| (11) | EP 3 397 616 B1 |
| (12) | EUROPEAN PATENT SPECIFICATION |
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| (54) | LSD1 INHIBITORS LSD1-INHIBITOREN INHIBITEURS DE LSD1 |
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| Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
CROSS REFERENCE
[0001] This application claims benefit of U.S. Provisional Application No. 62/272,082, filed December 29, 2015, and U.S. Provisional Application No. 62/295,369, filed February 15, 2016.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds that inhibit lysine-specific demethylase one (LSD1). In particular, the present invention relates to compounds that irreversibly inhibit the activity of LSD1, pharmaceutical compositions comprising the compounds and methods of use therefor.
BACKGROUND OF THE INVENTION
[0003] Lysine-specific demethylase one ("LSD1"), also known as KDM1A, is a flavin-dependent lysine demethylase that removes methyl groups from mono- and dimethylated lysine4 of the histone H3 protein through flavin adenine dinucleotide (FAD) dependent enzymatic oxidation (e.g., see Shi et al., (2004) Cell 119:941-953). In addition, LSD1 demethylates mono- and dimethylation of histone H3 lysine9 in prostate cancer cell lines and is essential for transcriptional regulation mediated by the androgen receptor (Metzger et al., Nature (2005) 437:436-439). LSD1 also demethylates a number of cellular proteins, such as p53, E2F1 and STAT3 and regulates their function.
[0004] LSD1 has been reported to be overexpressed in a wide variety of cancers and tissues, including lung cancer, bladder cancer, neuroblastoma, prostate cancer and breast cancer. LSD1 is thought to play a role in cellular proliferation and cancer cell growth by modulating prosurvival gene expression and p53 transcriptional activity (e.g., see Suzuki and Miyata (2011) J. Med. Chem. 54:8236-8250). LSD1 also plays a role in regulating viral gene transcription, e.g., Herpes Simplex Virus (HSV), by demethylating histone H3 lysine9 required for viral gene expression in the host. WO 2015/123408 discloses cyclopropylamine derivatives which are said to be LSD1 inhibitors useful in the treatment of diseases such as cancer. WO 2012/135113 relates to cyclopropylamines which are said to be inhibitors of LSD1, to pharmaceutical compositions containing them, and to their use in therapy for the treatment of cancers.
WO 2010/043721 describes phenylcyclopropylamine acetamide derivatives and their use in treating diseases.
[0005] With increasing evidence that LSD1 plays a critical role in a diverse set of cancers and diseases, a variety of LSD1 inhibitors, including irreversible LSD1 inhibitors, have been reported and are in clinical development. Irreversible cyclopropyl amine-containing inhibitors, e.g., reviewed in Suzuki and Miyata, ibid, have been shown to be potent inhibitors of the LSD1 enzyme; however, such compounds tend to lack robust cellular potency, have poor metabolic stability and high clearance in vivo.
SUMMARY OF THE INVENTION
[0006] The present inventors recognized a need to develop new LSD1 inhibitors that demonstrate improved cellular potency, efficacy, stability and safety. The compounds and compositions of the present invention advantageously overcome one or more of these shortcomings by providing potent, selective and orally active LSD1 inhibitors.
[0007] In one aspect of the invention, compounds are provided that irreversibly inhibit LSD1 activity. In certain embodiments, the compounds are represented by formula (I):
or a pharmaceutically acceptable salt thereof,
R1 is hydrogen, C1-C4 alkyl or C1-C4 acyl;
L is -(CH2)s-CR2R3-(CH2)m-;
R2 and R3 are each independently hydrogen, C1-C4 alkyl, -OR4 or aralkyl;
each R4 is independently hydrogen or C1-C4 alkyl;
X is -W-R5 or Y-R6;
W is -NR4- or -O-;
Y is -C(O)-, -S-, -SO-, -SO2-, -NR4SO2-, -SO2NR4- and -NR4C(O)-;
R5 is selected from the group consisting of acyl, C1-C4alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally independently substituted with one or more R8;
R6 is C1-C6 alkyl, -NR4R7 or heterocyclyl optionally independently substituted on one or more carbon atoms with C1-C6 alkyl, halogen, cyano, or haloalkyl, or optionally independently substituted on one or more nitrogen atoms with -C(O)C1-C6 alkyl; -C(O)OC1-C6 alkyl; -C(O)NR4C1-C6 alkyl, or -S(O)2NR4C1-C6 alkyl;
R7 is hydroxyl, alkoxy, -SO2C1-C6alkyl; -SO2cycloalkyl, or -SO2aryl, wherein the cycloalkyl and aryl of each of the -SO2cycloalkyl and -SO2aryl is optionally independently substituted with one or more R8;
each R8 is independently halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, -(CH2)nCOOR4, -(CH2)nC(O)NR4OC1-C6alkyl, -(CH2)nC(O)NR4SO2C1-C6alkyl, -(CH2)nC(O)NR4SO2cycloalkyl, -(CH2)nC(O)NR4SO2aryl,-C2-C6 alkenylC(O)OR4, -C2-C6 alkenylC(O)NR4SO2C1-C4alkyl, or -C2-C6 alkenylC(O)NR4SO2aryl, wherein each of the cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally independently substituted with one or more C1-C3 alkyl.
m is 0 or 1;
s is 0 or 1;
each n is 0, 1, or 2;
each p is 0, 1 or 2;
each RA is independently oxo or C1-C3 alkyl, or two RA groups on different ring atoms together form a C1-C3 bridge in which one of the bridge carbons is optionally replaced with -NH-;
each Q1, Q2 and Q3 is independently hydrogen, halogen, haloalkyl, C1-C4-alkyl, or C1-C4-alkoxy.
[0008] In another aspect of the invention, pharmaceutical compositions are provided comprising a therapeutically effective amount of a compound of formula (I) or formula (II) and a pharmaceutically acceptable excipient.
[0009] In yet another aspect of the invention, methods for inhibiting LSD1 activity in a cell comprising contacting the cell with a compound of formula (I) or formula (II) are provided. Also provided are methods for treating cancer in a patient comprising administering a therapeutically effective amount of a compound of formula (I) or formula (II) or pharmaceutical composition thereof to a patient in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The present invention relates to LSD1 inhibitors. In particular, the present invention relates to compounds that irreversibly inhibit the activity of SD1, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of use therefor.
DEFINITIONS
[0011] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. Terms and ranges have their generally defined definition unless expressly defined otherwise.
[0012] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an "alkyl" moiety generally refers to a monovalent radical (e.g. CH3-CH2-), in certain circumstances a bivalent linking moiety can be "alkyl," in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term "alkylene." (Similarly, in circumstances in which a divalent moiety is required and is stated as being "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).
[0013] As used herein, "LSD1" refers to a mammalian lysine-specific demethylase enzyme ("LSD1"), which removes methyl groups from mono- and dimethylated lysine4 and lysine9 of the histone H3 protein.
[0014] As used herein, an "LSD1 inhibitor" refers to compounds of the present invention that are represented by formulae (I) or (II) as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of LSD1. The LSD1 inhibitors of the present invention irreversibly inhibit LSD1 activity by forming a covalent adduct with the flavin ring of FAD in the active site of LSD1 following one electron oxidation and cyclopropyl ring opening.
[0016] The term "alkyl" as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, "alkyl" encompasses C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
[0017] The term "alkenyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, "alkenyl" encompasses C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 groups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
[0018] The term "alkynyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms. As such, "alkynyl" encompasses C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 groups. Examples alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
[0019] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Exemplary alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Exemplary alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.
[0024] The term "cycloalkyl" as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. As such, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 cyclic hydrocarbon groups. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
[0025] The term "heteroalkyl" refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced O, S, or NR4 wherein R4 is as defined herein.
[0026] An "aryl" group is a C6-C14 aromatic moiety comprising one to three aromatic rings. As such, "aryl" includes C6, C10, C13, and C14 cyclic hydrocarbon groups. An exemplary the aryl group is a C6-C10 aryl group. Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
[0027] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group wherein the moiety is linked to another group via the alkyl moiety. An exemplary aralkyl group is -(C1-C6)alkyl(C6-C10)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
[0028] A "heterocyclyl" or "heterocyclic" group is a mono- or bicyclic (fused or spiro) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, NR4, O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and/or S atoms.
[0029] The term "heterocyclylalkyl" refers to a heterocyclyl group as defined herein linked to the remaining portion of the molecule via an alkyl linker.
[0030] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S. "Heteroaryl" also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom. Examples of such multicyclic heteroaryl ring systems include 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-pyrido[3,2-b][1,4] oxazin-3 (4H)-one.
[0031] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
[0032] A "heteroaralkyl" or "heteroarylalkyl" group comprises a heteroaryl group covalently linked to another group via an alkyl linkerExamples of heteroalkyl groups comprise a C1-C6 alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and/or S atoms.
[0033] An "arylene," "heteroarylene," or "heterocyclylene" group is an bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
[0034] When a hydrocarbon (e.g., an alkyl or aryl) is described as having a certain range of numbers of carbon atoms (e.g., C1-C6 alkyl), it will be understood that it encompasses hydrocarbons with each number of carbons within that range. So, for example, "C1-C6 alkyl" represents the group "Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl."
[0035] As employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described as "optionally substituted" without expressly stating the substitutuents it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., a ring -CH- substituted with oxo is -C(O)-) nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups. Exemplary substituents, which are themselves not further substituted (unless expressly stated otherwise) are:
[0036] for Q1, Q2 and Q3: hydrogen, halogen, particularly F, Cl or Br, halohydrocarbyl, such as CF3, alkyl, such as C1-C4-alkyl, or alkoxy, such as C1-C4-alkoxy.
[0037] A moiety that is "optionally independently substituted" with one or more groups is unsubstituted, substituted with one group, or substituted with more than one group wherein each of the groups is selected independently of the others. For example, an alkyl optionally independently substituted with one or more halo, cyano, or -OH groups includes ethyl, trifluromethyl, and 1-chloro,2-hydroxypropyl.
[0038] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, flurochloromethyl, and fluoromethyl
[0039] The term "halogen" or "halo" as employed herein refers to chlorine, bromine, fluorine, or iodine.
[0040] As herein employed, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein. The term "acylamino" refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-). The term "carbamoyl" refers to an amide group attached at the carbonyl carbon atom (i.e., NH2-CO-). The term "sulfonamido" refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom. The term "ureido" as employed herein refers to a substituted or unsubstituted urea moiety.
[0041] The term "radical" as used herein means a chemical moiety comprising one or more unpaired electrons.
[0042] As used herein, "an effective amount" of a compound is an amount that is sufficient to to negatively modulate or inhibit the activity of LSD1.
[0043] As used herein, a "therapeutically effective amount" of a compound is an amount that is sufficient to ameliorate or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of LSD1. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
[0044] As used herein, "treatment" means any manner in which the symptoms or pathology of a condition, disorder or disease in a patient are ameliorated or otherwise beneficially altered.
[0045] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.
COMPOUNDS
[0046] In one aspect of the invention, compounds are provided represented by formula (I) or formula (II):
or a pharmaceutically acceptable salts thereof.
R1 is hydrogen, C1-C4 alkyl or C1-C4 acyl;
L is -(CH2)s-CR2R3-(CH2)m-;
R2 and R3 are each independently hydrogen, C1-C4 alkyl, -OR4 or aralkyl;
each R4 is independently hydrogen or C1-C4 alkyl;
X is -W-R5 or Y-R6;
W is -NR4- or -O-;
Y is -C(O)-, -S-, -SO-, -SO2-, -NR4SO2-, -SO2NR4- and -NR4C(O)-;
R5 is acyl, C1-C4 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally independently substituted with one or more R8;
R6 is C1-C6 alkyl, aryl, -NR4R7 or heterocyclyl optionally independently substituted on one or more carbon atoms with C1-C6 alkyl, halogen, cyano, or haloalkyl, or optionally independently substituted on one or more nitrogen atoms with -C(O)C1-C6 alkyl; -C(O)OC1-C6 alkyl; -C(O)NR4C1-C6 alkyl, or -S(O)2NR4C1-C6 alkyl;
R7 is hydroxyl, alkoxy, -SO2C1-C6alkyl; -SO2cycloalkyl, or -SO2aryl, wherein the cycloalkyl and aryl of each of the -SO2cycloalkyl and -SO2aryl is optionally independently substituted with one or more R8;
each R8 is independently halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, -(CH2)nCOOR4, -(CH2)nC(O)NR4OC1-C6alkyl,-(CH2)nC(O)NR4SO2C1-C6alkyl, -(CH2)nC(O)NR4SO2cycloalkyl, -(CH2)nC(O)NR4SO2aryl, -C2-C6 alkenylC(O)OR4, -C2-C6 alkenylC(O)NR4SO2C1-C4alkyl, or -C2-C6 alkenylC(O)NR4SO2aryl, wherein each of the cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally independently substituted with one or more C1-C3 alkyl or -CH2NR4SO2aryl.
m is 0 or 1;
s is 0 or 1;
each n is 0, 1, or 2;
each p is 0, 1 or 2;
each RA is independently oxo or C1-C3 alkyl, or two RA groups on different ring atoms together form a C1-C3 bridge in which one of the bridge carbons is optionally replaced with -NH-;
each Q1, Q2 and Q3 is independently hydrogen, halogen, haloalkyl, C1-C4-alkyl, or C1-C4-alkoxy.
[0047] In one aspect of the invention, X is -W-R5 and W is -O-, s is 1 and m is 0. In certain embodiments of this aspect, R5 is aryl optionally independently substituted with one or more R8. In some these embodiments, the aryl is phenyl optionally independently substituted with one or more R8. In some of these embodiments, each R8 is independently a heterocyclyl optionally independently substituted one or more C1-C3 alkyl or C1-C4 acyl, and the heterocyclyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, morpholinyl, dimethyl-morpholinyl, thiomorpholinyl, 1,4-dithianyl, or 1,3,5-trithianyl. In other of these embodiments, the heterocyclyl is:
[0048] In other embodiments of this aspect, R5 is phenyl optionally independently substituted with one or more R8, wherein each R8 is independently halogen, C1 - C6 alkyl,-(CH2)nCOOR4, -(CH2)pC(O)NR4OC1-C4alkyl, -(CH2)pC(O)NR4SO2C1-C4alkyl, -(CH2)nC(O)NR4SO2cycloalkyl, -(CH2)nC(O)NR4SO2aryl, -CH=CHC(O)OR4,-CH=CHC(O)NR4SO2C1-C4alkyl, or -CH=CHC(O)NR4SO2aryl. In some of these embodiments, there is a single R8 substitution which is -(CH2)nCOOR4.
[0049] In further embodiments of this aspect, R5 is heteroaryl optionally independently substituted with one or more R8. In certain embodiments, the heteroaryl optionally independently substituted with one or more R8 is the heteroaryl is pyridyl, 6-methyl-pyridyl, 4-carboxy-pyridyl, dihydroquinolinone, indolinone, quinazolinyl, quinolinyl, pyrimidinyl, 2-methyl-pyrimidinyl, pyridazinyl, 6-methyl-pyridiazinyl, pyrazolyl, 1-methyl-pyrazolyl, 5-methyl-pyrazolyl, 1,3-dimethyl-pyrazolyl, thiazolyl, 5-methyl-thiazolyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, thiadiazolyl or 5-methyl-thiadiazolyl.
[0050] In yet other embodiments, the heteroaryl is pyridyl optionally independently substituted with one or more R8. For some of these embodiments, R8 is heterocyclyl optionally independently substituted with one or more C1-C3 alkyl or C1 - C4 acyl. In some embodiments, the heterocyclyl optionally independently substituted with one or more C1-C3 alkyl or C1 - C4 acyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, morpholinyl, dimethyl-morpholinyl, thiomorpholinyl, 1,4-dithianyl, or 1,3,5-trithianyl. In other embodiments, the R8 heterocyclyl is:
In yet other embodiments of this aspect, R8 is halogen, C1-C6 alkyl, -(CH2)nCOOR4, -(CH2)pC(O)NR4OC1-C4alkyl, -(CH2)pC(O)NR4SO2C1-C4alkyl, -(CH2)nC(O)NR4SO2cycloalkyl, -(CH2)nC(O)NR4SO2aryl, -CH=CHC(O)OR4, -CH=CHC(O)NR4SO2C1-C4 alkyl, or -CH=CHC(O)NR4SO2aryl.
[0051] In other embodiments of this aspect for compounds of formula (II), RA is oxo and n is 1 or 2, thereby forming a piperdin-2-one or piperdin-2,6-dione. In alternative embodiments for compounds of formula (II), there are two RA groups on different piperidine ring atoms that form a C1-C3 bridge in which one of the carbon atoms of the bridge is optionally substituted by -NH-. Examples of piperidine groups with two RA groups forming a bridge include, but are not limited to, 3-azabicyclo[3.1.1]heptan-3-yl, 1-azabicyclo[2.2.2]octan-3-yl, 1-azabicyclo[2.2.2]octan-4-yl, 1-azabicyclo[3.2.1]octan-6-yl, and 3,7-diazabicyclo[3.3.1]nonanyl.
[0052] In certain embodiments of this aspect, R1 is hydrogen, C1-C4 alkyl or C1-C4 acyl and R2 and R3 are each independently hydrogen, C1-C4 alkyl, -OR4 or aralkyl, wherein R4 is hydrogen or alkyl. In certain embodiments, R2 is hydroxyl. In certain other embodiments, R2 and R3 are each independently hydrogen, methyl and benzyl. In certain other exemplary embodiments, R4 is hydrogen or methyl.
[0053] In certain other embodiments of this aspect, R1 is hydrogen, L is ethylene, W is -O-, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, morpholinyl, dimethyl-morpholinyl, or thiomorpholinyl.
[0054] In certain other embodiments of this aspect, R1 is methyl, L is ethylene, W is -O-, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, morpholinyl, dimethyl-morpholinyl, or thiomorpholinyl.
[0055] In certain other embodiments of this aspect, R1 is hydrogen, L is ethylene, W is -O-, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is:
[0056] In certain other embodiments of this aspect, R1 is methyl, L is ethylene, W is -O-, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is:
[0057] In certain other embodiments of this aspect, R1 is acyl, L is ethylene, W is -O-, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is:
[0058] In another aspect of the invention, R1 is hydrogen, s and m are each one, R2 is hydroxyl, R3 is hydrogen, W is -O-, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is:
[0059] In yet another aspect of the invention, R1 is hydrogen, L is ethylene, W is -O-, R5 is an R8 substituted pyridylene, and R8 is heterocyclyl, wherein the heterocyclyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, morpholinyl, dimethyl-morpholinyl, or thiomorpholinyl.
[0060] In certain other embodiments of this aspect, R1 is methyl, L is ethylene, W is -O-, R5 is an R8 substituted pyridylene, and R8 is heterocyclyl, wherein the heterocyclyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, morpholinyl, dimethyl-morpholinyl, or thiomorpholinyl.
[0061] In certain other embodiments of this aspect, R1 is hydrogen, L is ethylene, W is -O-, R5 is an R8 substituted pyridylene, and R8 is heterocyclyl, wherein the heterocyclyl is:
[0062] In certain embodiments, compounds of formula (I) and formula (II) wherein W is -O-are
1-phenoxy-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol;
1-(2-methoxy-3-phenoxy-propyl)-N-[trans-2-phenylcyclopropyl]piperidin-4-amine;
2-methyl-1-phenoxy-3-(4-(((trans)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol;
1-phenoxy-3-[3-[[[(trans)-2-phenylcyclopropyl]amino]methyl]azetidin-1-yl]propan-2-ol;
(R)-1-phenoxy-3-(4-(((1S,2R)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol;
(S)-1-phenoxy-3-(4-(((1S,2R)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol;
1-phenoxy-3-[(1R,5S)-6-[[(trans)-2-phenylcyclopropyl]amino]-3-azabicyclo[3.1.1]heptan-3-yl]propan-2-ol;
(trans)-N-[[1-(2-phenoxyethyl)azetidin-3-yl]methyl]-2-phenyl-cyclopropanamine;
(trans)-N-[[1-(3-phenoxypropyl)azetidin-3-yl]methyl]-2-phenyl-cyclopropanamine;
1-[2-(4-bromophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine;
1-(3-Phenoxypropyl)-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-Phenoxyethyl)-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;
2-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid;
N-(Methylsulfonyl)-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide;
2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-N-(phenylsulfonyl)acetamide;
N,N-Dimethyl-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide;
N-methoxy-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide;
1-[2-(4-morpholinophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine;
1-(2-(4-(4-methylpiperazin-1-yl)phenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)oxazolidin-2-one;
1-methyl-3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)imidazolidin-2-one;
3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one;
4-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)morpholin-3-one;
1-(4-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethan-1-one;
1-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)pyrrolidin-2-one;
1-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)piperidin-2-one;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(4-(piperidin-1-yl)phenoxy)ethyl)piperidm-4-amine;
2-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acetic acid;
4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)benzoic acid;
(E)-3-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylic acid;
2-(4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acetic acid;
4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)benzoic acid;
(E)-3-(4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylic acid;
(1R,2S)-N-((1-(2-(4-bromophenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
1-(2-(2,4-dichlorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
(1R,2S)-N-((1-(2-(2,4-dichlorophenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
1-(2-(2,4-difluorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
(1R,2S)-N-((1-(2-(2,4-difluorophenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
(E)-3-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)-N-(methylsulfonyl)acrylamide;
1-(2-((2-methylpyridin-4-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
(1R,2S)-2-phenyl-N-((1-(2-(p-tolyloxy)ethyl)azetidin-3-yl)methyl)cyclopropan-1-amine;
(1R,2S)-2-phenyl-N-((1-(2-(pyridin-2-yloxy)ethyl)azetidin-3-yl)methyl)cyclopropan-1-amine;
4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzoic acid;
N-(cyclopropylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamide;
4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-N-(phenylsulfonyl)benzamide;
(E)-N-(methylsulfonyl)-3-(4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylamide;
3-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one;
4-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)morpholin-3-one
1-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)piperidin-2-one;
(1R,2S)-2-phenyl-N-((1-(2-(4-(piperazin-1-yl)phenoxy)ethyl)azetidin-3-yl)methyl)cyclopropan-1-amine;
(1R,2S)-N-((1-(2-(4-(4-methylpiperazin-1-yl)phenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
1-(4-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethan-1-one;
1-(2-((5-methylpyridin-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((6-methylpyridin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
N-(methylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamide;
N-(ethylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamide;
(1S,2R)-N-((1-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
2-(4-(2-(3-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)acetic acid;
4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)benzoic acid
2-(4'-(2-(3-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)-[1,1'-biphenyl]-4-yl)-N-(phenylsulfonyl)acetamide;
3-(6-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)pyridin-3-yl)-1,3-oxazinan-2-one;
3-(5-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)pyridin-2-yl)-1,3-oxazinan-2-one;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(p-tolyloxy)ethyl)piperidin-4-amine;
3-(4-(2-(4-(methyl((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one;
2-(4-(2-(1-methyl-3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-
4-azetidin-1-yl)ethoxy)phenyl)-N-(methylsulfonyl)acetamide;
N-methyl-1-(2-((6-methylpyridin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
(1R,2S)-N-((1-(2-((6-methylpyridin-3-yl)oxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
4-(2-(1-methyl-3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-
4-azetidin-1-yl)ethoxy)-N-(methylsulfonyl)benzamide;
3-(5-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)pyridin-2-yl)-1,3-oxazman-2-one;
6-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one;
5-(2-(4-(((1R,2S)-2-phenylcyclopropyl)aminodin-1-yl)ethoxy)indolin-2-one;
1-(2-(3-ffuoro-4-methylphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(quinazolin-4-yloxy)ethyl)piperidin-4-amine;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(quinolin-4-yloxy)ethyl)piperidin-4-amine;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(pyrimidin-5-yloxy)ethyl)piperidin-4-amine;
1-(2-(3,5-difluorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-(3,5-dichlorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((6-methylpyridazin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
(E)-3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acrylic acid;
1-(2-(3-fluorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((6-methylpyridin-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((2-methylpyrimidin-5-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-(4-bromophenoxy)ethyl)-4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-2-one;
2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethan-1-ol;
N-(1-(2-(4-(2-oxo-1,3-oxazinan-3-yl)phenoxy)ethyl)piperidin-4-yl)-N-((1R,2S)-2-phenylcyclopropyl)acetamide;
1-(2-methoxyethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((1-methyl-1H-pyrazol-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
3-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one;
1-(2-isopropoxyethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
2-(2-fluoro-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid;
1-(2-(3,5-difluoro-4-methylphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((5-methyl-1,3,4-thiadiazol-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
2-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)isonicotinic acid;
3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)oxazolidin-2-one;
1-(2-(4-bromophenoxy)ethyl)-4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidine-2,6-dione;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(pyridin-3-yloxy)ethyl)piperidin-4-amine;
7-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-2H-benzo[b] [1,4]oxazin-3(4H)-one;
6-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzo[d]oxazol-2(3H)-one;
1-(2-((5-methylthiazol-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
3-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)isonicotinic acid;
2-(3-chloro-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid;
2-(3-fluoro-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid;
2-(3-methyl-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid;
4-(2-(4-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)piperidin-1-yl)ethoxy)benzoic acid;
and pharmaceutically acceptable salts of the foregoing compounds, including, but not limited to, di-hydrochloride salts.[0063] In another aspect of the invention, X is -W-R5 and W is -NR4-, s is 1 and m is 0. In certain embodiments of this aspect, R5 is aryl optionally independently substituted with one or more R8. In some these embodiments, the aryl optionally independently substituted with one or more R8 is phenyl. In some of these embodiments, each R8 is independently a heterocyclyl optionally independently substituted one or more C1-C3 alkyl or C1-C4 acyl, and the heterocyclyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, morpholinyl, dimethyl-morpholinyl, thiomorpholinyl, 1,4-dithianyl, or 1,3,5-trithianyl. In other of these embodiments, the heterocyclyl is:
[0064] In other embodiments of this aspect, R5 is phenyl optionally independently substituted with one or more R8, wherein each R8 is independently halogen, C1 - C6 alkyl,-(CH2)nCOOR4, -(CH2)pC(O)NR4OC1-C4alkyl, -(CH2)pC(O)NR4SO2C1-C4alkyl, -(CH2)nC(O)NR4SO2cycloalkyl, -(CH2)nC(O)NR4SO2aryl, -CH=CHC(O)OR4,-CH=CHC(O)NR4SO2C1-C4alkyl, or -CH=CHC(O)NR4SO2aryl. In some of these embodiments, there is a single R8 substitution which is -(CH2)nCOOR4.
