ii) a Wherein R is9And R9′Independently selected from hydrogen, C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group and C3-8-cycloalk (en) yl-C1-6-alk (en/yn) yl.
2. The compound of claim 1, wherein R1Is C1-6-alk (en/yn) yl or a hydrogen atom.
3. The compound of any one of claims 1-2, wherein s is 0.
4. The compound of any one of claims 1-2, wherein s is 1.
5. The compound of claim 4, wherein U is an oxygen atom.
6. The compound of any one of claims 1-5, wherein R2Selected from hydrogen, C1- 6Alk (en/yn) yl, C3-8Cycloalkane (alkene) yl, Ar-C1-6Alk (en/yn) yl, halogen, halo-C1-6-alk (en/yn) yl and cyano;
provided that when R is2When is halogen or cyano, s is 0; and
provided that when s is 0 and R2U is O or S when it is a hydrogen atom.
7. The compound of any one of claims 1-6, wherein Z is an oxygen atom.
8. The compound of any one of claims 1-6, wherein Z is a sulfur atom.
9. The compound of any one of claims 1-8, wherein q is 0.
10. The compound of any one of claims 1-8, wherein q is 1.
11. The compound of any one of claims 1-10, wherein X is CO.
12. The compound of any one of claims 1-11, wherein R3Is C1-6Alk (en/yn) yl, C3-8Cycloalkane (alkenyl) group, C3-8-cycloalk (en) yl-C1-6Alk (en/yn) yl, heterocycloalkan (en) yl-C1-6Alk (en/yn) yl, heterocycloalkan (en) yl, Ar-C1-6Alk (en/yn) yl, Ar-oxy-C1-6Alk (en/yn) yl, Ar-C1-6Alk (en/yn) oxy-C1-6Alk (en/yn) yl, C]6-alk (en/yn) oxy-carbonyl-Cl-alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, NR12W2', optionally substituted NR12R12′-C1-6-alk (en/yn) yl, and optionally substituted NR12R12′-C3-8-a cycloalk (en) yl group.
13. The compound of claim 12, wherein R12And R12′Independently selected from hydrogen, C1-6-alk (en/yn) yl and Ar.
14. The compound of any one of claims 1-13, wherein Y is formula XXIV.
15. The compound of any one of claims 1-13, wherein Y is formula XXV.
16. The compound of any one of claims 14-15, wherein W is an oxygen atom.
17. A compound according to any one of claims 14 to 15, wherein W is a sulphur atom.
18. The compound of any one of claims 1-13, wherein Y is formula XXVII.
19. The compound of any one of claims 1-13, wherein Y is formula XXXXI.
20. The compound of claim 19, wherein V is a nitrogen atom.
21. The compound of claim 19, wherein V is CH.
22. The compound of any one of claims 1-13, wherein Y is formula XXXXII.
23. The compound of claim 22, wherein T is a nitrogen atom.
24. The compound of claim 22, wherein T is an oxygen atom.
25. The compound of any one of claims 1-24, wherein each R5Independently selected from C1-6Alk (en/yn) yl, C1-6Alk (en/yn) yl heterocycloalkyl (en), Ar, C1-6Alk (en/yn) oxy, Ar-oxy, C1-6-alk (en/yn) oxy-carbonyl, halogen, halo-C1-6Alk (en/yn) yl, NR7R7′、S-R8And SO2R8Or is or
Two adjacent R5Together with the aromatic radical form an aromatic radical optionally containing5-8 membered ring of one or two heteroatoms.
