WO2014079850A1 - Substituted heterocyclic derivatives - Google Patents

Substituted heterocyclic derivatives Download PDF

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WO2014079850A1
WO2014079850A1 PCT/EP2013/074211 EP2013074211W WO2014079850A1 WO 2014079850 A1 WO2014079850 A1 WO 2014079850A1 EP 2013074211 W EP2013074211 W EP 2013074211W WO 2014079850 A1 WO2014079850 A1 WO 2014079850A1
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phenyl
methoxy
oxazol
acetamide
lower alkyl
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PCT/EP2013/074211
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French (fr)
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Simona M. Ceccarelli
Ravi Jagasia
Roland Jakob-Roetne
Jens-Uwe Peters
Juergen Wichmann
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • cycloalkyl denotes a cyclic alkyl group, containing from 3 to 6 ring carbon atoms.
  • R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
  • One further object of the present invention are compounds of formula
  • both R 1 and R 1 may be simultaneously hydrogen, but only one of R 1 and R 1 is lower alkyl, lower alkoxy, halogen, 0(CH 2 ) 2 -lower akoxy, 0(CH 2 ) 2 N(CH 3 ) 2 , or 0(CH 2 )-morpholinyl;
  • both R 1 and R 1 may be simultaneously hydrogen, but only one of R 1 and R 1 is lower alkyl, lower alkoxy, halogen, 0(CH 2 ) 2 -lower akoxy, 0(CH 2 ) 2 N(CH 3 ) 2 , or 0(CH 2 )-morpholinyl;
  • Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
  • Compounds of general formula I-l can be prepared by coupling the amine of general formula 15 to carboxylic acids of general 4, as described above.
  • Amines of general formula 15 can be prepared from the corresponding nitro derivatives 14, which are generated by reaction of the fluoro derivatives 13 with lH-1, 2, 4-triazole in the presence of a base.
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick- layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC.
  • the value of negative (neutral) control is determined for each assay plate by taking the average of 16 negative control wells.
  • the neurogenic compound response is calculated for each compound as (compound/Negative Control)* 100.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

Abstract

The present invention relates to compounds of general formula (I-1) or (I-2) wherein R1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH2)2-lower akoxy, O(CH2)2N(CH3)2, or O(CH2)-morpholinyl; R1' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH2)2-lower akoxy, O(CH2)2N(CH3)2, or O(CH2)-morpholinyl; with the proviso that both R1 and R1' may be simultaneously hydrogen, but only one of R1 and R1' is lower alkyl, lower alkoxy, halogen, O(CH2)2-lower akoxy, O(CH2)2N(CH3)2, or O(CH2)-morpholinyl; Het is a 5-or 6 membered heteroaryl group, wherein the heteroatom is selected from N, O or S; X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH2-S-, -CH2-S(O)2-, CH2-O- or -CH2-CRR'-; R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring; R2 is lower alkyl, -C(O)O-lower alkyl, C3-6-cycloalkyl optionally substituted by lower alkyl or =O, bridged cyclohexyl or C3-6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R2', selected from halogen, cyano, S(O)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[1,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-1H-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H- [1,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof. The compounds may be used for the treatment or prophylaxis of schizophrenia, obsessive-compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction, Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine and ***e.

Description

SUBSTITUTED HETEROCYCLIC DERIVATIVES
The present invention relates to compounds of general formula
Figure imgf000002_0001
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH2-S-, -CH2-S(0)2-, CH2-0- or -CH2-CRR'-;
R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring;
R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H-
[l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its
corresponding enantiomer and/or optical isomers thereof.
Now it has been shown that the present compounds stimulate neurogenesis from neural stem cells (NSCs). Neurogenesis occurs in the developing and adult brain. Conceptually, this process of neurogenesis can be divided into four steps: (i) proliferation of NSCs; (ii) neuronal fate determination of NSC; (iii) survival and maturation of new neurons; and (iv) functional integration of new neurons into the neuronal network.
Adult neurogenesis is a developmental process that occurs throughout live in the adult brain whereby new functional neurons are generated from adult neural stem cells. Constitutive adult neurogenesis under physiological conditions occurs mainly in two "neurogenic" brain regions, 1) the sub-granular zone (SGZ) in the dentate gyrus of the hippocampus, where new dentate granule cells are generated, 2) the sub- ventricular zone (SVZ) of the lateral ventricles, where new neurons are generated and then migrate through the rostral migratory stream (RMS) to the olfactory bulb to become interneurons.
Extensive evidence suggests that hippocampal adult neurogenesis plays an important role in cognitive and emotional states albeit the precise function remains elusive. It has been argued that the relatively small number of newborn granule neurons can affect global brain function because they innervate many interneurons within the dentate gyrus, each of which inhibits hundreds of mature granule cells leading to a neurogenesis-dependent feedback inhibition. In combination with a low threshold for firing the newborn neurons trigger responses to very subtle changes in context. Disturbances in this process may manifest behaviorally in deficits in pattern separation related to psychiatric diseases. For example, adult hippocampal neurogenesis correlates with cognitive and emotional capacity, e.g. physical exercise, exposure to an enriched environment and typical antidepressants concomitantly promote adult hippocampal
neurogenesis and cognition and/or emotional states, while chronic stress, depression, sleep deprivation and aging decrease adult neurogenesis and associate with negative cognitive and/or emotional states (Neuron 70, May 26, 2011, pp 582 -588 and pp 687 - 702; WO 2008/046072). Interestingly, antidepressants promote hippocampal adult neurogenesis and their effects on certain behaviors require the stimulation of neurogenesis. Neurogenesis in other adult CNS regions is generally believed to be very limited under normal physiological conditions, but could be induced after injury such as stroke, and central and peripheral brain damage.
It is therefore believed that stimulation of adult neurogenesis represents a neuro- regenerative therapeutic target for normal aging and in particular for a variety of
neurodegenerative and neuropsychiatric diseases, including schizophrenia, obsessive- compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorders, hearing loss (Neuroscience, 167 (2010) 1216-1226; Nature
Medicine, Vol. 11, number 3, (2005), 271-276) tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and disturbances due to radiation therapy, chronic stress, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine and ***e (US 2012/0022096).
The stimulation of adult neurogenesis represents also a therapeutic target for optic neuropathy (S. Isenmann, A. Kretz, A. Cellerino, Progress in Retinal and Eye Research, 22, (2003) 483) and macular degeneration (G. Landa, O. Butovsky, J. Shoshani, M. Schwartz, A. Pollack, Current Eye Research 33, (2008) 1011).
Hence, chemical stimulation of adult neurogenesis offers new regenerative avenues and opportunities to develop novel drugs for treating neurological diseases and neuropsychiatric disorders.
Therefore, the object of the present invention was to identify compounds that modulate neurogenesis. It has been found that the compounds of formula I are active in this area and they may therefore be used for the treatment of schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer' s disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and disturbances due to radiation therapy, chronic stress, optic neuropathy or macular degeneration, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine or ***e.
The most preferred indications for compounds of formula I are Alzheimer's disease, depression, anxiety disorders and stroke.
The present invention relates to compounds of formula I and to their pharmaceutically acceptable salts, in cases where this applies to mixtures of enantiomers or diastereomers or their enantiomerically or diastereomerically pure forms, to these compounds as pharmaceutically active substances, to the processes for their production, as well as to the use in the treatment or prevention of disorders, relating to neurogenesis, schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and disturbances due to radiation therapy, chronic stress, optic neuropathy or macular degeneration, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine or ***e.
and to pharmaceutical compositions containing the compounds of formula I.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term "lower alkyl" denotes a saturated, i.e. aliphatic hydrocarbon group including a straight or branched carbon chain with 1 - 4 carbon atoms. Examples for "alkyl" are methyl, ethyl, n-propyl, and isopropyl.
The term "lower alkyl substituted by halogen" denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen.
The term "lower alkoxy" denotes a group O-R' wherein R' is lower alkyl as defined above. The term "lower alkyl substituted by halogen" denotes a lower alkyl group as defined above and wherein at least one hydrogen atom is replaced by halogen.
The term "cycloalkyl" denotes a cyclic alkyl group, containing from 3 to 6 ring carbon atoms.
The term "cycloalkenyl" denotes a cyclic alkyl group, containing from 3 to 6 ring carbon atoms, and wherein one bond between the ring atoms is a double bond. The term "halogen" denotes chlorine, bromine, fluorine or iodine.
The bridged cyclohexyl group is bicycle[2.2.1]heptan-2-yl.
The term "five or six membered heterocycloalkyl" denotes a cycloalkyl ring, containing 5 or 6 carbon ring atoms, wherein at least one carbon atom is replaced by a N, O or S atom, for example piperazinyl, piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl or 1,1- dioxo-tetrahydro- 1 6-thiophenyl,
The term 5-or 6 membered heteroaryl group", wherein the heteroatom is selected from N, O or S" denotes the groups oxazolyl, thiophenyl, isoxazolyl, thiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrazolyl or 1,2,4-triazolyl.
The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable acid addition salt" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane- sulfonic acid, p-toluenesulfonic acid and the like.
One embodiment of the i a
Figure imgf000006_0001
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH2-S-, -CH2-S(0)2-, CH2-0- or -CH2-CRR'-; R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring;
R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H- [l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof.
One further embodiment of the invention are compounds of formula
Figure imgf000007_0001
1-2
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH2-S-, -CH2-S(0)2-, CH2-0- or -CH2-CRR'-;
R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring;
R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H- [l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.
One embodiment of the invention are further compounds of formula
Figure imgf000008_0001
wherein
R is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring; R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano,
S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H- [l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, for example the compounds.
N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide
N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-m-tolyl-acetamide
N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-pyridin-2-yl-acetamide
2-(2-Aminophenyl)-3'-methoxy-4'-(5-oxazolyl)acetanilide
2-(2,5-dimethoxyphenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(3-(difluoromethoxy)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide
2-(2,4-dichlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(4-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3-bromophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(4-bromophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(benzo[d][l,3]dioxol-5-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(2-chloro-6-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(2,6-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(2-(difluoromethoxy)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-(trifluoromethoxy)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-methoxyphenyl)acetamide
2-(4-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-p-tolylacetamide
2-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-o-tolylacetamide
2-(2-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide
2-(3,5-dimethylphenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(naphthalen-l-yl)acetamide
2-(3-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3,5-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3-fluoro-5-(trifluoromethyl)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(2,4-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)acetamide
2-(3,4-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(2,5-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(2,3-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3-chloro-4-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3-cyanophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(5-chloro-2-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(furan-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(5-fluoropyridin-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(thiophen-2-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(thiophen-3-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(pyridin-4-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(l-methyl-lH-indol-3-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(pyridin-3-yl)acetamide
2-(lH-indol-3-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(benzo[d]isoxazol-3-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methylisoxazol-5-yl)acetamide
2-(2,4-dimethylthiazol-5-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(5-methylthiophen-2-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)pentanamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)propionamide
2-cyclohexenyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-cyclohexyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-cyclopropyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-cyclopentyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-methylcyclohexyl)acetamide
2-(bicyclo[2.2.1]heptan-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(6-methoxy-3-oxo-2,3-dihydro-lH-inden-l-yl)-N-(3-methoxy-4-(oxazol-5- yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydrofuran-2-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H-pyran-2-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-2- yl)acetamide
2-(l,l-Dioxo-tetrahydro-l 6-thiophen-3-yl)-N-(3-methoxy-4-oxazol-5-yl-phenyl)-acetamide 2-cyclobutyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-oxocyclohexyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-phenylpropanamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3,3-dimethylbutanamide
N-(3-chloro-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenyl)acetamide
2-(3-methoxyphenyl)-N-(3-methyl-4-(oxazol-5-yl)phenyl)acetamide 2-(3-Methoxy-phenyl)-N-(3-methoxy-4-thiazol-5-yl-phenyl)-acetamide
N-(3-Methoxy-4-[l,3,4]oxadiazol-2-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide
2- (3-Methoxy-phenyl)-N-(3-methoxy-4-[l,2,4]triazol-l-yl-phenyl)-acetamide
3- methoxy-N-(3-methoxybenzyl)-4-(oxazol-5-yl)benzamide
N-(4-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
N- (4-fluorobenzyl) - 3 -methoxy-4- (oxazol- 5 -yl)benzamide
3 -methoxy-4- (oxazol- 5 -yl) -N- (2- (trifluoromethyl)benzyl)benzamide
N-(2-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
3-methoxy-N-(2-methylbenzyl)-4-(oxazol-5-yl)benzamide
N- (2-fluorobenzyl) - 3 -methoxy-4- (oxazol- 5 -yl)benzamide
N-(3-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
N-(3,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
N-(2,4-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
N- (3 -fluorobenzyl) - 3 -methoxy-4- (oxazol- 5 -yl)benzamide
N-(2,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
N-(2,3-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
3-methoxy-4-(oxazol-5-yl)-N-(thiophen-2-ylmethyl)benzamide
N-(2-fluoro-3-methoxybenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
N-(5-chloro-2-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
3-methoxy-N-((6-methoxypyridin-2-yl)methyl)-4-(oxazol-5-yl)benzamide 2-(3-methoxyphenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxybenzyl)-4-(oxazol-5-yl)benzamide
2-(3-methoxyphenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide
N-(3-methoxybenzyl)-4-(pyridin-4-yl)benzamide
2-(2-chlorophenyl)-N-(3-methoxy-4-(pyridin-4-yl)phenyl)acetamide
N-(2-chlorobenzyl)-3-methoxy-4-(pyridin-4-yl)benzamide
2-(2-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)acetamide 2-(2-chlorophenyl)-N-(2-methoxy-4-(lH-pyrazol-4-yl)phenyl)acetamide N-(2-chlorobenzyl)-2-methoxy-4-(lH-pyrazol-4-yl)benzamide
N-(2-chlorobenzyl)-3-methoxy-4-(lH-pyrazol-4-yl)benzamide
2-(2-chlorophenyl)-N-(3-methoxy-4-( 1H- 1 ,2,4-triazol- 1 -yl)phenyl)acetamide
2-(2-Chlorophenyl)-N-(2-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(2-Chlorophenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide N-(2-Chlorobenzyl)-2-methoxy-4-(oxazol-5-yl)benzamide
N-(4-(lH-pyrazol-4-yl)phenyl)-2-(2-chlorophenyl)acetamide
2-(2-Chlorophenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide
2-(2-Chlorophenyl)-N-(2-(2-(dimethylamino)ethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide 2-(2-Chlorophenyl)-N-(3-methoxy-4-(4-methyloxazol-5-yl)phenyl)acetamide
1- (2-Chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarboxamide
2- (2-Chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-methylpropanamide
N-(3-Methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenyl)-2-methylpropanamide
2-(2-Chlorophenyl)-N-(3-(2-(dimethylamino)ethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide 2,2,2-trifluoroacetate
2-(2-Chlorophenyl)-N-(2-(2-morpholinoethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide
2-(2-Chlorophenyl)-N-(3-(2-morpholinoethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide 2,2,2- trifluoroacetate
2-(2-Chlorophenyl)-N-(2-(2-methoxyethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide
2-(2-Chlorophenyl)-N-(3-(2-methoxyethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide
2-hydroxy-N- [3-methoxy-4-( lH-pyrazol-4-yl)phenyl] -2-phenylacetamide or
2- (2-chlorophenyl)-2-hydroxy-N- (3 -methoxy-4- ( 1 H-pyrazol-4-yl)phenyl)acetamide.
One further embodiment of the invention are compounds of formula
Figure imgf000013_0001
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring; R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano,
S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H- [l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof., for example the following compounds
iert-bbutyl [(RS)-[[[3-methoxy-4-(5-oxazolyl)phenyl]carbamoyl]phenyl]-(methyl)]carbamate N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylamino)acetamide
N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-phenylamino-acetamide
2-(4-chlorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-(trifluoromethyl)phenylamino)acetamide
2-(4-fluorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(4-(oxazol-5-yl)phenyl)-2-(phenylamino)acetamide
2-(4-fluorophenylamino)-N-(4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide N-(3-Methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-(3-methoxyphenylamino)acetamide
N-(3-Methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylamino)-2-methylpropanamide 2-(2-Chlorophenylamino)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-methylpropanamide
2-(2-Chlorophenylamino)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)acetamide
N-(3-Methoxy-4-(oxazol-5-yl)phenyl)-l-(3-methoxyphenylamino)cyclopropanecarboxamide
N-(3-Methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-methyl-2-(phenylamino)propanamide
l-(2-Chlorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarboxamide
N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-(3-methoxyphenylamino)-2-methylpropanamide or l-(2-Chlorophenylamino)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)cyclopropanecarboxamide.
One further embodiment of the invention are compounds of formula
Figure imgf000015_0001
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H- [l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, for example the compound
N-[3-methoxy-4-(5-oxazolyl)phenyl]-3,3-dimethyl-2-oxobutyramide.
One further object of the invention are compounds of formula
Figure imgf000016_0001
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H- [l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, for example the compounds
2-(Benzenesulfonyl)-3'-methoxy-4'-(5-oxazolyl)acetanilide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(phenylthio)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylthio)acetamide or
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylsulfonyl)acetamide.
One further object of the present invention are compounds of formula
Figure imgf000017_0001
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S; R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H-
[l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, for example the compound
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-phenoxyacetamide.
One further object of the present invention are compounds of formula
Figure imgf000018_0001
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring; R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H- [l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, for example the compounds
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-phenylpropanamide
N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
3-(4-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)propanamide
3-(3-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamide
3-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamide
N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3-phenylpropanamide
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)propanamide
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(3-chlorophenyl)propanamide
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(4-chlorophenyl)propanamide
N-(3-fluoro-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
N-(3-chloro-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
N-(2-chloro-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide N-(3-methyl-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
N-(2-methyl-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
N-(2-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
3-methoxy-N-phenethyl-4-(lH-pyrazol-4-yl)benzamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-methyl-3-phenylbutanamide
N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-methyl-3-phenylbutanamide
N- (4- ( 1 H-pyrazol-4-yl)phenyl) - 3 -methyl- 3 -phenylbutanamide
N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3-methyl-3-phenylbutanamide
N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-phenylbutanamide
3-(4-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-methylbutanamide
3-hydroxy-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-phenylbutanamide
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(4-chlorophenyl)-3-methylbutanamide
3-(3-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-methylbutanamide
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(3-chlorophenyl)-3-methylbutanamide
3-(2-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-methylbutanamide
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)-3-methylbutanamide
3 -hydroxy-N- [4-(l,3-oxazol- 5 -yl)phenyl] - 3 -phenylbutanamide
3-hydroxy-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-phenylbutanamide or
N- (4- ( 1 H-pyrazol-4-yl)phenyl) - 3 -hydroxy- 3 -phenylbutanamide .
A further embodiment of the invention are compounds, wherein Het is oxazolyl.
A further embodiment of the invention are compounds, wherein Het is thiazolyl.
A further embodiment of the invention are compounds, wherein Het is oxadiazolyl.
A further embodiment of the invention are compounds, wherein Het is pyridinyl.
A further embodiment of the invention are compounds, wherein Het is pyrazolyl.
A further embodiment of the invention are compounds, wherein Het is thiophenyl.
A further embodiment of the invention are compounds, wherein Het is isoxazolyl.
A further embodiment of the invention are compounds, wherein Het is or 1,2,4-triazolyl. The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) reacting a compound of formula
Figure imgf000021_0001
with a compound of formula
HO R
o in the presence of EDC or HATU
to a compound of formula
Figure imgf000021_0002
wherein the definitions are as described above, or b) reacting a compound of formula
Figure imgf000021_0003
with a compound of formula
in the presence of EDC or HATU
to a compound of formula
Figure imgf000021_0004
wherein the substituents are as described above,
and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts. The preparation of compounds of formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes 1 - 7. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary.
In more detail, the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The reaction sequence is not limited to the one displayed in scheme 1 - 7, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
Scheme 1
Figure imgf000022_0001
Compounds of general formula 1-1 can be prepared by coupling the amine of general formula 3 to the acids 4 according to methods well known in the art, for example by the use of (3- dimethylamino-propyl)-ethyl-carbodiimide (EDC) or (2-(7-aza-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate) (HATU) and diisopropylethylamine as coupling agents. The amine of general formula 3 can be prepared by reduction of the nitro derivatives 2, which are generated by reaction of the corresponding aldehydes 1 with toluene-4- sulfonylmethyl iso-cyanide (TOSMIC) and a base. The aldehydes 1 are generated by methods well known in the art or acquired from commercial vendors. Scheme 2
Figure imgf000023_0001
Compounds of general formula I-l can be prepared by coupling the amine of general formula 7 to carboxylic acids of general 4, as described above. Amines of general formula 7 can be prepared from the corresponding nitro derivatives 6, which are generated by reaction of the bromo derivatives 5 with thiazole in the presence of a palladium catalyst and a base, for example Pd(PPh3)4 and potassium acetate.