[0065] In further embodiments where W is -NR4-, R5 is heteroaryl optionally independently substituted with one or more R8. In certain embodiments, the heteroaryl optionally independently substituted with one or more R8 is the heteroaryl is pyridyl, 6-methyl-pyridyl, 4-carboxy-pyridyl, dihydroquinolinone, indolinone, quinazolinyl, quinolinyl, pyrimidinyl, 2-methyl-pyrimidinyl, pyridazinyl, 6-methyl-pyridiazinyl, pyrazolyl, 1-methyl-pyrazolyl, 5-methyl-pyrazolyl, 1,3-dimethyl-pyrazolyl, thiazolyl, 5-methyl-thiazolyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, thiadiazolyl or 5-methyl-thiadiazolyl. In yet other embodiments, the heteroaryl is pyridyl optionally independently substituted with one or more R8. For certain compounds, R8 is heterocyclyl optionally independently substituted one or more C1-C3 alkyl. In some embodiments, the heterocyclyl optionally independently substituted one or more C1-C3 alkyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, morpholinyl, dimethyl-morpholinyl, thiomorpholinyl, 1,4-dithianyl, or 1,3,5-trithianyl.
[0066] In other embodiments, the heterocyclyl optionally independently substituted one or more C1-C3 alkyl is
[0067] In yet other embodiments of this aspect, R5 is pyridyl and each R8 is independently halogen, alkyl, -(CH2)nCOOR4, -(CH2)pC(O)NR4OC1-C4alkyl, -(CH2)pC(O)NR4SO2C1-C4alkyl, -(CH2)nC(O)NR4SO2cycloalkyl, -(CH2)nC(O)NR4SO2aryl, -CH=CHC(O)OR4,-CH=CHC(O)NR4SO2C1-C4 alkyl, or -CH=CHC(O)NR4SO2aryl.
[0068] In other embodiments of this aspect for compounds of formula (II), there are two RA on the same carbon forming an oxo and n is 1 or 2, thereby forming a piperdin-2-one or piperdin-2,6-dione. In alternative embodiments for compounds of formula (II), there are two RA groups on different piperidine ring atoms that form a C1-C3 bridge in which one of the carbon atoms of the bridge is optionally substituted by -NH-. Examples of piperidine groups with two RA groups forming a bridge include, but are not limited to, 3-azabicyclo[3.1.1]heptan-3-yl, 1-azabicyclo[2.2.2]octan-3-yl, 1-azabicyclo[2.2.2]octan-4-yl, 1-azabicyclo[3.2.1]octan-6-yl, and 3,7-diazabicyclo[3.3.1]nonanyl.
[0069] In certain embodiments of this aspect, R1 is hydrogen, C1-C4 alkyl or C1-C4 acyl and R2 and R3 are each independently hydrogen, C1 - C4 alkyl, -OR4 or aralkyl, wherein R4 is hydrogen or alkyl. In certain embodiments, R2 is hydroxyl. In certain other embodiments, R2 and R3 are each independently hydrogen, methyl and benzyl. In certain other exemplary embodiments, R4 is hydrogen or methyl.
[0070] In certain other embodiments of this aspect, R1 is hydrogen, L is ethylene, W is-NR4-, R4 is hydrogen, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, morpholinyl, dimethyl-morpholinyl, or thiomorpholinyl.
[0071] In certain other embodiments of this aspect, R1 is methyl, L is ethylene, W is -NR4-, R4 is hydrogen, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, morpholinyl, dimethyl-morpholinyl, or thiomorpholinyl.
[0072] In certain other embodiments of this aspect, R1 is hydrogen, L is ethylene, W is -NR4-, R4 is hydrogen, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is:
[0073] In certain other embodiments of this aspect, R1 is methyl, L is ethylene, W is -NR4-, R4 is hydrogen, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is:
[0074] In certain other embodiments of this aspect, R1 is acyl, L is ethylene, W is -NR4-, R4 is hydrogen, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is:
[0075] In another aspect of the invention, R1 is hydrogen, s and m are each one, R2 is hydroxyl, R3 is hydrogen, W is -NR4-, R4 is hydrogen, R5 is an R8 substituted phenylene, and R8 is heterocyclyl, wherein the heterocyclyl is:
[0076] In certain other embodiments of this aspect, R1 is hydrogen, L is ethylene, W is -NR4-, R4 is hydrogen, R5 is an R8 substituted phenylene, and R8 is heteroaryl, wheherein the heteroaryl is pyridyl, dihydroquinolinone, indolinone, quinazolinyl, quinolinyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrazolyl, 1-methyl-pyrazolyl, 5-methyl-pyrazolyl, thiazolyl, benzo[d]oxazolone, thiazolyl or 5-methyl-thiazolyl.
[0077] In yet another aspect of the invention, R1 is hydrogen, L is ethylene, W is -NR4-, R4 is hydrogen, R5 is an R8 substituted pyridylene, and R8 is heterocyclyl, wherein the heterocyclyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, morpholinyl, dimethyl-morpholinyl, or thiomorpholinyl.
[0078] In certain other embodiments of this aspect, R1 is methyl, L is ethylene, W is -NR4-, R4 is hydrogen, R5 is an R8 substituted pyridylene, and R8 is heterocyclyl, wherein the heterocyclyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, morpholinyl, dimethyl-morpholinyl or thiomorpholinyl.
[0079] In certain other embodiments of this aspect, R1 is hydrogen, L is ethylene, W is-NR4-, R4 is hydrogen, R5 is an R8 substituted pyridylene, and R8 is heterocyclyl, wherein the heterocyclyl is:
[0080] In certain embodiments, compounds of formula (I) and formula (II) wherein W is -NR4- are:
1-anilino-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol;
1-(N-methylanilino)-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol;
1-(2-(phenylamino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-(methyl(phenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((4-bromophenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidm-4-amine;
1-(4-((2-(4-(((lR,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)piperidin-2-one;
3-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-one;
4-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)morpholin-3-one;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-((4-(piperidin-1-yl)phenyl)amino)ethyl)piperidin-4-amine;
1-(2-((4-morpholinophenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)pyrrolidin-2-one;
3-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)oxazolidin-2-one;
1-methyl-3-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)imidazolidin-2-one;
1-(4-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidm-1-yl)ethyl)amino)phenyl)piperazin-1-yl)ethan-1-one;
3-(4-((2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-one;
N,6-dimethyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)pyridin-3-amine;
1-(2-((4-bromophenyl)(methyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
3-(4-(methyl(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-one;
1-methyl-3-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)urea;
N-methyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)acetamide;
N,2-dimethyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)pyridin-4-amine;
1-(2-(4-bromo-2-fluorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
2-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)isonicotinic acid; and
3-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)isonicotinic acid.
and pharmaceutically acceptable salts of the foregoing compounds, including, but not limited to dihydrochloride salts.[0081] In yet another aspect of the invention, compounds of formula (I) and formula (II) are provided wherein Y is -C(O)-, s is 0, m is 0, R2 is C1-C4 alkyl or aralkyl, and R6 is heterocyclyl, wherein the heterocyclyl is piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, morpholinyl dimethyl-morpholinyl, or thiomorpholinyl. In certain embodiments of this aspect, Y is -C(O)-, s is 0, m is 0, R2 is methyl, and R6 is piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, morpholinyl, dimethyl-morpholinyl or thiomorpholinyl. In certain other embodiments of this aspect, Y is -C(O)-, s is 0, m is 0, R2 is benzyl, and R6 is piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, morpholinyl, dimethyl-morpholinyl or thiomorpholinyl.
[0082] In yet another aspect of the invention, compounds of formula (I) and formula (II) are provided wherein Y is -C(O)-, L is ethylene, and R6 is heterocyclyl optionally independently substituted one or more C1-C3 alkyl. In certain embodiments, the heterocyclyl optionally independently substituted one or more C1-C3 alkyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, morpholinyl, dimethyl-morpholinyl, thiomorpholinyl, 1,4-dithianyl, or 1,3,5-trithianyl. In other embodiments, the heterocyclyl is:
[0083] In yet another aspect of the invention, compounds of formula (I) and formula (II) are provided wherein Y is -C(O)-, L is propylene, and R6 is heterocyclyl optionally independently substituted one or more C1-C3 alkyl. In certain embodiments, the heterocyclyl optionally independently substituted one or more C1-C3 alkyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, morpholinyl, dimethyl-morpholinyl, thiomorpholinyl, 1,4-dithianyl, or 1,3,5-trithianyl. In other embodiments, the heterocyclyl is:
In other embodiments of this aspect, R6 is -NR4R7. In certain embodiments, R7 is hydroxyl, alkoxy, -SO2C1-C6alkyl; -SO2cycloalkyl, or -SO2aryl, wherein the cycloalkyl or aryl of each of the -SO2cycloalkyl and -SO2aryl is optionally independently substituted with one or more R8.
[0084] In certain embodiments, compounds of the invention wherein Y is -C(O)- are:
1-morpholino-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one;
N-methoxy-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamide;
1-morpholino-3-phenyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one;
3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanoic acid;
1-morpholino-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one;
N-(methylsulfonyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamide;
3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-(piperazin-1-yl)propan-1-one;
3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-N-(phenylsulfonyl)propanamide;
1-(4-methylpiperazin-l-yl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one;
N-(ethylsulfonyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamide;
3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-thiomorpholinopropan-1-one;
1-(4-methylpiperazin-1-yl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butan-1-one;
4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-(piperazin-1-yl)butan-1-one;
1-morpholino-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butan-1-one;
4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-N-(phenylsulfonyl)butanamide;
4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanoic acid;
N-(cyclopropylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamide;
N-(ethylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamide;
N-(methylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamide;
1-(cis-2,6-dimethylmorpholino)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one;
and pharmaceutically acceptable salts of the foregoing compounds, including, but not limited to, dihydrochloride salts.[0085] In still yet another aspect of the invention, Y is -NR4SO2- and R6 is C1-C6 alkyl, cycloalkyl or aryl, wherein the cycloalkyl or the aryl is optionally independently substituted with one or more C1-C3 alkyl, halogen, haloalkyl, amino or cyano.
[0086] In certain embodiments, compounds of formula (I) and formula (II) wherein Y is-NR4SO2- are:
N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)methanesulfonamide;
N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)benzenesulfonamide;
N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)propane-2-sulfonamide;
N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propyl) methanesulfonamide;
N-methyl-N-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)methanesulfonamide;
N-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)methanesulfonamide;
N-methyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)methanesulfonamide; and
N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)cyclopropanesulfonamide;
and pharmaceutically acceptable salts of the foregoing compounds, including, but not limited to, dihydrochloride salts.[0087] In another aspect of the invention, Y is -SO2NR4- and R6 is C1-C6 alkyl or aryl, wherein the aryl is optionally independently substituted with one or more C1-C3 alkyl, halogen, haloalkyl, amino or cyano.
[0088] In certain embodiments of this aspect of the invention, compounds of formula (I) and formula (II) wherein Y is -SO2NR4- are
N-phenyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethane-1-sulfonamide;
N-methyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethane-1-sulfonamide;
and pharmaceutically acceptable salts of the foregoing compounds, including, but not limited to, dihydrochloride salts.[0089] In still yet another aspect of the invention, Y is -NR4C(O)NR4R4 and each R4 is C1-C3 alkyl. An exemplary compound wherein Y is -NR4C(O)NR4R4 is 1,1-dimethyl-3-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)urea.
[0090] The compounds of formula (I) and formula (II) may be formulated into pharmaceutical compositions.
PHARMACEUTICAL COMPOSITIONS
[0091] In another aspect, the invention provides pharmaceutical compositions comprising a LSD1 inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be by the oral route.
[0092] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
[0093] As used herein, the term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
[0094] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
[0095] The pharmaceutical compositions comprising compounds of the present invention may be used in the methods described herein.
METHODS OF USE
[0096] In yet another aspect, the invention describes methods for inhibiting LSD1 activity in a cell, comprising contacting the cell in which inhibition of LSD1 activity is desired with a therapeutically effective amount of a compound of formula (I), pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof.
[0097] The compositions and methods provided herein are particularly deemed useful for inhibiting LSD1 activity in a cell. In one embodiment, a cell in which inhibition of LSD1 activity is desired is contacted with a therapeutically effective amount of a compound of formula (I) to negatively modulate the activity of LSD1. In other embodiments, a therapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing the compound of formula (I) may be used.
[0098] By negatively modulating the activity of LSD1, particularly in cases for cells overexpressing the LSD1 enzyme or somatic mutations that activate the LSD1 enzyme, the methods are designed to restore normal cellular transcription expression patterns, e.g., by altering methylation pattern of H3K4, to inhibition undesired cellular proliferation resulting from enhanced LSD1 activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of LSD1. The degree of mono- and dimethylation of histone H3K4 may be monitored in the cell using well known methods, including those described in Example 83 below, to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.
[0099] In another aspect, methods of treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of formula (I), pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are described.
[0100] The compositions and methods provided herein may be used for the treatment of a wide variety of cancer including tumors such as prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.
[0101] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. The degree of mono- and dimethylation of histone H3K4 may be monitored in the patient using well known methods, including those described in Example 83 below, to access the effectiveness of treatment, along with other prognostic or biological factors, and dosages may be adjusted accordingly by the attending medical practitioner.
REACTION SCHEMES AND EXAMPLES
[0102] The compounds of the present invention may be prepared using commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art.
[0103] For instance, compounds of the present invention may be prepared according to the general reaction schemes I - V.
[0104] Schemes Ia and Ib illustrate preparation of compounds of formula (I) or formula (II), respectively, wherein W is NR4 or O, (or Y is S, SO, or SO2) and L is an epichlorohydrin derivative. The epichlorihydrin A undergoes substitution with nucleophile W-R5 to afford intermediate B (Step 1). The substitution proceeds in solvents such as MeCN in the presence of a base such as K2CO3, typically at an elevated temperature. In the case where Y is SO or SO2, the initial substitution with a nucleophile of the form R6SH will be followed by oxidation to the sulfoxide or sulfone derivative yielding Y-R6. Reaction of B with amines C affords compounds D (Step 2). The epoxide ring opening also typically proceeds under conditions similar to Step 1. Removal of the protecting group in Step 3 to afford compounds E typically proceeds with an acid such as TFA in a solvent such as DCM.
[0105] Schemes IIa and IIb illustrate preparation of compounds of formula (I) and formula (II), respectively, wherein W is NR4 or O, (or Y is S, SO or SO2), and L is an alkyl derivative. Reagent F undergoes substitution with nucleophile W-R5 to afford intermediate G (Step 1). The substitution proceeds in solvents such as acetone in the presence of a base such as K2CO3. In the case where Y is SO or SO2, the initial substitution with a nucleophile of the form R6SH will be followed by oxidation to the sulfoxide or sulfone derivative yielding Y-R6. Reaction of G with amines C affords compounds H (Step 2). This substitution typically proceeds under conditions similar to Step 1. Alternative bases and solvents such as Cs2CO3 and MeCN may also be effective. Removal of the protecting group in Step 3 to afford compounds I typically proceeds with an acid such as TFA in a solvent such as DCM.
[0106] Scheme IIIa and Scheme IIIb illustrate preparation of compounds of formula (I) and formula (II), respectively, wherein Y is NR4SO2 or NR4C(O). Intermediate C undergoes alkylation with a nitrile derivative, which is subsequently reduced to afford free amines J. In one case, alkylation with, for example, chloromethyl acetonitrile in a solvent such as acetone with a base such as K2CO3 would afford an intermediate that could be reduced to give the amine where L is -CH2CH2-. Alternatively, amines J could arise from the alkylation of intermediates C with a protected amine derivative. Functionalization of amines J would give rise to derivatives K, which would give targets L upon deprotection. The functionalization of K would proceed, for example, by reaction with sulfonyl or acyl chlorides. Removal of the Boc protecting group in the final step proceeds with acids such as TFA in solvents such as DCM.
[0107] Schemes IVa and IVb illustrate preparation of compounds of formula (I) and formula (II), respectively, wherein Y is SO2NR4. Intermediate C undergoes addition, for example with a vinyl sulfonamide derivative M, to afford compounds N. Removal of the Boc protecting group in the final step proceeds with acids such as TFA in solvents such as DCM to afford derivatives O.
[0108] Schemes Va and Vb illustrate preparation of compounds of formula (I) and formula (II), respectively, wherein Y is -CO-. Intermediate C is alkylated with a halogen derivative P and the ester is cleaved to afford carboxylic acids S. This substitution proceeds in a solvent such as DMF with a base such as TEA and potassium iodide. Removal of the ester group occurs with a base such as NaOH in a solvent such as THF. Amide bond formation with a species R6 followed by removal of the protecting group affords compounds T. The amidation using R6 reaction proceeds, for example, in dichloromethane with EDC/HOBt. Removal of the Boc group proceeds, for example, with a dilute solution of HCl in dioxane.
[0109] The following Examples are intended to illustrate further certain embodiments of the invention.
EXAMPLE 1
1-phenoxy-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol (5)
Step 1. 2-(phenoxymethyl)oxirane (2)
[0111] A solution of 2-(chloromethyl)oxirane (3.93 g, 42.5 mmol, 3.33 mL, 2.00 eq), phenol (2.00 g, 21.3 mmol, 1.87 mL, 1.00 eq) and K2CO3 (8.81 g, 63.8 mmol, 3.00 eq) in MeCN (40.0 mL) was stirred at 80 °C for 12 hours. After completion, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: PE/EA 25/1) to give 2-(phenoxymethyl)oxirane (2.20 g, 13.9 mmol, 65.5 % yield, 95.0 % purity) as a colorless oil. LCMS [M+41+1]: 192.
1H NMR (400MHz, methanol-d4) δ = 7.27 - 7.23 (m, 2H), 6.94 - 6.91 (m, 3H), 4.28 - 4.25 (dd, J=11.2, 2.4 Hz, 1H), 3.86 - 3.81 (dd, J=11.2, 6.0 Hz, 1H), 3.32 - 3.30 (m, 1H), 2.86 - 2.83 (dd, J=5.2, 4.4 Hz, 1H), 2.72 - 2.71 (dd, J=5.2, 2.8 Hz, 1H).
Step 2. tert-butyl (1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl)-N-(trans-2-phenylcyclopropyl)carbamate (4)
[0112] A suspension of 2-(phenoxymethyl)oxirane (200 mg, 1.33 mmol, 1.00 eq), tert-butyl N-[trans-2-phenylcyclopropyl]-N-(4-piperidyl) carbamate (421 mg, 1.33 mmol, 1.00 eq) and K2CO3 (368 mg, 2.66 mmol, 2.00 eq) in MeCN (5.00 mL) was stirred at 80 °C for 14 hours. After completion, the mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE/EA 1/0 to 5/1) to give tert-Butyl N-[1-(2-hydroxy-3-phenoxy-propyl)-4-piperidyl]-N-[trans-2-phenylcyclo propyl]carbamate (400 mg, 857 umol, 64.5 % yield) as colorless oil. LCMS [M+1]: 467.
1H NMR (400MHz, chloroform-d) δ = 7.32 - 7.27 (m, 4H), 7.22 - 7.18 (m, 1H), 7.11 - 7.09 (m, 2H), 6.95 - 6.93 (m, 3H), 4.08 - 4.06 (m, 1H), 4.00 - 3.98 (m, 2H), 3.74 - 3.71 (m, 1H), 3.09 - 2.92 (m, 2H), 2.59 - 2.52 (m, 3H), 2.39 (m, 1H), 2.14 - 2.13 (m, 2H), 2.08 - 2.06 (m, 2H), 1.82 - 1.74 (m, 2H), 1.45 (m, 9H), 1.42 - 1.40 (m, 1H), 1.27 - 1.16(s, 1H)
Step 3. 1-phenoxy-3-(4-(((trans)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol (5)
[0113] A solution of tert-butyl N-[1-(2-hydroxy-3-phenoxy-propyl)-4-piperidyl]-N-[trans-2-phenylcyclopropyl]carbamate (150 mg, 321 umol, 1.00 eq) and TFA (366 mg, 3.21 mmol, 238 uL, 10.0 eq) in DCM (5.00 mL) was stirred at 28 °C for 1 hour. After completion, saturated NaHCO3 (10 mL) was added into the mixture. The mixture was extracted with DCM (3 × 20mL), the combined organic phase was concentrated under vacuum. The residue was purified by Prep-HPLC (Instrument: GX-A; Column: PhenomenexGemini 150∗25mm∗10um; Condition: water (0.05% ammonia hydroxide v/v)-ACN; Begin B: 55; End B: 85; Gradient Time (min): 12; 100%B Hold Time (min): 2; FlowRate(ml/min): 25). 1-phenoxy-3-(4-(((trans)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol (5) (51.0 mg, 139 umol, 43.3 % yield) was obtained as yellow oil. LCMS [M+1]: 367
1H NMR (400MHz, methanol-d4) δ = 7.27 - 7.21 (m, 4H), 7.14 - 7.12 (m, 1H), 7.05 - 7.03 (m, 2H), 6.94 - 6.92 (m, 3H), 4.13 (m, 1H), 4.12 - 3.91 (m, 2H), 3.07 (m, 2H), 2.65 - 2.60 (m, 3H), 2.33 - 2.31 (m, 3H), 1.95 - 1.90 (m, 3H), 1.55 - 1.52 (m, 2H), 1.09 - 1.03 (m, 2H).