26. The compound of claim 25, wherein R7And R7′Are all C 1-6-alk (en/yn) yl.
27. The compound of claim 25, wherein R8Is selected from C1-6-alk (en/yn) yl and Ar.
28. A compound according to any one of claims 1 to 27, selected from:
{4- [ (benzofuran-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid ethyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid ethyl ester;
{ 2-methyl-4- [ (5-phenyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid ethyl ester;
[4- (4-isopropyl-benzylamino) -2-methylphenyl ] -carbamic acid ethyl ester;
[4- (4-fluoro-benzylamino) -2-methylphenyl ] -carbamic acid propyl ester;
(4- { [4- (4-chloro-benzenesulfonyl) -3-methyl-thiophen-2-ylmethyl ] -amino } -2-methylphenyl) -carbamic acid propyl ester;
{4- [ (5-methyl-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{ 2-methyl-4- [ (5-phenyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
[4- (4-isopropyl-benzylamino) -2-methylphenyl ] -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
[ 2-chloro-4- (4-isopropyl-benzylamino) -phenyl ] -carbamic acid ethyl ester;
[ 2-chloro-4- (4-fluoro-benzylamino) -phenyl ] -carbamic acid ethyl ester;
2-chloro-4- { [4- (4-chloro-benzenesulfonyl) -3-methyl-thiophen-2-ylmethyl ] -amino } -phenyl) -carbamic acid propyl ester;
{4- [ (5-methyl-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{4- [ (benzofuran-2-ylmethyl) -amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid ethyl ester;
(4- (benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -carbamic acid methyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -carbamic acid isopropyl ester;
{4- [ (4-fluoro-benzyl) - (methyl) amino ] -2-methoxyphenyl } -carbamic acid propyl ester;
[4- (benzo [ b ] thiophen-2-ylmethyl- (methyl) amino) -2-methoxy-phenyl ] -carbamic acid propyl ester;
{4- [ (5-amino-thiophen-2-ylmethyl) - (methyl) amino ] -2-methoxy-phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-methoxy-phenyl } -carbamic acid propyl ester;
{ 2-methoxy-4- [ methyl- (5-methyl-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (4-fluorobenzyl) - (methyl) -amino ] -2-isopropoxyphenyl } -carbamic acid ethyl ester;
[4- (3-fluorobenzylamino) -2-methoxyphenyl ] -carbamic acid ethyl ester;
[4- (4-isopropylbenzylamino) -2-methoxyphenyl ] -carbamic acid ethyl ester;
{ 2-methoxy-4- [ (3-methylthiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid ethyl ester;
[4- (2, 4-difluorobenzylamino) -2-methoxyphenyl ] -carbamic acid ethyl ester;
[ 2-cyclopentyloxy-4- (4-methoxybenzylamino) -phenyl ] -carbamic acid ethyl ester;
[ 2-cyclopentyloxy-4- (3-fluoro-2-methylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
[4- (3-fluoro-2-methylbenzylamino) -2-phenylethoxyphenyl ] -carbamic acid ethyl ester;
[ 2-benzyloxy-4- (3-fluoro-2-methylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
[ 2-benzyloxy-4- (4-methylsulfanylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
{4- [ (benzo [ b ] thiophen-3-ylmethyl) -amino ] -2-cyclopentyloxyphenyl } -carbamic acid ethyl ester;
[4- (3-fluoro-2-methylbenzylamino) -2-isopropoxyphenyl ] -carbamic acid ethyl ester;
[ 2-benzyloxy-4- (3-methoxybenzylamino) -phenyl ] -carbamic acid ethyl ester;
{4- [ (benzo [1, 3] dioxol-5-ylmethyl) -amino ] -2-isopropoxyphenyl } -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
[ 2-cyano-4- (4-isopropylbenzylamino) -phenyl ] -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (4-isopropylbenzyl) - (methyl) amino ] -2-methylphenyl } -carbamic acid propyl ester;
{ 2-methyl-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{ 2-methyl-4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid ethyl ester;
{ 2-chloro-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid ethyl ester;
{ 2-chloro-4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -phenyl } -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-chlorophenyl } -carbamic acid propyl ester;
{ 2-chloro-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } carbamic acid ethyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (4-isopropyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ (4-isopropyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ methyl- (4-trifluoromethyl-benzyl) amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ methyl- (4-methylsulfanyl-benzyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -2-cyanophenyl } -carbamic acid propyl ester;
{4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -2-cyanophenyl } -carbamic acid propyl ester;
{ 2-cyano-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-bromo-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (4-isopropylbenzyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (4-tert-butyl-benzyl) - (methyl) amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ methyl- (4-trifluoromethyl-benzyl) -amino ] -phenyl } -carbamic acid propyl ester;
[ 2-iodo-4- (4-isopropyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[4- (4-tert-butyl-benzylamino) -2-iodophenyl ] -carbamic acid propyl ester;
[ 2-iodo-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[ 2-iodo-4- (4-methylsulfanyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
{ 2-iodo-4- [4- (4-methylpiperazin-1-yl) -benzylamino ] -phenyl } -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid ethyl ester;
[4- (4-tert-butyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid ethyl ester;
[4- (4-methylsulfanyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid ethyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-trifluoromethyl-phenyl } -carbamic acid propyl ester;
[4- (4-isopropylbenzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
[4- (4-tert-butyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
[ 2-trifluoromethyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[4- (4-dimethylamino-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
[4- (4-methylsulfanyl-benzylamino) -2-trifluoromethyl-phenyl ] -carbamic acid propyl ester;
{4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-cyanophenyl } -carbamic acid propyl ester;