Scheme 3
Figure imgf000024_0001
Compounds of general formula I-l can be prepared by coupling the amine of general formula 12 to carboxylic acids of general 4, as described above. Amines of general formula 12 can be prepared from the corresponding nitro derivatives 11. The synthesis of nitro derivatives 11 is accomplished by treatment of carboxylic acids of general formula 8 with tert-butyl carbazate in the presence of a coupling agent, as for example EDC, followed by removal of the tert-butyl protecting group under acidic conditions to yield hydrazides 10, which are then condensed with triethylorthoformate under acidic catalysis to yield compounds of general formula 11. Scheme 4
Figure imgf000025_0001
EDC or HATU 1-1 (for Het = tetrazolyl)
Compounds of general formula I-l can be prepared by coupling the amine of general formula 15 to carboxylic acids of general 4, as described above. Amines of general formula 15 can be prepared from the corresponding nitro derivatives 14, which are generated by reaction of the fluoro derivatives 13 with lH-1, 2, 4-triazole in the presence of a base.
Scheme 5
Figure imgf000025_0002
Compounds of general formula 1-2 are generated by coupling acids of general formula 18 to amines 19, according to the general conditions described above. Acids 18 can be obtained by reaction of the corresponding ester-aldehydes 16 with TOSMIC, as described above for compounds of general formula I, followed by hydrolysis of the ester. The aldehydes of general formula 16 can either be synthetized by methods well known in the art or acquired from commercial vendors. In analogy to the methods described above, other claimed compounds can be synthetized by using additional acids and amines not covered by the general formulas 4 and 19.
Scheme 6
Compounds of general formula 1-2 are generated by coupling aryl bromides of general formula 21 with boronic acid or boronic ester derivatives of general formula 22 in the presence of a palladium catalyst and a base, according to methods well known in the art. Aryl bromides of general formula 21 can be obtained from the corresponding amine 20 and acids 4, as described above.
Scheme 7
Figure imgf000026_0002
Compounds of general formula 1-2 are generated by coupling aryl bromides of general formula 24 with boronic acid or boronic ester derivatives of general formula 22 in the presence of a palladium catalyst and a base, according to methods well known in the art. Aryl bromides of general formula 24 can be obtained from the corresponding acids 23 and amines 19, as described above. Isolation and purification of the compounds
Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick- layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC.
Salts of compounds of formula I
The compounds of formula I are basic and may be converted to a corresponding acid addition salt. The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0 °C and 50 °C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the
compounds of the present invention have an activity as neurogenic agents. The compounds were investigated in accordance with the test given hereinafter. Neurogenesis assay
Neural Stem Cell Proliferation Assay
Neurogenic properties of small molecules are determined based on the proliferation of human embryonic stem cell derived neural stem cells (NSCs) which were derived via a dual smad inhibition as previously described (Chambers, S.M., et al., Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling, Nature biotechnology, 2009. 27(3): p. 275-80.)
Compounds respond is measured by the increase in cells based on ATP levels
(Promega:CellTiterGlo®) after an incubation period of 4 days.
NSCs are thawed and expanded over 3 passages. On the 14th day, NSCs are seeded in
Polyornithin/ Laminin coated 384 well plates at a cell density of 2 000 cells/cm in a media volume of 38 μΐ.
4 hours after cell seeding, compound solutions are added at a volume of 2 μΐ. Stock solutions of the compounds (water, 5% DMSO) are diluted to obtain a dose response (11 points, dilution factor is 2), ranging from 8 μΜ to 8 nM. Controls are run to consistently determine the neurogenic properties of the cells:
Negative (neutral) control is cell culture Media (final DMSO concentration: 0.25 %).
Positive controls are:
1. cell culture Media + 100 ng/ml FGF2 (final DMSO concentration: 0.1 %)
2. cell culture Media + 20 ng/ml EGF (final DMSO concentration: 0.1 %)
3. cell culture Media + 100 ng/ml Wnt3a (final DMSO concentration: 0.1 %)
After 4 days incubation at 37° C, 5 % C02, the amount of ATP per well is quantified. The ATP concentration is proportional to the cell number. ATP is quantified by using the Promega
CellTiterGlo® kit. The CellTiterGlo® reagents contain a cell lysis buffer, a thermo stable luciferase (UltraGlo™ recombinant luciferase), magnesium and luciferin. Luciferin reacts with
ATP producing oxyluciferin, AMP and light. The luminescence signal is proportional to the ATP content.
The value of negative (neutral) control is determined for each assay plate by taking the average of 16 negative control wells. The neurogenic compound response is calculated for each compound as (compound/Negative Control)* 100.
The values of EC15o from the dose response curve are determined for each test compound. The EC 150 is the compound concentration at which 150 % activity of control (100 %) is reached. The preferred compounds show a EC15o (μΜ) in the range of < 10 μΜ as shown in the table below.
List of examples and EC_i sn data
Figure imgf000029_0001
Figure imgf000030_0001
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-
3.9371 (3-methoxyphenylthio)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-
2.1355 (3-methoxyphenylsulfonyl)acetamide
2- (3 - (difluoromethoxy)phenyl) -N- (3 -
0.9282
<\ J methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-
0.2553 (2-(trifluoromethyl)phenyl)acetamide
2-(2,4-dichlorophenyl)-N-(3-methoxy-4-
1.199 (oxazol-5-yl)phenyl)acetamide
2-(4-chlorophenyl)-N-(3-methoxy-4-
0.4938 (oxazol-5-yl)phenyl)acetamide
2-(3-bromophenyl)-N-(3-methoxy-4-
0.264 (oxazol-5-yl)phenyl)acetamide
2-(4-bromophenyl)-N-(3-methoxy-4-
3.511 (oxazol-5-yl)phenyl)acetamide
Figure imgf000032_0001
2-(2-chlorophenyl)-N-(3-methoxy-4-
0.1226 (oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-o-
0.1776 u tolylacetamide
2-(2-fluorophenyl)-N-(3-methoxy-4-
0.1261 (oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-
1.1174 (3-(trifluoromethyl)phenyl)acetamide
2-(3,5-dimethylphenyl)-N-(3-methoxy-4-
1.6317 (oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-
1.2457 (naphthalen- 1 -yl)acetamide
2-(3-chlorophenyl)-N-(3-methoxy-4-
0.3985 (oxazol-5-yl)phenyl)acetamide
2-(3,5-difluorophenyl)-N-(3-methoxy-4-
0.4063 (oxazol-5-yl)phenyl)acetamide
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
63 2-cyclohexenyl-N-(3-methoxy-4-(oxazol-
1.3951 5-yl)phenyl)acetamide
64 2-cyclohexyl-N-(3-methoxy-4-(oxazol-5-
2.146 yl)phenyl) acetamide
65 2-cyclopropyl-N-(3-methoxy-4-(oxazol-5-
2.99 yl)phenyl) acetamide
66 2-cyclopentyl-N-(3-methoxy-4-(oxazol-5-
4.811 yl)phenyl) acetamide
67 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-
5.58 (4-methylcyclohexyl)acetamide
68 2-(bicyclo[2.2.1]heptan-2-yl)-N-(3-
3.5236 methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(6-methoxy-3-oxo-2,3-dihydro-lH-
69 inden-l-yl)-N-(3-methoxy-4-(oxazol-5- 4.7774 yl)phenyl) acetamide
70 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-
2.3832 (tetrahydro-2H-pyran-4-yl)acetamide
Figure imgf000038_0001
Figure imgf000039_0001
87 3-methoxy-4-(oxazol-5-yl)-N-(2-
2.2936 (trifluoromethyl)benzyl)benzamide
88 N-(2-chlorobenzyl)-3-methoxy-4-(oxazol-
0.1431 5-yl)benzamide
89 3-methoxy-N-(2-methylbenzyl)-4-(oxazol-
0.2745 5-yl)benzamide
90 N-(2-fluorobenzyl)-3-methoxy-4-(oxazol-
0.3165 5-yl)benzamide
91 N-(3-chlorobenzyl)-3-methoxy-4-(oxazol-
0.5191 5-yl)benzamide
92 N- (3 , 5 -difluorobenzyl) -3 -methoxy-4-
0.7367 (oxazol-5-yl)benzamide
93 N-(2,4-difluorobenzyl)-3-methoxy-4-
0.3217 (oxazol-5-yl)benzamide
94 N-(3-fluorobenzyl)-3-methoxy-4-(oxazol-
0.4529 5-yl)benzamide 95 N-(2,5-difluorobenzyl)-3-methoxy-4-
0.5766 (oxazol-5-yl)benzamide
96 N-(2,3-difluorobenzyl)-3-methoxy-4-
0.6873 (oxazol-5-yl)benzamide
97 3-methoxy-4-(oxazol-5-yl)-N-(thiophen-2-
0.4655 ylmethyl)benzamide
98 N-(2-fluoro-3-methoxybenzyl)-3-methoxy-
5.519 4-(oxazol-5-yl)benzamide
99 N-(5-chloro-2-fluorobenzyl)-3-methoxy-4-
1.0546 (oxazol-5-yl)benzamide Jj XJ 01 3-methoxy-N-((6-methoxypyridin-2- yl)methyl)-4-(oxazol-5-yl)benzamide
100 2.1657
101 2-(3-methoxyphenyl)-N-(4-(oxazol-5-
0.667 yl)phenyl) acetamide
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-
157 methyl- 3 -phenylbutanamide 0.36
N-(3-methoxy-4-(lH-pyrazol-4-
158 r >< yl)phenyl)- 3 -methyl- 3 -phenylbutanamide 0.06
N-(4-(lH-pyrazol-4-yl)phenyl)-3-methyl-
159 3 -phenylbutanamide 0.10
N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3-
160 methyl- 3 -phenylbutanamide 0.10
N-(3-methoxy-4-(lH-pyrazol-4-
161 yl)phenyl)-3-phenylbutanamide 0.08
3-(4-chlorophenyl)-N-(3-methoxy-4-(lH-
162 pyrazol-4-yl)phenyl)-3-methylbutanamide 0.31
Figure imgf000050_0001
3-hydroxy-N-(3-methoxy-4-(oxazol-5-
163 yl)phenyl)-3-phenylbutanamide 0.69
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(4-
164 chlorophenyl)-3-methylbutanamide 0.22
Figure imgf000050_0002
Figure imgf000051_0001
Figure imgf000052_0001
The compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula (I) and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I), but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
As mentioned earlier, medicaments containing a compound of formula (I) or
pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
As further mentioned earlier, the use of the compounds of formula (I) for the preparation of medicaments useful in the prevention and/or the treatment of the above recited diseases is also an object of the present invention.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
Pharmaceutical compositions comprising compounds of the invention:
Tablet Formulation (Wet Granulation)
Item Ingredients mg/tablet
5 mg 25 mg 100 mg 500 mg
1. Compound of formula I 5 25 100 500
2. Lactose Anhydrous DTG 125 105 30 150
3. Sta-Rx 1500 6 6 6 30
4. Microcrystalline Cellulose 30 30 30 150
5. Magnesium Stearate 1 1 1 1
Total 167 167 167 831
Manufacturing Procedure
1. Mix items 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 50°C.
3. Pass the granules through suitable milling equipment.
4. Add item 5 and mix for three minutes; compress on a suitable press. Capsule Formulation
Item Ingredients mg/capsule
5 mg 25 mg 100 mg 500 mg
1. Compound of formula I 5 25 100 500
2. Hydrous Lactose 159 123 148 —
3. Corn Starch 25 35 40 70
4. Talc 10 15 10 25
5. Magnesium Stearate 1 2 2 5
Total 200 200 300 600 Manufacturing Procedure
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.
Experimental Part Intermediates
In rmediate 1: 3-Methoxy-4-oxazol-5-yl-phenylamine
Figure imgf000054_0001
STEP
2-Methoxy-4-nitrobenzaldehyde (5.064 g, 27.1 mmol), toluene-4-sulfonylmethyl iso-cyanide (TOSMIC, 5.4 g, 27.1 mmol) and potassium carbonate (3.75 g, 27.1 mmol) were combined with methanol (55 ml) to give a thick suspension. The reaction mixture was heated to 80°C, upon which stirring became possible. The mixture was stirred for 3h at 80°C and at room temperature overnight. The precipitated solid was collected by filtration, washed with a small amount of diethyl ether and dried under vacuum. 5-(2-Methoxy-4-nitro-phenyl)-oxazole was obtained as a of a yellow solid (5.12g, 84.1%); MS (ISN) m/z = 221.05 [(M+H)+].
STEP B
5-(2-Methoxy-4-nitro-phenyl)-oxazole (10 g, 45.4 mmol) was dissolved in tetrahydrofurane (185 ml) and ethanol (37 ml). The mixture was set under an argon atmosphere before adding catalytic Pd/C (2.0 g, 1.88 mmol). The mixture was flushed with hydrogen gas and then stirred vigorously overnight. The catalyst was filtered off and washed with tetrahydrofurane and ethanol.
Evaporation yielded an oil, which crystallized after a few hours. 3-Methoxy-4-oxazol-5-yl- phenylamine was obtained as a yellow solid (8.54 g, 97%); MS (ISN) m/z = 191.08 [(M+H)+].
Intermediate 2: 3-Chloro-4-oxazol-5-yl-phenylamine
Figure imgf000055_0001
3-Chloro-4-oxazol-5-yl-phenylamine, orange solid, MS (ISN) m/z = 195.1 [(M+H)+], was prepared in two steps from 2-chloro-4-nitrobenzaldehyde in analogy to intermediate 1.
Intermediate 3: 3-Methyl-4-oxazol-5-yl-phenylamine
Figure imgf000055_0002
3-Methyl-4-oxazol-5-yl-phenylamine was prepared in two steps from 2-methyl-4- nitrobenzaldehyde in analogy to intermediate 1. 2-Methyl-4-nitrobenzaldehyde was prepared according to the following procedure:
2-methyl-4-nitrobenzonitrile (1 g, 6.17 mmol) was dissolved in dry toluene (24.0 ml). After cooling to 0°C, a solution of DIBAL-H (4.35 ml, 7.4 mmol) in toluene was added drop wise over 10 min. The mixture was stirred for 2h at 0°C. The mixture was quenched at 0°C by addition of HC1 2N (1 ml). After warming to room temperature and addition of further HC1 2N (1 ml), sodium sulfate was added under vigorous stirring. Filtration of the solids and evaporation yielded a crude, which was purified by flash chromatography (heptane/AcOEt), to yield 2- methyl-4-nitrobenzaldehyde as an orange solid (0.68 g, 67%)
Intermediate 4: 3-Methoxy-4-oxazol-5-yl-benzoic acid
Figure imgf000055_0003
STEP A
In a 250 mL round-bottomed flask, methyl 4-(bromomethyl)-3-methoxybenzoate (3.48 g, 13.4 mmol) was combined with dimethylformamide (50 ml) to give a colorless solution. Sodium acetate (2.2 g, 26.9 mmol) was added. The reaction mixture was stirred for 20 h, then filtered through sintered glass. Water was added and the reaction mixture was extracted with ethyl acetate .The combined organic layers were dried aver sodium sulfate and filtered and the solvent vas removed in vacuum to yield methyl 4-(acetoxymethyl)-3-methoxybenzoate as a white solid (3.1 g, 97%), which was used crude.
STEP B
In a 250 mL round-bottomed flask, methyl 4-(acetoxymethyl)-3-methoxybenzoate (3.0 g, 12.6 mmol) was combined with methanol (80 ml) to give a colorless solution. A solution of saturated HCl in ether (12.0 g, 10 ml) was added. The reaction mixture was heated to 80 °C and stirred for 1 h. The crude reaction mixture was concentrated in vacuum to yield methyl 4-(hydroxymethyl)- 3-methoxybenzoate as a white solid (1.9 g, 86%); MS (ISN) m/z = 197.1 [(M+H)+].
STEP C
In a 250 mL round-bottomed flask, methyl 4-(hydroxymethyl)-3-methoxybenzoate (2.24 g, 11.4 mmol) was combined with dichloromethane (150 ml) to give a colorless solution. Manganese dioxide (7.94 g, 91.3 mmol) was added. The reaction mixture was heated to 45 °C and stirred for 15 h. The reaction mixture was filtered through celite and concentrated in vacuum to yield methyl 4-formyl-3-methoxybenzoate as a white solid (1.9 g, 86%); MS (ISN) m/z = 195.1
[(M+H)+].
STEP D
In a 50 mL round-bottomed flask, methyl 4-formyl-3-methoxybenzoate (1.9 g, 9.78 mmol) was combined with methanol (20 ml) to give a colorless solution. Toluene-4-sulfonylmethyl iso- cyanide (TOSMIC, 1.91 g, 9.78 mmol) and potassium carbonate (1.35 g, 9.78 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 2 h, then cooled to room temperature. Water was added and the reaction mixture was then extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed under vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% EtOAc in heptane), to yield methyl 3-methoxy-4-(oxazol-5-yl)-benzoate as a white solid (1.43g, 62.5%); MS (ISN) m/z = 233.9 [(M+H)+].
STEP E
In a 10 mL round-bottomed flask, methyl 3-methoxy-4-(oxazol-5-yl)-benzoate (300 mg, 1.29 mmol) was combined with tetrahydrofurane (2 ml) and methanol (2 ml) to give a colorless solution. NaOH 1 M (4 ml, 4.00 mmol) was added and the reaction mixture was stirred at room temperature for 2h. HCl cone. (4.8 g, 4 mL) was added and the white precipitate was filtered and dried under high vacuum to yield 3-methoxy-4-(oxazol-5-yl)-benzoic acid as a white solid (266 mg, 94.3%); MS (ISN) m/z = 220.3 [(M+H)+] .
Intermediate 5: 3-Methoxy-4-thiazol-5-yl-phenylamine
Figure imgf000057_0001
Step A
A mixture of 2-bromo-5-nitroanisole (150 mg, 0.65 mmol), potassium acetate (96 mg, 0.97 mmol) and Pd(PPh3)4 (38mg, 0.03 mmol) in dimethylacetamide (4ml) in a sealed tube was purged with argon. To this mixture was then added thiazole (0.230 ml, 3.23 mmol). The resulting mixture was purged again with argon, then heated to 160°C for 3h. The reaction mixture was cooled to 25 °C, diluted with water and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. Purification by column chromatography (40%EtOAc/hexane) yielded 5-(2-methoxy-4-nitro-phenyl)-thiazole (65mg, 42.56%) as yellow solid.
STEP B
A mixture of 5-(2-methoxy-4-nitro-phenyl)-thiazole (160 mg, 0.68 mmol) and stannous dichloride (655 mg, 3.39 mmol) in ethanol (10 ml) was allowed to reflux for 75 min. The solvent was removed in vacuum, and the resultant residue was dissolved in ethyl acetate (20 ml). The organic layer was washed successively with 2N NaOH and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material thus obtained was diluted with dichloromethane (20ml), and filtered. Removal of the filtrate under reduced pressure afforded 3- methoxy-4-thiazol-5-yl-phenylamine (107 mg, 76.6%) as an orange oil. LC-MS (ESI): 207
[(M+H)+].
Intermediate 6: 3-Methoxy-4-[l,3,4]oxadiazol-2-yl-phenylamine
Figure imgf000058_0001
STEP A
To a solution of 2-methoxy-4-nitro-benzoic acid (1 g, 5.07 7 mmol) in dichloromethane (30 ml) were added tertbutylcarbazate (670 mg, 5.07 mmol) and EDCI.HC1 (1.167 g, 6.09 mmol) at 0°C. The reaction mixture was allowed to stir at 25°C for 6h. The reaction mixture was quenched with water and the organic layer was washed with saturated aqueous NaHC03 solution (10 ml) and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuum to afford N'-(2- methoxy-4-nitro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester (1.3 g, 82.33%) as yellow solid. LC-MS (ESI): 312 [(M+H)+].
STEP B
To a solution of N'-(2-methoxy-4-nitro-benzoyl)-hydrazine carboxylic acid tert-butyl ester (1.3 g, 4.18 mmol) in dioxane (10 ml) was added a solution of HC1 in dioxane (4N; 33 ml) drop wise at 0°C. The reaction mixture was allowed to stir at 25°C for 12h. The volatiles were removed in vacuum, and the resulting crude material was washed with a mixture of ethyl acetate in hexane to give 2-methoxy-4-nitro-benzoic acid hydrazide (750 mg, 84.96%) as yellow solid. LC-MS (ESI): 212 [(M+H)+].
STEP C
A solution of 2-methoxy-4-nitro-benzoic acid hydrazide (600 mg, 2.84 mmol), triethyl orthoformate (4.73 ml, 28.4 mmol) and a catalytic amount of p-toluensulfonic acid in dioxane (10 ml) in a sealed tube was heated at 120°C for 24h. The volatiles were removed in vacuum. The resulting crude material was purified by column chromatography (50% EtOAc/hexane) to yield 2-(2-methoxy-4-nitro-phenyl)-[l, 3, 4] oxadiazole (470 mg, 74.73%) as yellow solid.