EXAMPLE 2
1-(2-methoxy-3-phenoxy-propyl)-N-[trans-2-phenylcyclopropyl]piperidin-4-amine (7)
Step 1. tert-butyl N-[1-(2-methoxy-3-phenoxy-propyl)-4-piperidyl]-N-[trans- 2-phenylcyclopropyl]carbamate (6)
[0115] To a solution of 4 (150 mg, 321 umol, 1.00 eq) in THF (5.00 mL) was added NaH (15.4 mg, 6.4 mmol, 2.00 eq) at 0 °C. After stirring for 1 hour, MeI (2.41 g, 17.0 mmol, 1.06 mL, 52.8 eq) was added at 0 °C. The mixture was stirred at 28 °C for 2 hours. After completion, the mixture was poured into saturated NH4Cl aq (20 mL), extracted with DCM (3 × 30 mL), and the combined organic phase was concentrated under vacuum. The residue was purified by Prep-TLC (PE/EA 2/1, Rf =0.8). tert-butyl N-[1-(2-methoxy-3-phenoxy-propyl)-4-piperidyl]-N-[trans- 2-phenylcyclopropyl]carbamate (90.0 mg, 180 umol, 56.1 % yield, 96.2 % purity) was obtained as a yellow oil. LCMS [M+1]: 481
1H NMR (400MHz, methanol-d4) δ = 7.27 - 7.22 (m, 4H), 7.12 - 7.10 (m, 3H), 6.95 - 6.92 (m, 3H), 4.09 - 4.08 (m, 1H), 4.03 - 3.99 (m, 1H), 3.75 - 3.70 (m, 2H), 3.48 (s, 3H), 3.20 - 3.02 (m, 2H), 2.68 - 2.60 (m, 3H), 2.28 - 2.08 (m, 5H), 1.75 (m, 2H), 1.42 - 1.39 (m, 10H), 1.29 - 1.24 (m, 1H).
Step 2. 1-(2-methoxy-3-phenoxy-propyl)-N-[trans-2-phenylcyclopropyl]piperidin-4-amine (7)
[0116] Treatment of compound 6 with TFA in a manner similar to Example 1 afforded the title compound as a yellow oil (66.0 mg, 160 umol, 85.2 % yield, 92 % purity). LCMS [M+1]: 381
1H NMR (400MHz, methanol-d4) δ = 7.28 - 7.22 (m, 4H), 7.15 - 7.09 (m, 1H), 7.05 - 7.03 (m, 2H), 6.94 - 6.91 (m, 3H), 4.11 - 4.07 (m, 1H), 4.02 - 3.98 (m, 1H), 3.77 (m, 1H), 3.48 - 3.47 (m, 3H), 3.05 (m, 2H), 2.68 - 2.66 (m, 3H), 2.35 - 2.27 (m, 3H), 1.95 - 1.91 (m, 3H), 1.63 - 1.44 (m, 2H), 1.09 - 1.03 (m, 2H).
EXAMPLE 3
1-anilino-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl] propan-2-ol (10)
Step 1. N-(oxiran-2-ylmethyl)aniline (8)
[0119] After completion, the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC (Instrument: HPLC-D; Column: Phenomenex Synergi Max-RP 250∗80 10u; Condition: water (0.1%TFA)-ACN; Begin B: 0; End B: 25%ACN; Gradient Time (min): 37MIN; 52%; FlowRate(ml/min): 80). Compound 8 (800 mg, 3.22 mmol, 15.0 % yield, 60.0 % purity) was obtained as colorless oil. LCMS [M+1]: 150.
1H NMR (400MHz, methanol-d4) δ = 7.36 - 7.07 (m, 1H), 6.65 - 6.60 (m, 1H), 3.42 - 3.39 (m, 1H), 3.16 - 3.13 (m, 2H), 2.77 - 2.75 (m, 1H), 2.63 - 2.61 (m, 1H)
Step 2. tert-butyl N-[1-(3-anilino-2-hydroxy-propyl)-4-piperidyl]-N-[trans-2-phenylcyclopropyl]carbamate (9)
[0120] After completion, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: PE/EA 1/0 to 5/1). Compound 9 (250 mg, 537 umol, 53.2 % yield) was obtained as colorless oil. LCMS [M+1]: 466.
1H NMR (400MHz, methanol-d4) δ = 7.29 - 7.20 (m, 2H), 7.22 - 7.09 (m, 5H), 6.66 - 6.61 (m, 3H), 4.15 - 4.13 (m, 1H), 3.96 - 3.71 (m, 2H), 3.18 - 3.06 (m, 4H), 2.63 - 2.60 (m, 3H), 2.39 - 2.18 (m, 2H), 2.13 - 2.09 (m, 2H), 1.76 (m, 2H), 1.42 - 1.37 (m, 10H), 1.26 - 1.23 (m, 1H).
Step 3. 1-anilino-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl] propan-2-ol (10)
[0121] After completion, saturated NaHCO3 (10 mL) was added into the mixture. The mixture was extracted with DCM (3 × 20mL), the combined organic phase was concentrated under vacuum. The residue was purified by Prep-HPLC (Instrument: GX-I; Column: YMC-ActusODS-AQ 150∗30 5u; Condition: water (0.1%TFA)-ACN; Begin B: 8; End B: 38; Gradient Time (min): 11; 100%B Hold Time (min): 2; FlowRate (ml/min): 25). Compound 10 (83.0 mg, 189 umol, 35.3 % yield, 2HCl) was obtained as yellow oil. LCMS [M+1]: 366.
1H NMR (400MHz, methanol-d4) δ = 7.31 (m, 2H), 7.25 - 7.23 (m, 1H), 7.18 - 7.14 (m, 4H), 6.76 - 6.71 (m, 3H), 4.25 - 4.23 (dd, J=10.4, 3.2 Hz, 1H), 3.81 - 3.77 (m, 2H), 3.67 (m, 1H), 3.35 (m, 1H), 3.25 - 3.19 (m, 5H), 3.00 - 2.99 (m, 1H), 2.49 - 2.39 (m, 3H), 2.11 (m, 2H), 1.55 - 1.51 (m, 1H), 1.47 - 1.43 (m, 1H)
EXAMPLE 4
1-(N-methylanilino)-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol
Step 1. N-methyl-N-(oxiran-2-ylmethyl)aniline (11).
[0124] After completion, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by Prep-HPLC (Instrument: SFC-A; Column: Daiso 250∗50mm, 10um; Condition: water (0.1%TFA)-ACN; Begin B: 0%ACN; End B: 20%ACN; Gradient Time (min): 34MIN; 40%; FlowRate (ml/min): 80). Compound 11 (300 mg, 1.58 mmol, 8.47 % yield, 86.0 % purity) was obtained as a colorless oil.
1H NMR (400MHz, methanol-d4) δ = 7.22 - 7.17 (m, 2H), 6.81 - 6.79 (d, J=8.0 Hz, 2H), 6.70 - 6.67 (m, 1H), 3.70 - 3.66 (m, 1H), 3.36 - 3.31 (m, 2H), 2.97 (s, 3H), 2.77 - 2.75 (m, 1H), 2.56 - 2.54 (m, 1H).
Step 2. tert-butyl N-[1-[2-hydroxy-3-(N-methylanilino)propyl]-4-piperidyl]-N-[trans-2-phenylcyclopropyl]carbamate (12)
[0125] After completion, the mixture was cooled to 28 °C, the precipitate was filtered off. The filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (PE/EA 2/1, PI: Rf=0.6) Compound 12 (200 mg, 414 umol, 45.0 % yield, 99.2 % purity) was obtained as yellow oil. LCMS [M+1]: 480.
1H NMR (400MHz, methanol-d4) δ = 7.26 - 7.22 (m, 2H), 7.16 - 7.10 (m, 5H), 6.78 - 6.76 (m, 2H), 6.65 (m, 1H), 4.13 (br. s., 1H), 3.76 - 3.75 (m, 1H), 3.39 - 3.31 (m, 4H), 2.99 (s,, 3H), 2.67 - 2.64 (m, 5H), 2.13 - 2.11 (m, 3H), 1.90 - 1.83 (m, 2H), 1.42 - 1.37 (m, 10H), 1.24 - 1.22 (m, 1H)
[0126] After completion, the mixture was poured into saturated NaHCO3 aq (20.0 mL), then extracted with DCM (2 × 30.0 mL). The combined organic phase was concentrated under vacuum. The residue was purified by Prep-TLC (eluent: DCM/MeOH 20/1). Compound 13 (60.0 mg, 148 umol, 35.6 % yield, 93.8 % purity) was obtained as yellow oil. LCMS [M+1]: 380.
1H NMR (400MHz, methanol-d4) δ = 7.22 - 7.20 (m, 2H), 7.16 - 7.12 (m, 3H), 7.05 - 7.03 (m, 2H), 6.77 - 6.75 (d, J=8.8 Hz, 2H), 6.64 - 6.63 (m, 1H), 4.08 - 4.05 (m, 1H), 3.44 (m, 1H), 3.27 (m, 1H), 3.15 - 3.02 (m, 2H), 2.98 (s, 3H), 2.78 - 2.67 (m, 1H), 2.57 - 2.53 (m, 2H), 2.33 - 2.31 (m, 3H), 2.98 - 1.90 (m, 3H), 1.54 (m, 2H), 1.09 - 1.03 (m, 2H).
EXAMPLE 5
2-methyl-1-phenoxy-3-(4-(((trans)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol (16)
Step 1. tert-butyl N-[1-(2-oxo-3-phenoxy-propyl)-4-piperidyl]-N-[(trans)-2-phenylcyclopropyl]carbamate (14).
[0128] To a solution of oxalyl chloride (212 mg, 1.67 mmol, 146 uL, 3.00 eq) in DCM (0.5 mL) was added DMSO (304 mg, 3.90 mmol, 304 uL, 7.00 eq) in DCM (0.5 mL), followed by tert-butyl N-[1-(2-hydroxy-3-phenoxy-propyl)-4-piperidyl]-N-[(trans)-2-phenylcyclopropyl]carbamate (260 mg, 557.21 umol, 1.00 eq) in DCM (1 mL), then the mixture was stirred at -70 °C for 1.5 hours. A solution of TEA (845 mg, 8.36 mmol, 1.16 mL, 15.00 eq) in DCM (0.5 mL) was added to the solution at -70 °C, which was stirred at -70 ∼ -15 °C for 30 min. After completion, the mixture was quenched with water (10 mL), extracted with DCM (2 x 10 mL), the combined organic phase were washed with 1 N HCl (10 mL), saturated NaHCO3 aqueous (10 mL), brine (10 mL), dried and concentrated to get the crude product. Compound tert-butyl N-[1-(2-oxo-3-phenoxy-propyl)-4-piperidyl]-N-[(trans)-2-phenylcyclopropyl]carbamate (240 mg, 479 umol, 86.12% yield, 92.9% purity) was obtained as a yellow solid. LCMS [M+1]: 465.4.
Step 2. tert-butyl N-[1-(2-hydroxy-2-methyl-3-phenoxy-propyl)-4-piperidyl]-N-[(1S,2R)-2-phenylcyclopropyl]carbamate (15).
[0129] To a solution of tert-butyl N-[1-(2-oxo-3-phenoxy-propyl)-4-piperidyl]-N-[(trans)-2-phenylcyclopropyl]carbamate (240 mg, 516 umol, 1.00 eq) in THF (3.00 mL) was added CH3MgBr (3 M, 344 uL, 2.00 eq) dropwise at 0 °C, then the mixture was stirred at 0 ∼ 20 °C for 3 hours . After completion, the mixture was quenched with water (5 mL), diluted with EA (20 mL), washed with saturated NaHCO3 aq (10 mL), brine (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. Compound 15 (240 mg, 499 umol, 96% yield) was obtained as a yellow solid which was used for the next step directly without further purification. LCMS [M+1]: 481.2.
Step 3. 2-methyl-1-phenoxy-3-[4-[[(1S,2R)-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol (16).
[0130] To a mixture of tert-butyl N-[1-(2-hydroxy-2-methyl-3-phenoxy-propyl)-4-piperidyl]-N-[(trans)-2-phenylcyclopropyl]carbamate (240 mg, 499 umol, 1.00 eq) in DCM (4.00 mL) was added TFA (569 mg, 4.99 mmol, 369 uL, 10.0 eq) in one portion at 20 °C, then the mixture was stirred at the same temperature for 1 hour. After completion, saturated NaHCO3 aq (20 mL) was added into the mixture, the mixture was extracted with DCM (3 × 20 mL). The combined organic phase was washed with brine, dried and concentrated under vacuum. The residue was purified by prep-HPLC (Instrument: GX-D; Column: Boston Green ODS 150∗30 5u; Condition: water (0.225%FA)-ACN; Begin B: 6; End B: 36, Gradient Time (min): 11; 100%B Hold Time (min): 4; FlowRate (ml/min): 25) to give 16 as a colorless solid. LCMS [M+1]: 381.1.
1H NMR (400 MHz, METHANOL-d4) δ = 7.28 - 7.21 (m, 4H), 7.11 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 7.2 Hz, 2H), 6.93 - 6.90 (m, 3H), 3.86 - 3.84 (d, J = 7.2 Hz, 1H), 3.80 - 3.78 (d, J = 9.2 Hz, 1H), 2.95 - 2.88 (m, 2H), 2.58 - 2.54 (m, 1H), 2.49 (s, 2H), 2.29 - 2.22 (m., 3H), 1.89 - 1.79 (m, 3H), 1.46 - 1.40 (m, 2H), 1.25 (s, 3H), 1.07 - 0.97 (m, 3H)
EXAMPLE 6
1-phenoxy-3-[3-[[[(trans)-2-phenylcyclopropyl]amino]methyl]azetidin-1-yl]propan-2-ol (19)
Step 1. tert-butyl N-[[1-(2-hydroxy-3-phenoxy-propyl)azetidin-3-yl]methyl]-N-[(trans)-2-phenylcyclopropyl]carbamate (18).
[0132] To a solution of tert-butyl N-(azetidin-3-ylmethyl)-N-[(trans)-2-phenylcyclopropyl]carbamate (100 mg, 331 umol, 1.00 eq) in MeCN (3.00 mL) was added 2-(phenoxymethyl)oxirane 2 (74.5 mg, 496 umol, 67.1 uL, 1.50 eq) and K2CO3 (45.7 mg, 331 umol, 1.00 eq). The mixture was stirred at 80 °C for 12 hours. After completion, the mixture was filtered and the filtrate was concentrated under vacuum. Water (10 mL) and HCl (1M, 1 mL) was added into the mixture. The resulting mixture was extracted with DCM (3 × 20 mL), the combined organic phase was concentrated under vacuum to give compound 18 (200 mg, crude) was obtained as yellow oil. The crude was used to the next step directly. LCMS [M+1]: 453.
Step 2. 1-phenoxy-3-[3-[[[(trans)-2-phenylgyclopropyl]amino]methyl]azetidin-1-yl]propan-2-ol (19).
[0133] A solution of tert-butyl N-[[1-(2-hydroxy-3-phenoxy-propyl)azetidin-3-yl]methyl]-N-[(trans)-2-phenylcyclopropyl]carbamate (200mg, 442 umol, 1.00 eq) and TFA (50.4 mg, 442 umol, 32.7 uL, 1.00 eq) in DCM (3.00 mL) was stirred at 20 °C for 1 hour. After completion, saturated NaHCO3 aq (10 mL) was added into the mixture, the mixture was extracted with DCM (3 × 20 mL). The combined organic phase was concentrated under vacuum. The residue was purified by Prep-HPLC (Instrument: GX-D; Column: Boston Green ODS 150∗30 5u; Condition: water (0.225%FA)-ACN; Begin B: 6; End B: 36, Gradient Time (min): 11; 100%B Hold Time (min): 4; FlowRate (ml/min): 25) to give 1-phenoxy-3-[3-[[[(trans)-2-phenylcyclopropyl]amino] methyl]azetidin-1-yl]propan-2-ol (25.0 mg, 71.0 umol, 16.1 % yield) as yellow solid. LCMS [M+1]: 353.
1H NMR (400 MHz, methanol-d4) δ = 8.33 (br. s, 1H), 7.30 - 7.22 (m, 4H), 7.13 (m, 1H), 7.08 - 7.06 (m, 2H), 6.95 - 6.93 (m, 3H), 4.24 (br. s., 2H), 4.14 (br. s., 1H), 4.01 - 3.95 (m, 4H), 3.52 - 3.32 (m, 2H), 3.13 - 3.07 (m, 3H), 2.42 (br. s., 1H), 1.99 (br. s., 1H), 1.15 - 1.07 (m, 2H)
EXAMPLE 7
(R)-1-phenoxy-3-(4-(((1S,2R)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol (23)
Step 1. (2R)-2-(phenoxymethyl)oxirane (21).
[0135] To a solution of phenol (1.00 g, 10.6 mmol, 935 uL, 1.00 eq) in CH3CN (20.0 mL) was added K2CO3 (4.41 g, 31.9 mmol, 3.00 eq) in one portion at 20 °C, followed by (2R)-2-(chloromethyl)oxirane (1.97 g, 21.26 mmol, 1.67 mL, 2.00 eq), then the mixture was heated to 70∼80 °C and stirred for 8 hours. After completion, the mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product which was purified over column chromaotograph (PE/EA=50:1∼20:1). Compound (2R)-2-(phenoxymethyl)oxirane (1.12 g, 7.35 mmol, 69% yield, 98.5% purity) was obtained as colorless oil.
Step 2. N-[1-[(2R)-2-hydroxy-3-phenoxy-propyl]-4-piperidyl]-N-[(trans)-2-phenylcyclopropyl]carbamate (22).
[0136] To a solution of (2R)-2-(phenoxymethyl)oxirane (100 mg, 666 umol, 1.00 eq) and tert-butyl N-[(trans)-2-phenylcyclopropyl]-N-(4-piperidyl)carbamate (211 mg, 666 umol, 1.00 eq) in CH3CN (5.0 mL) was added K2CO3 (184 mg, 1.33 mmol, 2.00 eq) in one portion at 20 °C, then the mixture was heated to 80 °C and stirred for 18 hours. After completion, the mixture was filtered, and the filtration was concentrated to give the crude product which was purified over column chromatography (PE/EA=5:1∼2:1). Compound 22 (200 mg, 407 umol, 61% yield) was obtained as colorless oil. LCMS [M+1]: 467.2.
Step 3. (2R)-1-phenoxy-3-[4-[[(trans)-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol (23).
[0137] To a mixture of 22 (200 mg, 428 umol, 1.00 eq) in DCM (4.00 mL) was added TFA (831 mg, 7.28 mmol, 540 uL, 10.0 eq) in one portion at 20 °C, then the mixture was stirred at the same temperature for 1 hour. After completion, saturated NaHCO3 aq (20 mL) was added into the mixture, the mixture was extracted with DCM (3 × 20 mL). The combined organic phase was washed with brine, dried and concentrated under vacuum. The residue was purified by prep-HPLC (Instrument: GX-D; Column: Boston Green ODS 150∗30 5u; Condition: water (0.225%FA)-ACN; Begin B: 6; End B: 36, Gradient Time (min): 11; 100%B Hold Time (min): 4; FlowRate (ml/min): 25) to give (2R)-1-phenoxy-3-[4-[[(trans)-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol 23 (90.8 mg, 185 umol, 43.2 % yield, 98.0% purity) as a yellow solid. LCMS [M+1]: 367.1.
1H NMR (400 MHz, DMSO-d6) δ = 7.30 - 7.22 (m, 4H), 7.20 - 7.11 (m, 1H), 7.03 - 7.01 (m, 2H), 6.94 - 6.92 (d, J =7.8 Hz, 3H), 4.78 - 4.77 (d, 1H), 3.97 - 3.94 (m, 1H), 3.93 - 3.87 (m, 1H), 3.85 - 3.81 (m, 1H), 2.90 - 2.72 (m, 2H), 2.45 - 2.36 (m, 1H), 2.34 (br. s., 2H), 2.24 - 2.16 (m, 1H), 2.08 - 1.94 (m, 2H), 1.82 - 1.67 (m, 3H), 1.41 - 1.19 (m, 2H), 0.96 - 0.92 (m, 2H).
EXAMPLE 8
(S)-1-phenoxy-3-(4-(((1S,2R)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol (27)
Step 1. (2S)-2-(phenoxymethyl)oxirane (25).
[0140] After completion, the mixture was filtered and the filtrate was concentrated to give the crude product which was purified over column chromaotograph (PE/EA=50:1∼20:1). Compound 25 (1.12 g, 7.35 mmol, 69% yield, 98.5% purity) was obtained as colorless oil. LCMS [M+1]: 150.
Step 2. tert-butyl N-[1-[(2S)-2-hydroxy-3-phenoxy-propyl]-4-piperidyl]-N-[(trans)-2-phenylcyclopropyl]carbamate (26).
Step 3. (2S)-1-phenoxy-3-[4-[[(trans)-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol (27)
[0142] The residue was purified by prep-HPLC (Instrument: GX-D; Column: Boston Green ODS 150∗30 5u; Condition: water (0.225%FA)-ACN; Begin B: 6; End B: 36, Gradient Time (min): 11; 100%B Hold Time (min): 4; FlowRate (ml/min): 25) to give (2S)-1-phenoxy-3-[4-[[(trans)-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol (27) (179 mg, 371 umol, 51% yield, 99.7% purity) as a yellow solid. LCMS [M+1]: 367.
1H NMR (400 MHz, DMSO-d6) δ =7.30 - 7.20 (m, 4H),7.12 - 7.08 (m, 1H), 7.03 - 7.01 (m, 2H), 6.94 - 6.92 (d, J = 7.6 Hz, 3H), 4.79 - 4.78 (m, 1H), 3.99 - 3.93 (m, 1H), 3.93 - 3.87 (m, 1H), 3.86 - 3.80 (m, 1H), 2.90 - 2.72 (m, 2H), 2.45 - 2.36 (m, 1H), 2.34 (br. s., 2H), 2.24 - 2.16 (m, 1H), 2.08 - 1.94 (m, 2H), 1.82 - 1.67 (m, 3H), 1.33 - 1.25 (m, 2H), 0.95 - 0.93 (m, 2H)
EXAMPLE 9
1-phenoxy-3-[(1R,5S)-6-[[(trans)-2-phenylcyclopropyl]amino]-3-azabicyclo[3.1.1]heptan-3-yl]propan-2-ol (31).
Step 1. tert-butyl N-[(5S)-3-benzyl-3-azabicyclo[3.1.1]heptan-6-yl]-N-[(trans)-2-phenylcyclopropyl]carbamate (29).
[0144] To a solution of 3-benzyl-N-(2-phenylcyclopropyl)-3-azabicyclo[3.1.1]heptan-6-amine (50.0 mg, 157 umol, 1.00 eq) in MeOH (2.00 mL) was added (Boc)2O (343 mg, 1.57 mmol, 361 uL, 10.0 eq). The mixture was stirred at 50 °C for 15 hours. After completion, the mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (PE/EA from 100/1 to 5/1) to give tert-butyl N-[(5S)-3-benzyl-3-azabicyclo[3.1.1]heptan-6-yl]-N-[(trans)-2 -phenylcyclopropyl]carbamate 29 (50.0 mg, 119 umol, 76.1 % yield) as yellow oil. LCMS [M+1]: 419.
Step 2. (5S)-N-[(trans)-2-phenylcyclopropyl]-3-azabicyclo[3.1.1]heptan-6-amine (30).
[0145] To a solution of 29 (50.0 mg, 119 umol, 1.00 eq) and K2CO3 (144 mg, 1.43 mmol, 12.0 eq) in DCM (3.00 mL) was added 1-chloroethyl chloroformate (51.2 mg, 358 umol, 3.00 eq). After stirring at 20 °C for 1.5 hours, the reaction mixture was filtered. The filtrate was concentrated under vacuum. The residue was dissolved in MeOH (3.00 mL). The solution was refluxed (65 °C) for 2 hour. After completion, the mixture was filtered and concentrated under vacuum to give (5S)-N-[(trans)-2-phenylcyclopropyl]-3-azabicyclo[3.1.1]heptan-6-amine 30 (27.0 mg, crude) as yellow oil. The crude material was used to the next step directly.