[ 2-cyano-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
{ 2-bromo-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid propyl ester;
[ 2-bromo-4- (4-isopropylbenzylamino) -phenyl ] -carbamic acid propyl ester;
[ 2-bromo-4- (4-tert-butyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[ 2-bromo-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
[ 2-bromo-4- (4-methylsulfanyl-benzylamino) -phenyl ] -carbamic acid propyl ester;
n- {4- [ (5-bromo-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -butyramide;
N- {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-methoxyphenyl } -butyramide;
n- [4- (4-isopropylbenzylamino) -2-methoxyphenyl ] -butyramide;
n- [4- (4-tert-butyl-benzylamino) -2-methoxyphenyl ] -butyramide;
n- [ 2-methoxy-4- (4-trifluoromethyl-benzylamino) -phenyl ] -butyramide;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-furan-2-yl-phenyl } -carbamic acid propyl ester;
[ 2-furan-2-yl-4- (4-isopropylbenzylamino) -phenyl ] -carbamic acid propyl ester;
[5- (4-fluorobenzylamino) -biphenyl-2-yl ] -carbamic acid propyl ester;
{5- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -biphenyl-2-yl } -carbamic acid propyl ester;
[5- (4-isopropylbenzylamino) -biphenyl-2-yl ] -carbamic acid propyl ester;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2-phenylacetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3, 3-dimethylbutanamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3-phenylpropanamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -butyramide;
pentanoic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
Cyclopropanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
cyclobutanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
cyclopentanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -amide;
cyclohexanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) (methyl) amino ] -phenyl } -amide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2-thiophen-2-yl-acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (3-methoxy-phenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-chloro-phenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-methoxy-phenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-fluoro-phenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3-cyclohexylpropionamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2, 2-dimethylpropionamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-phenoxyacetamide;
N- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-phenylacetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -3, 3-dimethylbutanamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -butyramide;
pentanoic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
cyclopropanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
cyclobutanecarboxylic acid { 2-chloro-4- ((5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
cyclopentanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
cyclohexanecarboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2-thiophen-2-yl-acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (3-methoxyphenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-chlorophenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-methoxyphenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2- (4-fluorophenyl) -acetamide;
2, 3-dihydro-benzo [1, 4] dioxine-6-carboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
2, 3-dihydro-benzofuran-5-carboxylic acid { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -amide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -3-cyclohexylpropionamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -2, 2-dimethylpropionamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -2-phenylacetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -3, 3-dimethylbutanamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -3-phenylpropanamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -butyramide;
2, 2, 2-trichloro-N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -acetamide;
cyclopropanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methyl-phenyl } -amide;
cyclobutanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -amide;
cyclopentanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -amide;
Cyclohexanecarboxylic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -amide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2-thiophen-2-yl-acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2- (3-methoxyphenyl) -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -malonamic acid methyl ester;
2- (4-chlorophenyl) -N- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2- (4-methoxyphenoxy) -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -2- (4-fluorophenyl) -acetamide;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -3-cyclohexylpropionamide;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid phenyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid benzyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid isobutyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid butyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid hexyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 4-nitrobenzyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid but-3-enyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid but-2-ynyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 2, 2-dimethylpropyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 2-chlorobenzyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 3-chloropropyl ester;
{ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -carbamic acid 2-benzyloxyethyl ester;
3- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -1-methyl-1-propyl-urea;
1- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -3- (2-fluorophenyl) -urea;
n- [ 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2, 2, 2-trifluoroacetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -phenyl } -2, 2, 2-trifluoroacetamide;