STEP D. To a degassed solution of 2-(2-methoxy-4-nitro-phenyl)-[l, 3, 4] oxadiazole (400 mg, 1.81 mmol) in a mixture of ethanol and ethyl acetate (1: 1; 6 ml) was added catalytic amount of 5% Pd-C (20 mg) under nitrogen. The reaction mixture was set under a hydrogen atmosphere and stirred at 25°C for 24 h. The mixture was filtered through a bed of celite, and the residue washed with methanol (10 ml). The combined filtrates were evaporated in vacuum to give 3- methoxy-4-[l, 3, 4] oxadiazol-2-yl-phenylamine (190 mg, 55.07%) as yellow solid. LC-MS (ESI): 192 [(M+H)+].
Intermediate 7: 3-Methoxy-4-[l,2,4]triazol-l-yl-phenylamine
Figure imgf000059_0001
STEP A
A mixture of l-fluoro-2-methoxy-4-nitrobenzene (3 g, 17.27 mmol), lH-1, 2, 4-triazole
(1.19 g, 17.27 mmol) and K2C03 (2.38 g, 17.27 mmol) in dimethlyformamide (20 ml) was stirred for 2h at 110°C in a sealed tube. The reaction mixture was cooled to 25°C, poured into ice cold water, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered, and evaporated in vacuum. The crude material thus obtained was diluted with DMSO, and filtered. The solid residue was washed with water and hexane. The filtrate was purified by prep-HPLC and combined with the solid to afford 4-(2-methoxy-4-nitro-phenyl)-4H-[l, 2, 4] triazole (650 mg, 19%) as light yellow solid. LC-MS (ESI): 221 [(M+H)+].
STEP B
Following the same method as was adopted for the preparation of 3-methoxy-4-[l, 3, 4] oxadiazol-2-yl-phenylamine, l-(2-methoxy-4-nitro-phenyl)-lH-[l, 2, 4] triazole (330 mg, 1.49 mmol). was hydrogenated to yield 3-methoxy-4-[l,2,4]triazol-l-yl-phenylamine as a light brown solid (207mg, 72.62%). LC-MS (ESI): 191 [(M+H)+].
Intermediate 8: N-(4-Bromo-3-methoxy-phenyl)-2-(2-chloro-phenyl)-acetamide
Figure imgf000059_0002
4-Bromo-3-methoxyaniline (1 g, 4.95 mmol) and 2-(2-chlorophenyl)acetic acid (887 mg, 5.2 mmol) were combined with dichloromethane (20 ml). After cooling to 0°C, EDC (996 mg, 5.2 mmol) was added. The mixture was stirred for 30 minutes at 0°C then back to RT for 1.5h. A white suspension appeared, which was filtered and washed with dichloromethane. The title compound was obtained as a white solid (1.2g, 66%). LC-MS (ESI): 356.3 [(M+H)+].
Intermediate 9: N-(4-Bromo-2-methoxy-phenyl)-2-(2-chloro-phenyl)-acetamide
Figure imgf000059_0003
The title compound was obtained in analogy to intermediate 8, using 4-bromo-2-methoxyaniline as starting material. Off-white solid, LC-MS (ESI): 356.3 [(M+H)+].
Intermediate 10: 4-Bromo-N-(2-chloro-benzyl)-2-methoxy-benzamide
Figure imgf000060_0001
(2-Chlorophenyl)methanamine (500 mg, 426 μΐ, 3.53 mmol) and 4-bromo-2-methoxybenzoic acid (938 mg, 4.06 mmol) were combined with dichloromethane (10 ml). The reaction was cooled to 0°C and EDC (778 mg, 4.06 mmol) was added. The reaction was stirred at 0°C for 30 minutes then at room temperature for 48h. The reaction mixture was washed with NaHC03sat, dried over Na2S04, filtered and evaporated. The title compound was used crude, Off-white solid (1.14g, 91%). LC-MS (ESI): 356.3 [(M+H)+].
Intermediate 11: 4-Bromo-N-(2-chloro-benzyl)-3-methoxy-benzamide
Figure imgf000060_0002
The title compound was obtained in analogy to intermediate 9, using 4-bromo-3-methoxybenzoic acid as starting material. Off-white solid, LC-MS (ESI): 356.3 [(M+H)+].
Example 1
N-(3-Methoxy-4-oxaz -5-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide
Figure imgf000060_0003
3-Methoxy-4-oxazol-5-yl-phenylamine (Intermediate 1) (3.792 g, 19.9 mmol) and 2-(3- methoxyphenyl) acetic acid (5.3 g, 31.9 mmol) were combined with dichloromethane (200 ml). The mixture was cooled to 0°C and treated with (3-dimethylamino-propyl)-ethyl-carbodiimide (6.12 g, 31.9 mmol). The mixture was stirred for 30min at 0°C, then at RT for 23 h.
The mixture was washed with saturated sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and evaporated. The resulting yellow solid (8.2 g) was suspended in ethyl acetate and the solid filtered and washed. The filtrate was evaporated and purified by flash chromatography (heptane/ethyl acetate) and combined with the solid to yield N-(3-methoxy-4- oxazol-5-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide as a white solid (5.4 g, 80.3%). MS (ISN) m/z = 339.5 [(M+H)+].
Example 2
N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-m-tolyl-acetamide
Figure imgf000061_0001
A solution of 2-(3-methylphenyl)acetic acid (21.5 mg, 0.14 mmol) in dimethylformamide (0.3 ml) was treated with a 0.47 mM solution of (2-(7-aza-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate) (HATU) (0.3 mL, 0.14 mmol). Diisopropylethylamine (18.5 mg, 0.024 mL, 0.14 mmol) was added to the reaction mixture. A 0.52 mM solution of 3- methoxy-4-oxazol-5-yl-phenylamine (Intermediate 1) (0.3 mL, 0.16 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 48h, then purified by direct injection in preparative HPLC (Column: Preparative : Gemini Axia CI 8 5u 11 OA 5 micron 100 x 30 mm. Analytic :Gemini NX 3u 110A 50 x 4.6 mm; Solvent A : Water + ( 0.1% Formic acid or 0.1%. Triethylamine); Solvent B: Methanol or Acetonitrile; Method : Gradient: 20%B to 95%B Flow: 40ml/min; Detector: UV/MS/ELSD). Evaporation of the relevant fractions yielded N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-m-tolyl-acetamide as a white powder (28 mg, 60.7%); MS (ISN) m/z = 322.6 [(M+H)+].
Example 3
N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-pyridin-2-yl-acetamide
Figure imgf000061_0002
The title compound, white solid (24 mg, 55%), MS (ISP) m/z = 310.3 [(M+H)+] was prepared in analogy to the general method of example 2 from pyridin-2-yl-acetic acid and intermediate 1.
Example 4
2-(Benzenesulfonyl)-3'-methoxy-4'-(5-oxazolyl)acetanilide
Figure imgf000061_0003
The title compound, white solid, MS (ISP) m/z = 373.3 [(M+H)+] was prepared in analogy to the general method of example 2 from benzenesulfonyl-acetic acid and intermediate 1.
Example 5
tert-Butyl [(RS)-[[[3-methoxy-4-( -oxazolyl)phenyl]carbamoyl]phenyl]-(methyl)]carbamate
Figure imgf000062_0001
The title compound, white solid, MS (ISP) m/z = 424.5 [(M+H)+] was prepared in analogy to the general method of example 2 from (D,L)-iert-butoxycarbonyl-phenylglycine and intermediate 1.
Example 6
2-(2-Aminophenyl -3'-methoxy-4'-(5-oxazolyl)acetanilide
Figure imgf000062_0002
STEP1: N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-(2-nitro-phenyl)-acetamide was prepared in analogy to the general method of example 2 from 2-(2-nitrophenyl)acetic acid and intermediate 1 STEP2: The title compound, white solid, MS (ISP) m/z = 324.3 [(M+H)+], was prepared by hydrogenation of N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-(2-nitro-phenyl)-acetamide, in analogy to the standard procedure illustrated by the preparation of intermediate 1, step B.
Example 7
N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3,3-dimethyl-2-oxobutyramide
Figure imgf000062_0003
The title compound, MS (ISP) m/z = 303.3 [(M+H)+], can be prepared in analogy to example 2 from trimethyl-piruvic acid and intermediate 1.
Example 8
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide
Figure imgf000063_0001
The title compound, yellow solid, (95 mg, 98.4%), MS (ISP) m/z = 368.1 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-((3- methoxyphenyl)(methyl)amino)acetic acid and intermediate 1. Example 9
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylamino)acetamide
Figure imgf000063_0002
In a 10 mL round-bottomed flask, 3-methoxy-4-(oxazol-5-yl)aniline (Intermediate 1) (50 mg, 0.263 mmol) was combined with dichloromethane (2.0 ml) to give a light yellow solution.
Bromoacetyl bromide (53.1 mg, 0.023 ml, 0.263 mmol) was added the reaction mixture was stirred at room temperature for 15 min. Triethylamine (26.6 mg, 0.037 ml, 0.263 mmol) was added. The reaction mixture was stirred 15 min and 3-methoxyaniline (64.7 mg, 0.526 mmol) was added. The mixture was diluted with tetrahydrofurane and the dichloromethane was partially removed in vacuum. The reaction mixture was heated to 70 °C and stirred for 4 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography to yield the title compound as a yellow solid (47 mg, 50.6%); MS (ISP) m/z = 354.2 [(M+H)+].
Example 10
N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-phenylamino-acetamide
Figure imgf000063_0003
The title compound, yellow solid, MS (ISP) m/z = 324.3 [(M+H)+], could be prepared in analogy to example 9 using aniline. Example 11
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(phenylthio)acetamide
Figure imgf000064_0001
The title compound, yellow solid, (88 mg, 99%), MS (ISP) m/z = 341.1 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(phenylthio)acetic acid and intermediate 1.
Example 12
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-phenoxyacetamide
Figure imgf000064_0002
The title compound, yellow solid, (85 mg, 99%), MS (ISP) m/z = 325.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-phenoxyacetic acid and intermediate 1.
Example 13
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-phenylpropanamide
Figure imgf000064_0003
The title compound, yellow solid, (87 mg, 100%), MS (ISP) m/z = 323.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 3-phenylpropanoic acid and intermediate 1.
Example 14
2-(2,5-dimethoxyphenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000065_0001
The title compound, yellow solid, (103 mg, 94%), MS (ISP) m/z = 369.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2,5-dimethoxyphenyl)acetic acid and intermediate 1.
Example 15
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylthio)acetamide
Figure imgf000065_0002
The title compound, yellow solid, (96 mg, 99%), MS (ISP) m/z = 371.1 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-methoxyphenylthio)acetic acid and intermediate 1.
Example 16
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylsulfonyl)acetamide
Figure imgf000065_0003
In a 50 mL round-bottomed flask, N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3- methoxyphenylthio)acetamide (96 mg, 0.26 mmol) was combined with methanol (10 ml) to give a yellow solution. Oxone (239 mg, 0.39 mmol) was added. The reaction mixture was stirred for 15 h. The reaction mixture was filtered through glass fiber paper then concentrated in vacuum. The crude material was purified by flash chromatography to yield the title compound as a yellow solid (73 mg, 70%); MS (ISP) m/z = 403.0 [(M+H)+]. Example 17
2-(3-(difluoromethoxy)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000066_0001
The title compound, yellow solid, (45 mg, 76%), MS (ISP) m/z = 375.2 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-(difluoromethoxy)phenyl)acetic acid and intermediate 1. Example 18
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide
Figure imgf000066_0002
The title compound, yellow solid, (27 mg, 50%), MS (ISP) m/z = 377.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2-(trifluoromethyl)phenyl)acetic acid and intermediate 1.
Example 19
2-(2,4-dichlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000066_0003
The title compound, yellow solid, (15 mg, 27%), MS (ISP) m/z = 376.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2,4-dichlorophenyl)acetic acid and intermediate 1.
Example 20
2-(4-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000066_0004
The title compound, yellow solid, (26 mg, 52%), MS (ISP) m/z = 343.4 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(4-chlorophenyl)acetic acid and intermediate 1.
Example 21
2-(3-bromophenyl -N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000067_0001
The title compound, yellow solid, (24 mg, 43%), MS (ISP) m/z = 386.6 [(M+H)+], was in analogy to the general method of example 2 from 2-(3-bromophenyl)acetic acid and intermediate 1.
Example 22
2-(4-bromophenyl)-N-(3-methox -4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000067_0002
The title compound, yellow solid, (19 mg, 34%), MS (ISP) m/z = 386.5 [(M+H)+], was prepared in analogy to the general method of example 2 from 2- (4-bromophenyl) acetic acid and intermediate 1.
Example 23
2-(benzo[d][l,3]dioxol-5- l)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000067_0003
The title compound, yellow solid, (28 mg, 55%), MS (ISP) m/z = 352.9 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(benzo[d][l,3]dioxol-5-yl)acetic acid and intermediate 1. Example 24
2-(2-chloro-6-fluorophen l)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000068_0001
The title compound, yellow solid, (28 mg, 54%), MS (ISP) m/z = 360.9 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2-chloro-6-fluorophenyl)acetic acid and intermediate 1.
Example 25
2-(2,6-difluorophenyl)-N- 3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000068_0002
The title compound, yellow solid, (34 mg, 70%), MS (ISP) m/z = 344.9 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2,6-difluorophenyl)acetic acid and intermediate 1.
Example 26
2-(2-(difluoromethoxy)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000068_0003
The title compound, yellow solid, (30 mg, 56%), MS (ISP) m/z = 375.4 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2-(difluoromethoxy)phenyl)acetic acid and intermediate 1.
Example 27
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-(trifluoromethoxy)phenyl)acetamide
Figure imgf000069_0001
The title compound, yellow solid, (23 mg, 41%), MS (ISP) m/z = 392.7 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2-(trifluoromethoxy)phenyl)acetic acid and intermediate 1.
Example 28
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-methoxyphenyl)acetamide
Figure imgf000069_0002
The title compound, yellow solid, (35 mg, 72%), MS (ISP) m/z = 338.7 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2-methoxyphenyl)acetic acid and intermediate 1.
Example 29
2-(4-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000069_0003
The title compound, yellow solid, (32 mg, 69%), MS (ISP) m/z = 327.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(4-fluorophenyl)acetic acid and intermediate 1.
Example 30
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-p-tolylacetamide
Figure imgf000070_0001
The title compound, yellow solid, (19.1 mg, 41%), MS (ISP) m/z = 323.6 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-p-tolylacetic acid and intermediate 1.
Example 31
2-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000070_0002
The title compound, yellow solid, (29 mg, 59%), MS (ISP) m/z = 343.4 [(M+H)+], was in analogy to the general method of example 2 from 2-(2-chlorophenyl)acetic acid and intermediate 1.
Example 32
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-o-tolylacetamide
Figure imgf000070_0003
The title compound, yellow solid, (33.4 mg, 72.5%), MS (ISP) m/z = 323.3 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-o-tolylacetic acid and intermediate 1.
Example 33
2-(2-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000071_0001
The title compound, yellow solid, (28 mg, 60%), MS (ISP) m/z = 326.9 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2-fluorophenyl)acetic acid and intermediate 1. Example 34
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide
Figure imgf000071_0002
The title compound, yellow solid, (22 mg, 41%), MS (ISP) m/z = 377.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-(trifluoromethyl)phenyl)acetic acid and intermediate 1.
Example 35
2-(3,5-dimethylphenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000071_0003
The title compound, yellow solid, (29 mg, 60%), MS (ISP) m/z = 337 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3,5-dimethylphenyl)acetic acid and intermediate 1.
Example 36
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(naphthalen-l-yl)acetamide
Figure imgf000072_0001
The title compound, yellow solid, (28 mg, 54%), MS (ISP) m/z = 358.9 [(M+H)+], was in analogy to the general method of example 2 from 2-(naphthalen-l-yl)acetic acid and intermediate 1.
Example 37
2-(3-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000072_0002
The title compound, yellow solid, (30 mg, 61%), MS (ISP) m/z = 342.8 [(M+H)+], was in analogy to the general method of example 2 from 2-(3-chlorophenyl)acetic acid and intermediate 1.
Example 38
2-(3,5-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000072_0003
The title compound, yellow solid, (30 mg, 60%), MS (ISP) m/z = 345.4 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3,5-difluorophenyl)acetic acid and intermediate 1.
Example 39
2-(3-fluoro-5-(trifluoromethyl)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000073_0001
The title compound, yellow solid, (25.3 mg, 45%), MS (ISP) m/z = 394.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-fluoro-5- (trifluoromethyl)phenyl) acetic acid and intermediate 1. Example 40
2-(2,4-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000073_0002
The title compound, yellow solid, (31 mg, 63%), MS (ISP) m/z = 344.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2,4-difluorophenyl)acetic acid and intermediate 1.
Example 41
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)acetamide
Figure imgf000073_0003
The title compound, yellow solid, (25 mg, 46%), MS (ISP) m/z = 387.3 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(4-(methylsulfonyl)phenyl)acetic acid and intermediate 1.
Example 42
2-(3,4-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000074_0001
The title compound, yellow solid, (28 mg, 56%), MS (ISP) m/z = 345.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3,4-difhiorophenyl)acetic acid and intermediate 1.
Example 43
2-(3-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000074_0002
The title compound, yellow solid, (25 mg, 53%), MS (ISP) m/z = 326.9 [(M+H)+], was in analogy to the general method of example 2 from 2-(3-fluorophenyl)acetic acid and intermediate 1.
Example 44
2-(2,5-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000074_0003
The title compound, yellow solid, (30.5 mg, 62%), MS (ISP) m/z = 344.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2,5-difluorophenyl)acetic acid and intermediate 1.
Example 45
2-(2,3-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000075_0001
The title compound, yellow solid, (30 mg, 60%), MS (ISP) m/z = 344.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2,3-difhiorophenyl)acetic acid and intermediate 1. Example 46
2-(3-chloro-4-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000075_0002
The title compound, yellow solid, (29 mg, 56%), MS (ISP) m/z = 360.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-chloro-4-fluorophenyl)acetic acid and intermediate 1.
Example 47
2-(3-cyanophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000075_0003
The title compound, yellow solid, (30 mg, 62.5%), MS (ISP) m/z = 333.9 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-cyanophenyl)acetic acid and intermediate 1.
Example 48
2-(5-chloro-2-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000076_0001
The title compound, yellow solid, (25 mg, 48%), MS (ISP) m/z = 360.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(5-chloro-2-fluorophenyl)acetic acid and intermediate 1.
Example 49
2-(furan-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000076_0002
The title compound, yellow solid, (31.1 mg, 73%), MS (ISP) m/z = 299.1 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(furan-2-yl)acetic acid and intermediate 1.
Example 50
2-(5-fluoropyridin-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000076_0003
The title compound, yellow solid, (28 mg, 59%), MS (ISP) m/z = 328.1 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(5-fluoropyridin-2-yl)acetic acid and intermediate 1.
Example 51
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(thiophen-2-yl)acetamide
Figure imgf000077_0001
The title compound, yellow solid, (22 mg, 49%), MS (ISP) m/z = 314.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(thiophen-2-yl)acetic acid and
intermediate 1.
Example 52
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(thiophen-3-yl)acetamide
Figure imgf000077_0002
The title compound, yellow solid, (23.3 mg, 52%), MS (ISP) m/z = 315.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(thiophen-3-yl)acetic acid and intermediate 1.
Example 53
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(pyridin-4-yl)acetamide
Figure imgf000077_0003
The title compound, yellow solid, (30 mg, 67%), MS (ISP) m/z = 310.3 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(pyridin-4-yl)acetic acid and intermediate 1.
Example 54
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(l-methyl-lH-indol-3-yl)acetamide
Figure imgf000078_0001
The title compound, yellow solid, (35.2 mg, 68%), MS (ISP) m/z = 362.0 [(M+H)+], was prepared in analogy to the general method of example 2-(l-methyl-lH-indol-3-yl)acetic acid and intermediate 1.
Example 55
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(pyridin-3-yl)acetamide
Figure imgf000078_0002
The title compound, yellow solid, (78.2 mg, 88%), MS (ISP) m/z = 309.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(pyridin-3-yl)acetic acid and intermediate 1.
Example 56
2-(lH-indol-3-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000078_0003
The title compound, yellow solid, (27 mg, 54%), MS (ISP) m/z = 348.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(lH-indol-3-yl)acetic acid and intermediate 1.
Example 57
2-(benzo[d]isoxazol-3-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000079_0001
The title compound, yellow solid, (25 mg, 50%), MS (ISP) m/z = 350.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(benzo[d]isoxazol-3-yl)acetic acid and intermediate 1.
Example 58
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methylisoxazol-5-yl)acetamide
Figure imgf000079_0002
The title compound, yellow solid, (10.5 mg, 23.5%), MS (ISP) m/z = 314.3 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-methylisoxazol-5-yl)acetic acid and intermediate 1.