Step 3. 1-phenoxy-3-[(1R,5S)-6-[[(trans)-2-phenylcyclopropyl]amino]-3-azabicyclo[3.1.1]heptan-3-yl]propan-2-ol (31).
[0146] A mixture of 30 (27.0 mg, 118. umol, 1.00 eq),2-(phenoxymethyl)oxirane (26.6 mg, 177 umol, 24.0 uL, 1.50 eq) and K2CO3 (32.7 mg, 237 umol, 2.00 eq) in MeCN (5.00 mL) was stirred at 80 °C for 2 hours under N2. After completion, the mixture was concentrated under vacuum and purified by Prep-HPLC(Instrument: GX-B; Column: Welch Ultimate AQ-C18 150∗30mm∗5um; Condition: water(0.1%TFA)-ACN; Begin B: 22; End B: 52; Gradient Time(min): 12; 100%B Hold Time(min): 2; FlowRate(ml/min): 25) to give 1-phenoxy-3-[(1R,5S)-6-[[(trans)-2-phenylcyclopropyl]amino]-3-azabicyclo[3.1.1]heptan-3-yl]propan-2-ol 31 (2.80 mg, 7.07 umol, 8.92 % yield, 95.6 % purity) as yellow oil. LCMS [M+1]: 379.
1H NMR (400 MHz, METHANOL-d4) δ = 7.32 - 7.26 (m, 4H), 7.24 - 7.22 (m, 1H), 7.18 - 7.16 (m, 2H), 6.96 - 6.94 (m, 3H), 4.41 (d, J=6.8 Hz, 1H), 4.06 - 4.00 (m, 4H), 3.76 (br. s., 3H), 3.53 - 3.48 (m, 2H), 3.01 (br. s., 1H), 2.85 (br. s., 3H), 2.50 (d, J=3.2 Hz, 1H), 2.15 - 2.12 (m, 1H), 1.56 - 1.51 (m, 1H), 1.42 - 1.36 (m, 1H).
EXAMPLE 10
(trans)-N-[[1-(2-phenoxyethyl)azetidin-3-yl]methyl]-2-phenyl-cyclopropanamine (35)
Step 1. 2-bromoethoxybenzene (33).
[0148] A mixture of phenol (200 mg, 2.13 mmol, 187 uL, 1.00 eq), 1,2-dibromoethane (2.40 g, 12.8 mmol, 962 uL, 6.00 eq) and K2CO3 (1.76 g, 12.8 mmol, 6.00 eq) in acetone (200 mL) was stirred at 80 °C under N2 for 15 hours. After completion, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC(PE/EA 10/1) to give 2-bromoethoxybenzene (160 mg, 738 umol, 35 % yield, 92.8 % purity) as colorless oil.
1H NMR (400 MHz, METHANOL-d4) δ = 7.29 - 7.25 (m, 2H), 6.94 - 6.91 (m, 3H), 4.30 - 4.27 (m, 2H), 3.69 - 3.63 (m, 2H).
Step 2. tert-butyl N-[[1-(2-phenoxyethyl)azetidin-3-yl]methyl]-N-[(trans)-2-phenylcyclopropyl]carbamate (34).
[0149] A mixture of 33 (66.5 mg, 331 umol, 1.00 eq), 17 (100 mg, 331 umol, 1.00 eq) and Cs2CO3 (215 mg, 661 umol, 2.00 eq) in MeCN (2.00 mL) was stirred at 80 °C under N2 for 2 hours. After completion, the mixture was filtered and the filtrate was concentrated under vacuum to give tert-butyl N-[[1-(2-phenoxyethyl)azetidin-3-yl]methyl]-N-[(trans)-2-phenylcyclopropyl]carbamate 34 (150 mg, crude) as yellow oil. LCMS [M+1]: 423.
Step 3. (trans)-N-[[1-(2-phenoxyethyl)azetidin-3-yl]methyl]-2-phenyl-cyclopropanamine (35).
[0150] A mixture of 34 (139 mg, 329 umol, 1.00 eq) and TFA (375 mg, 3.29 mmol, 244 uL, 10.00 eq) in DCM (2.00 mL) was stirred at 10 °C for 1 hour. The mixture was concentrated under vacuum and purified by Prep-HPLC (Instrument: GX-E; Column: Phenomenex Synergi C18 150∗30mm∗4um; Condition: water(0.05%HCl)-ACN; Begin B:16; End B: 36; Gradient Time(min):7.8; 100%B Hold Time(min): 2; FlowRate(ml/min): 25) to give (trans)-N-[[1-(2-phenoxyethyl)azetidin-3-yl]methyl]-2-phenyl-cyclopropanamine 35 (23.0 mg, 67.5 umol, 21 % yield, 94.6 % purity) as white solid. LCMS [M+1]: 323.
1H NMR (400 MHz, METHANOL-d4) δ = 7.35 - 7.29 (m, 4H), 7.24 - 7.18 (m, 3H), 7.01 - 6.97 (m, 3H), 4.43 (br. S., 2H), 4.33 - 4.25 (m, 4H), 3.70 - 3.57 (m, 4H), 3.44 - 3.40 (m, 1H), 3.01 - 3.00 (d, J=3.2 Hz, 1H), 2.61 - 2.58 (m, 1H), 1.63 - 1.59 (m, 1H), 1.43 - 1.29 (m, 1H).
EXAMPLE 11
(trans)-N-[[1-(3-phenoxypropyl)azetidin-3-yl]methyl]-2-phenyl-cyclopropanamine (38)
Step 1. 3-bromopropoxybenzene (36).
[0152] A mixture of phenol (200 mg, 2.13 mmol, 187 uL, 1.00 eq), 1,3-dibromopropane (2.57 g, 12.8 mmol, 1.30 mL, 6.00 eq) and K2CO3 (1.76 g, 12.8 mmol, 6.00 eq) in acetone (200 mL) was stirred at 80 °C under N2 for 15 hours. After completion, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (PE/EA 10/1) to give 3-bromopropoxybenzene (260 mg, 1.21 mmol, 57 % yield) as colorless oil.
1H NMR (400 MHz, METHANOL-d4) δ = 7.28 - 7.23 (m, 2H), 6.93 - 6.90 (m, 3H), 4.10 - 4.07 (t, J=3.6 Hz, 2H), 3.63 - 3.60 (t, J=6.4 Hz, 2H), 2.31 - 2.24 (m, 2H).
Step 2. tert-butyl N-[[1-(3-phenoxypropyl)azetidin-3-yl]methyl]-N-[(trans)-2-phenylcyclopropyl]carbamate (37).
[0153] A mixture of 36 (71.1 mg, 331 umol, 1.00 eq), 17 (100 mg, 331 umol, 1.00 eq) and Cs2CO3 (215 mg, 661 umol, 2.00 eq) in MeCN (2.00 mL) was stirred at 80 °C under N2 for 2 hours. After completion, the mixture was filtered and the filtrate was concentrated under vacuum to give tert-butyl N-[[1-(3-phenoxypropyl)azetidin-3-yl]methyl]-N-[(trans)-2-phenylcyclopropyl]carbamate 37 (200 mg, crude) as yellow oil. LCMS [M+1]: 437.
Step 3. (trans)-N-[[1-(3-phenoxypropyl)azetidin-3-yl]methyl]-2-phenyl-cyclopropanamine (38).
[0154] A mixture of 37 (144 mg, 330 umol, 1.00 eq) and TFA (376 mg, 3.30 mmol, 244 uL, 10.0 eq) in DCM (2.00 mL) was stirred at 10 °C for 1 hour. After completion, the mixture was concentrated under vacuum. The residue was purified by Prep-HPLC(Instrument: GX-E; Column: Phenomenex Synergi C18 150∗30mm∗4um; Condition: water(0.05%HCl)-ACN; Begin B:20; End B: 40; Gradient Time(min):7.8; 100%B Hold Time(min): 2; FlowRate(ml/min): 28) to give (trans)-N-[[1-(3-phenoxypropyl)azetidin-3-yl]methyl]-2-phenyl-cyclopropanamine 38 (10.0 mg, 29.0 umol, 9 % yield, 97.4 % purity) as colorless oil. LCMS [M+1]: 337.
1H NMR (400 MHz, METHANOL-d4) δ = 7.32 - 7.18 (m, 7H), 6.96 - 6.94 (m, 3H), 4.30 - 4.29 (m, 3H), 4.10 - 4.07 (m, 3H), 3.67 - 3.58 (m, 2H), 3.50 - 3.48 (m, 2H), 3.39 (m, 1H), 3.00 - 2.99 (m, 1H), 2.60 (br. s., 1H), 2.09 - 2.07 (d, J=6 Hz, 2H), 1.64 - 1.58 (m, 1H), 1.42 - 1.37 (m, 1H)
EXAMPLE 12
1-[2-(4-bromophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine
Step 1. 1-bromo-4-(2-bromoethoxy)benzene (40).
[0156] To a solution of 4-bromophenol (10.0 g, 57.8 mmol, 1.00 eq) and 1,2-dibromoethane (65.2 g, 347 mmol, 26.2 mL, 6.00 eq) in acetone (200mL) was added K2CO3 (47.9 g, 347 mmol, 6.00 eq). The mixture was stirred at 80 °C for 15 hours. After completion, the mixture was filtered and concentrated under vacuum. The residue was dissolved in water (50 mL) and extracted with DCM (2 × 100 mL). The combined organic phase was washed with brine (80 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give 1-bromo-4-(2-bromoethoxy)benzene (13.0 g, crude) as light brown solid. The crude was used to the next step directly.
Step 2. 1-[2-(4-bromophenoxy)ethyl]piperidin-4-one (41).
[0157] To a mixture of 40 (8.00 g, 28.6 mmol, 1.00 eq) and piperidin-4-one (7.75 g, 57.2 mmol, 2.00 eq, HCl) in MeCN (120 mL) was added Cs2CO3 (18.6 g, 57.2 mmol, 2.00 eq). The mixture was stirred at 80 °C for 15 hours under N2. After completion, the mixture was filtered and the filtrated was concentrated under vacuum. The residue was purified by silica gel chromatography (PE/EA from 10/1 to 1/1) to give 1-[2-(4-bromophenoxy)ethyl]piperidin-4-one 41 (6.30 g, 16.5 mmol, 58 % yield, 78.0 % purity) as yellow oil. LCMS [M+1]: 299.
Step 3. 1-[2-(4-bromophenoxy)ethyl]-N-[(1R,2S)-2-phenylgyclopropyl]piperidin-4-amine (43).
[0158] To a soluton of 41 (269 mg, 901 umol, 1.20 eq) and (1R,2S)-2-phenylcyclopropanamine 42 (100 mg, 751 umol, 1.00 eq) in MeOH (3.00 mL) was added AcOH (45.1 mg, 751 umol, 42.9 uL, 1.00 eq) at -10 °C. After stirring for 1 hour, NaBH3CN (142 mg, 2.25 mmol, 3.00 eq) was added into the mixture. The mixture was stirred at -10 °C for 1 hour. After completion, the mixture was poured into saturated NH4Cl aq (20 mL). The resulting mixture was extracted with DCM (2 × 30 mL). The combined organic phase was concentrated under vacuum then was purified by Prep-HPLC(Instrument: gx-1; Column: Agela DuraShell 150mm_25mm_5um; Condition: water (0.05% ammonia hydroxide v/v)-ACN; Begin B:55; End B: 85; Gradient Time(min):10; 100%B Hold Time(min): 3; FlowRate(ml/min): 25) to give 1-[2-(4-bromophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine 43 (44.0 mg, 96.2 umol, 13 % yield, 90.8 % purity) as yellow oil. LCMS [M+1]: 417.
1H NMR (400 MHz, METHANOL-d4) δ = 7.38 - 7.36 (d, J=8.4 Hz, 2H), 7.26 - 7.20 (m, 2H), 7.12 - 7.11 (m, 1H), 7.04 - 7.02 (d, J=7.6 Hz, 2H), 6.87 - 6.84 (d, J=8.8 Hz, 2H), 4.10 - 4.07 (t, J=5.6 Hz, 2H), 3.03 - 3.00 (d, J=11.6 Hz, 2H), 2.79 - 2.76 (t, J=5.6 Hz, 2H), 2.66 (m, 1H), 2.31 - 2.30 (m, 1H), 2.21 - 2.15 (t, J=12.7 Hz, 2H), 1.93 - 1.87 (m, 3H), 1.53 - 1.48 (m, 2H), 1.07 - 1.01 (m, 2H).
EXAMPLE 13
1-(3-Phenoxypropyl)-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine (46)
Step 1. 1-(3-Phenoxypropyl)piperidin-4-one (45).
[0160] A suspension of the phenoxypropyl bromide (44) (0.3 mL, 1.90 mmol, d = 1.365), piperidone hydrochloride hydrate (0.44 g, 2.86 mmol), K2CO3 (1.05 g, 7.62 mmol), anhydrous Na2SO4 (0.54 g, 3.81 mmol) and KI (47 mg, 0.286 mmol) in MeCN (20 mL) was stirred at reflux conditions for 2.5 hrs. The mixture was cooled to RT, diluted with water and extracted with EA. The extract was dried over Na2SO4, filtered, concentrated and the residue was purified by flash column chromatography, eluent 5% MeOH in EA, to afford title compound 45 (0.45 g, quant. yield) as oil.
1H NMR: 500 MHz, CDCl3, δ (ppm): 7.30-7.26 (m, 2H), 6.96-6.90 (m 3H), 4.06 (t, J = 6.3 Hz, 2H), 2.78 (t, J = 6.1 Hz, 4H), 2.66 (t, J = 7.1 Hz, 2H), 2.46 (t, J = 6.8 Hz, 4H), 2.04-1.99 (m, 2H). MS: 233.3 (calcd.), 234.1 (M+H+, found).
Step 2. 1-(3-Phenoxypropyl)-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine (46)
[0161] A suspension of ketone 45 (0.49 g, 2.10 mmol) and (trans)-2-phenylcyclopropanamine hydrochloride (0.43 g, 2.52 mmol) in DCE (15 mL) was stirred at RT for 2.0 hrs, cooled to 0°C then treated with the borohydride (0.80 g, 7.78 mmol). The mixture was allowed to warm to RT and stirred over 4 hrs, diluted with DCM and washed with conc. NaHCO3 solution. The organic phase was further washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography, eluent 5 then 10% MeOH in DCM (MeOH contained 2% ammonia) to form title compound 46 (0.29 g, 39% yield) as honey-like material.
1H NMR: 500 MHz, CD3OD, δ (ppm): 7.29-7.23 (m, 4H), 7.16-7.05 (m, 1H), 7.08-7.05 (m, 2H), 6.94-6.90 (m, 3H), 4.03 (t, J = 6.2 Hz, 2H), 3.02 (bd, J = 11.7, 2H), 2.73-2.67 (m, 1H), 2.60-2.57 (m, 2H), 2.36-2.33 (m, 1H), 2.16-2.10 (m, 2H), 2.03-1.90 (m, 5H), 1.56-1.48 (m, 2H), 1.11-1.03 (m, 2H). MS: 350.5 (calcd.), 351.1 (M+H+, found).
EXAMPLE 14
1-(2-Phenoxyethyl)-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine (49)
Step 1. 1-(2-Phenoxyethyl)piperidin-4-one (48).
[0163] A suspension of the phenoxyethyl bromide (47) (0.30 g, 1.49 mmol), piperidone hydrochloride hydrate (0.34 g, 2.24 mmol), K2CO3 (0.83 g, 5.97 mmol), anhydrous Na2SO4 (0.42 g, 2.98 mmol) and KI (37 mg, 0.224 mmol) in MeCN (15 mL) was stirred at reflux conditions for 2.5 hrs. The mixture was cooled to RT, diluted with water and extracted with EA. The extract was dried over Na2SO4, filtered, concentrated and the residue was subjected to flash chromatography, eluent 5% MeOH in DCM, to afford title compound 48 (0.20 g, 60% yield) as a liquid.
1H NMR: 500 MHz, CDCl3, δ (ppm): 7.31-7.28 (m, 2H), 6.98-6.91 (m 3H), 4.15 (t, J = 5.6 Hz, 2H), 2.95 (t, J = 5.6 Hz, 2H), 2.91 (t, J = 6.1 Hz, 4H), 2.49 (t, J = 6.3 Hz, 4H). MS: 219.3 (calcd.), 219.9 (M+H+, found).
Step 2. 1-(2-Phenoxyethyl)-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine (49)
[0164] A suspension of ketone 48 (0.19 g, 0.866 mmol) and (trans)-2-phenylcyclopropanamine hydrochloride (0.18 g, 1.04 mmol) in DCE (10 mL) was stirred at RT for 2.0 hrs, cooled to 0°C then treated with the borohydride (0.33 g, 1.56 mmol). The mixture was allowed to warm to RT and stirred over 4 hrs. The mixture was then diluted with DCM and washed with conc. NaHCO3 solution. The organic phase was further washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography, eluent 5 then 10% MeOH in DCM (MeOH contained 2% ammonia) afford title compound 49 (0.19 g, 65% yield) as honey-like material.
1H NMR: 500 MHz, CD3OD, δ (ppm): 7.30-7.23 (m, 4H), 7.16-7.12 (m, 1H), 7.07-7.05 (m, 2H), 6.96-6.92 (m, 3H), 4.14 (t, J = 5.7 Hz, 2H), 3.07 (bd, J = 12.2, 2H), 2.83 (t, J = 5.6 Hz, 2H), 2.73-2.67 (m, 1H), 2.36-2.33 (m, 1H), 2.27-2.19 (m, 2H), 2.01-1.90 (m, 3H), 1.58-1.50 (m, 2H), 1.11-1.03 (m, 2H). MS: 336.5 (calcd.), 337.1 (M+H+, found).
EXAMPLE 15
2-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid di-hydrochloride (56)
Step 1. Methyl 2-(4-(2-bromoethoxy)phenyl)acetate (51).
[0166] A suspension of methyl 2-(4-hydroxyphenyl)acetate (50) (5.0 g, 30.1 mmol), 1,2-dibromoethane (16 mL, 186 mmol, d = 2.18), K2CO3 (11.50 g, 84.4 mmol) and KI (200 mg, 1.20 mmol) in MeCN (90 mL) was stirred at reflux conditions for 24 hrs. The mixture was diluted with water and extracted with EA. The extract was dried over anhydrous Na2SO4, filtered and concentrated in vacuum at 40°C. The resultant oil was further kept in a higher vacuum at 60°C to possibly remove the excess of dibromoethane then purified by flash chromatography, eluent DCM-hexanes (1:1) then EA-hexanes (8:17) to afford title compound 51 (5.05 g, 62% yield).
1H NMR: 500 MHz, CDCl3, δ (ppm): 7.20 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.28 (t, J = 6.3 Hz, 2H), 3.69 (s, 3H), 3.63 (t, J = 6.3 Hz, 2H), 3.53 (s, 2H).
Step 2. Methyl 2-(4-(2-(4-oxopiperidin-1-yl)ethoxy)phenyl)acetate (52).
[0167] A suspension of the bromide 51 (5.05 g, 18.49 mmol), piperidone hydrochloride hydrate (4.54 g, 29.6 mmol), K2CO3 (10.22 g, 74.0 mmol), anhydrous Na2SO4 (5.25 g, 37.0 mmol) and KI (153 mg, 0.924 mmol) in MeCN (100 mL) was stirred at reflux conditions for 18 hrs. The mixture was cooled to RT, diluted with water and extracted with EA. The extract was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography, eluent 10% MeOH in DCM (MeOH contained 2% ammonia) to afford title compound 52 (5.19 g, 96% yield) as oil.
1H NMR: 500 MHz, CD3OD, δ (ppm): 7.19 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.13 (t, J = 5.6 Hz, 2H), 3.68 (s, 3H), 3.56 (s, 2H), 2.93 (t, J = 5.6 Hz, 2H), 2.89 (t, J = 6.1 Hz, 4H), 2.48 (t, J = 6.2 Hz, 4H). MS: 291.3 (calcd.), 292.0 (M+H+, found).
Step 3. Methyl 2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetate (53).
[0168] A suspension of ketone 52 (2.5 g, 8.58 mmol), (1R, 2S)-2-phenylcyclopropanamine (2R, 3R)-tartaric acid salt (3.16 g, 11.16 mmol) and a few drops of 6N HCl solution in a solvent mixture DCE (10 mL) and DCM (5 mL) was stirred at RT for 3.0 hrs, cooled to 0°C then treated with the borohydride (3.27 g, 15.45 mmol). The mixture was allowed to warm to RT and stirred over 14 hrs. The mixture was then diluted with DCM and washed with a NaHCO3 solution. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography, eluent 10% MeOH in DCM (MeOH contained 2% ammonia to afford title compound 53 (1.65 g, 47% yield) as honey-like material whose estimated purity was ca 90%. The material was taken to the next step without additional purification. MS: 408.5 (calcd.), 409.0 (M+H+, found).
Step 4. Methyl 2-(4-(2-(4-((tert-butoxycarbonyl)((1R,2S)-2-phenylgyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetate (54).
[0169] To a solution of amine 53 (1.65 g, 4.04 mmol) in DCM (20 mL) was added TEA (1.69 mL, 12.12 mmol, d = 0.726). The mixture was cooled by an ice-bath then treated with a solution of the Boc-anhydride (1.763 g, 8.08 mmol) in DCM (20 mL). The mixture was stirred at 0-5°C for 30 min then at ambient temperature for 4 hrs, diluted with DCM, washed with diluted brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography, eluent EA-hexanes (1:1) to afford title compound 54 (1.50 g, 73% yield) as honey-like material. The material contained some residual EA.
1H NMR: 500 MHz, CD3OD, δ (ppm): 7.29-7.25 (m, 2H), 7.22-7.14 (m, 5H), 6.91 (d, J = 8.7 Hz, 2H), 4.13 (t, J = 5.6 Hz, 2H), 3.78-3.71 (m, 1H), 3.69 (s, 3H), 3.60 (s, 2H), 3.17-3.09 (m, 2H), 2.82 (t, J = 5.6 Hz, 2H), 2.64-2.61 (m, 1H), 2.28-2.12 (m, 4H), 2.06-2.03 (m, 1H), 1.85-1.82 (m, 1H), 1.78-1.75 (m, 1H), 1.46-1.42 (m, 10H), 1.28-1.24 (m, 1H). MS: 508.7 (calcd.), 509.2 (M+H+, found).
Step 5. 2-(4-(2-(4-((tert-Butoxycarbonyl)((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid (55).
[0170] To a solution of ester 54 (1.50 g, 2.95 mmol) in 70% aqueous EtOH (35 mL) was added a solution of LiOH x H2O (0.25 g, 5.90 mmol) in water (9 mL). The reaction mixture was stirred at rt for 1 hr, acidified with HCl to pH 5-6 then evaporated to its maximum. The residue was treated with brine and extracted with DCM. The extract was dried over anhydrous Na2SO4, filtered and the filtrate was evaporated to form foam which was let dry in vacuum overnight to afford title compound 55 (1.42 g, 97% yield). The material was used in the next step with no additional purification. MS: 494.6 (calcd.), 495.2 (M+H+, found).
Step 6. 2-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid di-hydrochloride (56)
[0171] A 4M solution of HCl in dioxane (2 ml, 8.00 mmol) was added to a suspension of the compound 55 (0.200 g, 0.404 mmol) in dioxane (2 mL) at rt and the reaction mixture was stirred at ambient temperature for 3 hrs. The mixture was evaporated to dryness and the resultant white precipitate was triturated with a mixture of MeOH and acetone, collected by filtration and dried to afford title compound 56 (0.17 g, 90% yield) as white solid.