N- {5- [ (5-chloro-thiophen-2-ylmethyl) amino ] -4' -dimethylamino-biphenyl-2-yl } -2- (4-fluorophenyl) -acetamide;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-chlorophenyl) -acetamide;
[4- (3-fluoro-4-trifluoromethyl-benzylamino) -2-methylphenyl ] -carbamic acid ethyl ester;
2- (4-fluorophenyl) -N- { 2-methyl-4- [ (6-p-tolyloxypyridin-3-ylmethyl) -amino ] -phenyl } -acetamide;
n- [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -butyramide;
2- (4-fluorophenyl) -N- { 2-methyl-4- [ (6-trifluoromethylpyridin-3-ylmethyl) -amino ] -phenyl 2-acetamide;
pentanoic acid {4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -2-methylphenyl } -amide;
3, 3-dimethyl-N- { 2-methyl-4- [ (6-p-tolyloxypyridin-3-ylmethyl) -amino ] -phenyl } -butyramide;
[ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -carbamic acid ethyl ester;
n- { 2-chloro-4- [ (5-chloro-thiophen-2-ylmethyl) - (methyl) amino ] -phenyl } -2- (4-chlorophenyl) -propionamide;
[4- (4-chloro-benzylamino) -2-methylphenyl ] -carbamic acid ethyl ester;
{4- [ (6-methoxy-benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-quinolin-3-yl-phenyl } -carbamic acid ethyl ester;
{4- [ (5-dimethylamino-3-methyl-benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid propyl ester;
3, 3-dimethyl-N- { 2-methyl-4- [ (6-trifluoromethylpyridin-3-ylmethyl) -amino ] -phenyl } - ] butyramide;
n- (4- { [6- (4-cyanophenoxy) -pyridin-3-ylmethyl ] -amino } -2-methylphenyl) -2- (4-fluorophenyl) -acetamide;
{ 2-benzyloxy-4- [ (4-fluorobenzyl) - (methyl) amino ] -phenyl } -thiocarbamic acid S-ethyl ester;
{ 2-cyclopentyloxy-4- [ (4-fluorobenzyl) - (methyl) amino ] -phenyl } -thiocarbamic acid S-ethyl ester;
n- {4- [ (6-chloropyridin-3-ylmethyl) -amino ] -2-methylphenyl } -2- (4-fluorophenyl) -acetamide;
{4- [ (7-dimethylamino-benzo [ b ] thiophen-2-ylmethyl) amino ] -2-methylphenyl } -carbamic acid propyl ester;
1- { 2-cyclopentyloxy-4- [ (4-fluorobenzyl) - (methyl) amino ] -phenyl } -3-ethyl-urea;
2-amino-4-methyl-pentanoic acid [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -amide;
{4- [ (6-methoxy-benzo [ b ] thiophen-2-ylmethyl) -amino ] -2-methylphenyl } -carbamic acid ethyl ester;
2-amino-4-methyl-pentanoic acid [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -amide;
2- (4-fluorophenyl) -N- { 2-methyl-4- [ (4-methyl-2-phenylpyrimidin-5-ylmethyl) -amino ] -phenyl } -acetamide;
3, 3-dimethyl-N- { 2-methyl-4- [ (2-phenylpyrimidin-5-ylmethyl) -amino ] -phenyl } -butyramide;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-pyridin-3-yl-phenyl } -carbamic acid ethyl ester;
1-amino-cyclopropanecarboxylic acid [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -amide;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-pyridin-4-yl-phenyl } -carbamic acid ethyl ester;
2-piperidin-1-yl-N- [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -acetamide;
n- (4- { [5- (4-chlorophenoxy) -1, 3-dimethyl-1H-pyrazol-4-ylmethyl ] -amino } -2-methylphenyl) -2, 2-dimethylpropionamide;
2, 2-dimethyl-N- { 2-methyl-4- [ (6-phenoxypyridin-3-ylmethyl) -amino ] -phenyl } -propionamide;
n- [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -2-pyrrolidin-1-yl-acetamide;
[4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2- (6-methoxypyridin-3-yl) -phenyl ] -carbamic acid ethyl ester;
4- [ (3-methyl-4-propoxycarbonylamino-phenylamino) -methyl ] -benzoic acid methyl ester;
2-morpholin-4-yl-N- [ 2-methyl-4- (4-trifluoromethyl-benzylamino) -phenyl ] -acetamide;
2, 2-dimethyl-N- { 2-methyl-4- [ (3-methyl-5-phenylisoxazol-4-ylmethyl) -amino ] -phenyl } -propionamide;
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-iodophenyl } -carbamic acid ethyl ester;
n- {4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-iodophenyl } -2- (4-fluorophenyl) -acetamide and
{4- [ (5-chloro-thiophen-2-ylmethyl) -amino ] -2-quinolin-5-yl-phenyl } -carbamic acid ethyl ester
Or a salt thereof.
29. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents and a compound according to any one of claims 1-28.
30. Use of a pharmaceutical composition according to claim 29 for increasing the ion flow in potassium channels of a mammal, such as a human.
31. Use according to claim 30 for the prevention, treatment or inhibition of a disorder or condition responsive to an increase in ion flow in potassium channels, such disorder or condition preferably being of the central nervous system.
32. The use according to claim 31, wherein the condition or disease is selected from seizure disorders such as convulsions, epilepsy and status epilepticus.
33. Use according to claim 31, wherein the condition or disorder is selected from neuropathic pain and migraine pain disorders such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy and neuropathic pain associated with migraine.
34. Use according to claim 31, characterized in that the disorder or condition is selected from anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, behavioral anxiety, post-traumatic stress disorder, acute stress response, adaptation disorders, hypochondriasis, separation anxiety disorder, agoraphobia, specific phobias, anxiety disorders due to general medical conditions and substance-induced anxiety disorders.
35. Use according to claim 31, characterized in that the disorder or condition is selected from the group consisting of neurodegenerative disorders such as alzheimer's disease, huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and other infection-related encephalopathies caused by rubella virus, herpes virus, borrelia and unknown pathogens, Creutzfeld-Jakob disease, parkinson's disease, wound-induced neurodegeneration.
36. Use according to claim 31, wherein the condition or disorder is selected from the group consisting of neuronal hyperexcitability states such as states in drug withdrawal or intoxication.
HK06111365.8A 2003-03-21 2004-03-18 Substituted p-diaminobenzene derivatives HK1090560A (en)

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