Example 59
2-(2,4-dimethylthiazol-5-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000079_0003
The title compound, yellow solid, (12.6 mg, 26%), MS (ISP) m/z = 344.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(2,4-dimethylthiazol-5-yl)acetic acid and intermediate 1.
Example 60
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(5-methylthiophen-2-yl)acetamide
Figure imgf000080_0001
The title compound, yellow solid, (19.2 mg, 41%), MS (ISP) m/z = 329.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(5-methylthiophen-2-yl)acetic acid and intermediate 1.
Example 61
N-(3-methoxy-4-(oxazol-5-yl)phenyl)pentanamide
Figure imgf000080_0002
The title compound, yellow solid, (23 mg, 58%), MS (ISP) m/z = 275.1 [(M+H)+], was in analogy to the general method of example 2 from pentanoic acid and intermediate 1.
Example 62
N-(3-methoxy-4-(oxazol-5-yl)phenyl)propionamide
Figure imgf000080_0003
The title compound, yellow solid, (22 mg, 62%), MS (ISP) m/z = 247.2 [(M+H)+], was in analogy to the general method of example 2 from propionic acid and intermediate 1.
Example 63
2-cyclohexenyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000080_0004
The title compound, yellow solid, (32.3 mg, 72%), MS (ISP) m/z = 312.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-cyclohexenylacetic acid and intermediate 1.
Example 64
2-cyclohexyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000081_0001
The title compound, yellow solid, (11.3 mg, 25%), MS (ISP) m/z = 315.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-cyclohexylacetic acid and intermediate 1.
Example 65
2-cyclopropyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000081_0002
The title compound, yellow solid, (20.7 mg, 53%), MS (ISP) m/z = 272.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-cyclopropylacetic acid and intermediate 1.
Example 66
2-cyclopentyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000081_0003
The title compound, yellow solid, (27 mg, 62%), MS (ISP) m/z = 301.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-cyclopentylcetic acid and intermediate 1. Example 67
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-methylcyclohexyl)acetamide
Figure imgf000082_0001
The title compound, yellow solid, (25 mg, 53%), MS (ISP) m/z = 329.5 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(4-methylcyclohexyl)acetic acid and intermediate 1.
Example 68
2-(bicyclo[2.2.1]heptan-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000082_0002
The title compound, yellow solid, (23 mg, 50%), MS (ISP) m/z = 326.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(bicyclo[2.2.1]heptan-2-yl)acetic acid and intermediate 1.
Example 69
2-(6-methoxy-3-oxo-2,3-dihydro-lH-inden-l-yl)-N-(3-methoxy-4-(oxazol-5- yl)phenyl)acetamide
Figure imgf000082_0003
The title compound, yellow solid, (26 mg, 47%), MS (ISP) m/z = 392.9 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(6-methoxy-3-oxo-2,3-dihydro-lH-inden- l-yl)acetic acid and intermediate 1. Example 70
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide
Figure imgf000083_0001
The title compound, yellow solid, (31 mg, 68%), MS (ISP) m/z = 316.9 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(tetrahydro-2H-pyran-4-yl)acetic acid and intermediate 1.
Example 71
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydrofuran-2-yl)acetamide
Figure imgf000083_0002
The title compound, yellow solid, (20 mg, 46%), MS (ISP) m/z = 303.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(tetrahydrofuran-2-yl)acetic acid and intermediate 1.
Example 72
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H-pyran-2-yl)acetamide
Figure imgf000083_0003
The title compound, yellow solid, (27 mg, 60%), MS (ISP) m/z = 316.8 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(tetrahydro-2H-pyran-2-yl)acetic acid and intermediate 1.
Example 73
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-2- yl)acetamide
Figure imgf000084_0001
The title compound, yellow solid, (37 mg, 69%), MS (ISP) m/z = 369.9 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazin-2-yl)acetic acid and intermediate 1.
Example 74
2-(l,l-Dioxo etrah dro-lλ6-thiophen-3- l)-N-(3-methox -4-oxazol-5- l-phen l)-acetamide
Figure imgf000084_0002
The title compound, yellow solid, (34 mg, 67%), MS (ISP) m/z = 350.7 [(M+H)+], was prepared in analogy to the general method of example 2 from (l,l-dioxo-tetrahydro-llambda*6*-th iophen-3-yl)-acetic acid and intermediate 1.
Example 75
2-cyclobutyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000084_0003
The title compound, yellow solid, (25 mg, 60%), MS (ISP) m/z = 286.9 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazin-2-yl)acetic acid and intermediate 1.
Example 76
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-oxocyclohexyl)acetamide
Figure imgf000084_0004
The title compound, yellow solid, (28 mg, 59%), MS (ISP) m/z = 328.7 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(4-oxocyclohexyl)acetic acid and intermediate 1.
Example 77
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-phenylpropanamide
Figure imgf000085_0001
The title compound, yellow solid, (34 mg, 73%), MS (ISP) m/z = 322.5 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-phenylpropanoic acid and intermediate 1.
Example 78
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3,3-dimethylbutanamide
Figure imgf000085_0002
The title compound, yellow solid, (18 mg, 43.5%), MS (ISP) m/z = 289.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 3,3-dimethylbutanoic acid and intermediate 1.
Example 79
N-(3-chloro-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenyl)acetamide
Figure imgf000085_0003
The title compound, off-white solid, (30 mg, 29.4%), MS (ISP) m/z = 343.1 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-methoxyphenyl)acetic acid and intermediate 2. Example 80
2-(3-methoxyphenyl)-N-(3-methyl-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000086_0001
The title compound, off-white solid, (288 mg, 78%), MS (ISP) m/z = 323.3 [(M+H)+], was prepared in analogy to the general method of example 1 from 2-(3-methoxyphenyl)acetic acid and intermediate 3.
Example 81
2-(3-Methoxy-phenyl)-N-(3-methoxy-4-thiazol-5-yl-phenyl)-acetamide
The title compound, light yellow solid, (89 mg, 57%), LC-MS (ESI) = 355.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-methoxyphenyl)acetic acid and intermediate 5.
Example 82
N-(3-Methoxy-4-[l,3,4]oxadiazol-2-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide
Figure imgf000086_0003
The title compound, white solid, (51 mg, 14.3%), LC-MS (ESI) = 340.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-methoxyphenyl)acetic acid and intermediate 6.
Example 83
2-(3-Methoxy-phenyl)-N-(3-methoxy-4-[l,2,4]triazol-l-yl-phenyl)-acetamide
Figure imgf000087_0001
The title compound, yellow solid, (44 mg, 41%), LC-MS (ESI) = 338.0 [(M+H)+], was prepared in analogy to the general method of example 2 from 2-(3-methoxyphenyl)acetic acid and intermediate 7.
Example 84
3-methoxy-N-(3-methoxybenzyl)-4-(oxazol-5-yl)benzamide
Figure imgf000087_0002
In a 5 mL round-bottomed flask, 3-methoxy-4-(oxazol-5-yl)benzoic acid (Intermediate 4, 100 mg, 0.46 mmol), diisopropylethylamine (59.0 mg, 0.46 mmol) and HATU (173 mg, 0.46 mmol) were combined with dimethylformamide (3 ml) to give a yellow solution. The reaction mixture was stirred for 15 min. (3-Methoxyphenyl)methanamine (62.6 mg, 0.46 mmol) was added. The reaction mixture was stirred for 15 h. The crude reaction mixture was concentrated in vacuum and purified by flash chromatography to yield the title compound as a white solid (84 mg,
54.4%), MS (ISP) m/z = 339.3 [(M+H)+].
Example 85
N-(4-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000087_0003
The title compound, white solid, (35 mg, 91%), MS (ISP) m/z = 343.0 [(M+H)+], was prepared in analogy to the general method of example 84 from (4-chlorophenyl)methanamine and intermediate 4. Example 86
N-(4-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000088_0001
The title compound, white solid, (26 mg, 64%), MS (ISP) m/z = 327.1 [(M+H)+], was prepared in analogy to the general method of example 84 from (4-fluorophenyl)methanamine and intermediate 4.
Example 87
3-methoxy-4-(oxazol-5-yl)-N-(2-(trifluoromethyl)benzyl)benzamide
Figure imgf000088_0002
The title compound, white solid, (29 mg, 62%), MS (ISP) m/z = 377.3 [(M+H)+], was prepared in analogy to the general method of example 84 from (2-trifluoromethyl)phenyl)methanamine and intermediate 4.
Example 88
N-(2-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000088_0003
The title compound, white solid, (35 mg, 81%), MS (ISP) m/z = 343.0 [(M+H)+], was prepared in analogy to the general method of example 84 from (2-chlorophenyl)methanamine and intermediate 4.
Example 89
3-methoxy-N-(2-methylbenzyl)-4-(oxazol-5-yl)benzamide
Figure imgf000089_0001
The title compound, white solid, (30 mg, 74%), MS (ISP) m/z = 323.0 [(M+H)+], was prepared in analogy to the general method of example 84 from o-tolylmethanamine and intermediate 4.
Example 90
N-(2-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000089_0002
The title compound, white solid, (24 mg, 58%), MS (ISP) m/z = 327.3 [(M+H)+], was prepared in analogy to the general method of example 84 from (2-fluorophenyl)methanamine and intermediate 4.
Example 91
N-(3-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000089_0003
The title compound, white solid, (25 mg, 57%), MS (ISP) m/z = 343.0 [(M+H)+], was prepared in analogy to the general method of example 84 from (3-chlorophenyl)methanamine and intermediate 4.
Example 92
N-(3,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000090_0001
The title compound, white solid, (34 mg, 78%), MS (ISP) m/z = 345.1 [(M+H)+], was prepared in analogy to the general method of example 84 from (3,5-difluorophenyl)methanamine and intermediate 4.
Example 93
N-(2,4-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000090_0002
The title compound, white solid, (33 mg, 76%), MS (ISP) m/z = 345.0 [(M+H)+], was prepared in analogy to the general method of example 84 from (2,4-difluorophenyl)methanamine and intermediate 4.
Example 94
N-(3-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000090_0003
The title compound, white solid, (31 mg, 75%), MS (ISP) m/z = 327.3 [(M+H)+], was prepared in analogy to the general method of example 84 from (3-fluorophenyl)methanamine and intermediate 4.
Example 95
N-(2,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000091_0001
The title compound, white solid, (32.5 mg, 75%), MS (ISP) m/z = 345.0 [(M+H)+], was prepared in analogy to the general method of example 84 from (2,5-difluorophenyl)methanamine and intermediate 4.
Example 96
N-(2,3-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000091_0002
The title compound, white solid, (32 mg, 74%), MS (ISP) m/z = 345.1 [(M+H)+], was prepared in analogy to the general method of example 84 from (2,3-difluorophenyl)methanamine and intermediate 4.
Example 97
3-methoxy-4-(oxazol-5-yl)-N-(thiophen-2-ylmethyl)benzamide
Figure imgf000091_0003
The title compound, white solid, (35 mg, 88%), MS (ISP) m/z = 315.0 [(M+H)+], was prepared in analogy to the general method of example 84 from thiophen-2-ylmethanamine and
intermediate 4.
Example 98
N-(2-fluoro-3-methoxybenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000092_0001
The title compound, white solid, (61 mg, 75%), MS (ISP) m/z = 357.1 [(M+H)+], was prepared in analogy to the general method of example 84 from (2-fluoro-3-methoxyphenyl)methanamine hydrobromide and intermediate 4.
Example 99
N-(5-chloro-2-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000092_0002
The title compound, white solid, (79 mg, 96%), MS (ISP) m/z = 361.0 [(M+H)+], was prepared in analogy to the general method of example 84 from (5-chloro-2-fluorophenyl)methanamine hydrobromide and intermediate 4.
Example 100
3-methoxy-N-((6-methoxypyridin-2-yl)methyl)-4-(oxazol-5-yl)benzamide
Figure imgf000092_0003
The title compound, white solid, (61 mg, 78%), MS (ISP) m/z = 340.3 [(M+H)+], was prepared in analogy to the general method of example 84 from (6-methoxypyridin-2-yl)methanamine hydrochloride and intermediate 4.
Example 101
2-(3-methoxyphenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000093_0001
The title compound, white solid, (23.2 mg, 38%), MS (ISP) m/z = 309.5 [(M+H)+], was prepared in analogy to the general method of example 2 from 4-(oxazol-5-yl)aniline and 2-(3- methoxyphenyl) acetic acid.
Example 102
N-(3-methoxybenzyl)-4-(oxazol-5-yl)benzamide
Figure imgf000093_0002
The title compound, white solid, (11.5 mg, 19%), MS (ISP) m/z = 309.5 [(M+H)+], was prepared in analogy to the general method of example 84 from 4-(oxazol-5-yl)benzoic acid and (3-methoxyphenyl)methanamine.
Example 103
2-(3-methoxyphenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide
Figure imgf000093_0003
The title compound, white solid, (16 mg, 25%), MS (ISP) m/z = 319.5 [(M+H)+], was in analogy to the general method of example 2 from 4-(pyridin-4-yl)aniline and 2-(3- methoxyphenyl) acetic acid.
Example 104
N-(3-methoxybenzyl)-4-(pyridin-4-yl)benzamide
Figure imgf000093_0004
The title compound, white solid, (1.2 mg, 2%), MS (ISP) m/z = 319.5 [(M+H)+], was prepared in analogy to the general method of example 84 from 4-(pyridin-4-yl)benzoic acid and (3- methoxyphenyl)methanamine.
Example 105
2-(2-chlorophenyl)-N-(3-methoxy-4-(pyridin-4-yl)phenyl)acetamide
Figure imgf000094_0001
N-(4-bromo-3-methoxyphenyl)-2-(2-chlorophenyl)acetamide (Intermediate 8) (200 mg, 564 μιηοΐ), pyridin-4-ylboronic acid (83.2 mg, 677 μιηοΐ) K2C03 (390 mg, 2.82 mmol) and
Pd(Ph P)4 (97.8 mg, 84.6 μιηοΐ) were combined in a flask and flushed with argon for five minutes. A mixture of toluene (3 ml), ethanol (1.00 ml) and water (500 μΐ) was added. The reaction was heated at 80°C for 18.5h. The reaction mixture was poured on water (20 ml), washed with EtOAc (20 ml) and the organic phase was separated, dried with Na2S04, filtered and concentrated in vacuo. The crude material (292.8 mg) was dissolved in dichloromethane and purified by flash chromatography on silica gel (dichlorometane/methanol gradient), to yield the title compound as a white solid (107 mg, 104%), MS (ISP) m/z = 353.4 [(M+H)+].
Example 106
N-(2-chlorobenzyl)-3-methoxy-4-(pyridin-4-yl)benzamide
Figure imgf000094_0002
The title compound, light yellow solid, (108 mg, 54%), MS (ISP) m/z = 353.4 [(M+H)+], was prepared in analogy to example 105 by combining intermediate 11 with pyridin-4-ylboronic acid.
Example 107
2-(2-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)acetamide
Figure imgf000095_0001
The title compound, light yellow solid, (16 mg, 8.6%), MS (ISP) m/z = 342.4 [(M+H)+], was prepared in analogy to example 105 by combining intermediate 8 with 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole.
Example 108
2-(2-chlorophenyl)-N-(2-methoxy-4-(lH-pyrazol-4-yl)phenyl)acetamide
Figure imgf000095_0002
The title compound, white solid, (48 mg, 17%), MS (ISP) m/z = 342.4 [(M+H)+], was prepared in analogy to example 105 by combining intermediate 9 with 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole.
Example 109
N-(2-chlorobenzyl)-2-methoxy-4-(lH-pyrazol-4-yl)benzamide
Figure imgf000095_0003
The title compound, white solid, (37.4 mg, 18%), MS (ISP) m/z = 342.4 [(M+H)+], was prepared in analogy to example 105 by combining intermediate 10 with 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole.
Example 110
N-(2-chlorobenzyl)-3-methoxy-4-(lH-pyrazol-4-yl)benzamide
Figure imgf000096_0001
The title compound, white solid, (57 mg, 28%), MS (ISP) m/z = 342.4 [(M+H)+], was prepared in analogy to example 105 by combining intermediate 11 with 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole.
Example 111
N-(3-methoxy-4-(lH- razol-4-yl)phenyl)-3-phenylpropanamide
Figure imgf000096_0002
STEP A.
In a 25 mL round-bottomed flask, 3-phenylpropanoic acid (446 mg, 2.97 mmol) was combined with DMF (10 ml) to give a colorless solution. 2-(3H-[l,2,3]Triazolo[4,5-b]pyridin-3-yl)- 1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.88 g, 4.95 mmol) and
Diisopropylethylamine (959 mg, 1.3 ml, 7.42 mmol) were added, and the reaction mixture was stirred 10 min at RT. Then, 4-bromo-3-methoxyaniline (500 mg, 2.47 mmol) was added. The mixture was stirred 4 h at RT, was then poured into water, and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 50% ethyl acetate in heptane) to yield N-(4-bromo-3-methoxyphenyl)-3-phenylpropanamide as a white powder (792.2 mg, 95.8 %). MS (m/e) = 336.4 [M+H+].
STEP B.
In a sealed tube, N-(4-bromo-3-methoxyphenyl)-3-phenylpropanamide (100 mg, 299 μιηοΐ) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (88.0 mg, 299 μιηοΐ) were combined with dioxane (2 ml) to give a light yellow solution. Sodium carbonate solution (2M, 299 μΐ, 598 μιηοΐ) was added. Argon was bubbled through the solution during 5 min.[l, -Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.9 mg, 15.0 μιηοΐ) was added. Argon was bubbled through the solution for another 5 minutes. The reaction mixture was heated to 110 °C and stirred for 4 d. The reaction mixture was then poured into saturated NaHC03 solution and extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo. The reaction mixture was purified by preparative HPLC (Zorbax Eclipse XDB-C18 21,2x50mm flow: 25 ml/min, gradient: acetonitrile / water (0.1% formic acid) = 95%-5% to 5%-95%) to yield N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3- phenylpropanamide as a white solid (11 mg, 11.4 %, MS (m/e) = 322.16 [M+H+]).
Example 112
3-(4-chlorophenyl)-N-( -methoxy-4-(lH-pyrazol-4-yl)phenyl)propanamide
Figure imgf000097_0001
The title compound was prepared in analogy to Example 111, using 3-(4-chlorophenyl)propanoic acid in STEP A. The compound was obtained as a brown powder (MS (m/e) = 356.12 [M+H+]).
Example 113
2-(2-chlorophenyl)-N-(3-methoxy-4-(lH-l,2,4-triazol-l-yl)phenyl)acetamide
Figure imgf000097_0002
The title compound, light brown solid, (42 mg, 47%), MS (m/e) = 343.1 [M+H+], was prepared in analogy to the general method of example 2 from (2-chloro-phenyl)-acetic acid and intermediate 7.
Example 114
2-(4-chlorophenylamin -N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000097_0003
3-Methoxy-4-(oxazol-5-yl)aniline (intermediate 1, 50 mg, 263 μιηοΐ), 2-(4- chlorophenylamino)acetic acid (48.8 mg, 263 μιηοΐ) and 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3- yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (150 mg, 394 μιηοΐ) were combined with DMF (2.00 ml) to give a light brown solution. Diisopropylethylamine (102 mg, 138 μΐ, 789 μιηοΐ) was added. The reaction mixture was stirred over night at RT, and was purified by preparative HPLC (Zorbax Eclipse XDB-C18 21,2x50mm flow: 25 ml/min, gradient: acetonitrile / water (0.1% formic acid) = 95%-5% to 5%-95%) to yield the title compound as a light brown solid (25.6 mg, 27.2 %, MS (m/e) = 358.1 [M+H+]).
Figure imgf000098_0001
The title compound was prepared in analogy to example 114, using 2-(3- (trifluoromethyl)phenylamino)acetic acid. The compound was obtained as a light brown solid (43.7 mg, 42.3%, MS (m/e) = 392.12 [M+H+]).
Example 116
2-(4-fluorophenylamin -N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000098_0002
The title compound was prepared in analogy to example 114, using 2-(4- fluorophenylamino)acetic acid. The compound was obtained as a light brown solid (33.6 mg, 37.4 %, MS (m/e) = 342.12 [M+H+]).
Example 117
N-(4-(oxazol-5- l)phenyl)-2-(phenylamino)acetamide
Figure imgf000098_0003
The title compound was prepared in analogy to example 114, using 4-(oxazol-5-yl)aniline and 2- (phenylamino)acetic acid. The compound was obtained as a light brown solid (26.5 mg, 28.9 %,
MS (m/e) = 294.13 [M+H+]).
Example 118
2-(4-fluorophenylamino)-N-(4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000099_0001
The title compound was prepared in analogy to example 114, using 4-(oxazol-5-yl)aniline and 2- (4-fluorophenylamino)acetic acid. The compound was obtained as a off-white powder (27.7 mg, 28.5 , MS (m/e) = 312.12 [M+H+]).