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 12.25 (bs, 1H), 10.74 (bs, 1H), 9.99 (bs, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 5H), 6.94 (d, J= 8.6 Hz, 2H), 4.37 (bt, 2H), 3.66 (bs, 2H), 3.50 (s, 2H), 3.46 (bs, 3H), 3.46 (bs, 2H), 2.96 (bs, 1H), 2.58-2.54 (m, 1H), 2.31 (bs, 2H), 2.10 (bs, 2H), 1.60-1.56 (m, 1H), 1.31-1.27 (m, 1H). MS: 394.5 (calcd.), 395.0 (M+H+, found).
EXAMPLES 16 and 17
N-(Methylsulfonyl)-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide di-hydrochloride (58) and
2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-N-(phenylsulfonyl)acetamide di-hydrochloride (60)
Step 1. tert-Butyl(1-(2-(4-(2-(methylsulfonamido)-2-oxoethyl)phenoxy)ethyl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate (57).
[0173] To a solution of acid 55 (200 mg, 0.404 mmol) in DCM (5 mL) at 0°C was added CDI (72 mg, 0.445 mmol). The reaction mixture was stirred for 5 min at 0°C, then for another hour at ambient temperature. To the mixture were added methyl sulfonamide (42 mg, 0.445 mmol) and the DBU (0.121 mL, 0.809 mmol, d = 1.018). The combined mixture was stirred overnight, diluted with more DCM and washed with 10% aqueous NaH2PO4 solution then brine. The organic phase was dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography, eluent 10, then 15% MeOH in DCM (MeOH contained 2% ammonia) to afford title compound 57 (0.208 mg, 90% yield) as off-white solid.
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 7.27-7.24 (m, 2H), 7.17-7.10 (m, 5H), 6.88 (d, J = 8.7 Hz, 2H), 4.06 (t, J = 5.7 Hz, 2H), 3.61-3.54 (m, 1H), 3.47 (s, 2H), 3.14 (s, 3H), 3.07-3.03 (m, 2H), 2.77 (bt, 2H), 2.59-2.56 (m, 1H), 2.23-2.16 (m, 2H), 2.08-1.99 (m, 2H), 1.93-1.85 (m, 1H), 1.72-1.64 (m, 2H), 1.35-1.32 (m, 10H), 1.22-1.18 (m, 1H). MS: 571.7 (calcd.), 572.2 (M+H+, found).
Step 2. N-(Methylsulfonyl)-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropvl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide di-hydrochloride (58).
[0174] A 4M solution of HCl in dioxane (3 ml, 12 mmol) was added to a solution of compound 57 (205 mg, 0.359 mmol) in dioxane (2 mL) at rt. The mixture was stirred at ambient temperature for 3 hrs, evaporated to dryness and the resultant white precipitate was triturated with a mixture of acetone and MeOH, collected by filtration and dried to afford title compound 58 (146 mg, 75% yield) as a white solid.
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 11.92 (bs, 1H), 10.65 (bs, 1H), 9.91 (bs, 2H), 7.33-7.30 (m, 2H), 7.24-7.18 (m, 5H), 6.96 (d, J = 8.6 Hz, 2H), 4.37 (bt, 2H), 3.67 (bs, 2H), 3.55 (s, 2H), 3.46 (bs, 3H), 3.22 (s, 3H), 3.12 (bs, 2H), 2.97 (bs, 1H), 2.55 (bs, 1H), 2.30 (bs, 2H), 2.08 (bs, 2H), 1.57 (bs, 1H), 1.32-1.28 (m, 1H). MS: 471.6 (calcd.), 472.1 (M+H+, found).
Step 1. tert-Butyl (1-(2-(4-(2-oxo-2-(phenylsulfonamido)ethyl)phenoxy)ethyl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate (59).
[0175] To a solution of the acid 55 (200 mg, 0.404 mmol) and benzene sulfonamide (95 mg, 0.607 mmol) in DCM (7 mL) was added EDC x HCl (155 mg, 0.809 mmol) and DMAP (99 mg, 0.809 mmol) at RT. The reaction mixture was stirred at the same conditions overnight, diluted with more DCM then washed with a NaHCO3 solution, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography, eluent 10 % MeOH in DCM (MeOH contained 2% ammonia). The material required a second purification by flash chromatography, eluent 5% MeOH (with 2% ammonia) in DCM to afford title compound 59 (86 mg, 34% yield) as white solid. MS: 633.8 (calcd.), 634.2 (M+H+, found).
Step 2. 2-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-N-(phenylsulfonyl)acetamide di-hydrochloride (60).
[0176] A 4M solution of HCl in dioxane (1.0 ml, 4 mmol) was added to a solution of compound 59 (86 mg, 0.136 mmol) in dioxane (1.5 mL) at rt. The mixture was stirred at ambient temperature for 3 hrs, evaporated to dryness and the resultant white solid was triturated with acetone, collected by filtration, re-dissolved in water, frozen and freeze-dried to afford title compound 60 (59 mg, 72% yield) as white solid.
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 12.35 (bs, 1H), 10.73 (bs, 1H), 9.97 (bs, 2H), 7.90-7.88 (m, 2H), 7.72-7.69 (m, 1H), 7.62-7.59 (m, 2H), 7.33-7.29 (m, 2H), 7.24-7.18 (m, 3H), 7.11 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.35 (bt, 2H), 3.64 (bd, 2H), 3.50 (s, 2H), 3.44 (bs, 3H), 3.10 (bs, 2H), 2.96 (bs, 1H), 2.55 (bs, 1H), 2.29 (bs, 2H), 2.09 (bs, 2H), 1.59 (bs, 1H), 1.31-1.27 (m, 1H). MS: 533.7 (calcd.), 534.2 (M+H+, found).
EXAMPLES 18 and 19
N,N-Dimethyl-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide d-hydrochloride (62) and N-methoxy-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide (64)
Step 1. tert-Butyl(1-(2-(4-(2-(dimethylamino)-2-oxoethyl)phenoxy)ethyl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate (61).
[0178] To a solution of acid 55 (200 mg, 0.404 mmol) in DMF (4 mL) were added HOBT x H2O (124 mg, 0.809 mmol) followed by EDC x HCl (233 mg, 1.213 mmol). The reaction mixture was stirred at RT over 2 hrs. Then Me2NH x HCl (165 mg, 2.200 mmol) was added followed by TEA (0.282 mL, 2.022 mmol, d = 0.726). The resultant mixture was stirred overnight then diluted with brine. A gummy precipitate was formed which was collected by filtration and re-dissolved in acetone. The solution was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography, eluent 5% MeOH in DCM (MeOH contained 2% ammonia) to afford title compound 61 (144 mg, 68% yield) as glass-like solid. MS: 521.7 (calcd.), 522.3 (M+H+, found).
Step 2. N,N-Dimethyl-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide d-hydrochloride (62).
[0179] A 4M solution of HCl in dioxane (2 ml, 8 mmol) was added to a solution of compound 61 (144 mg, 0.276 mmol) in dioxane (2 mL) at rt. The mixture was stirred at ambient temperature for 3 hrs, evaporated to dryness and the resultant yellowish gummy precipitate was dissolved in MeOH and filtered. The filtrate was evaporated almost completely and treated with excess acetone. A white precipitate was formed which was collected by filtration, re-dissolved in water, frozen and freeze-dried to afford title compound 62 (113 mg, 83% yield) as off-white solid.
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 10.83(bs, 1H), 10.03 (bs, 2H), 7.33-7.29 (m, 2H), 7.24-7.15 (m, 5H), 6.93 (d, J = 8.6 Hz, 2H), 4.37 (bt, 2H), 3.67 (bd, 2H), 3.61 (s, 2H), 3.46 (bs, 3H), 3.14 (bs, 2H), 2.98 (s, 3H), 2.97 (bs, 1H), 2.81 (s, 3H), 2.59-2.56 (m, 1H), 2.32 (bs, 2H), 2.11 (bs, 2H), 1.61-1.57 (m, 1H), 1.31-1.26 (m, 1H). MS: 421.6 (calcd.), 422.3 (M+H+, found).
Step 1. tert-Butyl(1-(2-(4-(2-(methoxyamino)-2-oxoethyl)phenoxy)ethyl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate (63).
[0180] To a solution of acid 55 (185 mg, 0.374 mmol) in DCM (5 mL) were added TEA (0.21 mL, 1.496 mmol, d = 0.726), EDC x HCl (143 mg, 0.748 mmol), and the NH2OMe x HCl (66 mg, 0.785 mmol). The mixture was stirred overnight, diluted with DCM and washed with diluted brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography, eluent 5% MeOH (containing 2% ammonia) in DCM to afford title compound 63 (73 mg, 37% yield) as white foam. MS: 523.7 (calcd.), 524.2 (M+H+, found).
Step 2. N-Methoxy-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide (64).
[0181] A 4M solution of HCl in dioxane (1.0 ml, 4 mmol) was added to a solution of compound 63 (73 mg, 0.139 mmol) in dioxane (1 mL) at rt. The mixture was stirred at ambient temperature for 3 hrs, evaporated to dryness and the resultant white precipitate was triturated with acetone, collected by filtration, re-dissolved in water, frozen and freeze-dried to afford title compound 64 (67 mg, 93% yield) as white solid.
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 11.34 (bs, 1H), 10.89 (bs, 1H), 10.08 (bs, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 5H), 6.94 (d, J = 8.6 Hz, 2H), 4.37 (bt, 2H), 3.66 (bd, 2H), 3.56 (s, 3H), 3.45 (bs, 3H), 3.23 (s, 2H), 3.14 (bs, 2H), 2.95 (bs, 1H), 2.60-2.56 (m, 1H), 2.32 (bs, 2H), 2.12 (bs, 2H), 1.62-1.58 (m, 1H), 1.30-1.26 (m, 1H). MS: 423.6 (calcd.), 424.2 (M+H+, found).
EXAMPLE 20
1-[2-(4-morpholinophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine (66)
Step 1. tert-butyl N-[1-[2-(4-bromophenoxy)ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (65)
[0183] A mixture of 1-[2-(4-bromophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine (43, Example 12), (7.20 g, 17.3 mmol, 1.00 eq) and (Boc)2O (7.57 g, 34.7 mmol, 7.96 mL, 2.00 eq) in DCM (10.0 mL) was stirred at 50 °C for 5 hours. After completion, the mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (PE/EA from 10/1 to 0/1) to give tert-butyl N-[1-[2-(4-bromophenoxy)ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl] carbamate (6.00 g, 9.89 mmol, 57 % yield, 85.0 % purity) as yellow oil which was re-purified by Prep-HPLC(Instrument: HPLC-A; Column: Phenomenex Gemini C18 250∗50mm∗10 um; Condition: water (0.05% ammonia hydroxide v/v)-ACN; Begin B:70; End B: 95; Gradient Time(min): 31,85%; 100%B Hold Time(min): 5; FlowRate(ml/min):80) to give tert-butyl N-[1-[2-(4-bromophenoxy)ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (1.9 g purity 98.5 %) as white solid. LCMS [M+1]: 517
1H NMR (400 MHz, METHANOL-d4) δ = 7.42 - 7.40 (m, 2H), 7.24 - 7.22 (m, 2H), 7.15 - 7.10 (m, 3H), 6.92 - 6.90 (m, 2H), 4.23 - 4.21 (m, 2H), 3.82 - 3.79 (m, 1H), 3.42 - 3.31 (m, 2H), 3.24 - 3.22 (m, 2H), 2.67 - 2.66(m, 2H), 2.59 (m, 1H), 2.44 - 2.17 (m, 3H), 2.12 - 2.11 (m, 1H), 1.98 - 1.84 (m, 2H), 1.40 - 1.38 (m, 9H), 1.25 - 1.22 (m, 1H)
Step 2. 1-[2-(4-morpholinophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]lpiperidin-4-amine (66)
[0184] To a solution of tert-butyl N-[1-[2-(4-bromophenoxy)ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (100 mg, 194 umol, 1.00 eq) and morpholine (33.8 mg, 388 umol, 34.1 uL, 2.00 eq) in DMAC (1.00 mL) was added RuPhos (9.05 mg, 19.4 umol, 0.10 eq), Pd2(dba)3 (8.88 mg, 9.70 umol, 0.05 eq) and Cs2CO3 (190 mg, 582 umol, 3.00 eq). The mixture was stirred at 85 °C under N2 for 5 hours. After completion, water (10 mL) was added into the mixture. The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic phase was concentrated under vacuum. The residue was purified by prep-TLC (DCM/MeOH 20/1) to give 1-[2-(4-morpholinophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine (100 mg, 83.3 % purity, 82.4% yield) as yellow oil. LCMS [M+1]: 522
Step 3. 1-[2-(4-morpholinophenoxy)ethyl]-N-[(1R,2S)-2-phenylgyclopropyl]piperidin-4-amine (67, Example 20)
[0185] A mixture of tert-butyl N-[1-[2-(4-morpholinophenoxy)ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (100 mg, 192 umol, 1.00 eq) and TFA (219 mg, 1.92 mmol, 142 uL, 10.0 eq) in DCM (1.00 mL) was stirred at 15 °C for 1 hour. After completion, the reaction mixture was concentrated under vacuum. The rediue was purified by prep-HPLC (Instrument: LC-E; Column: Phenomenex Synergi C18 150∗30mm∗4um; Condition: water (0.05% ammonia hydroxide v/v)-ACN; Begin B:1; End B: 21; Gradient Time(min):10.5; 100%B Hold Time(min): 2; FlowRate(ml/min): 25). The desired fractions were collected and lyophilized to give 1-[2-(4-morpholinophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine (40 mg, 75.34 umol, 39.30 % yield, 3 HCl) as a white solid. LCMS [M+1]: 422
1H NMR (400 MHz, methanol-d4) δ = 7.77 (d, J=8.8 Hz, 2H), 7.33 - 7.19 (m, 7H), 4.52 - 4.49 (m, 2H), 4.16 - 4.12 (m, 4H), 3.87 - 3.67 (m, 9H), 3.34 (m, 2H), 3.05 - 3.04 (m, , 1H), 2.60 - 2.59 (m, 1H), 2.48 - 2.45 (m, 2H), 2.25 - 2.22 (m, 2H), 1.62 - 1.60 (m, 1H), 1.45 - 1.29 (m, 1H).
[0186] Following the teachings of the Reaction Schemes and synthetic routes set forth herein, the following compounds were prepared:
| Exemplary Compounds of Formula (I) and Formula (II) | ||||
| Ex. # | Structure | Method | LCMS [M+1] Observed | 1H NMR |
| 21 |
|
Example 20 | 435.2 | (400 MHz, METHANOL-d4) δ = 7.42 - 7.40 (m, 2H), 7.24 - 7.22 (m, 2H), 7.15 - 7.10 (m, 3H), 6.92 - 6.90 (m, 2H), 4.23 - 4.21 (m, 2H), 3.82 - 3.79 (m, 1H), 3.42 - 3.31 (m, 2H), 3.24 - 3.22 (m, 2H), 2.67 - 2.66(m, 2H), 2.59 (m, 1H), 2.44 - 2.17 (m, 3H), 2.12 - 2.11 (m, 1H), 1.98 - 1.84 (m, 2H), 1.40 - 1.38 (m, 9H), 1.25 - 1.22 (m, 1H) |
| 1-(2-(4-(4-methylpiperazin-1-yl)phenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 22 |
|
Example 20 | 422.1 | (400 MHz, deuterium oxide) δ = 7.40 - 7.33 (m, 4H), 7.30 - 7.26 (m, 1H), 7.17 (d, J=7.2 Hz, 2H), 7.03 (d, J=9.2 Hz, 2H), 4.59 (t, J=8.0 Hz, 2H), 4.38 - 4.37 (m, 2H), 4.08 - 4.04 (m, 2H), 3.85 - 3.69 (m, 3H), 3.65 - 3.55 (m, 2H), 3.30-3.15 (m, 2H), 2.99 - 2.96 (m, 1H), 2.52 - 2.40 (m, 3H), 2.11 - 1.95 (m, 2H), 1.54 - 1.43 (m, 2H). |
| 3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)oxazolidin-2-one | ||||
| 23 |
|
Example 20 | 435.3 | (400 MHz, deuterium oxide) δ = 7.36 - 7.28 (m, 5H), 7.17 (d, J=7.6 Hz, 2H), 6.99 (d, J=9.6 Hz, 2H), 4.36 - 4.33 (m, 2H), 3.80 - 3.71 (m, 5H), 3.63 - 3.55 (m, 2H), 3.50 - 3.46 (m, 2H), 3.26 - 3.15 (m, 2H), 2.99 - 2.97 (m, 1H), 2.78 (s, 3H), 2.50 - 2.43 (m, 3H), 2.07 - 1.93 (m, 2H), 1.52 - 1.44 (m, 2H). |
| 1-methyl-3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)imidazolidin-2-one | ||||
| 24 |
|
Example 20 | 436.3 | (400 MHz, deuterium oxide) δ = 7.31 - 7.27 (m, 2H), 7.24 - 7.20 (m, 3H), 7.11 (d, J=7.2 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 4.37 (t, J=5.2 Hz, 2H), 4.33 - 4.31 (m, 2H), 3.78 - 3.75 (d, J=11.6 Hz, 2H), 3.70-3.60 (m, 1H), 3.59 - 3.54 (m, 4H), 3.30-3.20 (m, 2H), 2.95 - 2.91 (m, 1H), 2.45 - 2.35 (m, 3H), 2.12 - 2.06 (m, 2H), 2.04-1.90 (m, 2H), 1.48 - 1.35 (m, 2H). |
| 3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one | ||||
| 25 |
|
Example 20 | 436.2 | (400 MHz, deuterium oxide) δ = 7.32 - 7.27 (m, 2H), 7.25 - 7.23 (m, 3H), 7.15 (d, J=7.2 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.37 - 4.35 (m, 2H), 4.29 (s, 2H), 4.02 (t, J=4.8 Hz, 2H), 3.85-3.77 (m, 2H), 3.75 - 3.65 (m, 3H), 3.60 - 3.55 (m, 2H), 3.23 - 3.15 (m, 2H), 2.97 - 2.93 (m, 1H), 2.48 - 2.41 (m, 3H), 2.05 - 1.95 (m, 2H), 1.50 - 1.42 (m, 2H). |
| 4-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)morpholin-3-one | ||||
| 26 |
|
Example 20 | 463.4 | (400 MHz, deuterium oxide) δ = 7.56 - 7.36 (d, J=8.8 Hz, 2H), 7.36 - 7.33 (m, 2H), 7.29 - 7.25 (m, 1H), 7.18 - 7.14 (m, 4H), 4.45 - 4.38 (m, 2H), 4.05 - 3.95 (m, 4H), 3.83 - 3.62 (m, 9H), 3.23 - 3.15 (m, 2H), 3.01 - 2.95 (m, 1H), 2.55 - 2.44 (m, 3H), 2.17 (s, 3H), 2.10 - 1.95 (m, 2H), 1.55 - 1.40 (m, 2H). |
| 1-(4-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethan-1-one | ||||
| 27 |
|
Example 20 | 420.4 | (400 MHz, deuterium oxide) δ = 7.37 - 7.33 (m, 4H), 7.32 - 7.28 (m, 1H), 7.18 - 7.16 (d, J=7.6 Hz, 2H), 7.04 - 7.02 (d, J=8.4 Hz, 2H), 4.38 - 4.36 (m, 2H), 3.84 - 3.82 (m, 4H), 3.77 - 3.68 (m, 1H), 3.63 - 3.55 (m, 2H), 3.25-3.13 (m, 2H), 3.00 - 2.97 (m, 1H), 2.57 (t, J=8.0 Hz, 2H), 2.50 - 2.40 (m, 3H), 2.17 - 2.11 (m, 2H), 2.08 - 1.95 (br. s., 2H), 1.52 - 1.44 (m, 2H) |
| 1-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)pyrrolidin-2-one | ||||
| 28 |
|
Example 20 | 434.2 | (400 MHz, D2O) δ = 7.36 - 7.33 (m, 2H), 7.29 - 7.27 (m, 1H), 7.19 - 7.15 (m, 4H), 7.03 (d, J=8.8 Hz, 2H), 4.37 (br. s., 2H), 3.83 (d, J=12.4 Hz, 2H), 3.90-3.80 (m, 1H), 3.65 - 3.55 (d, J=4.0 Hz, 4H), 3.25-3.10 (m, 2H), 3.03 - 2.95 (m, 1H), 2.55 - 2.40 (m, 5H), 2.10-1.95 (br. s., 2H), 1.95-1.80 (m, 4H), 1.55 - 1.42 (m, 2H). |
| 1-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)piperidin-2-one | ||||
| 29 |
|
Example 12 | 336.0 | (400MHz, methanol-d4) δ 7.48 - 7.38 (m, 2H), 7.37 - 7.31 (m, 2H), 7.30 - 7.24 (m, 3H), 7.24 - 7.18 (m, 3H), 3.92 - 3.81 (m, 4H), 3.81 - 3.71 (m, 1H), 3.60 - 3.48 (m, 2H), 3.32 - 3.24 (m, 2H), 3.06 (td, J=3.6, 7.2 Hz, 1H), 2.60 - 2.55 (m, 1H), 2.52 - 2.41 (m, 2H), 2.31 - 2.14 (m, 2H), 1.65 - 1.55 (m, 1H), 1.52 - 1.41 (m, 1H). |
| 1-(2-(phenylamino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 30 |
|
Example 20 | 420.0 | (400 MHz, chloroform-d) δ = 7.27 - 7.23 (m, 2H), 7.20 - 7.15 (m, 1H), 7.02 (d, J=7.6 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.82 (d, J=9.2 Hz, 2H), 4.06 (t, J=6.0 Hz, 2H), 3.72 (q, J=6.8 Hz, 1H), 3.05 - 2.95 (m, 5H), 2.80 (t, J=5.6 Hz, 2H), 2.73 - 2.60 (m, 1H), 2.41 - 2.30 (m, 1H), 2.25-2.10 (m, 2H), 1.93 - 1.74 (m, 3H), 1.73 - 1.69 (m, 2H), 1.56 - 1.53 (m, 3H), 1.50 - 1.40 (m, 2H), 1.27 - 1.23 (m, 2H), 1.07 (m, 1H), 1.00 - 0.98 (m, 1H). |
| N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(4-(piperidin-1-yl)phenoxy)ethyl)piperidin-4-amine | ||||
| 31 |
|
Example 7 | 425.2 | (400 MHz, methanol-d4) δ = 7.35 - 7.31 (m, 2H), 7.27 - 7.18 (m, 5H), 6.94 - 6.91 (d, J=8.8 Hz, 2H), 4.42 - 4.40 (m, 1H), 4.05 - 3.99 (m, 2H), 3.92 - 3.80 (m, 2H), 3.75 - 3.65 (m, 1H), 3.55 (s, 2H), 3.46 - 3.35 (m, 2H), 3.30 - 3.15 (m, 2H), 3.03 - 3.01 (m, 1H), 2.54 - 2.52 (m, 1H), 2.48 - 2.39 (m, 2H), 2.20 - 2.05 (m, 2H), 1.58 - 1.56 (m, 1H), 1.48 - 1.45 (m, 1H). |
| 2-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acetic acid | ||||
| 32 |
|
Example 12 | 350.2 | (400MHz, methanol-d4) δ 7.54 - 7.46 (m, 2H), 7.44 - 7.40 (m, 2H), 7.38 - 7.28 (m, 2H), 7.25 - 7.23 (m, 1H), 7.23 - 7.17 (m., 3H), 4.05 (t, J=6.8 Hz, 2H), 3.90 - 3.70 (m, 3H), 3.45 - 3.40 (m, 2H), 3.30 - 3.25 (m, 2H), 3.28(s, 3H), 3.10 - 3.04 (m, 1H), 2.60 - 2.55 (m, 1H), 2.54 - 2.45 (m, 2H), 2.25 - 2.17 (m, 2H), 1.65 - 1.58 (m, 1H), 1.47 - 1.43 (m, 1H) |
| 1-(2-(methyl(phenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 33 |
|
Example 12 | 416.1 | (400 MHz, methanol-d4) δ 7.50 (d, J=8.8 Hz, 2H), 7.38 - 7.18 (m, 5H), 7.11 (d, J=8.8 Hz, 2H), 3.93 - 3.67 (m, 5H), 3.55 - 3.52 (m, 2H), 3.26 - 3.22 (m, 2H), 3.11 - 3.02 (m, 1H), 2.63 - 2.59 (m, 1H), 2.53 - 2.47 (m, 2H), 2.29 - 2.16 (m, 2H), 1.70 - 1.57 (m, 1H), 1.49 - 1.45 (m, 1H) |
| 1-(2-((4-bromophenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 34 |
|
Example 7 | 411.4 | (400 MHz, D2O) δ = 7.94 - 7.93 (d, J=8.8 Hz, 2H), 7.37 - 7.34 (m, 2H), 7.30 - 7.26 (m, 1H), 7.18 (d, J=7.2 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 4.48 - 4.46 (m, 1H), 4.17 - 4.09 (m, 2H), 3.85 - 3.38 (m, 3H), 3.48 - 3.35 (m, 2H), 3.32 - 3.05 (m, 2H), 3.02 - 2.95 (m, 1H), 2.52 - 2.40 (m, 3H), 2.13 - 2.95 (m, 2H), 1.54 - 1.45 (m, 2H). |
| 4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)benzoic acid | ||||
EXAMPLE 35
(E)-3-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylic acid (73)
Step 1. 2-[(4-bromophenoxy)methyl]oxirane
[0188] To a mixture of 4-bromophenol (10.0 g, 57.8 mmol, 2.00 eq) and 2-(chloromethyl)oxirane (12.9 g, 140 mmol, 11.0 mL, 4.85 eq) in MeCN (200 mL) was added K2CO3 (11.9 g, 86.7 mmol, 3.00 eq) in one portion. The mixture was stirred at 90 °C for 12 hours. After completion, the mixture was concentrated, diluted with DCM (150 mL), then washed with H2O (150mL). The organic phase was washed with brine (150 mL × 2), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate= 100/1∼50/1) to give 2-[(4-bromophenoxy)methyl]oxirane (9.10 g, crude) as white solid
1H NMR (400 MHz, chloroform-d) δ 7.46 - 7.36 (m, 1H), 6.88 - 6.79 (m, 1H), 4.25 - 4.22 (m, 1H), 3.95 - 3.91 (m, 1H), 3.41 - 3.31 (m, 1H), 3.00 - 2.87 (m, 1H), 2.82 - 2.72 (m, 1H).