Example 119
3-(3-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamide
Figure imgf000099_0002
The title compound was prepared in analogy to Example 114, using 3-(3-chlorophenyl)propanoic acid. The compound was obtained as a brown solid (MS (m/e) = 357.10 [M+H+]).
Example 120
3-(2-chlorophenyl)-N-(3-methox -4-(oxazol-5-yl)phenyl)propanamide
Figure imgf000099_0003
The title compound was prepared in analogy to Example 114, using 3-(2-chlorophenyl)propanoic acid in STEP A. The compound was obtained as a brown solid (MS (m/e) = 357.10 [M+H+]).
Example 121
N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3-phenylpropanamide
Figure imgf000099_0004
STEP A.
Under an atmosphere of nitrogen, in a 50 mL round-bottomed flask, pyridin-4-ylboronic acid (1 g, 8.14 mmol), 4-bromo-3-methoxyaniline (1.64 g, 8.14 mmol) tetrakis(triphenylphosphine)palladium (0) (18.8 mg, 16.3 μηιοΐ) and sodium carbonate (3.02 g, 28.5 mmol) were combined with DMF (14 ml) and water (4 ml) to give a light brown suspension. The reaction was stirred overnight at reflux. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried aver sodium sulfate and filtered and the solvent vas removed in vacuum. 3-Methoxy-4-(pyridin-4-yl)aniline was isolated from the residue by column chromatography (silica gel, 20g, 50% to 100% EtOAc in heptane) as a brown solid (240 mg, 15%, MS (m/e) = 201.5 [M+H+]).
STEP B.
In a sealed tube, 3-methoxy-4-(pyridin-4-yl)aniline (60 mg, 300 μιηοΐ), 3-phenylpropanoic acid (45.0 mg, 300 μηιοΐ) and DIPEA (65.8 mg, 89.0 μΐ, 509 μηιοΐ) were combined with DMF (500 μΐ). Then HATU (194 mg, 509 μηιοΐ, Eq: 1.7) was added.
The mixture was stirred for 5 d at RT. The crude material was purified by preparative HPLC (column: zorbax C18 21.2x50mm flow: 20 ml/min, gradient: acetonitrile / water (+0.1% formic acid) =(95%-5% to 5%-95%) in 8 min) to give N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3- phenylpropanamidea yellow solid (34.7mg, 34.8 %, MS (m/e) = 333.16 [M+H+]).
Example 122
N-(4-(lH-pyrazol-4- l)phenyl)-3-(2-chlorophenyl)propanamide
Figure imgf000100_0001
STEP A.
To a solution of l-bromo-4-nitro-benzene (2 g, 9.90 mmol) in dioxane (160 ml) and water (40 ml) was added potassium carbonate (4.10 mg, 29.70 mmol), and the reaction mixture was purged with argon for 1 Omin. [l-(tert-Butoxycarbonyl)-lH-pyrazol-4-yl]boronic acid pinacol ester (4.36 g, 14.85 mmol) and Pd(dppf)2Cl2*CH2Cl2 (323 mg, 0.39 mmol) were added to the reaction mixture and purged again with argon for lOmin. The reaction mixture was heated to 80 °C for 16 h. The solvent was evaporated under reduced pressure, and the resulting crude mass was diluted with water (60 ml), and extracted with dichloromethane (2x80 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated off in vacuo. The resulting crude mass was purified by column chromatography (silica gel, 50-60% ethyl acetate/hexane) to get 4-(4-nitro-phenyl)-lH-pyrazole (1.86g, 99.41%) as yellow solid. MS: 190.0 (M+H+). STEP B.
To a solution of 4-(4-nitro-phenyl)-lH-pyrazole (3.98 g, 21.05 mmol) in THF (150 ml) were added triethylamine (4.40 ml, 31.58 mmol) and (Boc)20 (7.25 ml, 31.58 mmol), and the reaction mixture was stirred at 25 °C for 16 h. The solvent was evaporated off in vacuo, and the resulting crude mass was purified by column chromatography (silica gel, 20-30% ethyl acetate/hexane) to give tert-butyl 4-(4-nitrophenyl)-lH-pyrazole-l-carboxylate (4 g, 65.66%) as a white solid. MS: 290.2 (M+H+).
STEP C.
To a solution of tert-butyl 4-(4-nitrophenyl)-lH-pyrazole-l-carboxylate (2g, 6.92mmol) in MeOH (190 ml) was added 10% Pd/C (100 mg), and the reaction mixture was stirred at 25 °C under H2 balloon atmosphere for 3 h. The mixture was filtered, and the filtrate was evaporated off under reduced pressure to give tert-butyl 4-(4-aminophenyl)-lH-pyrazole-l-carboxylate (1.75g, 97.8%) as off-white solid. MS: 260.0 (M+H+).
STEP D.
In a sealed tube, tert-butyl 4-(4-aminophenyl)-lH-pyrazole-l-carboxylate (120 mg, 463 μιηοΐ), 3-(2-chlorophenyl)propanoic acid (85.4 mg, 463 μιηοΐ) and DIPEA (102 mg, 137 μΐ, 787 μιηοΐ) were combined with DMF (1 ml). Then HATU (264 mg, 694 μιηοΐ) was added. The mixture was stirred overnight at RT, and then poured into 30 ml ethyl acetate and extracted with water (3 x 15 mL) and brine. The organic layers were dried over sodium sulfate and concentrated in vacuo. tert-Butyl 4-(4-(3-(2-chlorophenyl)propanamido)phenyl)-lH-pyrazole-l-carboxylate was obtained as a light brown foam (240mg, 97.4 %). MS (m/e) = 326.5.
STEP E.
Under an atmosphere of nitrogen, in a 25 mL round-bottomed flask, tert-butyl 4-(4-(3-(2- chlorophenyl)propanamido)phenyl)-lH-pyrazole-l-carboxylate (240mg, 451 μιηοΐ) was combined with CH2C12 (2 ml) to give a light brown solution. Then trifluoroacetic acid (1.03 g, 695 μΐ, 9.02 mmol) was added slowly. The mixture was stirred for 1 h at RT. The crude reaction mixture was concentrated in vacuo and was purified by preparative HPLC (zorbax C18
21.2x50mm flow: 20 ml/min, gradient: acetonitrile / water (+0.1% formic acid) = (95%-5% to 5%-95%) in 8 min). N-(4-(lH-Pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)propanamide was obtained as a off-white solid (49.9mg, 34.0 %). MS (m/e) = 326.10 [M+H+] .
Example 123
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(3-chlorophenyl)propanamide
Figure imgf000102_0001
The title compound was prepared in analogy to example 122, using 3-(3-chlorophenyl)propanoic acid in STEP D. MS (m/e) = 326.1 [M+H+]. Example 124
N-(4-(lH-pyrazol- -yl)phenyl)-3-(4-chlorophenyl)propanamide
Figure imgf000102_0002
The title compound was prepared in analogy to example 122, using 3-(4-chlorophenyl)propanoic acid in STEP D. MS (m/e) = 326.11 [M+H+].
Example 125
N-(3-fluoro-4-(lH- razol-4-yl)phenyl)-3-phenylpropanamide
Figure imgf000102_0003
STEP A.
In a sealed tube, 4-bromo-3-fluoroaniline (150 mg, 789 μιηοΐ), 3-phenylpropanoic acid (119 mg, 789 μιηοΐ), and DIPEA (173 mg, 234 μΐ, 1.34 mmol) were combined with DMF (1.5 ml). Then HATU (450 mg, 1.18 mmol) was added and the mixture was stirred overnight at RT. The reaction mixture was poured into ethyl acetate and extracted with water. The organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by preparative HPLC (zorbax CI 8 21.2x50mm flow: 20 ml/min, gradient: acetonitrile / water (+0.1% formic acid) =(95%-5% to 5%-95%) in 8 min). N-(4-Bromo-3-fluorophenyl)-3- phenylpropanamide was obtained as a light brown solid (180 mg, 70.8%). MS (m/e) = 322.4 [M+H+].
STEP B.
In a sealed tube, N-(4-bromo-3-fluorophenyl)-3-phenylpropanamide (100 mg, 310 μιηοΐ), tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (91.3 mg, 310 μηιοΐ) and sodium carbonate (776 μΐ, 1.55 mmol) were combined with dioxane (5 ml). Argon was bubbled through the reaction mixture for 5 min. Then l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (25.3 mg, 31.0 μιηοΐ) was added. Argon was bubbled again through the reaction mixture for 5 min. The reaction was stirred overnight at 85 °C. The reaction mixture was poured into ethyl acetate and extracted with water. The organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by preparative HPLC (zorbax CI 8 21.2x50mm flow: 20 ml/min, gradient: acetonitrile / water (+0.1% formic acid) =(95%-5% to 5%-95%) in 8 min). N-(3-fluoro-4-(lH-pyrazol-4- yl)phenyl)-3-phenylpropanamide was obtained as a brown solid (13.4mg, 14.0 %). MS (m/e) = 310.13 [M+H+].
Example 126
N-(3-chloro-4-(lH- razol-4-yl)phenyl)-3-phenylpropanamide
Figure imgf000103_0001
The title compound was prepared in analogy to example 122, using 4-bromo-3-chloro-aniline STEP A. MS (m/e) = 326.10 [M+H+].
Example 127
N-(2-chloro-4-(lH- razol-4-yl)phenyl)-3-phenylpropanamide
Figure imgf000103_0002
The title compound was prepared in analogy to example 122, using 4-bromo-2-chloro-aniline STEP A. MS (m/e) = 326.10 [M+H+].
Example 128
N-(3-methyl-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
Figure imgf000103_0003
The title compound was prepared in analogy to example 122, using 4-bromo-3-methyl-aniline in STEP A. MS (m/e) = 306.16 [M+H+].
Example 129
N-(2-methyl-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
Figure imgf000104_0001
The title compound was prepared in analogy to example 122, using 4-bromo-2-methyl-aniline STEP A. MS (m/e) = 306.16 [M+H+].
Example 130
N-(2-methoxy-4-(lH- razol-4-yl)phenyl)-3-phenylpropanamide
Figure imgf000104_0002
The title compound was prepared in analogy to example 122, using 4-bromo-2-methoxy-aniline in STEP A. MS (m/e) = 322.16 [M+H+].
Example 131
3-methoxy-N-phenethyl-4-(lH-pyrazol-4-yl)benzamide
Figure imgf000104_0003
STEP A.
In a sealed tube, 4-bromo-3-methoxybenzoic acid (500 mg, 2.16 mmol), 2-phenylethylamine (262 mg, 272 μΐ, 2.16 mmol) and 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3- tetramethylisouronium hexafluorophosphate(V) (1.23 g, 3.25 mmol) were combined with DMF (10 ml) to give a light brown solution. Diisopropylethylamine (839 mg, 1.13 ml, 6.49 mmol) was added. The reaction mixture was stirred over night at rt. The reaction mixture was then poured into water and was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in heptane) to yield 4-bromo-3-methoxy-N- phenethylbenzamide as a light yellow solid (0.58 g, 77.4 %, MS (m/e) = 334.4 [M+H+]).
STEP B.
In a sealed tube, 4-bromo-3-methoxy-N-phenethylbenzamide (250 mg, 748 μιηοΐ) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (220 mg, 748 μιηοΐ) were combined with dioxane (5 ml) to give a light yellow solution. Sodium carbonate solution (2M, 748 μΐ, 1.5 mmol) was added. Argon was bubbled through the solution for 5 min. [Ι, - Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.4 mg, 37.4 μιηοΐ) was added, and Argon was bubbled through the solution for another 5 min. The reaction mixture was heated to 85 °C over the weekend and then poured into satd. NaHC03 and extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo. The reaction mixture was purified by preparative HPLC (Zorbax Eclipse XDB-C18 21,2x50mm flow: 25 ml/min, gradient: acetonitrile / water (0.1% formic acid) = 95%-5% to 5%-95%) to yield 3- methoxy-N-phenethyl-4-(lH-pyrazol-4-yl)benzamide as a white solid (63 mg, 26 %, MS (m/e) = 322.16 [M+H+].
Example 132
2-(2-Chlorophenyl)-N- 2-methoxy-4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000105_0001
3-Methoxy-4-nitrobenzaldehyde (CAS 80410-57-7, 500 mg, 2.76 mmol), 4-tolylsulfonyl-methyl isocyanide (TosMIC, 539 mg, 2.76 mmol) and potassium carbonate (381 mg, 2.76 mmol) were combined with methanol (5.5 ml). The reaction mixture was stirred at 80 °C for 3 hours, then at room temperature overnight. The reaction mixture was filtered and the solid was dissolved in dichloromethane (40 ml), washed with water (30 ml), then brine (30 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo which gave 5-(3-methoxy-4- nitrophenyl)oxazole (403 mg, 66%) as orange solid. MS: m/e = 221.4 [M+H]+.
STEP B.
Figure imgf000106_0001
In a two necked vessel 5-(3-methoxy-4-nitrophenyl)oxazole (397mg, 1.80 mmol) was diluted with tetrahydrofurane (8 ml)/ethanol (1.6 ml). Under an argon atmosphere palladium (10% on carbon, 79.4 mg, 74.6 μιηοΐ) was added. The reaction mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered, washed with ethanol and the liquid phase was concentrated in vacuo to yield 2-methoxy-4-(oxazol-5-yl)aniline (342 mg; 99.8%) as yellow solid. MS: m/e = 191.5 [M+H]+.
TEP C.
Figure imgf000106_0002
2-Methoxy-4-(oxazol-5-yl)aniline (150mg, 789 μιηοΐ) was combined with dichloromethane (7.3 ml). 2- (2-Chlorophenyl) acetic acid (215 mg, 1.26 mmol) was added. The mixture was cooled to 0 °C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (242 mg, 1.26 mmol) was added. Reaction mixture was stirred for 30 minutes at 0 °C and then stirred at RT overnight. The reaction mixture was diluted with dichloromethane (20 ml), washed with saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml). The organic phase was dried over sodium sulfate, and filtered and concentrated in vacuo. Purification by chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 70:30) gave 2-(2-chlorophenyl)-N-(2-methoxy-4-(oxazol-5- yl)phenyl)acetamide (243 mg, 90%) as white solid. MS: m/e = 343.4 [M+H]+.
Example 133
2-(2-Chlorophenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide
Figure imgf000106_0003
4-(Oxazol-5-yl)aniline (150 mg, 936 μιηοΐ) and 2-(2-chlorophenyl)acetic acid (256 mg, 1.5 mmol) were combined with dichloromethane (9 ml). At 0°C N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (287 mg, 1.5 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min, then allowed to return to room temperature and was left stirring overnight. The reaction mixture was diluted with dichloromethane (20ml) and washed with saturated aqueous sodium bicarbonate (15 ml). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 80) yielded 2-(2-chlorophenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide (146 mg, 50%) as yellow solid. MS: m/e = 313.4 [M+H]+.
Example 134
N-(2-Chlorobenzyl)-2-methoxy-4-(oxazol-5-yl)benzamide
Figure imgf000107_0001
Methyl 4-formyl-2-methoxybenzoate (CAS 55204-14-3, 444 mg, 2.29 mmol) was combined with methanol(4.7 ml). 4-Tolylsulfonyl-methyl isocyanide (447 mg, 2.29 mmol) and potassium carbonate (316 mg, 2.29 mmol) were added. The reaction mixture was heated at 80 °C for 2 hours and stirred overnight at room temperature. The reaction mixture was poured on water and extracted with dichloromethane (3 x 20 ml) and washed with brine(15 ml). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo and dried to yield methyl 2- methoxy-4-(oxazol-5-yl)benzoate (472 mg, 88%) as orange solid. MS: m/e = 234.5 [M+H]+. STEP B.
Figure imgf000107_0002
Methyl 2-methoxy-4-(oxazol-5-yl)benzoate (467 mg, 2.00 mmol) was combined with methanol (3.2 ml) and tetrahydrofurane(3.2 ml). Aqueous sodium hydroxide (IN, 6.79 ml, 6.79 mmol) was added. The reaction mixture was stirred for 1 hour. Hydrochloric acid (IN, 6.79 ml, 6.79 mmol) was added. The precipitate was filtered and dried in vacuo to yield 2-methoxy-4-(oxazol-5- yl)benzoic acid (369 mg, 84%) as yellow solid. MS: m/e = 220.4 [M+H]+.
STEP C.
Figure imgf000108_0001
2-Methoxy-4-(oxazol-5-yl)benzoic acid (150mg, 684 μηιοΐ) and (2-chlorophenyl)methanamine (102 mg, 86.7 μΐ, 719 μιηοΐ) were combined with dichloromethane (7.3 ml). The reaction mixture was cooled to 0 °C and N-(3-dimethylaminopropyl)-N' -ethylcarbodiimide hydrochloride (138 mg, 719 μιηοΐ) was added. The reaction mixture was stirred at 0 °C for 40 min and then at room temperature overnight. The reaction mixture was diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. Chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 100:0) gave N-(2-chlorobenzyl)-2methoxy-4-(oxazol-5-yl)benzamide (176 mg, 75%) as white solid. MS: m/e = 343.4 [M+H]+.
RO6924780-000-001
Example 135
N-(4-(lH-pyrazol- -yl)phenyl)-2-(2-chlorophenyl)acetamide
Figure imgf000108_0002
N-(4-bromophenyl)-2-(2-chlorophenyl)acetamide (CAS 847938-76-5, 200mg, 616 μιηοΐ), 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (239 mg, 1.23 mmol), Pd(Ph3P)4 (107 mg, 92.4 μιηοΐ) and potassium carbonate (426 mg, 3.08 mmol) were flushed with argon for five minutes, then dioxane (8.22 ml) and water (2.05 ml) were added. The reaction mixture was stirred under argon at 95 °C overnight. The reaction mixture was poured on water (20 ml) and extracted with ethyl acetate. The organic phase was partly distilled off and filtered using a sintered glass funnel. The white solid was dried in vacuo to yield N-(4-(lH-pyrazol-4- yl)phenyl)-2-(2-chlorophenyl)acetamide (39 mg, 21%). MS: m/e = 312.5 [M+H]+. Example 136
2-(2-Chlorophenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide
Figure imgf000108_0003
N-(4-Bromophenyl)-2-(2-chlorophenyl)acetamide (CAS 847938-76-5, 200 mg, 616 μηιοΐ), pyridin-4-ylboronic acid (90.9 mg, 739 μιηοΐ), potassium carbonate (426 mg, 3.08 mmol) and Pd(Ph3P)4 (107 mg, 92.4 μιηοΐ) were combined and flushed with argon for five minutes.
Toluene (3 ml), ethanol (1.00 ml) and water (500 μΐ) were added and the reaction mixture was stirred at 80 °C overnight. The reaction mixture was poured on water (20 ml) and extracted with AcOEt (2 x 20 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography (silicagel, methanol / dichloromethane = 0: 100 to 5:95) gave 2- (2- chlorophenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide (74.7 mg, 38%) as white solid. MS: m/e = 323.4 [M+H]+.
Example 137
2- 2-Chlorophenyl)-N-(2-(2-(dimethylamino)ethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide
Figure imgf000109_0001
4-Bromo-2-(2-(dimethylamino)ethoxy)aniline (CAS 1072906-05-8, 130 mg, 503 μιηοΐ) was combined with dimethylformamide (3.7 ml). 2-(2-Chlorophenyl)acetic acid (103 mg, 603 μιηοΐ) O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 258 mg, 804 μιηοΐ) and N,N-diisopropylethylamine (162 mg, 215 μΐ, 1.26 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. Reaction mixture was poured on water (10 ml), saturated aqueous sodium bicarbonate was added (10 ml) and EtOAc (2 x 10 ml) was used to extract. The organic phase was washed with water (2 x 10 ml) and dried over sodium sulfate, filtered, concentrated in vacuo and dried in vacuo to yield N-(4-bromo-2-(2- (dimethylamino)ethoxy)phenyl)-2-(2-chlorophenyl)acetamide (238 mg, quant.) as pink solid. MS: m/e = 413.3 [M+H]+.
STEP B.
Figure imgf000110_0001
N-(4-bromo-2-(2-(dimethylamino)ethoxy)phenyl)-2-(2-chlorophenyl)acetamide (196.2 mg, 477 μιηοΐ), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (185 mg, 953 μιηοΐ), Pd(Ph3P)4 (82.6 mg, 71.5 μιηοΐ) and potassiumcarbonate(329 mg, 2.38 mmol) were combined and flushed with argon for five minutes. Dioxane (3.18 ml) and water (794 μΐ) were added and flushed with argon. Reaction mixture was stirred at 95 °C overnight. Reaction mixture was poured on water (20 ml) and extracted with ethyl acetate (2 x 20 ml). Chromatography (silicagel, methanol / dichloromethane = 0: 100 to 23:77) yielded 2-(2-chlorophenyl)-N-(2-(2- (dimethylamino)ethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide (43.5 mg, 23%) as off-white solid. MS: m/e = 399.5 [M+H]+.
Example 138
2-(2-Chlorophenyl)-N-( -methoxy-4-(4-methyloxazol-5-yl)phenyl)acetamide
Figure imgf000110_0002
3-Methoxy-4-(4-methyloxazol-5-yl)aniline (CAS 1239719-44-8, 23.5 mg, 115 μηιοΐ) was combined with dichloromethane (1.15 ml). 2-(2-Chlorophenyl)acetic acid (31.4 mg, 184 μιηοΐ) was added. The reaction mixture was cooled to 0 °C and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (35.3 mg, 184 μιηοΐ) was added. Reaction mixture was stirred for 30 min, and allowed to warm to room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (10 ml) and washed with saturated aqueous sodium bicarbonate (10 ml) and brine (10 ml). The organic phases were combined and concentrated in vacuo.
Chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 80:20) yielded 2-(2-chlorophenyl)- N-(3-methoxy-4-(4-methyloxazol-5-yl)phenyl)acetamide (38.4 mg, 94%) as waxy yellow solid. MS: m/e = 357.4 [M+H]+.
Example 139
N-(3-methoxy-4-(lH^yrazol-4-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide
Figure imgf000111_0001
4-Bromo-3-methoxyaniline (150 mg, 742 μmol) was combined with dichloromethane (3ml). 2- ((3-Methoxyphenyl)(methyl)amino)acetic acid (CAS 1247372-54-8, 210 mg, 1.08 mmol) was added. Reaction mixture was cooled to 0°C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (206 mg, 1.08 mmol) was added. The reaction mixture was stirred for 30 minutes at 0°C, then allowed to warm to room temperature. After 3 hours the reaction mixture was diluted with dichloromethane(lOml) and washed with saturated aqueous sodium bicarbonate (10ml). Chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 55:45) yielded N-(4- bromo-3-methoxyphenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide (228 mg, 81%) as yellow oil. MS: m/e = 379.5 [M+H]+.
Ste B.
Figure imgf000111_0002
N-(4-bromo-3-methoxyphenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide (225 mg, 594 μιηοΐ), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (230 mg, 1.19 mmol), Pd(Ph3P)4 (103 mg, 89.0 μιηοΐ) and potassium carbonate(410 mg, 2.97 mmol) were combined and purged with argon for 5 minutes. Dioxane (7.36 ml) and water (1.84 ml) were added and the reaction mixture was purged with argon and then stirred overnight at 95 °C. The reaction mixture was cooled to room temperature. Reaction mixture was poured on water (20 ml), washed with ethyl acetate (2 x 20 ml), dried over sodium sulfate, filtered, and concentrated in vacuo.
Chromatography (silicagel, methanol / dichloromethane = 0: 100 to 8:92) and precipitation in diethyl ether yielded N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-((3- methoxyphenyl)(methyl)amino)acetamide (2.8 mg, 1.3%) as off-white solid. MS: m/e = 367.2 [M+H]+. -I l l-
Example 140
N-(3-Methoxy-4-(lH-pyraz l-4- l)phenyl)-2-(3-methoxyphenylamino)acetamide
Figure imgf000112_0001
4-Bromo-3-methoxyaniline (150mg, 742 μηιοΐ) was combined with dichloromethane (3 ml). 2- (3-Methoxyphenylamino)acetic acid (195 mg, 1.08 mmol) was added. The reaction mixture was cooled to 0°C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (206 mg, 1.08 mmol) was added. The reaction mixture was stirred at 0°C for 30 minutes, then allowed to warm to room temperature for 3 hours. Chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 70:30) yielded N-(4-bromo-3-methoxyphenyl)-2-(3-methoxyphenylamino)acetamide (185 mg, 68%) as light brown oil. MS: m/e = 367.4 [M+H]+.
STEP B.
Figure imgf000112_0002
N-(4-Bromo-3-methoxyphenyl)-2-(3-methoxyphenylamino)acetamide (184.6 mg, 505 μιηοΐ), bis(diphenylphosphino)ferrocene-palladium(II)dichloride (18.5 mg, 25.3 μιηοΐ) and 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (98.1 mg, 505 μιηοΐ) were combined with dioxane (17 ml) and water (1.7 ml). The reaction mixture was stirred at 95°C overnight.
Chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 50:50) and precipitation with diethyl ether/ pentane yielded N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-(3- methoxyphenylamino)acetamide (13.4 mg, 7.5%) as off-white solid. MS: m/e = 353.2 [M+H]+.
Example 141
l-(2-Chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarboxamide
Figure imgf000113_0001
l-(2-Chlorophenyl)cyclopropanecarboxylic acid (414 mg, 2.1 mmol) was combined with dichloromethane(10 ml). Two drops of dimethylformamide were added. At 0 °C oxalyl chloride (2.00 g, 1.38 ml, 15.8 mmol) was added. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo, dissolved in toluene and concentrated in vacuo. The mixture was dissolved in dichloromethane (5 ml), and added slowly to a solution of 3-methoxy- 4-(oxazol-5-yl)aniline (intermediate 1, 200 mg, 1.05 mmol) and triethylamine (223 mg, 308 μΐ, 2.21 mmol) in dichloromethane (10 ml). Reaction mixture was stirred at room temperature overnight. The reaction mixture was poured on water (20 ml) and extracted with
dichloromethane (2 x 20 ml). Purification by Chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 50:50) yielded l-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5- yl)phenyl)cyclopropanecarboxamide (13.6 mg, 3.5%) as off-white solid. MS: m/e = 369.4
[M+H]+.
Example 142
2-(2-Chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-methylpropanamide
Figure imgf000113_0002
The title compound, off-white solid (11 mg, 2.7%), MS (ISP) m/z = 371.4 [(M+H)+] v prepared in analogy to the general method of example 141 from 2-(2-chlorophenyl)-2- methylpropanoic acid and intermediate 1.
Example 143
N-(3-Methoxy-4-(oxazol-5- l)phenyl)-2-(3-methoxyphenyl)-2-methylpropanamide
Figure imgf000113_0003
The title compound, off-white solid (25 mg, 13%), MS (ISP) m/z = 367.5 [(M+H)+] was prepared in analogy to the general method of example 141 from 2-(3-methoxyphenyl)-2- methylpropanoic acid and intermediate 1. Example 144
N-(3-Methoxy-4-(oxazol-5-yl) henyl)-2-(3-methoxyphenylamino)-2-methylpropanamide
Figure imgf000114_0001
3-Methoxy-4-(oxazol-5-yl)aniline (intermediate 1, 200 mg), 2-(3-methoxyphenylamino)-2- methylpropanoic acid (264 mg, 1.26 mmol) and diisopropylethylamine (231 mg, 312 μΐ, 1.79 mmol) were combined with dimethylformamide(10 ml). The reaction mixture was stirred at room temperature under argon atmosphere. 0-(7-Azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU, 680 mg, 1.79 mmol) was added. The reaction mixture was stirred at room temperature overnight. Reaction mixture was poured on water and extracted with dichloromethane. Chromatography (silicagel, ethyl acetate / heptane = 33:67 to 75:25) yielded N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylamino)-2- methylpropanamide (246 mg, 62%) as off-white solid. MS: m/e = 382.5 [M+H]+. Example 145
2-(2-Chlorophenylamino)-N-(3-methox -4-(lH-pyrazol-4-yl)phenyl)-2-methylpropanamide
Figure imgf000114_0002
4-Bromo-3-methoxyaniline (380 mg, 1.88 mmol), 2-(2-chlorophenylamino)-2-methylpropanoic acid (482 mg, 2.26 mmol) and diisopropylethylamine (413 mg, 558 μΐ, 3.2 mmol) were combined with dimethylformamide (15 ml). 0-(7-Azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU, 1.22 g, 3.2 mmol) was added. The reaction mixture was stirred at room temperature overnight. Reaction mixture was poured on water and extracted with dichloromethane. Chromatography (silicagel, ethyl acetate / heptane = 20:80 to 50:50) yielded N-(4-bromo-3-methoxyphenyl)-2-(2-chlorophenylamino)-2-methylpropanamide (457 mg, 61%) as brown solid. MS: m/e =399.3 [M+H]+. STEP B.
Figure imgf000115_0001
N-(4-Bromo-3-methoxyphenyl)-2-(2-chlorophenylamino)-2-methylpropanamide (200 mg, 503 μιηοΐ), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (111 mg, 553 μιηοΐ) and cesium carbonate (180 mg, 553 μιηοΐ) were combined with dioxane (10 ml) and water (1.0 ml). Under argon atmosphere, bis(diphenylphosphino)ferrocene-palladium(II)dichloride (73.6 mg, 101 μιηοΐ) was added. The reaction mixture was stirred at 85 °C during the weekend. The mixture was concentrated in vacuo and purified by chromatography (silicagel, methanol / dichloromethane = 0: 100 to 5:95; then preparative HPLC, Gemini NX 3u 50x4.6mm, C18 reverse phase, methanol / formic acid = 98:2) to yield 2-(2-chlorophenylamino)-N-(3-methoxy- 4-(lH-pyrazol-4-yl)phenyl)-2-methylpropanamide (23.3 mg, 12%) as off-white solid. MS: m/e =385.4 [M+H]+.
Example 146
2-(2-Chlorophenylamin -N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)acetamide
Figure imgf000115_0002
2-(2-Chlorophenylamino)acetic acid (150mg, 808 μιηοΐ) and 4-bromo-3-methoxyaniline (171 mg, 849 μιηοΐ) were combined with dichloromethane (10 ml). At 0°C N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (163 mg, 849 μιηοΐ) was added. The reaction mixture was stirred at 0 °C for 30 min, then at RT overnight. The mixture was poured on water (20 ml) and extracted with dichloromethane (3 x 15 ml). Chromatography (silicagel, ethyl acetate / heptane = 20:80 to 50:50) yielded N-(4-bromo-3-methoxyphenyl)-2-(2- chlorophenylamino)acetamide (225 mg, 75%) as yellow solid. MS: m/e =371.1 [M+H]+.
STEP B.
Figure imgf000116_0001
N-(4-Bromo-3-methoxyphenyl)-2-(2-chlorophenylamino)acetamide (220mg, 595 μηιοΐ), 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (134 mg, 655 μmol) and
bis(diphenylphosphino)ferrocene-palladium(II)dichloride (43.5 mg, 59.5 μιηοΐ) and cesium carbonate (213 mg, 655 μιηοΐ) were combined with dioxane (10 ml)/water (1.00 ml) under argon atmosphere. Reaction mixture was heated to 80 °C and stirred overnight. The mixture was purified with preparative HPLC (Gemini NX 3u 50x4.6mm, CI 8 reverse phase, methanol / formic acid = 98:2) to yield 2-(2-chlorophenylamino)-N-(3-methoxy-4-(lH-pyrazol-4- yl)phenyl)acetamide (6 mg, 2.8%) as brown solid. MS: m/e =357.4 [M+H]+.
Example 147
N-(3-Methoxy-4-(oxazol-5-yl)phen l)-l-(3-methoxyphenylamino)cyclopropanecarboxamide
Figure imgf000116_0002
l-(3-Methoxyphenylamino)cyclopropanecarboxylic acid (54.5 mg, 263 μιηοΐ), 3-methoxy-4- (oxazol-5-yl)aniline (intermediate 1, 50 mg, 263 μιηοΐ) and diisopropylethylamine (57.8 mg,
78.1 μΐ, 447 μιηοΐ) were combined with dimethylformamide (10 ml) under argon atmosphere. O- (7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 170 mg, 447 μιηοΐ) was added. The reaction mixture was stirred at room temperature overnight.
Purification by preparative HPLC (Gemini NX 3u 50x4.6mm, C18 reverse phase, methanol / formic acid = 98:2) and precipitation in diethyl ether and heptane yielded the title compound as an off-white solid RO6959544-000-001 (9.5 mg; 9.5%). MS: m/e = 380.4 [M+H]+.
Example 148
N-(3-Methoxy-4-(lH-pyrazol-4- l)phenyl)-2-methyl-2-(phenylamino)propanamide
Figure imgf000116_0003
STEP A.
Figure imgf000117_0001
2-Methyl-2-(phenylamino)propanoic acid (106 mg, 594 μηιοΐ), 4-bromo-3-methoxyaniline (100 mg, 495 μηιοΐ) and diisopropylethylamine (109 mg, 147 μΐ, 841 μmol) were combined with dimethylformamide (10 ml). Under an argon atmosphere 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU, 320 mg, 841 μιηοΐ) was added. The reaction mixture was stirred overnight at room temperature. Reaction mixture was concentrated in vacuo and poured on water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The organic phases were collected and dried on MgS04 and concentrated in vacuo. Purification by chromatography (silicagel, ethyl acetate / heptane = 20:80 to 50:50) yielded N-(4-bromo-3-methoxyphenyl)-2- methyl-2-(phenylamino)propanamide (112 mg; 62%) as orange waxy solid. MS: m/e = 363.4 [M+H]+.
STEP B.
Figure imgf000117_0002
In a 25ml round-bottom flask N-(4-bromo-3-methoxyphenyl)-2-methyl-2- (phenylamino)propanamide (100 mg, 275 μιηοΐ), tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (162 mg, 551 μιηοΐ) and cesium carbonate (179 mg, 551 μιηοΐ) were combined with dioxane (10 ml)/water (1ml). Under argon
bis(diphenylphosphino)ferrocene-palladium(II)dichloride (40.3 mg, 55.1 μιηοΐ) was added. The reaction mixture was stirred at 70°C for 2 hours. The mixture was concentrated in vacuo and purified by chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 20:80) to yield tert- butyl 4-(2-methoxy-4-(2-methyl-2-(phenylamino)propanamido)phenyl)-lH-pyrazole-l- carboxylate (91 mg, 73%) as colorless waxy solid. MS: m/e = 451.5 [M+H]+.
STEP C.
Figure imgf000117_0003
In a 25 ml round-bottom flask, tert-butyl 4-(2-methoxy-4-(2-methyl-2-
(phenylamino)propanamido)phenyl)-lH-pyrazole-l-carboxylate (30 mg, 66.6 μιηοΐ, Eq: 1.00) was combined with dichloromethane (10 ml). At 0°C trifluoroacetic acid (11.4 mg, 7.7 μΐ, 99.9 μιηοΐ) was added and stirred at 0°C for 1 hour, then at RT for 3 hours. The reaction mixture was poured on water (10 ml) and extracted with dichloromethane (3 x 10 ml) and washed with saturated aqueous sodium bicarbonate(15 ml). The reaction mixture was purified by
chromatography (silicagel, methanol / dichloromethane = 0: 100 to 10:90) to yield N-(3- methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-methyl-2-(phenylamino)propanamide (17.5 mg, 75%) as off-white solid. MS: m/e = 351.5 [M+H]+.
Example 149
l-(2-Chlorophenylamino)-N-(3-methox -4-(oxazol-5-yl)phenyl)cyclopropanecarboxamide
Figure imgf000118_0001
In a 25 mL round-bottomed flask, l-(2-chlorophenylamino)cyclopropanecarboxylic acid (100 mg, 473 μιηοΐ), 3-methoxy-4-(oxazol-5-yl)aniline (intermediate 1, 75 mg, 394 μιηοΐ) and 0-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 255 mg, 670 μιηοΐ) were combined with dimethylformamide (5 ml). Diisopropylethylamine (86.6 mg, 117 μΐ, 670 μιηοΐ) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The reaction mixture was poured on water (50 ml) and extracted with ethyl acetate (3 x 30 ml). The organic phase was washed with saturated aqueous sodium bicarbonate (20 ml). Purification by chromatography (preparative HPLC, Gemini NX 3u 50x4.6mm, C18 reverse phase, methanol / formic acid = 98:2; then silicagel, ethyl acetate / heptane = 0: 100 to 50:50) yielded l-(2-chlorophenylamino)-N-(3-methoxy-4-(oxazol-5- yl)phenyl)cyclopropanecarboxamide (64.3 mg; 43%) as off-white solid. MS: m/e = 384.5
[M+H]+.
Example 150
2-(2-Chlorophenyl)-N-(3-(2-(dimethylamino)ethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide
2,2,2-trifluoroacetate
Figure imgf000119_0001
STEP A.
Figure imgf000119_0002
In a 25 mL round-bottomed flask, 4-bromo-3-(2-(dimethylamino)ethoxy)aniline (CAS 170230- 19-0, 170 mg, 656 μιηοΐ) and 2-(2-chlorophenyl)acetic acid (134 mg, 787 μιηοΐ) were combined with dichloromethane (5 ml). At 0°C N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (151 mg, 787 μιηοΐ) was added and reaction mixture was stirred at 0°C for 15 minutes and at room temperature overnight. The reaction mixture was poured on water (20 ml) and extracted with dichloromethane(3 x 20 ml). The organic phases were combined and washed with saturated aqueous sodium bicarbonate (20 ml). Chromatography (silicagel, methanol / dichloromethane = 0: 100 to 10:90) yielded N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-2- (2-chlorophenyl)acetamide (90.8 mg, 34%) as waxy white solid. MS: m/e = 413.2 [M+H]+. TEP B.
Figure imgf000119_0003
In a 25 mL round-bottomed flask, N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2- chlorophenyl)acetamide (90 mg, 219 μιηοΐ), tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (77.2 mg, 262 μιηοΐ) and
bis(diphenylphosphino)ferrocene-palladium(II)dichloride (32.0 mg, 43.7 μιηοΐ) were combined with dioxane (5 ml) and water (500 μΐ). The reaction mixture was stirred at 70 °C overnight. The reaction mixture was concentrated in vacuo and purified by chromatography (silicagel, methanol / dichloromethane = 0: 100 to 10:90) to yield tert-butyl 4-(4-(2-(2-chlorophenyl)acetamido)-2-(2- (dimethylamino)ethoxy)phenyl)-lH-pyrazole-l-carboxylate (76.5 mg, 70%) as waxy brown solid. MS: m/e = 499.6 [M+H]+.
Figure imgf000120_0001
In a 25 mL round-bottomed flask, tert-butyl 4-(4-(2-(2-chlorophenyl)acetamido)-2-(2- (dimethylamino)ethoxy)phenyl)-lH-pyrazole-l-carboxylate (75 mg, 150 μιηοΐ) and
trifluoroacetic acid (17.1 mg, 11.6 μΐ, 150 μmol) were combined with dichloromethane (5 ml) and stirred at room temperature overnight. Trifluoroacetic acid (17.1 mg, 11.6 μΐ, 150 μιηοΐ) was added and the reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was concentrated in vacuo. Purification by chromatography (silicagel, methanol / dichloromethane = 0:100 to 20:80) and precipitation in diethylether and pentane gave 2-(2-chlorophenyl)-N-(3-(2- (dimethylamino)ethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide 2,2,2-trifluoroacetate (57.3 mg, 74%) as off-white solid. MS: m/e = 399.2 [M+H]+.
Example 151
N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-(3-methoxyphenylamino)-2- meth lpropanamide
Figure imgf000120_0002
TEP A.
Figure imgf000120_0003
N-(4-Bromo-3-methoxyphenyl)-2-(3-methoxyphenylamino)-2-methylpropanamide (50 mg, 127 μιηοΐ), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (63.6 mg, 216 μιηοΐ) and cesium carbonate (70.4 mg, 216 μιηοΐ) were combined with dioxane (5 ml)/water (0.5 ml). Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (18.6 mg, 25.4 μιηοΐ) was added. The reaction mixture was heated at 75 °C overnight. The mixture was concentrated in vacuo and purified by chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 50:50) to yield tert-butyl 4-(2-methoxy-4-(2-(3-methoxyphenylamino)-2- methylpropanamido)phenyl)-lH-pyrazole-l-carboxylate (23.5 mg, 31 ) as off-white solid . MS: m/e = 481.5 [M+H]+.
STEP B.
Figure imgf000121_0001
In a 25 mL round-bottomed flask, tert-butyl 4-(2-methoxy-4-(2-(3-methoxyphenylamino)-2- methylpropanamido)phenyl)-lH-pyrazole-l-carboxylate (23.5 mg, 48.9 μιηοΐ) and
trifluoroacetic acid (6.69 mg, 4.52 μΐ, 58.7 μιηοΐ) were combined with dichloromethane (5 ml). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. Purification by chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 75:25, and silicagel, methanol / dichloromethane = 0: 100 to 5:95) yielded N-(3-methoxy-4-(lH-pyrazol-4- yl)phenyl)-2-(3-methoxyphenylamino)-2-methylpropanamide (6.4 mg, 34%) as off-white solid. MS: m/e = 381.3 [M+H]+.