Step 2. tert-butyl N-[1-[3-(4-bromophenoxy)-2-hydroxy-propyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate
[0189] To a mixture of 2-[(4-bromophenoxy)methyl]oxirane (3.00 g, 13.10 mmol, 1.00 eq) and tert-butyl N-[(1R,2S)-2-phenylcyclopropyl]-N-(4-piperidyl)carbamate (4.56 g, 14.4 mmol, 1.10 eq) in MeCN (50.0 mL) was added K2CO3 (3.62 g, 26.2 mmol, 2.00 eq), and the reaction was stirred at 85 °C for 12 hours. After completion, the reaction was added water (80 mL), then extracted with EA (60 mL × 2), the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1-3/1) to give the product tert-butyl N-[1-[3-(4-bromophenoxy)-2-hydroxy-propyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (5.50 g, 9.79 mmol, 74.7 % yield, 97.1 % purity) as yellow solid. LCMS [M+1]: 545,547
1H NMR (400 MHz, chloroform-d) δ 7.29 (d, J=8.8 Hz, 2H), 7.24 - 7.17 (m, 2H), 7.15 - 7.07 (m, 1H), 7.01 (d, J=7.2 Hz, 2H), 6.73 (d, J=8.8 Hz, 2H), 4.02 - 3.91 (m, 1H), 3.88 - 3.85 (m, 2H), 3.70 - 3.39 (m, 2H), 3.07 - 2.92 (m, 1H), 2.85 - 2.78 (m, 1H), 2.57 - 2.36 (m, 3H), 2.35 - 2.21 (m, 1H), 2.14 - 1.83 (m, 4H), 1.77 - 1.61 (m, 2H), 1.47 - 1.24 (m, 10H), 1.21 - 1.14 (m, 1H).
Step 3. (E)-3-[4-[3-[4-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]-2-hydroxy-propoxy]phenyl]prop-2-enoate
[0190] Compound 71: To a mixture of tert-butyl N-[1-[3-(4-bromophenoxy)-2-hydroxypropyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (800 mg, 1.47 mmol, 1.00 eq) and methyl prop-2-enoate (470 mg, 5.46 mmol, 489 uL, 3.71 eq) in DMF (15.0 mL) was added KOAc (158 mg, 1.61 mmol, 1.10 eq), Pd(OAc)2 (32.9 mg, 147 umol, 0.10 eq) and tris-o-tolylphosphane (44.6 mg, 147 umol, 0.10 eq), the reaction was stirred at 120 °C for 12 hours. After completion, the reaction was added water (30 mL), extracted with EA (25 mL × 2), the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1∼1/1) to give the product (E)-3-[4-[3-[4-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]-2-hydroxy-propoxy]phenyl]prop-2-enoate (400 mg, 719 umol, 48.9 % yield, 99% purity) as yellow oil. LCMS [M+1]: 551
Step 4. (E)-3-[4-[3-[4-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]-2-hydroxy-propoxy]phenyl]prop-2-enoic acid
[0191] To a mixture of methyl (E)-3-[4-[3-[4-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]-2-hydroxy-propoxy]phenyl]prop-2-enoate (200 mg, 363 umol, 1.00 eq) in MeOH (3.00 mL) and H2O (1.00 mL) was added NaOH (58.1 mg, 1.45 mmol, 4.00 eq), and the reaction was stirred at 15 °C for 12 hours. After completion, the reaction was added water (10 mL), then extracted with DCM (15 mL × 2), the combined organic layers were dried over Na2SO4, filtered and concentrated to give (E)-3-[4-[3-[4-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]-2-hydroxy-propoxy]phenyl]prop-2-enoic acid (150 mg, 254 umol, 69.9 % yield, 90.8 % purity) as yellow solid which was used for the next step without further purification. LCMS [M+1]: 537
Step 5. E)-3-[4-[2-hydroxy-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]propoxy]phenyl]prop-2-enoic acid
[0192] To a mixture of (E)-3-[4-[3-[4-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]-2-hydroxy-propoxy]phenyl]prop-2-enoic acid (150 mg, 279 umol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 48.3 eq), the reaction was stirred at 15 °C for 1 hour. After completion, the reaction was concentrated, diluted with CH3CN (3 mL), then the mixture was adjusted with Na2CO3 solid to pH 6∼7, the solid was filtered. The filtrate was purified by Prep-HPLC (Instrument: GX-B; Column: Welch Ultimate AQ-C18 150 ∗ 30 mm ∗ 5 um; Condition: water (0.1 % TFA)-ACN; Begin B: 20; End B: 43; Gradient Time (min): 10; 100 % B Hold Time (min): 3; FlowRate (ml/min): 25) to give (E)-3-[4-[2-hydroxy-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]propoxy]phenyl]prop-2-enoic acid (64.0 mg, 96.1 umol, 34.4 % yield, 99.8 % purity, 2 TFA) as white solid. LCMS [M+1]: 437
1H NMR (400 MHz, methanol-d4) δ 7.64 (d, J=16. 0 Hz, 1H), 7.60 - 7.57 (m, 2H), 7.39 - 7.31 (m, 2H), 7.30 - 7.17 (m, 3H), 7.02 (d, J=8.8 Hz, 2H), 6.37 (d, J=16.0 Hz, 1H), 4.46 - 4.42 (m, 1H), 4.16 - 4.03 (m, 2H), 3.88 - 3.84 (m, 2H), 3.75 - 3.69 (m, 1H), 3.41 - 3.48 (m, 2H), 3.32 - 3.15 (m, 2H), 3.03 - 3.01 (m, 1H), 2.58 - 2.35 (m, 3H), 2.25 - 2.01 (m, 2H), 1.61 - 1.43 (m, 2H).
EXAMPLE 36
Synthesis of Intermediate 79: tert-butyl ((1R,2S)-2-phenylcyclopropyl)(piperidin-4-yl)carbamate
[0195] Compound 75: To a mixture of tert-butyl 4-oxopiperidine-1-carboxylate (100 g, 502 mmol, 1.00 eq) in dioxane (750 mL) was added HCl/dioxane (750 mL), and the reaction was stirred at 15 °C for 12 hours. After completion, the precipitated solid was filtered, washed with dioxane (400 mL), then the solid was dried under vacuum. The product piperidin-4-one (66.0 g, 487 mmol, 97.0 % yield, HCl) was obtained as white solid.
1H NMR (400 MHz, Deuterium oxide) δ 3.20 (t, J = 5.8 Hz, 4H), 1.92 (t, J = 5.8 Hz, 4H)
[0196] Compound 76: To a mixture of 75 (66.0 g, 487 mmol, 1.00 eq, HCl) in DCM (600 mL) was added TEA (197 g, 1.95 mol, 270 mL, 4.00 eq) and (CF3CO)2O (307 g, 1.46 mol, 203 mL, 3.00 eq) dropwise at 0 °C, the mixture was stirred at 0 - 15 °C for 12 hours under N2. After completion, the reaction mixture was washed with water (2 × 800 mL), diluted with HCl aqueous (0.5 N, 2 × 800 mL), sat. aqueous NaHCO3 (2 × 800 mL) successively, the organic layer was dried over Na2SO4, filtered and concentrated. The residue was triturated with petroleum ether (200 mL), the precipitated solid was filtered and dried under vacuum to give 1-(2,2,2-trifluoroacetyl)piperidin-4-one (34.5 g, 177 mmol, 36.3 % yield) as yellow solid.
1H NMR (400 MHz, Chloroform-d) δ 4.01 - 3.89 (m, 4H), 2.62 - 2.56 (m, 4H) Compound 77: To a mixture of (1R,2S)-2-phenylcyclopropanamine (23.0 g, 173 mmol, 1.00 eq) and 1-(2,2,2-trifluoroacetyl)piperidin-4-one (35.4 g, 181 mmol, 1.05 eq) in MeOH (500 mL) was added AcOH (31.1 g, 518 mmol, 29.6 mL, 3.00 eq), the reaction was stirred at 15 °C for 0.5 hour, then the mixture was cooled to - 10 °C and NaBH3CN (32.6 g, 518 mmol, 3.00 eq) was added to the mixture, the mixture was stirred at - 10 ∼ 15 °C for 11.5 hours. After completion, the reaction mixture was added to H2O (500 mL) and concentrated. The residue was extracted with DCM (2 × 400 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated. The product 2,2,2-trifluoro-1-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl] ethanone (59.2 g, crude) was obtained as yellow solid which was used for the next step without further purification. LCMS [M+1]: 313 Compound 78: To a mixture of 2,2,2-trifluoro-1-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]ethanone (59.2 g, 189 mmol, 1.00 eq) in MeOH (200 mL) was added (Boc)2O (82.7 g, 379 mmol, 87.1 mL, 2.00 eq) and TEA (57.5 g, 568 mmol, 78.8 mL, 3.00 eq), the mixture was stirred at 50 °C for 12 hours. After completion, the reaction mixture was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 5/1) to give tert-butyl N-[(1R,2S)-2-phenylcyclopropyl]-N-[1-(2,2,2-trifluoroacetyl)-4-piperidyl] carbamate (42.3 g, 79.8 mmol, 42.1 % yield, 77.8 % purity) as colorless oil. LCMS [M-99]: 313
[0197] Compound 79: To a mixture of tert-butyl N-[(1R,2S)-2-phenylcyclopropyl]-N-[1-(2,2,2-trifluoroacetyl)-4-piperidyl]carbamate (40.0 g, 96.9 mmol, 1.00 eq) in MeOH (200 mL) and H2O (50.0 mL) was added K2CO3 (53.6 g, 388 mmol, 4.00 eq), the mixture was stirred at 15 °C for 12 hours. After completion, the reaction mixture was added water (500 mL), then extracted with DCM (3 × 400 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated to give tert-butyl N-[(1R,2S)-2-phenylcyclopropyl]-N-(4-piperidyl)carbamate (27.3 g, 65.4 mmol, 88.9 % yield, 75.8 % purity) as yellow solid. LCMS [M+1]: 317.
1H NMR (400 MHz, Methanol-d4) δ 7.32 - 7.22 (m, 2H), 7.19 - 7.11 (m, 3H), 3.82 - 3.73 (m, 1H), 3.16 - 3.03 (m, 2H), 2.67 - 2.57 (m, 3H), 2.16 - 2.11 (m, 1H), 2.08 - 1.71 (m, 4H), 1.46 - 1.39 (m, 10H), 1.34 - 1.20 (m, 1H).
1-[2-[(2-methy1-4-pyridyl)oxy]ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine
[0200] Compound 80: To a solution of tert-butyl N-[(1R,2S)-2-phenylcyclopropyl]-N-(4-piperidyl)carbamate (300 mg, 948 umol, 1.00 eq) and 2-bromoethanol (237 mg, 1.90 mmol, 135 uL, 2.00 eq) in MeCN (6.00 mL) was added K2CO3 (262 mg, 1.90 mmol, 2.00 eq). The mixture was stirred at 85 °C for 5 hours. After completion, the precipitate was filtrated off and the filtrate was concentrated under vacuum. The residue was purified by silica gel (DCM/MeOH from 100/1 to 10/1), and the combined fractions were concentrated. tert-butyl N-[1-(2-hydroxyethyl)-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate 80 (300 mg, 798 umol, 84.1 % yield, 95.8 % purity) was obtained as yellow oil. LCMS [M-55]: 305
[0201] Compound 81: To a solution of tert-butyl N-[1-(2-hydroxyethyl)-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (100 mg, 277 umol, 1.00 eq) in DMF (2.00 mL) was added NaH (22.2 mg, 555 umol, 60 % purity, 2.00 eq). After stirring at 15 °C for 1 hour, 2-methyl-4-chloropyridine (76.6 mg, 555 umol, 2.00 eq) was added. The mixture was stirred at 85 °C for 15 hours. The precipitate was filtrated off and the filtrate was concentrated under vacuum and purified by Prep-TLC (DCM/MeOH 10/1, Rf: 0.3).
[0202] tert-butyl N-[1-[2-[(2-methyl-4-pyridyl)oxy]ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (200 mg, 213 umol, 76.6 % yield, 48.0 % purity) was obtained as a yellow oil. LCMS [M+1]: 452
[0203] Compound 82, Example 36: A mixture of tert-butyl N-[1-[2-[(2-methyl-4-pyridyl)oxy]ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (200 mg, 443 umol, 1.00 eq) and TFA (1.51 g, 13.3 mmol, 984uL, 30.00 eq) in DCM (2.00 mL) was stirred at 15 °C for 1 hour. After completion, the reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150∗25mm∗10um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 35%-65%,10min). The desired fractions were collected and lyophilized to give 1-[2-[(2-methyl-4-pyridyl)oxy]ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine (39.0 mg, 111 umol, 25.1 % yield) as colorless oil. LCMS [M+1]: 352.
1H NMR (400 MHz, METHANOL-d4) δ = 8.19 - 8.18 (d, J=6 Hz, 1H), 7.23 - 7.20 (m, 2H), 7.11 (m, 1H), 7.04 - 7.02 (m, 2H), 6.86 (, 1H), 6.86 - 6.80 (m, 1H), 4.20 - 4.18 (t, J=5.2 Hz, 2H), 3.02 - 2.99 (br d, J=11.6 Hz, 2H), 2.81 - 2.79 (br t, J=5.6 Hz, 2H), 2.66 (m, 1H), 2.46 (s, 3H), 2.30 - 2.29 (m, 1H), 2.19 - 2.18 (m, 2H), 1.94 - 1.88 (m, 3H), 1.50 (m, 2H), 1.07 - 1.01 (m, 2H)
EXAMPLE 37
1-morpholino-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one
[0205] Compound 85, Example 37, was prepared from 2-chloropropionic acid: Compound 83: N-Methylmorpholine (1.50 ml, 13.8 mmol), followed by 1-hydroxybenzotriazole (1.48 g, 11.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (2.31 g, 12.0 mmol) were added to a stirred, ice-cooled solution of 2-chloropropionic acid (1.00 g, 9.20 mmol) in dichloromethane (30.0 ml). The resulting solution was stirred at about 0° C for 45 minutes. Morpholine (2.40 ml, 27.6 mmol) was then added, the cooling bath removed and the reaction mixture stirred at 20 °C for 12 hrs. The residue was partitioned between ethyl acetate (50.0 mL) and water (30.0 mL), then the separated organic phase and washed with brine (30.0 mL), dried over sodium sulfate, and evaporated under reduced pressure to give a residue. The residue was purified by prep-TLC (dichloromethane/Methanol 10/1) to give 2-chloro-1-morpholinopropan-1-one (500 mg, 2.81 mmol, 30.5 % yield) as colorless oil.
1H NMR (400 MHz, methanol-d4) δ = 4.91 (q, J = 6.4 Hz, 1H), 3.75 - 3.50 (m, 8H), 1.62 (d, J = 6.4 Hz, 3H).
[0206] Compound 84: To a solution of 2-chloro-1-morpholino-propan-1-one (100 mg, 562 umol, 1.00 eq.) in DMF (5.00 mL) was added DIEA (291 mg, 2.25 mmol, 393 uL, 4.00 eq.), tert-butyl N-[(1R,2S)-2-phenylcyclopropyl]-N-(4-piperidyl)carbamate (356 mg, 1.13 mmol, 2.00 eq.) and potassium iodide (18.6 mg, 112 umol, 0.20 eq.). The reaction mixture was stirred at 50 °C for 12 hrs. Then the reaction mixture was partitioned between water (30.0 mL) and ethyl acetate (50.0 mL). The organic phase was separated, washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate 1/1) to give tert-butyl N-[1-[(1R)-1-methyl-2-morpholino-2-oxo-ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (120 mg, 262 umol, 46.5 % yield) as a white solid. LCMS [M+1]:458.
[0207] Compound 85: A solution of tert-butyl N-[1-[(1R)-1-methyl-2-morpholino -2-oxoethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (120 mg, 262 umol, 1.00 eq.) in HCl/dioxane (4 M, 2 mL) was stirred at 0 °C for 2 hrs. A white solid was formed. The reaction mixture was filtered and the filter cake was concentrated to give (2R)-1-morpholino-2-[4-[[(1R, 2S)-2-phenylcyclopropyl]amino]-1-piperidyl]propan-1-one (70.0 mg, 195 umol, 74.7 % yield) as a white solid. LCMS [M+1]:358.
1H NMR (400MHz, methanol-d4) δ = 7.37 - 7.30 (m, 2H), 7.29 - 7.17 (m, 3H), 4.61 (br d, J = 6.4 Hz, 1H), 3.93 (br d, J = 10.8 Hz, 1H), 3.81 - 3.50 (m, 10H), 3.31 - 3.17 (m, 2H), 3.09 - 3.01 (m, 1H), 2.66 - 2.37 (m, 3H), 2.31 - 1.99 (m, 2H), 1.67 - 1.59 (m, 1H), 1.57 (d, J = 6.4Hz, 3H), 1.52 - 1.37 (m, 1H).
EXAMPLE 38
1-methyl-3-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)urea
[0210] Compound 86: To a mixture of tert-butyl N-[(1R,2S)-2-phenylcyclopropyl]-N-(4-piperidyl)carbamate (5.00 g, 15.8 mmol, 1.00 eq.) and 2-(2-bromoethyl)isoindoline-1,3-dione (6.02 g, 23.7 mmol, 1.50 eq.) in acetonitrile (50.0 mL) was added potassium carbonate (8.74 g, 63.2 mmol, 4.00 eq.) and potassium iodide (263 mg, 1.58 mmol, 0.1 eq.), and then warmed to reflux at 90 °C for 18 hrs. Once complete, the reaction mixture was concentrated in vacuo to remove the solvent, water (40 mL) was added, and the aqueous layer extracted with DCM (50.0 mL × 3). The combined organic fractions were dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate 10:1 to 2:1) to give tert-butyl (1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate (4.50 g, 9.19 mmol, 58.2 % yield) as a yellow oil.
1H NMR (400 MHz, CD3Cl) δ = 7.88 - 7.81 (m, 2H), 7.76 - 7.69 (m, 2H), 7.24 - 7.12 (m, 3H), 7.06 - 7.01 (m, 2H), 3.85 - 3.75 (m, 2H), 3.74 - 3.62 (m, 1H), 3.12 - 2.94 (m, 2H), 2.67 - 2.55 (m, 2H), 2.54 - 2.47 (m, 1H), 2.12 - 2.06 (m, 2H), 1.95 (dq, J = 3.6, 12.0 Hz, 1H), 1.83 (dq, J = 40, 12.0 Hz, 1H), 1.77 - 1.70 (m, 1H), 1.66 (br s, 2H), 1.40 (s, 9H), 1.37 - 1.30 (m, 1H), 1.20 (q, J=6.4 Hz, 1H).
[0211] Compound 87: To a solution of tert-butyl N-[1-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (4.40 g, 8.99 mmol, 1.00 eq.) in ethanol (50.0 mL) was added hydrazine monohydrate (4.59 g, 89.9 mmol, 4.46 mL, 98.0 % purity, 10.0 eq.). The mixture was stirred at 90 °C for 1 hr. Once complete, the reaction mixture was concentrated in vacuo to remove the solvent; water (50 mL) was added and the aqueous phase extracted with ethyl acetate (40.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give tert-butyl (1-(2-aminoethyl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate (3.40 g, 8.61 mmol, 95.7 % yield, 91 % purity) as a light-yellow oil. LCMS [M+1]: 360
[0212] Compound 88: To a mixture of tert-butyl N-[1-(2-aminoethyl)-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (200 mg, 556 umol, 1.00 eq) in DCM (10 mL) was added TEA (169 mg, 1.67 mmol, 231 uL, 3.00 eq) and a solution of phenyl carbonchloridate (104 mg, 668 umol, 83.6 uL, 1.20 eq) in DCM (5 mL). The reaction was stirred at -10 - 0 °C for 3 hours under N2. After completion, the reaction was diluted with DCM (10 mL), then washed with H2O (3 × 25 mL), the organic layer was dried over Na2SO4, filtered and concentrated to give the product tert-butyl N-[1-[2-(phenoxycarbonylamino)ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (200 mg, crude) as yellow solid which was used for the next step without further purification.
[0213] Compound 89: A mixture of tert-butyl N-[1-[2-(phenoxycarbonylamino)ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (200 mg, 417 umol, 1.00 eq) in methylamine (2 M, 4.62 mL, 22.1 eq) (in THF) was stirred at 15 °C for another 3 hours under N2. After completion, the reaction was diluted with DCM (15 mL), then washed with H2O (3 × 20 mL), the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (Dichloromethane:Methanol=10:1). The product tert-butyl N-[1-[2-(methylcarbamoylamino)ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (130 mg, 312 umol, 74.8 % yield, 100 % purity) was obtained as white solid. LCMS [M+1]: 417
[0214] Compound 90: To a mixture of tert-butyl N-[1-[2-(methylcarbamoylamino)ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (130 mg, 312 umol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 43.3 eq), and the reaction was stirred at 15 °C for 1 hour. After completion, the reaction was concentrated, diluted with CH3CN (3 mL), then the mixture was adjusted with Na2CO3 solid to pH 7∼8, and the remaining solid was removed by filtration. The filtrate was purified by prep-HPLC (Instrument: GX-A; Column: Phenomenex Gemini 150∗25mm∗10um ; Condition: water (0.05% ammonia hydroxide v/v)-ACN; Begin B: 28; End B: 50; Gradient Time (min): 10; 100%B Hold Time (min): 2; FlowRate (ml/min): 25), the obtained product was concentrated and then lyophilized to give 1-methyl-3-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]ethyl]urea (92.7 mg, 291 umol, 93.2 % yield, 99.2 % purity) as colorless oil. LCMS [M+1]: 317
1H NMR (400 MHz, Methanol-d4) δ 7.27 - 7.17 (m, 2H), 7.13 - 7.08 (m, 1H), 7.07 - 6.99 (m, 2H), 3.24 (t, J=6.6 Hz, 2H), 2.94 - 2.91 (m, 2H), 2.72 - 2.59 (m, 4H), 2.44 (t, J=6.8 Hz, 2H), 2.34 - 2.24 (m, 1H), 2.13 - 2.00 (m, 2H), 1.98 - 1.84 (m, 3H), 1.53 - 1.39 (m, 2H), 1.09 - 0.99 (m, 2H).