Example 152
2-(2-Chlorophenyl)-N-(2-(2-morpholinoethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide
Figure imgf000121_0002
Figure imgf000121_0003
In a 50 mL round-bottomed flask, 4-bromo-2-(2-morpholinoethoxy)aniline (CAS 1219728-38-7, 526 mg, 1.75 mmol) and 2-(2-chlorophenyl)acetic acid (358 mg, 2.1 mmol) were combined with dichloromethane (10 ml). At 0°C N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (402 mg, 2.1 mmol) was added. The solution was stirred for 15 minutes at 0°C and then at room temperature overnight. The reaction mixture was poured on water (20 ml) and extracted with dichloromethane (3 x 20 ml). The organic phases were combined and washed with saturated aqueous sodium bicarbonate (20 ml). The organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo to yield N-(4-bromo-2-(2-morpholinoethoxy)phenyl)- 2-(2-chlorophenyl)acetamide (741 mg, 94%) as pink solid. MS: m/e = 455.5 [M+H]+.
TEP B.
Figure imgf000122_0001
In a 25 mL round-bottomed flask, N-(4-bromo-2-(2-morpholinoethoxy)phenyl)-2-(2- chlorophenyl)acetamide (100 mg, 220 μιηοΐ), tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (77.8 mg, 264 μιηοΐ) and cesium carbonate (86.2 mg, 264 μιηοΐ) were combined with dioxane (10 ml) and water (1.0 ml).
Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (32.3 mg, 44.1 μιηοΐ) was added and the reaction mixture was stirred at 70 °C for 1 hour. The reaction mixture was purified by chromatography (silicagel, methanol / dichloromethane = 0: 100 to 10:90) to yield tert-butyl 4-(4- (2-(2-chlorophenyl)acetamido)-3-(2-morpholinoethoxy)phenyl)-lH-pyrazole-l-carboxylate (104 mg, 87%) as brown solid. MS: m/e = 541.6 [M+H]+.
STEP C.
Figure imgf000122_0002
In a 50 mL round-bottomed flask, tert-butyl 4-(4-(2-(2-chlorophenyl)acetamido)-3-(2- morpholinoethoxy)phenyl)-lH-pyrazole-l-carboxylate (100 mg, 185 μιηοΐ) and trifluoroacetic acid (25.3 mg, 17.1 μΐ, 222 μιηοΐ) were combined with dichloromethane (5 ml). The mixture was stirred at room temperature and then overnight at 50 °C for 4 hours. The reaction mixture was concentrated in vacuo. Purification by chromatography (silicagel, methanol / dichloromethane = 5:95 to 10:90 and silicagel, methanol / dichloromethane = 0: 100 to 5:95) yielded 2- (2- chlorophenyl)-N-(2-(2-morpholinoethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide (33.8 mg, 42%) as off-white solid. MS: m/e = 441.3 [M+H]+.
Example 153
l-(2-Chlorophenylamino)-N-(3-methoxy-4-(lH-pyrazol-4- l)phenyl)cyclopropanecarboxamide
Figure imgf000123_0001
In a 25 mL round-bottomed flask, l-(2-chlorophenylamino)cyclopropanecarboxylic acid (201 mg, 950 μιηοΐ), 4-bromo-3-methoxyaniline (160 mg, 792 μιηοΐ) and 0-(7-azabenzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate (HATU, 512 mg, 1.35 mmol) were combined with dimethylformamide (10 ml). Diisopropylethylamine (174 mg, 235 μΐ, 1.35 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. Reaction mixture was poured on water (50 ml) and extracted with ethyl acetate (3 x 30 ml). The organic phase was washed with saturated aqueous sodium bicarbonate (20 ml). Purification by chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 50:50) yielded N-(4-bromo-3-methoxyphenyl)-l-(2-chlorophenylamino)cyclopropanecarboxamide (148 mg, 47%) as off-white solid. MS: m/e = 397.4 [M+H]+.
STEP B.
Figure imgf000123_0002
In a 25 mL round-bottomed flask, N-(4-bromo-3-methoxyphenyl)-l-(2- chlorophenylamino)cyclopropanecarboxamide (140 mg, 354 μιηοΐ), tert-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (125 mg, 425 μιηοΐ) and cesium carbonate (231 mg, 708 μιηοΐ) were combined with dioxane (5 ml) and water (0.5 ml). Under argon atmosphere bis(diphenylphosphino)ferrocene-palladium(II)dichloride (51.8 mg, 70.8 μιηοΐ) was added. The reaction mixture was heated at 70 °C overnight. The reaction mixture was concentrated in vacuo and purified by chromatography (silicagel, ethyl acetate / heptane = 0:100 to 25:75) to yield tert-butyl 4-(4-(l-(2-chlorophenylamino)cyclopropanecarboxamido)-2- methoxyphenyl)-lH-pyrazole-l-carboxylate (110 mg, 52%) as off-white solid. MS: m/e = 483.2 [M+H]+.
STEP C.
Figure imgf000124_0001
In a 50 mL round-bottomed flask, tert-butyl 4-(4-(l-(2- chlorophenylamino)cyclopropanecarboxamido)-2-methoxyphenyl)-lH-pyrazole-l-carboxylate (100 mg, 207 μιηοΐ) and trifluoroacetic acid (23.7 mg, 16 μΐ, 208 μιηοΐ) were combined with dichloromethane (5 ml) and stirred at room temperature overnight. Trifluoroacetic acid (23.7 mg, 16 μΐ, 208 μιηοΐ) was added and the reaction mixture was stirred at 70 °C for 4 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (10 ml) and extracted with dichloromethane(2 x 20 ml). The organic phase was dried with MgS04, filtered and concentrated in vacuo which gave l-(2-chlorophenylamino)-N-(3-methoxy-4-(lH-pyrazol-4- yl)phenyl)cyclopropanecarboxamide (57.2 mg, 72%) as off-white solid. MS: m/e = 483.2
[M+H]+.
Example 154
2-(2-Chlorophenyl)-N-(3-(2-morpholinoethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide 2,2,2- trifluoroacetate
Figure imgf000125_0001
STEP A.
Figure imgf000125_0002
In a 50 mL round-bottomed flask, 2-bromo-5-nitrophenol (500 mg, 2.18 mmol) and cesium carbonate (1.06 g, 3.27 mmol) were combined with dimethylformamide (20 ml) and stirred at room temperature for 15 minutes. 4-(2-Chloroethyl)morpholine (391 mg, 360 μΐ, 2.61 mmol) was added and the reaction mixture was stirred at room temperature over the weekend. The reaction mixture was heated to 70 °C and stirred for 1 hour. The reaction mixture was concentrated in vacuo and poured on water (10 ml). The mixture was acidified with 2M aqueous HCl and washed with ethyl acetate (3 x 20 ml). The aqueous solution was basified with saturated aqueous sodium bicarbonate, and extracted with ethylacetate (3 x 30 ml). The organic phases were dried over magnesium sulfate and concentrated under vacuo to yield 4-(2-(2-bromo-5- nitrophenoxy)ethyl)morpholine (762 mg, quant.) as yellow oil. MS: m/e = 333.1 [M+H]+.
Figure imgf000125_0003
In a 50 mL round-bottomed flask, 4-(2-(2-bromo-5-nitrophenoxy)ethyl)morpholine (350 mg, 1.06 mmol) and iron (413 mg, 7.4 mmol) were combined with methanol (14 ml) and
hydrochloric acid (37% ,1.4 ml). The reaction mixture was stirred at 80°C overnight. The mixture was filtered using dicalite and concentrated in vacuo. The mixture was poured on water (20 ml) and was extracted using ethyl acetate (3 x 25 ml). The aqueous phase was basified with sodium bicarbonate to pH 8 and a solid precipitate was formed. The mixture was filtered and the liquid phase was extracted with ethyl acetate (3 x 25 ml). The organic phases were combined, dried with magnesium sulfate, filtered and concentrated in vacuo to yield 4-bromo-3-(2- morpholinoethoxy) aniline (266 mg, 83%) as orange viscous orange oil. MS: m/e = 301.1
[M+H]+.
Figure imgf000126_0001
In a 25 mL round-bottomed flask, 4-bromo-3-(2-morpholinoethoxy)aniline (250 mg, 830 μιηοΐ) and 2-(2-chlorophenyl)acetic acid (170 mg, 996 μιηοΐ) were combined with dichloromethane (10 ml). At 0 °C N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (191 mg, 996 μιηοΐ) was added. The reaction mixture was stirred at room temperature for 2 hours. Reaction mixture was poured on water (20 ml) and extracted with dichloromethane (3 x 20 ml). The organic phases were combined and dried over magnesiumsulfate and concentrated in vacuo. Purification by chromatography (silicagel, methanol / ethylacetate = 0: 100 to 5:95) gave N-(4- bromo-3-(2-morpholinoethoxy)phenyl)-2-(2-chlorophenyl)acetamide (214 mg, 57%) as off- white solid. MS: m/e = 455.1 [M+H]+.
Figure imgf000126_0002
In a 25 mL round-bottomed flask, N-(4-bromo-3-(2-morpholinoethoxy)phenyl)-2-(2- chlorophenyl)acetamide (200 mg, 441 μιηοΐ), tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (194 mg, 661 μιηοΐ) and cesium carbonate (215 mg, 661 μιηοΐ) were combined with dioxane (10 ml) and water (1 ml). Under an argon atmosphere bis(diphenylphosphino)ferrocene-palladium(II)dichloride (96.8 mg, 132 μιηοΐ) was added. The reaction mixture was stirred at 70 °C for 4 hours. The reaction mixture was concentrated in vacuo and purified by chromatography (silicagel, methanol / dichloromethane = 0:100 to 5:95, and then by preparative HPLC, Gemini NX 3u 50x4.6mm, C18 reverse phase, acetonitrile / triethylamine = 98:2) to yield tert-butyl 4-(4-(2-(2-chlorophenyl)acetamido)-2-(2- morpholinoethoxy)phenyl)-lH-pyrazole-l-carboxylate (111 mg, 47%) as waxy brown solid. MS: m/e = 541.4 [M+H]+.
Figure imgf000127_0001
In a 25 mL round-bottomed flask, tert-butyl 4-(4-(2-(2-chlorophenyl)acetamido)-2-(2- morpholinoethoxy)phenyl)-lH-pyrazole-l-carboxylate (100 mg, 185 μιηοΐ) and trifluoroacetic acid (42.1 mg, 28.5 μΐ, 370 μιηοΐ) were combined with dichloromethane (5 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2 hours. Trifluoroacetic acid (42.1 mg, 28.5 μΐ, 370 μιηοΐ) was added and reaction mixture was heated at 50 °C for 2 hours. Trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred at 50 °C for 30 minutes. The reaction mixture was concentrated in vacuo. Purification by flash column chromatography (silicagel, methanol / dichloromethane = 2:98 to 10:90) and trituration with yielded 2-(2-chlorophenyl)-N-(3-(2-morpholinoethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide 2,2,2-trifluoroacetate (30.5 mg, 30%) as off-white solid. MS: m/e = 441.2 [M+H]+.
Example 155
2-(2-Chlorophenyl)-N-(2-(2-methoxyethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide
Figure imgf000127_0002
STEP A.
Figure imgf000128_0001
In a 25 mL round-bottomed flask, 4-bromo-2-(2-methoxyethoxy)aniline (CAS 1219730-72-9, 100 mg, 406 μιηοΐ) and 2-(2-chlorophenyl)acetic acid (83.2 mg, 488 μιηοΐ) were combined with dichloromethane (5 ml) to give a light yellow solution. At 0 °C N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (93.5 mg, 488 μιηοΐ) was added. The reaction mixture was stirred at 0 °C for 30 minutes then stirred at room temperature over the weekend. The reaction mixture was poured on water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The organic phases were combined, dried with magnesium sulfate, filtered and concentrated in vacuo which gave N-(4-bromo-2-(2-methoxyethoxy)phenyl)-2-(2-chlorophenyl)acetamide (185 mg, quant.) as off-white solid. MS: m/e = 400.1 [M+H]+.
STEP B.
Figure imgf000128_0002
In a 25 mL round-bottomed flask, N-(4-bromo-2-(2-methoxyethoxy)phenyl)-2-(2- chlorophenyl)acetamide (80 mg, 201 μιηοΐ), tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (70.8 mg, 241 μιηοΐ) and cesium carbonate (98.1 mg, 301 μιηοΐ) were combined with dioxane (5 ml) and water (500 μΐ) to give a light yellow solution. Under argon atmosphere bis(diphenylphosphino)ferrocene-palladium(II)dichloride (29.4 mg, 40.1 μιηοΐ) was added. The reaction mixture was heated to 70 °C for 1 hour. The reaction mixture was concentrated in vacuo and purified by chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 50:50) to yield tert-butyl 4-(4-(2-(2-chlorophenyl)acetamido)-3-(2- methoxyethoxy)phenyl)-lH-pyrazole-l-carboxylate (28.1 mg, 29%) as waxy white solid. MS: m/e = 386.2 [M+H]+.
STEP C.
Figure imgf000129_0001
In a 25 mL round-bottomed flask, tert-butyl 4-(4-(2-(2-chlorophenyl)acetamido)-3-(2- methoxyethoxy)phenyl)-lH-pyrazole-l-carboxylate (28 mg, 57.6 μιηοΐ) and trifluoroacetic acid (19.7 mg, 13.3 μΐ, 173 μιηοΐ) were combined with dichloromethane (2 ml) to give a light yellow solution. The reaction mixture was heated at 40 °C for 1 hour. Trifluoroacetic acid (1 ml) was added. The reaction mixture was stirred at 40 °C for 30 minutes. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic phases were combined and dried with magnesium sulfate, filtered and concentrated in vacuo which gave 2-(2- chlorophenyl)-N-(2-(2-methoxyethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide (14.4 mg, 65%) as white solid. MS: m/e = 386.2 [M+H]+.
Example 156
2-(2-Chlorophenyl)-N-(3-(2-methoxyethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide
Figure imgf000129_0002
In a 25 mL round-bottomed flask, 2-bromo-5-nitrophenol (600 mg, 2.75 mmol, Eq: 1.00), cesium carbonate (1.35 g, 4.13 mmol, Eq: 1.5) and potassium iodide (91.4 mg, 550 μιηοΐ, Eq: 0.2) were combined with dimethylformamide (10 ml) and under argon l-bromo-2- methoxyethane (574 mg, 388 μΐ, 4.13 mmol, Eq: 1.5) was added. The reaction mixture was stirred at 30 °C for 2 hours. The reaction mixture was concentrated in vacuo and water was added (40 ml). The reaction mixture was extracted with ethyl acetate (3 x 30 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield l-bromo-2-(2- methoxyethoxy)-4-nitrobenzene (748 mg, 98%) as a brown solid. 1H-NMR (ppm, 300 MHz, CDC13): 7.76-7.77 (m, 1H), 7.72-7.73 (m, 2 H), 4.29 (t, 2 H), 3.85 (t, 2 H), 3.49 (s, 3 H).
Figure imgf000130_0001
In a 50 mL round-bottomed flask, l-bromo-2-(2-methoxyethoxy)-4-nitrobenzene (200 mg, 724 μιηοΐ) and iron (283 mg, 5.07 mmol) were combined with methanol (5 ml). Hydrochloric acid, (37%, 500 μΐ) was added slowly. The reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was cooled to room temperature and filtered over dicalite and concentrated in vacuo. Purification by chromatography (silicagel, methanol / dichloromethane = 2:98 to 5:95) yielded 4-bromo-3-(2-methoxyethoxy)aniline (85 mg, 48%) as brown oil. MS: m/e = 248.1
[M+H]+.
Figure imgf000130_0002
In a 25 mL round-bottomed flask, 4-bromo-3-(2-methoxyethoxy)aniline ( 85 mg, 345 μιηοΐ) and 2-(2-chlorophenyl)acetic acid (70.7 mg, 414 μιηοΐ) were combined with dichloromethane (5 ml). At 0 °C N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (79.5 mg, 414 μιηοΐ) was added. The reaction mixture was stirred for 30 minutes at 0 °C then at room temperature overnight. The reaction mixture was poured on water (20 ml) and extracted with
dichloromethane (2 x 20 ml) and the organic phases were combined and washed with saturated aqueous sodium bicarbonate. The organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo. Precipitation in methanol gave a solid which was pure N-(4-bromo-3-(2- methoxyethoxy)phenyl)-2-(2-chlorophenyl)acetamide (81.4 mg; 59.1%), an off-white solid. MS: m/e = 400.1 [M+H]+.
STEP D.
Figure imgf000130_0003
In a 25 mL round-bottomed flask, N-(4-bromo-3-(2-methoxyethoxy)phenyl)-2-(2- chlorophenyl)acetamide (80 mg, 201 μιηοΐ), tert-butyl 4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)- lH-pyrazole-l-carboxylate (71.4 mg, 241 μιηοΐ) and cesium carbonate (98.1 mg, 301 μιηοΐ) were combined with dioxane (5 ml) and water (500 μΐ). Under an argon atmosphere
bis(diphenylphosphino)ferrocene-palladium(II)dichloride (29.4 mg, 40.1 μιηοΐ) was added. The reaction mixture was heated to 70 °C for 1 hour. Bis(diphenylphosphino)ferrocene- palladium(II)dichloride (29.4 mg, 40.1 μιηοΐ) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3-dioxolan- 2-yl)-lH-pyrazole-l-carboxylate (29.7 mg, 100 μmol) were added. The reaction mixture was heated at 70 °C overnight. The reaction mixture was concentrated in vacuo and purified by chromatography (silicagel, ethyl acetate / heptane = 0: 100 to 50:50) to yield tert-butyl 4-(4-(2-(2- chlorophenyl)acetamido)-2-(2-methoxyethoxy)phenyl)- lH-pyrazole- 1-carboxylate (57.6 mg, 59%) as yellow solid. MS: m/e = 386.2 [M-BOC+H]+.
Figure imgf000131_0001
In a 25 mL round-bottomed flask, tert-butyl 4-(4-(2-(2-chlorophenyl)acetamido)-2-(2- methoxyethoxy)phenyl)-lH-pyrazole- 1-carboxylate (55 mg, 113 μιηοΐ) and trifluoroacetic acid (1.48 g, 1 ml, 13.0 mmol) were combined with dichloromethane (2 ml) to give an orange solution. The reaction mixture was stirred at 40°C for 1 hour. The reaction mixture was basified using saturated aqueous sodium bicarbonate, and extracted with dichloromethane (3 x 20 ml). The organic phase was dried with magnesiumsulfate, filtered and concentrated in vacuo. The solid was triturated in diethyl ether and pentane which gave 2-(2-chlorophenyl)-N-(3-(2- methoxyethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide (31.7 mg, 73%) as an off-white solid. MS: m/e = 386.2 [M+H]+.
Example 157
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-methyl-3-phenylbutanamide
Figure imgf000131_0002
The title compound was prepared in analogy to Example 1, using 3-methyl-3-phenyl-butanoic acid. The compound was obtained as a brown gum (MS (m/e) = 351.17 [M+H+]).
Example 158
N-(3-methoxy-4-(lH- razol-4-yl)phenyl)-3-methyl-3-phenylbutanamide
Figure imgf000132_0001
The title compound was prepared in analogy to Example 111, using 3-methyl-3-phenylbutanoic acid in STEP A. The compound was obtained as a brown solid (MS (m/e) = 350.19 [M+H+]).
Example 159
N-(4-(lH-pyrazol-4- l)phenyl)-3-methyl-3-phenylbutanamide
Figure imgf000132_0002
The title compound was prepared in analogy to Example 122, using 3-methyl-3-phenylbutanoic acid in STEP D. The compound was obtained as a brown solid (MS (m/e) = 320.17 [M+H+]).
Example 160
N-(3-methoxy-4-(pyridin-4- l)phenyl)-3-methyl-3-phenylbutanamide
Figure imgf000132_0003
The title compound was prepared in analogy to Example 121, using 3-methyl-3-phenylbutanoic acid in STEP B. The compound was obtained as a brown gum (MS (m/e) = 361.19 [M+H+]).
Example 161
N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-phenylbutanamide
Figure imgf000133_0001
The title compound was prepared in analogy to Example 111, using 3-phenylbutanoic acid in STEP D. The compound was obtained as a brown solid (MS (m/e) = 336.17 [M+H+]). Example 162
3-(4-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-methylbutanamide
Figure imgf000133_0002
The title compound was prepared in analogy to Example 111, using 3-(4-chlorophenyl)-3- methylbutanoic acid in STEP D. The compound was obtained as a brown solid (MS (m/e) = 384.15 [M+H+]).
Example 163
3-hydroxy-N-(3-methox -4-(oxazol-5-yl)phenyl)-3-phenylbutanamide
Figure imgf000133_0003
The title compound was prepared in analogy to Example 1, using 3-hydroxy-3-phenylbutanoic acid. The compound was obtained as a brown semisolid (MS (m/e) = 353.1 [M+H+]).
Example 164
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(4-chlorophenyl)-3-methylbutanamide
Figure imgf000133_0004
The title compound was prepared in analogy to Example 122, using 3-(4-chlorophenyl)-3- methylbutanoic acid in STEP D. The compound was obtained as a white powder (MS (m/e) = 354.14 [M+H+]).