EXAMPLE 39
N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]ethyl]propane-2-sulfonamide
[0217] Compound 91: To a mixture of tert-butyl N-[1-(2-aminoethyl)-4-piperidyl]-N-[(1R, 2S)-2-phenylcyclopropyl]carbamate (500 mg, 1.39 mmol, 1.00 eq.) in DCM (20.0 mL) was added TEA (422 mg, 4.17 mmol, 578 uL, 3.00 eq.) and propane-2-sulfonyl chloride (396 mg, 2.78 mmol, 310 uL, 2.00 eq.) at 0 °C. The mixture was warmed to 25 °C slowly and stirred for 15 hrs at 25 °C. Once complete, the reaction mixture was poured into sat. sodium bicarbonate (30.0 mL), and extracted with DCM (40.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove solvent to give tert-butyl (1-(2-(1-methylethylsulfonamido)ethyl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate (700 mg, crude) as an orange oil which used for the next step without further purification. LCMS [M+1]: 466
[0218] Compound 92: To a solution of tert-butyl N-[1-[2-(isopropylsulfonylamino)ethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (700 mg, 1.50 mmol, 1.00 eq.) in DCM (10.0 mL) was added TFA (10.0 mL) at 0 °C, and the resulting mixture was stirred for 1 hr at 0 - 25 °C. Once complete, the reaction mixture was concentrated in vacuo to remove solvent, diluted with acetonitrile (3.00 mL), and the pH was adjusted with sodium hydroxide (1 M) to pH = 7 - 8. Solids were removed by filtration, and the residue was purified by prep-HPLC (base condition) to give compound N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)propane-2-sulfonamide (260 mg, 680 umol, two steps 48.9 % yield, 95.6 % purity) as a yellow oil. LCMS [M+1]: 366.
1H NMR (400 MHz, CD3OD) δ = 7.25 - 7.18 (m, 2H), 7.14 - 7.08 (m, 1H), 7.05 - 7.00 (m, 2H), 3.29 - 3.22 (m, 1H), 3.18 (t, J = 6.8 Hz, 2H), 2.93 (d, J = 11.6 Hz, 2H), 2.64 (m, J = 4.0, 10.8 Hz, 1H), 2.50 (t, J = 6.8 Hz, 2H), 2.34 - 2.26 (m, 1H), 2.15 - 2.01 (m, 2H), 1.98 - 1.84 (m, 3H), 1.52 - 1.39 (m, 2H), 1.32 (d, J = 6.8 Hz, 6H), 1.10 - 0.97 (m, 2H).
EXAMPLE 40
(E)-3-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acrylic acid (98)
Step 1. (E)-Methyl 3-(4-(2-(4-oxopiperidin-1-yl)ethoxy)phenyl)acrylate (94)
[0220] A suspension of (E)-methyl 3-(4-(2-bromoethoxy)phenyl)acrylate (93) (3.00 g, 10.52 mmol, described in WO 2008/033747), 4-piperidone hydrochloride hydrate (1.697 g, 11.05 mmol), K2CO3 (4.36 g, 31.6 mmol), KI (105 mg, 0.631 mmol) and anhydrous Na2SO4 (2.99 g, 21.04 mmol) in DMF (25 mL) was stirred at 90°C overnight, cooled to RT, diluted with brine and extracted with EA. The extract was washed with brine and dried over anhydrous Na2SO4, filtered and evaporated. The remaining oil was purified by flash column chromatography, eluent 10% hexanes in EA then pure EA to afford title compound 94 (1.65 g, 52% yield) as a white solid.
1H NMR: 500 MHz, CDCl3, δ (ppm): 7.65 (d, J = 16.0 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.32 (d, J = 16.0 Hz, 1H), 4.17 (t, J = 5.6 Hz, 2H), 3.79 (s, 3H), 2.95 (t, J = 5.6 Hz, 2H), 2.90 (t, J = 6.1 Hz, 4H), 2.49 (t, J = 6.2 Hz, 4H). MS: 303.4 (calcd.), 304.2 (M+H+) and 322.1 (M+H2O+H+) (found).
Step 2. (E)-Methyl 3-(4-(2-(4-(((1R.2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acrylate (95)
[0221] To the suspension of the (1R,2S)-2-phenylcyclopropanamine (2R, 3R)-tartaric acid salt (2.03 g, 7.07 mmol) and ketone 94 (1.65 g, 5.44 mmol) in a mixture of DCM (10 mL) and DCE (10 mL) were added 4A molecular sieves (2 g) and glacial AcOH (0.5 mL). The resultant mixture was stirred at RT for 6 hrs, cooled to 0°C and treated with the borohydride (2.075 g, 9.79 mmol). The mixture was stirred at 0°C for 30 min then allowed to warm to RT and stirred altogether for 18 hrs. The mixture was then diluted with DCM and filtered through a pad of celite. The filtrate was sequentially washed with a NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, concentrated and the residue was purified by flash column chromatography, eluent 10% MeOH in DCM (MeOH contained 2% ammonia), to afford title compound 95 (1.27 g, 56% yield) as an oil which has solidified in vacuum. MS: 420.5 (calcd.), 421.2 (M+H+, found).
Step 3. (E)-Methyl 3-(4-(2-(4-((tert-butoxycarbonyl)((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acrylate (96)
[0222] To a solution of amine 95 (1.27 g, 3.02 mmol) in DCM (10 mL) was added TEA (2.53 mL, 18.12 mmol). The mixture was cooled by an ice-bath then treated with a solution of the Boc-anhydride (2.64 g, 12.08 mmol) in DCM (15 mL). The mixture was stirred at 0-5°C for 30 min then at ambient temperature for 8 hrs, diluted with DCM, washed with water, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluent EA-hexanes (4:1) to afford title compound 96 (1.189 g, 76% yield) as a honey-like material that contains ca 0.7 M of EA (NMR). The product was taken to the next step as is.
1H NMR: 500 MHz, MeOD, δ (ppm): 7.64 (d, J = 16.0 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.26-7.23 (m, 2H), 7.16-7.11 (m, 3H), 6.97 (d, J = 8.8 Hz, 2H), 6.39 (d, J = 16.0 Hz, 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.77 (s, 3H), 3.75-3.68 (m, 1H), 3.15-3.11 (m, 1H), 3.10-3.06 (m, 1H), 2.81 (t, J = 5.5 Hz, 2H), 2.62-2.59 (m, 1H), 2.25-2.09 (m, 4H), 2.06-1.98 (m, 1H), 1.82-1.79 (m, 1H), 1.76-1.72 (m, 1H), 1.43-1.39 (m, 10H), 1.25-1.21 (m, 1H). MS: 520.7 (calcd.), 521.3 (M+H+, found).
Step 4. (E)-3-(4-(2-(4-((tert-butoxycarbonyl)((1R,2S)-2-phepylgyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acrylic acid (97)
[0223] To a solution of ester 96 (1.189 g, 2.284 mmol) in THF (15 mL) was added a solution of LiOH x H2O (422 mg, 10.05 mmol) in water (15 mL). The reaction mixture was stirred at rt for 48 hrs, acidified to pH 4 with HCl then evaporated to its maximum to remove the THF. The residual aqueous solution was diluted with brine and extracted with DCM. The extract was dried over anhydrous Na2SO4, filtered and the filtrate was evaporated in vacuum to afford title compound 97 (1.014 g, 88% yield) as a white fluffy material. MS: 506.6 (calcd.), 507.3 (M+H+, found).
Step 5. (E)-3-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acrylic acid di-hydrochloride (98)
[0224] To a solution of compound 97 (200 mg, 0.395 mmol) in dioxane (3.0 mL) at rt was added a 4M solution of HCl in dioxane (3.0 ml, 11.84 mmol)). The mixture was stirred at ambient temperature for 3 hrs, evaporated to dryness in vacuum; and the resultant white precipitate was triturated with acetone, collected by filtration and dried to afford title compound 98 (169 mg 89% yield) as a white solid.
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 12.25 (bs, 1H), 10.85 (bs, 1H), 10.01 (bs, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 15.9 Hz, 1H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 6.41 (d, J = 16.0 Hz, 1H), 4.45 (bt, 2H), 3.68 (bs, 2H), 3.66 (bs, 1H), 3.48 (bs, 3H), 3.14 (bs, 2H), 2.97 (bs, 1H), 2.57 (m, 1H), 2.32 (bs, 2H), 2.12 (bs, 1H), 1.61-1.57 (m, 1H), 1.31-1.27 (m, 1H). MS: 406.5 (calcd.), 407.3 (M+H+, found).
EXAMPLE 41
N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]propyl]methanesulfonamide
[0227] Compound 100: To a solution of 1-aminopropan-2-ol (1.00 g, 13.3 mmol, 1.04 mL, 1.00 eq) in pyridine (1.70 mL) was added DMAP (48.8 mg, 399 umol, 0.03 eq) at 0 °C. MsCl (3.05 g, 26.6 mmol, 2.06 mL, 2.00 eq) was added into the mixture drop-wise. The reaction mixture was stirred at 0-10 °C for 1 hour. After completion, water (10 mL) and HCl (1M, 10 mL) was added into the mixture. The resulting mixture was extracted with DCM (3×30 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum to give [2-(methanesulfonamido)-1-methyl-ethyl] methanesulfonate (700 mg, 3.03 mmol, 22.7 % yield) as yellow oil.
1H NMR (400 MHz, CHLOROFORM-d) δ =5.13 - 5.11 (m, 1H), 4.92 - 4.87 (m, 1H), 3.48 - 3.40 (s, 1H), 3.30 - 3.32 (s, 1H), 3.09 (s, 3H), 3.02 (m, 3H), 1.46 (s, 3H).
[0228] Compound 101: To a solution of tert-butyl N-[(1R,2S)-2-phenylcyclopropyl]-N-(4-piperidyl)carbamate (100 mg, 316 umol, 1.00 eq) and [2-(methanesulfonamido)-1-methyl-ethyl] methanesulfonate (73.1 mg, 316 umol, 1.00 eq) in MeCN (3.00 mL) was added K2CO3 (87.4 mg, 632 umol, 2.00 eq). The reaction mixture was stirred at 85 °C for 3 hours. After completion, the precipitate was filtrated off and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (DCM/MeOH=10/1). tert-Butyl N-[1-[2-(methanesulfonamido)-1-methylethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (80.0 mg, 177 umol, 56.1 % yield) was obtained as yellow oil. LCMS [M+1]: 452.
[0229] Compound 102: To a solution of tert-butyl N-[1-[2-(methanesulfonamido)-1-methylethyl]-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (50.0 mg, 111 umol, 1.00 eq) in DCM (1.00 mL) was added TFA (379 mg, 3.32 mmol, 246 uL, 30.0 eq). The reaction mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150∗25∗10um; mobile phase: [water(0.05%HCl)-ACN];B%: 5%-25%,7.8min). The desired fractions were collected and lyophilized to give N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]propyl]methanesulfonamide (12.0 mg, 28.3 umol, 25.5 % yield, 2HCl) as white solid. LCMS [M+1]: 352.
1H NMR (400 MHz, DEUTERIUM OXIDE) δ = 7.33 - 7.22 (m, 3H), 7.14 - 7.12 (m, 2H), 3.97 (br s, 2H), 3.67 - 3.63 (m, 2H), 3.15 (m, 3H), 3.09 (s, 3H), 2.94 (m, 1H), 2.92 (m, 1H), 2.46 - 2.39 (m, 3H), 2.08 (m, 1H), 1.93 (m,1H), 1.48 - 1.30 (m, 2H), 1.23 (m, 3H).
EXAMPLE 42
1-[2-(4-bromophenoxy)ethyl]-4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-2-one
[0232] Compound 103: To a mixture of piperidine-2,4-dione (84.9 mg, 751 umol, 1.00 eq) in MeOH (4.00 mL) was added (1R,2S)-2-phenylcyclopropanamine (100 mg, 751 umol, 1.00 eq) at 25 °C. After stirring at 25 °C for 1 hour, AcOH (90.2 mg, 1.50 mmol, 85.9 uL, 2.00 eq) was added. The resulting mixture was stirred at 25 °C for 2 hours. After completion, water (20 mL) was added into the combined mixture. The resulting mixture was extracted with DCM (3×30 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under vacuum. 4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-2-one (200 mg, crude) was obtained as yellow oil. The crude was used to the next step directly.
[0233] Compound 104: To a solution of 4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-2-one (340 mg, 1.48 mmol, 1.00 eq) in MeOH (2.00 mL) was added Boc2O (644 mg, 2.95 mmol, 678 uL, 2.00 eq) and Et3N (299 mg, 2.95 mmol, 409 uL, 2.00 eq). The reaction mixture was stirred at 60 °C for 2 hours. After completion, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (DCM/MeOH from 50/1 to 20/1). tert-butyl N-(2-oxo-4-piperidyl)-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (200 mg, 551 umol, 37.2 % yield, 91.0 % purity) was obtained as yellow oil. LCMS [M-55]: 275.
[0234] Compound 105: To a solution of tert-butyl N-(2-oxo-4-piperidyl)-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (150 mg, 454 umol, 1.00 eq) in DMF (2.00 mL) was added NaH (36.3 mg, 908 umol, 60 % purity, 2.00 eq) at 0 °C. After stirring at 0 °C for 1 hour, 1-bromo-4-(2-bromoethoxy)benzene (254 mg, 908 umol, 2.00 eq) was added. The reaction mixture was stirred at 0-10 °C for 1 hour. After completion, water (10 mL)was added into the mixture. The resulting mixture was extracted with DCM (3×30 mL). The combined organic phase was dried with anhydrous Na2SO4, filtrated and concentrated under vacuum. The residue was purified by prep-TLC (DCM/MeOH=10/1). tert-butyl N-[1-[2-(4-bromophenoxy)ethyl]-2-oxo-4-piperidyl]-N-[(1R,2S)-2-phenylcyclo propyl]carbamate (40.0 mg, 75.6 umol, 16.6 % yield) as yellow oil. LCMS [M+1, M+3]: 529, 531.
[0235] Compound 106: To a solution of tert-butyl N-[1-[2-(4-bromophenoxy)ethyl]-2-oxo-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (40.0 mg, 75.6 umol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (4 M, 2.00 mL, 105.9 eq). The reaction mixture was stirred at 28 °C for 1 hour. After completion, the reaction mixture was concentrated under vacuum to give 1-[2-(4-bromophenoxy)ethyl]-4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-2-one (27.0 mg, 52.5 umol, 69.5 % yield, 97.6 % purity, 2HCl) as yellow solid. LCMS [M+1, M+23]: 429, 451.
1H NMR (400 MHz, METHANOL-d4) δ = 7.38 - 7.23 (m, 5H), 7.13 - 7.11 (m, 2H), 6.83 - 6.81 (m, 2H), 4.16 (br s, 2H), 3.70 - 3.44 (m, 5H), 2.85 - 2.83 (m, 2H), 2.45 - 2.40 (m, 2H), 2.26 (br s, 1H), 1.92 - 1.74 (m, 1H), 1.45 - 1.39 (m, 2H).
EXAMPLE 43
2-(2-Fluoro-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)pipendin-1-yl)ethoxy)phenyl)acetic acid di-hydrochloride (113)
Step 1. Methyl 2-(4-(2-bromoethoxy)-2-fluorophenyl)acetate (108)
[0237] A suspension of methyl 2-(2-fluoro-4-hydroxyphenyl)acetate (107) (4.0 g, 21.72 mmol, WO 2012/138845), 1,2-dibromoethane (12.0 mL, 139 mmol), K2CO3 (8.41 g, 60.8 mmol) and KI (100 mg, 0.602 mmol) in MeCN (70 mL) was stirred for 24 hr at reflux conditions. The mixture was then cooled to RT, diluted with water and extracted with EA. The extract was dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The resultant oil was subjected to flash column chromatography, eluent EA-hexanes (1:4) to afford title compound 108 (4.65 g, 74% yield) as yellowish oil.
1H NMR: 500 MHz, CDCl3, δ (ppm): 7.16 (t, J = 8.5 Hz, 1H), 6.69-6.63 (m, 2H), 4.26 (t, J = 6.3 Hz, 2H), 3.70 (s, 3H), 3.62, (t, J = 6.2 Hz, 2H), 3.61 (s, 2H).
Step 2. Methyl 2-(2-fluoro-4-(2-(4-oxopiperidin-1-yl)ethoxy)phenyl)acetate (109)
[0238] A suspension of the bromide 108 (4.65 g, 15.97 mmol), piperidone hydrochloride hydrate (3.68 g, 23.96 mmol), K2CO3 (8.83 g, 63.9 mmol), anhydrous Na2SO4 (4.54 g, 31.9 mmol) and KI (265 mg, 1.597 mmol) in MeCN (90 mL) was stirred at reflux conditions for 18 hrs. The mixture was cooled to RT, diluted with water and extracted with EA. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluent 10% MeOH in DCM (MeOH contained 2% ammonia) to afford title compound 109 (4.60 g, 93% yield) as an oil.
1H NMR: 500 MHz, CDCl3, δ (ppm): 7.15 (t, J = 8.6 Hz, 1H), 6.69-6.63 (m, 2H), 4.11 (t, J = 5.6 Hz, 2H), 3.70 (s, 3H), 3.60 (s, 2H), 2.92 (t, J = 5.6 Hz, 2H), 2.89 (t, J = 6.1 Hz, 4H), 2.48 (t, J = 6.2 Hz, 4H). MS: 309.3 (calcd.), 310.2 (M+H+, found).
Step 3 Methyl 2-(2-fluoro-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetate (110)
[0239] To the suspension of (1R,2S)-2-phenylcyclopropanamine (2R, 3R)-tartaric acid salt (3.36 g, 11.85 mmol) and ketone 109 (2.82 g, 9.12 mmol) in a mixture of DCE (20 mL) and DCM (20 mL) were added 4A molecular sieves (3 g) and glacial acetic acid (0.5 mL). The resultant mixture was stirred at RT for 16 hrs, cooled to 0°C then treated with the borohydride (3.48 g, 16.41 mmol). The mixture was stirred at 0°C for 30 min then allowed to warm to RT, stirred altogether for 3 hrs, diluted with DCM and filtered through a celite pad. The filtrate was sequentially washed with a 10% NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluent 10% MeOH in DCM (MeOH contained 2% ammonia) to afford title compound 110 (4.07 g, 105% yield) as an oil. The material was taken to the next step with no extra purification. MS: 426.5 (calcd.), 427.2 (M+H+, found).
Step 4. Methyl 2-(4-(2-(4-((tert-butoxycarbonyl)((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-2-fluorophenyl)acetate (111)
[0240] To a solution of the amine 110 (4.07 g, 9.54 mmol) in DCM (40 mL) was added TEA (4.0 ml, 28.7 mmol). The mixture was cooled by an ice-bath then treated with a solution of Boc-anhydride (4.17 g, 19.08 mmol) in DCM (40 mL). The mixture was stirred at 0-5°C for 30 min then at ambient temperature overnight, diluted with DCM, washed with dilute brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluent EA-hexanes (1:1, then 4:1) to afford title compound 111 (3.72 g, 74% yield) as a honey-like material. The product contained ca 0.5 M of EA and was taken to the next step as is.
1H NMR: 500 MHz, CDCl3, δ (ppm): 7.28-7.25 (m, 2H, overlaps with the residual solvent signal), 7.18-7.11 (m, 2H), 7.09-7.07 (m, 2H), 6.67-6.61 (m, 2H), 4.04 (t, J = 5.9 Hz, 2H), 3.79-3.73 (m, 1H), 3.70 (s, 3H), 3.60 (s, 2H), 3.05-2.97 (m, 2H), 2.76 (t, J = 5.9 Hz, 2H), 2.56-2.53 (m, 1H), 2.20-2.05 (m, 4H), 1.97-1.89 (m, 1H), 1.80-1.71 (m, 2H), 1.42 (s, 9H), 1.40-1.37 (m, 1H), 1.23-1.19 (m, 1H). MS: 526.6 (calcd.), 527.4 (M+H+, found).
Step 5. 2-(4-(2-(4-((tert-Butoxycarbonyl)((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-2-fluorophenyl)acetic acid (112)
[0241] To a solution of ester 111 (3.72 g, 7.06 mmol) in THF (35 mL) was added a solution of LiOH hydrate (741 mg, 17.66 mmol) in 35 mL water. The reaction mixture was stirred at rt for 2 hrs, acidified to pH 6-7 then evaporated to its maximum. The residue was treated with brine and extracted with DCM. The extract was dried over anhydrous Na2SO4, filtered and the filtrate was evaporated to afford title compound 112 (3.57 g, 99% yield) as a white fluffy solid. MS: 512.6 (calcd.), 513.3 (M+H+, found).
Step 6. 2-(2-Fluoro-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid di-hydrochloride (113)
[0242] To a solution of the compound 112 (3.57 g, 6.96 mmol) in dioxane (20 mL) was added a 4M solution of HCl in dioxane (40 ml, 160 mmol) at rt. The mixture was stirred for 3 hrs, diluted with acetone and evaporated almost to completion. The resultant white precipitate was triturated with acetone, collected by filtration and dried in vacuum to afford title compound 113 (2.908 g, 86% yield) as a white solid.
1H NMR: 500 MHz, DMSO6, δ (ppm): 12.39 (bs, 1H), 11.05 and 10.86 (two bs, 1H), 10.05 (bs, 2H), 7.33-7.19 (m, 6H), 6.90 (dd, J = 2.4 and 11.7 Hz, 1H), 6.81 (dd, J = 2.2 and 8.4 Hz, 1H), 4.42 (bt, 2H), 3.68 (bs, 1H), 3.66 (bs, 1H), 3.55 (s, 2H), 3.46 (bs, 3H), 3.13 (bs, 2H), 2.97 (bs, 1H), 2.58 (m, 1H), 2.33 (bs, 2H), 2.11 (bs, 2H), 1.62-1.58 (m, 1H), 1.31-1.28 (m, 1H). MS: 412.5 (calcd.), 413.2 (M+H+, found).
EXAMPLE 44
N,2-dimethyl-N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]ethyl]pyridin-4-amine
[0245] Compound 115: To a solution of 4-chloro-2-methyl-pyridine (1.00 g, 7.84 mmol, 1.00 eq) and tert-butyl N-[2-(methylamino)ethyl]carbamate (1.37 g, 7.84 mmol, 1.00 eq) in DMAC (20.0 mL) was added K2CO3 (2.17 g, 15.7 mmol, 2.00 eq), RuPhos (366 mg, 784 umol, 0.10 eq) and Pd2(dba)3 (359 mg, 392 umol, 0.05 eq). The reaction mixture was stirred at 90 °C under N2 for 12 hours. After completion, water (15 mL) was added into the mixture. The resulting mixture was extracted with EA (3 × 20 mL). The combined organic phase was concentrated under vacuum. The residue was purified by silica gel chromatography (DCM/MeOH from 30/1 to 5/1) to give tert-butyl N-[2-[methyl-(2-methyl-4-pyridyl)amino]ethyl]carbamate (1.80 g, 5.83 mmol, 74.3 % yield, 85.9 % purity) as yellow oil. LCMS [M+1]: 266.
1H NMR (400 MHz, METHANOL-d4) δ = 7.94 - 7.93 (d, J = 6.0 Hz, 1H), 6.56 - 6.54 (m, 2H), 3.52 - 3.48 (t, J = 6.4 Hz, 2H), 3.26 - 3.24 (m, 2H), 3.02 (s, 3H), 2.38 (s, 3H), 1.39 (s, 9H).