Example 165
3-(3-chlorophenyl)-N-(3-methox -4-(lH-pyrazol-4-yl)phenyl)-3-methylbutanamide
Figure imgf000134_0001
The title compound was prepared in analogy to Example 111, using 3-(3-chlorophenyl)-3- methylbutanoic acid in STEP D. The compound was obtained as a light yellow solid (MS (m/e) = 384.15 [M+H+]).
Example 166
N-(4-(lH-pyrazol-4-yl henyl)-3-(3-chlorophenyl)-3-methylbutanamide
Figure imgf000134_0002
The title compound was prepared in analogy to Example 122, using 3-(3-chlorophenyl)-3- methylbutanoic acid in STEP D. The compound was obtained as a white powder (MS (m/e) = 354.13 [M+H+]).
Example 167
3-(2-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-methylbutanamide
Figure imgf000134_0003
The title compound was prepared in analogy to Example 111, using 3-(2-chlorophenyl)-3- methylbutanoic acid in STEP D. The compound was obtained as a white powder (MS (m/e) 384.15 [M+H+]).
Example 168
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)-3-methylbutanamide
Figure imgf000135_0001
The title compound was prepared in analogy to Example 122, using 3-(2-chlorophenyl)-3- methylbutanoic acid in STEP D. The compound was obtained as a white powder (MS (m/e) = 354.14 [M+H+]).
Example 169
3-hydroxy-N-[4-(l 3-oxazol-5-yl)phenyl]-3-phenylbutanamide
Figure imgf000135_0002
The title compound was prepared in analogy to example 114, using 4-(oxazol-5-yl)aniline and 3- hydroxy-3-phenylbutanoic acid. The compound was obtained as a light light yellow foam (92 mg 76 , MS (m/e) = 323.14 [M+H+]).
Example 170
3-hydroxy-N-(3-methox -4-(lH-pyrazol-4-yl)phenyl)-3-phenylbutanamide
Figure imgf000135_0003
The title compound was prepared in analogy to Example 111, using 3-hydroxy-3-phenylb acid. The compound was obtained as a brown powder (MS (m/e) = 352.16 [M+H+]).
Example 171
N-(4-(lH-pyrazol-4-yl)phenyl)-3-hydroxy-3-phenylbutanamide
Figure imgf000135_0004
The title compound was prepared in analogy to example 122, using 3-hydroxy-3-phenylbutanoic acid in STEP D. The compound was obtained as a light brown solid (MS (m/e) = 322.16
[M+H+]).
Example 172
2-hydroxy-N-[3-methox -4-(lH-pyrazol-4-yl)phenyl]-2-phenylacetamide
Figure imgf000136_0001
STEP A.
To a solution of l-bromo-2-methoxy-4-nitro-benzene (200 mg, 0.86 mmol) in dioxane (160 ml) and H20 (40 ml) were added K2C03 (357.4 mg, 2.58 mmol) and the reaction mixture was purged with argon for 10 min. [l-(tert-Butoxycarbonyl)-lH-pyrazol-4-yl]boronic acid pinacol ester (380 mg, 1.29 mmol) and Pd(dppf)2Cl2*DCM (323mg, 0.39mmol) were added to the reaction mixture and purged again with argon for lOmin. The reaction mixture was heated at 80 °C for 16 h. Solvent was evaporated off under reduced pressure, and the resulting crude mass was diluted with water (60 ml), and extracted with DCM (2x80 ml). The combined organic layers were dried over anhydrous Na2S04, filtered, and evaporated off in vacuo. The resulting crude mass was purified by column chromatography over silica gel (50-60% EtOAc/hexane) to get 4-(2- methoxy-4-nitro-phenyl)-lH-pyrazole (1.86g, 99.41%) as a green solid (130mg, 68. %). MS (m/e) = 220.0 (M+H+).
STEP B.
To a solution of 4-(2-methoxy-4-nitro-phenyl)-lH-pyrazole (3.98 g, 21.05 mmol) in THF (150 ml) were added TEA (4.40 ml, 31.58 mmol) and (boc)20 (7.25 ml, 31.58 mmol), and the reaction mixture was stirred at 25 °C for 16 h. Solvent was evaporated off in vacuo, and the resulting crude mass was purified by column chromatography over silica gel (20- 30%EtOAc/hexane) to get tert-butyl 4-(2-methoxy-4-nitrophenyl)-lH-pyrazole-l-carboxylate as a white solid (4g, 66.27%)
STEP C.
To a solution of tert-butyl 4-(2-methoxy-4-nitrophenyl)-lH-pyrazole-l-carboxylate (2 g, 6.92 mmol) in MeOH (190 ml) was added 10% Pd/C (100 mg), and the reaction mixture was stirred at 25°C under H2 atmosphere for 3 h. The mixture was filtered, and the filtrate was evaporated off under reduced pressure to get tert-butyl 4-(4-amino-2-methoxyphenyl)-lH-pyrazole-l- carboxylate (1.75g, 97.8%) as off-white solid. MS (m/e) = 260.0 (M+H+). STEP D.
tert-Butyl 4-(4-amino-2-methoxyphenyl)-lH-pyrazole-l-carboxylate (150 mg, 518 μιηοΐ) and 2- hydroxy-2-phenylacetic acid (78.9 mg, 518 μιηοΐ) were combined with DMF (2 ml) to give a light brown solution. DIPEA (201 mg, 1.56 mmol) and 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)- 1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (296 mg, 778 μιηοΐ) was added.The reaction mixture was stirred over night at rt. The reaction mixture was purified by preparative HPLC ( column: Zorbax Eclipse XDB-C18 21,2x50mm flow: 25 ml/min, gradient: acetonitrile / water (0.1% formic acid) =(95%-5% to 5%-95%) as eluent to yield the title compound as a orange solid (73 mg, 28.2 %).
STEP E.
tert-Butyl 4-(4-(2-hydroxy-2-phenylacetamido)-2-methoxyphenyl)-lH-pyrazole-l-carboxylate (73 mg, 146 μιηοΐ) was combined with DCM (1 ml) to give a light brown solution. 2,2,2- Trifluoroacetic acid (75 μΐ) was added. The reaction mixture was stirred over night at rt. The crude reaction mixture was concentrated in vacuo. The reaction mixture was purified by preparative HPLC ( column: Zorbax Eclipse XDB-C 18 21,2x50mm flow: 25 ml/min, gradient: acetonitrile / water (0.1% formic acid) =(95%-5% to 5%-95%) as eluent to yield the title compound as a light brown solid (13.1 mg, 27.7 %, MS (m/e) = 324.13 [M+H]+).
Example 173
2-(2-chlorophenyl)-2-hydroxy-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)acetamide
Figure imgf000137_0001
The title compound was prepared in analogy to example 172, using 2-(2-chlorophenyl)-2- hydroxyacetic acid in STEP D. The compound was obtained as a white solid (MS (m/e) = 358.09 [M+H+]).

Claims

Claims
1. A compound of formula
Figure imgf000138_0001
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH2-S-, -CH2-S(0)2-, CH2-0- or -CH2-CRR'-;
R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring;
R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H- [l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.
2. A compound of formula 1-1 according to claim 1,
Figure imgf000139_0001
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH2-S-, -CH2-S(0)2-, CH2-0- or -CH2-CRR'-;
R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring;
R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4-dihydro-2H- [l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof.
3. A compound of formula 1-2 according to claim 1
Figure imgf000140_0001
is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S; is -CRR'-, -CRR'-NR'-, -C(O)-, -CH2-S-, -CH2-S(0)2-, CH2-0- or -CH2-CRR'-; are independently from each other hydrogen, lower alkyl, ydroxyl or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring; R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH- indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4- dihydro-2H-[l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.
4. A compou
Figure imgf000141_0001
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring;
R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH- indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4- dihydro-2H-[l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.
5. A compound of formulas I-IA or I-2A according to claim 4, wherein the compounds are N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide
N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-m-tolyl-acetamide
N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-pyridin-2-yl-acetamide
2-(2-Aminophenyl)-3'-methoxy-4'-(5-oxazolyl)acetanilide
2-(2,5-dimethoxyphenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3-(difluoromethoxy)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide
2-(2,4-dichlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(4-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(3-bromophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(4-bromophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(benzo[d][l,3]dioxol-5-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(2-chloro-6-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(2,6-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(2-(difluoromethoxy)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-(trifluoromethoxy)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-methoxyphenyl)acetamide
2-(4-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-p-tolylacetamide
2-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-o-tolylacetamide
2-(2-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide
2-(3,5-dimethylphenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(naphthalen-l-yl)acetamide
2-(3-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3,5-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3-fluoro-5-(trifluoromethyl)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(2,4-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)acetamide
2-(3,4-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(2,5-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(2,3-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3-chloro-4-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(3-cyanophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(5-chloro-2-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(furan-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(5-fluoropyridin-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(thiophen-2-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(thiophen-3-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(pyridin-4-yl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(l-methyl-lH-indol-3-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(pyridin-3-yl)acetamide
2-(lH-indol-3-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(benzo[d]isoxazol-3-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methylisoxazol-5-yl)acetamide
2-(2,4-dimethylthiazol-5-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(5-methylthiophen-2-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)pentanamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)propionamide
2-cyclohexenyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-cyclohexyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-cyclopropyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-cyclopentyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-methylcyclohexyl)acetamide
2-(bicyclo[2.2.1]heptan-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
2-(6-methoxy-3-oxo-2,3-dihydro-lH-inden-l-yl)-N-(3-methoxy-4-(oxazol-5- yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydrofuran-2-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H-pyran-2-yl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-2- yl)acetamide
2-(l,l-Dioxo-tetrahydro-llambda*6*-thiophen-3-yl)-N-(3-methoxy-4-oxazol-5-yl-phenyl)- acetamide
2-cyclobutyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-oxocyclohexyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-phenylpropanamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3,3-dimethylbutanamide
N-(3-chloro-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenyl)acetamide
2-(3-methoxyphenyl)-N-(3-methyl-4-(oxazol-5-yl)phenyl)acetamide
2-(3-Methoxy-phenyl)-N-(3-methoxy-4-thiazol-5-yl-phenyl)-acetamide
N-(3-Methoxy-4-[l,3,4]oxadiazol-2-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide
2-(3-Methoxy-phenyl)-N-(3-methoxy-4-[l,2,4]triazol-l-yl-phenyl)-acetamide 3-methoxy-N-(3-methoxybenzyl)-4-(oxazol-5-yl)benzamide N-(4-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
N- (4-fluorobenzyl) - 3 -methoxy-4- (oxazol- 5 -yl)benzamide
3 -methoxy-4- (oxazol- 5 -yl) -N- (2- (trifluoromethyl)benzyl)benzamide N-(2-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
3-methoxy-N-(2-methylbenzyl)-4-(oxazol-5-yl)benzamide
N- (2-fluorobenzyl) - 3 -methoxy-4- (oxazol- 5 -yl)benzamide
N-(3-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
N-(3,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
N-(2,4-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
N- (3 -fluorobenzyl) - 3 -methoxy-4- (oxazol- 5 -yl)benzamide
N-(2,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
N-(2,3-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
3-methoxy-4-(oxazol-5-yl)-N-(thiophen-2-ylmethyl)benzamide
N-(2-fluoro-3-methoxybenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide N-(5-chloro-2-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide
3-methoxy-N-((6-methoxypyridin-2-yl)methyl)-4-(oxazol-5-yl)benzamide 2-(3-methoxyphenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxybenzyl)-4-(oxazol-5-yl)benzamide
2-(3-methoxyphenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide
N-(3-methoxybenzyl)-4-(pyridin-4-yl)benzamide
2-(2-chlorophenyl)-N-(3-methoxy-4-(pyridin-4-yl)phenyl)acetamide N-(2-chlorobenzyl)-3-methoxy-4-(pyridin-4-yl)benzamide
2-(2-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)acetamide 2-(2-chlorophenyl)-N-(2-methoxy-4-(lH-pyrazol-4-yl)phenyl)acetamide N-(2-chlorobenzyl)-2-methoxy-4-(lH-pyrazol-4-yl)benzamide
N-(2-chlorobenzyl)-3-methoxy-4-(lH-pyrazol-4-yl)benzamide
2-(2-chlorophenyl)-N-(3-methoxy-4-(lH-l,2,4-triazol-l-yl)phenyl)acetamide 2-(2-Chlorophenyl)-N-(2-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(2-Chlorophenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide
N-(2-Chlorobenzyl)-2-methoxy-4-(oxazol-5-yl)benzamide
N-(4-(lH-pyrazol-4-yl)phenyl)-2-(2-chlorophenyl)acetamide
2-(2-Chlorophenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide 2-(2-Chlorophenyl)-N-(2-(2-(dimethylamino)ethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide 2-(2-Chlorophenyl)-N-(3-methoxy-4-(4-methyloxazol-5-yl)phenyl)acetamide
1- (2-Chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarboxamide
2- (2-Chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-methylpropanamide
N-(3-Methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenyl)-2-methylpropanamide
2-(2-Chlorophenyl)-N-(3-(2-(dimethylamino)ethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide 2,2,2-trifluoroacetate
2-(2-Chlorophenyl)-N-(2-(2-morpholinoethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide 2-(2-Chlorophenyl)-N-(3-(2-morpholinoethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide 2,2,2- trifluoroacetate
2-(2-Chlorophenyl)-N-(2-(2-methoxyethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide
2-(2-Chlorophenyl)-N-(3-(2-methoxyethoxy)-4-(lH-pyrazol-4-yl)phenyl)acetamide
2-hydroxy-N- [3-methoxy-4- ( 1 H-pyrazol-4-yl)phenyl] -2-phenylacetamide or
2-(2-chlorophenyl)-2-hydroxy-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)acetamide.
6. A comp
Figure imgf000146_0001
I-2B wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from
N, O or S; R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring;
R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH- indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4- dihydro-2H-[l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.
7. A compound of formula I- IB or I-2B according to claim 6, wherein the compounds are iert-bbutyl [(RS)-[[[3-methoxy-4-(5-oxazolyl)phenyl]carbamoyl]phenyl]-(methyl)]carbamate N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylamino)acetamide
N-(3-Methoxy-4-oxazol-5-yl-phenyl)-2-phenylamino-acetamide
2-(4-chlorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-(trifluoromethyl)phenylamino)acetamide 2-(4-fluorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide
N-(4-(oxazol-5-yl)phenyl)-2-(phenylamino)acetamide
2-(4-fluorophenylamino)-N-(4-(oxazol-5-yl)phenyl)acetamide
N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide N-(3-Methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-(3-methoxyphenylamino)acetamide
N-(3-Methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylamino)-2-methylpropanamide
2- (2-Chlorophenylamino)-N- (3 -methoxy-4- ( 1 H-pyrazol-4-yl)phenyl)-2-methylpropanamide
2- (2-Chlorophenylamino)-N- (3 -methoxy-4- ( 1 H-pyrazol-4-yl)phenyl)acetamide
N-(3-Methoxy-4-(oxazol-5-yl)phenyl)-l-(3-methoxyphenylamino)cyclopropanecarboxamide
N-(3-Methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-methyl-2-(phenylamino)propanamide l-(2-Chlorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarboxamide
N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-2-(3-methoxyphenylamino)-2-methylpropanamide or
1 -(2-Chlorophenylamino)-N- (3 -methoxy-4- ( 1 H-pyrazol-4- yl)phenyl)cyclopropanecarboxamide.
8. A compound of formulas I-1C or I-2C according to claim 1
Figure imgf000148_0001
wherein
R is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R r is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from
N, O or S; is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH- indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4- dihydro-2H-[l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.
9. A compound of formulas I-IC or I-2C according to claim 8, wherein the compound is N-[3-methoxy-4-(5-oxazolyl)phenyl]-3,3-dimethyl-2-oxobutyramide.
10. A compo -2D or I- IF or I-2F according to claim 1
Figure imgf000149_0001
Figure imgf000149_0002
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from
N, O or S;
R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N,
O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH- indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4- dihydro-2H-[l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.
11. A compound of formulas I-ID and I-2D or I-IF or I-2F according to claim 10, wherein the compounds are
2-(Benzenesulfonyl)-3'-methoxy-4'-(5-oxazolyl)acetanilide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(phenylthio)acetamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylthio)acetamide or
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylsulfonyl)acetamide.
12.A compou
Figure imgf000150_0001
wherein R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from
N, O or S;
R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH- indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4- dihydro-2H-[l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof
13. A compound of formula I-IG or I-2G according to claim 12, wherein the compound is N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-phenoxyacetamide.
14. A compound of formula I-1H or I-2H according to claim 1
Figure imgf000152_0001
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; R1 is hydrogen, lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy,
0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl;
with the proviso that both R1 and R1 may be simultaneously hydrogen, but only one of R1 and R1 is lower alkyl, lower alkoxy, halogen, 0(CH2)2-lower akoxy, 0(CH2)2N(CH3)2, or 0(CH2)-morpholinyl; Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from
N, O or S;
R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring; R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower alkyl or =0, bridged cyclohexyl or C3_6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R 2' , selected from halogen, cyano, S(0)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[l,3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2,3-dihydro-lH- indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3,4- dihydro-2H-[l,4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, for example the compounds
15. A compound of formula I-IH or I-2H according to claim 14, wherein the compounds are N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-phenylpropanamide
N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
3-(4-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)propanamide
3-(3-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamide
3-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamide
N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3-phenylpropanamide
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)propanamide
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(3-chlorophenyl)propanamide
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(4-chlorophenyl)propanamide
N-(3-fluoro-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
N-(3-chloro-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
N-(2-chloro-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
N-(3-methyl-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
N-(2-methyl-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
N-(2-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-phenylpropanamide
3-methoxy-N-phenethyl-4-(lH-pyrazol-4-yl)benzamide
N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-methyl-3-phenylbutanamide
N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-methyl-3-phenylbutanamide
N- (4- ( 1 H-pyrazol-4-yl)phenyl) - 3 -methyl- 3 -phenylbutanamide
N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3-methyl-3-phenylbutanamide
N-(3-methoxy-4-( lH-pyrazol-4-yl)phenyl)-3-phenylbutanamide
3-(4-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-methylbutanamide 3-hydroxy-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-phenylbutanamide
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(4-chlorophenyl)-3-methylbutanamide
3-(3-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-methylbutanamide N-(4-(lH-pyrazol-4-yl)phenyl)-3-(3-chlorophenyl)-3-methylbutanamide
3-(2-chlorophenyl)-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-methylbutanamide
N-(4-(lH-pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)-3-methylbutanamide
3 -hydroxy-N- [4-(l,3-oxazol- 5 -yl)phenyl] - 3 -phenylbutanamide 3-hydroxy-N-(3-methoxy-4-(lH-pyrazol-4-yl)phenyl)-3-phenylbutanamide or N- (4- ( 1 H-pyrazol-4-yl)phenyl) - 3 -hydroxy- 3 -phenylbutanamide .
16. A process for the manufacture of a compound of formula I-l or 1-2 as defined of claims 1 to 15, which process comprises a) reacting a compound of formula
Figure imgf000154_0001
with a compound of formula
Figure imgf000154_0002
in the presence of EDC or HATU
to a compound of formula
Figure imgf000154_0003
wherein the definitions are as described above, or b) reacting a compound of formula
Figure imgf000154_0004
with a compound of formula
Figure imgf000154_0005
19 in the presence of EDC or HATU
to a compound of formula
Figure imgf000155_0001
wherein the substituents are as described above,
and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
17. A compound according to any one of claims 1 to 15 when manufactures by a process according to claim 16.
18. Pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutical acceptable carrier and/or adjuvant.
19. Pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutical acceptable carrier and/or adjuvant for use in the treatment of schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer' s disease, mild cognitive impairment, chemotherapy- induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorders, hearing loss, tinnitus,
spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and disturbances due to radiation therapy, chronic stress, optic neuropathy or macular degeneration, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine or ***e.
20. Compounds according to any one of claims 1 to 15 for use as therapeutic active substances.
21. Compounds according to any one of claims 1 to 15 for use as therapeutic active substances in the treatment of schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy- induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and disturbances due to radiation therapy, chronic stress, optic neuropathy or macular degeneration, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine or ***e.
22. The use of a compound according to any one of claims 1 to 15 for the preparation of medicaments for the therapeutic and/or prophylactic treatment of schizophrenia, obsessive- compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia,
amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and
disturbances due to radiation therapy, chronic stress, optic neuropathy or macular
degeneration, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine or ***e.
23. A method for the treatment or prophylaxis schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and disturbances due to radiation therapy, chronic stress, optic neuropathy or macular degeneration, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine or ***e, which method comprises administering an effective amount of a compound as defined in any one of claim 1 to 15.
24. The use of a compound according to any one of claims 1 to 15 for the treatment or prophylaxis of schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post- traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy- induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and disturbances due to radiation therapy, chronic stress, optic neuropathy or macular degeneration, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine or ***e..
25. The invention as hereinbefore described.
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