[0246] Compound 116: To a mixture of tert-butyl N-[2-[methyl-(2-methyl-4-pyridyl)amino]ethyl]carbamate (1.30 g, 4.90 mmol, 1.00 eq) in MeOH (10.0 mL) was added HCl/dioxane (4.90 mmol, 10.0 mL, 1.00 eq). The reaction mixture was stirred at 25 °C for 2 hours. After completion, the reaction mixture was concentrated under vacuum. The residue was dissolve in MeOH (20 mL) and a basic ion-exchange resin was added into the mixture. The resulting mixture was stirred at 25 °C for 5 hours. The solids were removed by filtration and the filtrate was concentrated under vacuum to give N'-methyl-N'-(2-methyl-4-pyridyl)ethane-1,2-diamine (500 mg, 2.23 mmol, 45.5 % yield, 90.0 % purity, HCl) as yellow oil.
[0247] Compound 117: To a mixture of N'-methyl-N'-(2-methyl-4-pyridyl)ethane-1,2-diamine (1.00 g, 6.05 mmol, 1.00 eq) and K2CO3 (125 mg, 908 umol, 0.150 eq) in EtOH (14.0 mL) was added the mixture of 1-benzyl-1-methyl-1-azinan-4-one (3.01 g, 9.08 mmol, 1.50 eq) in H2O (4.00 mL) at 90 °C for 0.5 hour. The reaction mixture was stirred at 90 °C for another 1 hour. After completion, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (DCM / MeOH from 30/1 to 10/1). Then purified by prep-HPLC (column: Phenomenex Synergi Max-RP 250∗50mm∗10 um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 15%-40%,25MIN;69%min) to give 1-[2-[methyl-(2-methyl-4-pyridyl)amino]ethyl]piperidin-4-one (350 mg, 1.35 mmol, 22.4 % yield, 95.6 % purity) as a colorless oil. LCMS [M+1]: 248.
[0248] 1H NMR (400 MHz, METHANOL-d4) δ = 7.97 - 7.95 (m, 1H), 6.56 - 6.51 (m, 2H), 3.65 - 3.55 (m, 2H), 3.07 - 3.03 (d, J = 16.4 Hz, 3H), 2.86 - 2.85 (m, 2H), 2.72 - 2.71 (m, 1H), 2.57 (m, 3H), 2.46 - 2.44 (m, 2H), 2.39 (s, 3H), 1.79 (m, 2H).
[0249] Compound 118: To a solution of (1R,2S)-2-phenylcyclopropanamine (20.0 mg, 150 umol, 1.00 eq) in MeOH (3.00 mL) was added 1-[2-[methyl-(2-methyl-4-pyridyl)amino]ethyl]piperidin-4-one (44.6 mg, 180 umol, 1.20 eq) at -10 °C, then AcOH (18.0 mg, 300 umol, 17.2 uL, 2.00 eq) was added. 1 hour later, NaBH(OAc)3 (95.5 mg, 451 umol, 3.00 eq) was added. The reaction mixture was stirred at -10 -25 °C for 2 hours. After completion, water (10 mL) was added into the mixture. The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic phase was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150∗25∗10um; mobile phase: [water(0.05%HCl)-ACN];B%: 0%-20%,7.8min).
[0250] The desired fraction were collected and lyophilized to give N,2-dimethyl-N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]ethyl]pyridin-4-amine (32.0 mg, 67.2 umol, 44.7 % yield, 99.5 % purity, 3HCl) as a yellow oil. LCMS [M+1]: 365.
1H NMR (400 MHz, D2O) δ = 7.98 - 7.96 (d, J = 7.6 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.32 - 7.30 (m, 1H), 7.20 - 7.18 (m, 2H), 6.85 (d, J=6.8 Hz, 1H), 6.80 - 6.79 (m, 1H), 4.01 - 3.97 (m, 2H), 3.77 - 3.74 (m, 3H), 3.46 - 3.42 (m, 2H), 3.23 (m, 2H), 3.17 (s, 3H), 3.01 - 2.99 (m, 1H), 2.52 - 2.49 (m, 6H), 2.07 - 1.94 (m, 2H), 1.55 - 1.47 (m, 2H).
EXAMPLE 45
N-phenyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethanesulfonamide
[0253] Compound 120: To a solution of 2-chloroethanesulfonyl chloride (70.0 mg, 429 umol, 44.8 uL, 1.00 eq.) in DCM (5.00 mL) was added TEA (108 mg, 1.07 mmol, 148 uL, 2.50 eq.) and aniline (31.9 mg, 343 umol, 31.3 uL, 0.80 eq.) at 20 °C. After stirring for 2 hrs, tert-butyl ((1R, 2S)-2-phenylcyclopropyl)(piperidin-4-yl)carbamate (163 mg, 515 umol, 1.20 eq.) was added and stirred for 0.5 hrs more. The reaction mixture was concentrated. The residue was purified by prep-TLC to give tert-butyl ((1R,2S)-2-phenylcyclopropyl)(1-(2-(N-phenylsulfamoyl)ethyl)piperidin-4-yl)carbamate (60.0 mg, 273 umol, 63.6 % yield) as a yellow solid. LCMS [M+1]: 500.
[0254] Compound 121: To a solution of tert-butyl ((1R, 2S)-2-phenylcyclopropyl) (1-(2-(N-phenylsulfamoyl)ethyl)piperidin-4-yl)carbamate (60.0 mg, 120 umol, 1.00 eq.) in DCM (3.00 mL) was added TFA (1.85 g, 16.2 mmol, 1.20 mL, 134 eq.) at 0 °C. Then the reaction mixture was stirred at 20 °C for 12 hr. The reaction mixture was neutralized to 7-8 with saturated sodium bicarbonate and then concentrated. The solid was removed by filtration and the filtrate was concentrated to give a residue which purified by prep-HPLC (formic acid) to give N-phenyl-2-(4-(((1R, 2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethanesulfonamide (10.0 mg, 25.0 umol, 20.8 % yield) as a white solid. LCMS [M+1]: 400.
1H NMR (400 MHz, methanol-d4) δ = 8.23 (br s, 2H), 7.36 - 7.29 (m, 2H), 7.27 - 7.20 (m, 4H), 7.11 (td, J = 7.2, 11.2 Hz, 2H), 7.03 (d, J = 7.6 Hz, 2H), 3.27 - 3.19 (m, 2H), 2.73 - 2.63 (m, 4H), 2.62 - 2.55 (m, 1H), 2.35 - 2.26 (m, 1H), 1.97 - 1.82 (m, 3H), 1.73 (br d, J = 11.2 Hz, 2H), 1.34 - 1.21 (m, 2H), 1.07 - 0.94 (m, 2H).
EXAMPLE 46
1-morpholino-3-phenyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one
[0257] Compound 123: To a mixture of 2-amino-3-phenyl-propanoic acid (2.00 g, 12.1 mmol, 1.00 eq) in MeOH (30.0 mL) was added SOCl2 (4.32 g, 36.3 mmol, 2.63 mL, 3.00 eq) in portions at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour, then the mixture was heated to 70 °C and stirred at 70 °C for 2.5 hours. After completion, the reaction mixture was concentrated. The residue was diluted with EA (30 mL), washed with sat. aq. NaHCO3 (2 × 30 mL), the organic layer was washed with brine (2 × 30 mL), dried over Na2SO4, filtered and concentrated. The product methyl 2-amino-3-phenyl-propanoate (1.80 g, 10.0 mmol, 82.9 % yield) was obtained as a yellow oil.
1H NMR (400 MHz, Chloroform-d) δ 7.36 - 7.20 (m, 5H), 3.79 - 3.73 (m, 4H), 3.12 (dd, J=5.2, 13.6 Hz, 1H), 2.88 (dd, J=8.0, 13.6 Hz, 1H)
[0258] Compound 124: To a mixture of methyl 2-amino-3-phenyl-propanoate (1.80 g, 10.0 mmol, 1.00 eq) and K2CO3 (208 mg, 1.51 mmol, 0.15 eq) in EtOH (20.0 mL) was added a mixture of 1-benzyl-1-iodo-1-methyl-2,3,5,6-tetrahydropyridin-4-one (4.99 g, 15.1 mmol, 1.50 eq) in H2O (10.0 mL) in portions at 78 °C, then the mixture was heated to 90 °C and stirred at 90 °C for 3 hours. After completion, the reaction mixture was diluted with water (30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=10/1∼5/1) to give ethyl 2-(4-oxo-1-piperidyl)-3-phenyl-propanoate (2.00 g, 6.73 mmol, 67.1 % yield, 92.7 % purity) as yellow oil.
1H NMR (400 MHz, Chloroform-d) δ 7.33 - 7.21 (m, 5H), 4.15 - 4.07 (m, 2H), 3.63 (dd, J=6.8, 8.8 Hz, 1H), 3.17 - 2.97 (m, 4H), 2.95 - 2.84 (m, 2H), 2.51 - 2.37 (m, 4H), 1.19 (t, J=7.2 Hz, 3H)
[0259] Compound 125: To a mixture of ethyl 2-(4-oxo-1-piperidyl)-3-phenyl-propanoate (500 mg, 1.82 mmol, 1.00 eq) in MeOH (10.0 mL) and H2O (2.00 mL) was added NaOH (291 mg, 7.28 mmol, 4.00 eq), the reaction mixture was stirred at 20 °C for 3 hours. After completion, the reaction mixture was adjusted to pH ∼6, then concentrated. The solid was dissolved with MeOH (10 mL), concentrated, the residue was triturated with DCM (15 mL), the solid was filtered and dried. The product 2-(4-oxo-1-piperidyl)-3-phenyl-propanoic acid (380 mg, 1.34 mmol, 73.6 % yield, HCl) was obtained as gray solid.
1H NMR (400 MHz, DMSO-d6) δ 7.34 - 7.16 (m, 5H), 3.55 (dd, J=6.8, 8.0 Hz, 1H), 3.04 - 2.76 (m, 6H), 2.46 - 2.21 (m, 4H)
[0260] Compound 126: To a mixture of 2-(4-oxo-1-piperidyl)-3-phenyl-propanoic acid (200 mg, 809 umol, 1.00 eq) in DMF (8.00 mL) wasd added HATU (615 mg, 1.62 mmol, 2.00 eq) and DIPEA (209 mg, 1.62 mmol, 282 uL, 2.00 eq) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 hour, morpholine (141 mg, 1.62 mmol, 142 uL, 2.00 eq) was added, and the mixture was stirred at 0-15 °C for 11.5 hours. After completion, the reaction mixture was diluted with water (30 mL), then extracted with DCM (2 × 15 mL), the combined organic layer was washed with brine (2 × 40 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate=1:1) to give 1-(1-benzyl-2-morpholino-2-oxoethyl)piperidin-4-one (140 mg, 442 umol, 54.7 % yield, 100 % purity) as yellow solid. LCMS [M+1]: 317.
1H NMR (400 MHz, Chloroform-d) δ 7.32 - 7.20 (m, 5H), 3.85 (dd, J=4.0, 10.0 Hz, 1H), 3.62 - 3.41 (m, 6H), 3.29 - 3.02 (m, 5H), 2.99 - 2.92 (m, 3H), 2.46 (t, J=6.0 Hz, 4H)
[0261] Compound 127: To a mixture of 1-(1-benzyl-2-morpholino-2-oxo-ethyl)piperidin-4-one (140 mg, 442 umol, 1.00 eq) in MeOH (10.0 mL) was added (1R,2S)-2-phenylcyclopropanamine (58.9 mg, 442 umol, 1.00 eq) and AcOH (53.1 mg, 885 umol, 50.6 uL, 2.00 eq) at -10 °C. The resulting mixture was stirred at -10 °C for 0.5 hour, NaBH3CN (83.4 mg, 1.33 mmol, 3.00 eq) was added in portions, and the mixture was stirred at 0 - 15 °C for 11.5 hours. After completion, the reaction mixture was diluted with water (15 mL), then extracted with DCM (2 × 15 mL), the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (Instrument: GX-F; Column: Phenomenex Gemini 150∗25mm∗10um; Condition: water (0.05 % HCl)-ACN; Begin B: 5; End B: 29; Gradient Time (min): 8; 100%B Hold Time (min): 2; FlowRate (ml/min): 25), the obtained product was concentrated and then lyophilized. The product 1-morpholino-3-phenyl-2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]-1-piperidyl]propan-1-one (85.0 mg, 168 umol, 37.9 % yield, 100 % purity, 2HCl) was obtained as a white solid. LCMS [M+1]: 434.
1H NMR (400 MHz, Deuterium oxide) δ 7.41 - 7.29 (m, 5H), 7.28 - 7.18 (m, 3H), 7.15 (d, J=8.0 Hz, 2H), 4.16 - 3.92 (m, 1H), 3.75 - 3.71 (m, 1H), 3.62 - 3.45 (m, 4H), 3.41 - 3.06 (m, 7H), 3.04 - 2.90 (m, 2H), 2.85 - 2.62 (m, 1H), 2.56 - 2.33 (m, 3H), 2.33 - 2.20 (m, 1H), 2.16 - 1.91 (m, 2H), 1.53 - 1.39 (m, 2H)
EXAMPLE 47
1-(2-(4-bromophenoxy)ethyl)-4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidine-2,6-dione
[0264] Compound 129: To a mixture of 4-bromophenol (2.00 g, 11.6 mmol, 1.00 eq) and 2-bromoacetonitrile (1.66 g, 13.9 mmol, 924 uL, 1.20 eq) in MeCN (30.0 mL) was added K2CO3 (3.99 g, 28.9 mmol, 2.50 eq), and the mixture was stirred at 80 °C for 3 hours. After completion, solids were removed by filtration and the filtrate concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 10:1) to give 2-(4-bromophenoxy)acetonitrile (2.10 g, 9.83 mmol, 85.1 % yield, 99.3 % purity) as white solid.
1H NMR (400 MHz, Chloroform-d) δ 7.49 (d, J=9.2 Hz, 2H), 6.90 (d, J=9.2 Hz, 2H), 4.77 (s, 2H).
[0265] Compound 130: To a mixture of 2-(4-bromophenoxy)acetonitrile (1.90 g, 8.96 mmol, 1.00 eq) in THF (20.0 mL) was added BH3.THF (1 M, 26.9 mL, 3.00 eq) in portions at 0 °C, the reaction was stirred at 0 °C for 2 hours, then the reaction mixture was heated to 80 °C and stirred at 80 °C for 12 hours. After completion, the reaction mixture was quenched with MeOH (30 mL) until no gas was formed, then concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=5:1 to Dichloromethane: Methanol=10:1) to give 2-(4-bromophenoxy)ethanamine (1.60 g, 7.26 mmol, 80.9 % yield, 97.9 % purity) as yellow oil. LCMS [M+1, M+3]: 216, 218.
[0266] Compound 132: To a mixture of dimethyl 3-oxopentanedioate (686 mg, 3.94 mmol, 567 uL, 1.05 eq) and (1R,2S)-2-phenylcyclopropanamine (500 mg, 3.75 mmol, 1.00 eq) in MeOH (15.0 mL) was added AcOH (450 mg, 7.50 mmol, 429 uL, 2.00 eq) at -10 °C. The mixture was stirred at -10 °C for 1 hour, then NaBH3CN (707 mg, 11.3 mmol, 3.00 eq) was added to the mixture in portions at -10 °C, and the reaction was stirred at -10 ∼ 0 °C for 2 hours. After completion, the reaction mixture was added to water (20 mL), then extracted with DCM (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give dimethyl 3-[[(1R,2S)-2-phenylcyclopropyl]amino]pentanedioate (1.00 g, crude) as yellow oil. LCMS [M+1]: 292.
[0267] Compound 133: A mixture of dimethyl 3-[[(1R,2S)-2-phenylcyclopropyl]amino] pentanedioate (900 mg, 3.09 mmol, 1.00 eq) in (Boc)2O (9.50 g, 43.5 mmol, 10.0 mL, 14.1 eq) was stirred at 15 °C for 12 hours. After completion, the mixture was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 5/1) to give dimethyl 3-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]pentanedioate (500 mg, 1.20 mmol, 38.7 % yield, 93.7 % purity) as a colorless oil. LCMS [M-99]: 292
1H NMR (400 MHz, Chloroform-d) δ 7.31 - 7.25 (m, 2H), 7.22 - 7.08 (m, 3H), 4.38 - 4.29 (m, 1H), 3.71 (s, 3H), 3.64 (s, 3H), 3.10 - 2.93 (m, 2H), 2.77 - 2.63 (m, 3H), 2.18 - 2.14 (m, 1H), 1.48 - 1.35 (m, 10H), 1.31 - 1.14 (m, 1H).
[0268] Compound 134: To a mixture of dimethyl 3-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]pentanedioate (400 mg, 1.02 mmol, 1.00 eq) in EtOH (15.0 mL) was added KOH (80.8 mg, 1.22 mmol, 85 % purity, 1.20 eq), and the reaction was stirred at 15 °C for 4 hours. After completion, the reaction mixture was adjusted with 1 M HCl to pH ∼6, then extracted with DCM (2 × 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 3-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-5-ethoxy-5-oxo-pentanoic acid (270 mg, 684 umol, 67.1 % yield, 99.2 % purity) as yellow oil. LCMS [M-99]: 292.
[0269] Compound 135: To a mixture of 3-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-5-ethoxy-5-oxo-pentanoic acid (330 mg, 843 umol, 1.00 eq) in DMF (10.0 mL) wasd added HATU (641 mg, 1.69 mmol, 2.00 eq) and DIPEA (218 mg, 1.69 mmol, 294 uL, 2.00 eq) at 0 °C. After the reaction was stirred at 0 °C for 0.5 hour, 2-(4-bromophenoxy)ethanamine (237 mg, 1.10 mmol, 1.30 eq) was added, and the mixture was stirred at 0 - 15 °C for 11.5 hours. After completion, the reaction mixture was added to water (15 mL), then extracted with DCM (2 × 15 mL), the combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=50:1∼3:1) to give ethyl 5-[2-(4-bromophenoxy)ethylamino]-3-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-5-oxo-pentanoate (330 mg, 515 umol, 61.1 % yield, 92 % purity) as a yellow oil. LCMS [M-99]: 489,491.
[0270] Compound 136: To a mixture of ethyl 5-[2-(4-bromophenoxy)ethylamino]-3-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-5-oxo-pentanoate (250 mg, 424 umol, 1.00 eq) in MeOH (2.00 mL) and H2O (500 uL) was added NaOH (67.9 mg, 1.70 mmol, 4.00 eq), and the mixture was stirred at 15 °C for 3 hours. After completion, the reaction mixture was diluted with 0.5 M HCl aqueous solution to pH∼7, then the mixture was added to water (10 mL), and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 5-[2-(4-bromophenoxy)ethylamino]-3-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-5-oxo-pentanoic acid (180 mg, 306 umol, 72.1 % yield, 95.4 % purity) as yellow solid. LCMS [M-99, M+23]: 463, 585.
[0271] Compound 137: To a mixture of 5-[2-(4-bromophenoxy)ethylamino]-3-[tert-butoxycarbonyl-[(1R,2S)-2-phenylcyclopropyl]amino]-5-oxo-pentanoic acid (120 mg, 214 umol, 1.00 eq) in THF (4.00 mL) was added Ac2O (43.6 mg, 427 umol, 40.0 uL, 2.00 eq), and the reaction was stirred at 70 °C for 12 hours under N2. After completion, the reaction mixture was concentrated. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate=3:1) to give tert-butyl N-[1-[2-(4- bromophenoxy)ethyl]-2,6-dioxo-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (60.0 mg, 109 umol, 51.4 % yield, 99.5 % purity) as a white solid. LCMS [M-55, M+23]: 487, 567.
1H NMR (400 MHz, Chloroform-d) δ 7.40 - 7.19 (m, 5H), 7.11 - 7.04 (m, 2H), 6.81 - 6.74 (m, 2H), 4.18 (t, J=6.2 Hz, 2H), 4.13 - 4.03 (m, 3H), 3.45 - 3.30 (m, 2H), 2.93 - 2.82 (m, 2H), 2.74 - 2.67 (m, 1H), 2.19 - 2.06 (m, 1H), 1.42 (s, 9H), 1.33 - 1.25 (m, 2H).
[0272] Compound 138: To a mixture of tert-butyl N-[1-[2-(4-bromophenoxy)ethyl]-2,6-dioxo-4-piperidyl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate (60.0 mg, 110 umol, 1.00 eq) in DCM (500 uL) was added TFA (770 mg, 6.75 mmol, 500 uL, 61.2 eq), and the reaction was stirred at 15 °C for 1 hour. After completion, the reaction mixture was concentrated. The residue was purified by prep-HPLC ((Instrument: GX-E; Column: Phenomenex Synergi C18 150∗25∗10um; Condition: water (0.05 % HCl)-ACN; Begin B: 35; End B: 55; Gradient Time (min): 7.8; 100%B Hold Time (min): 2; FlowRate (ml/min): 28). The obtained product was concentrated and then lyophilized. The product 1-[2-(4-bromophenoxy)ethyl]-4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidine-2,6-dione (30.8 mg, 63.9 umol, 57.9 % yield, 99.8 % purity, HCl) was obtained as a yellow oil. LCMS [M+1]: 443, 445.
1H NMR (400 MHz, Methanol-d4) δ 7.41 - 7.31 (m, 4H), 7.29 - 7.17 (m, 3H), 6.85 (d, J=8.4 Hz, 2H), 4.20 - 4.06 (m, 5H), 3.32 - 3.22 (m, 2H), 3.18 - 3.01 (m, 3H), 2.65 - 2.54 (m, 1H), 1.68 - 1.56 (m, 1H), 1.53 - 1.43 (m, 1H).
EXAMPLE 48
1-Morpholino-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one di-hydrochloride (142)
Step 1. Methyl 3-(4-((tert-butoxycarbonyl)((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-vl)propanoate (139)
[0274] To a solution of the intermediate 79 (1.00 g, 3.16 mmol) in DMF (8 mL) were added TEA (1.189 mL, 8.53 mmol), KI (131 mg, 0.790 mmol) and methyl-3-bromopropionate (0.345 mL, 3.16 mmol). The reaction mixture was stirred at RT for 4 hrs, diluted with brine and extracted with EA. The extract was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was subjected to flash column chromatography, eluent EA-hexanes (4:1) to afford title compound 65 (1.027 g, 81% yield) as a gum. The product contains 0.18 M of EA per 1M of the desired compound.
1H NMR: 500 MHz, acetone-d6, δ (ppm): 7.32-7.28 (m, 2H), 7.21-7.18 (m, 3H), 3.68-3.62 (m, 1H), 3.65 (s, 3H), 3.00-2.93 (m, 2H), 2.65-2.61 (m, 3H), 2.48 (t, J = 7.2 Hz, 2H), 2.19-2.10 (m, 3H), 2.06-2.00 (m, 2H), 1.76-1.67 (m, 2H), 1.43 (s, 9H), 1.42-1.38 (m, 1H), 1.29-1.25 (m, 1H). MS: 402.5 (calcd.), 403.3 (M+H+, found).
Step 2. 3-(4-((tert-Butoxycarbonyl)((1R2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanoic acid (140)
[0275] To a solution of ester 139 (1.027 g, 2.55 mmol) in THF (20 mL) was added a solution of NaOH (153 mg, 3.83 mmol) in water (10 mL). The reaction mixture was stirred at rt for 2 hrs. acidified to pH 5 with HCl. The acidic solution was evaporated in vacuum to form a glassy solid. The material was then suspended in DCM, treated with hexanes and evaporated to afford the title compound 140 (1.13 g, 99% yield) as white fluffy solid which contained 1.5 eq of NaCl. The material was taken to the next step as is. MS: 388.5 (calcd.), 389.7 (M+H+, found).
Step 3. tert-Butyl (1-(3-morpholino-3-oxopropyl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate (141)
[0276] To a suspension of acid 140 (800 mg, 1.79 mmol) in DCM (30 mL) was added HOBt hydrate (548 mg, 3.58 mmol), EDC hydrochloride (1.029 g, 5.37 mmol) and morpholine (0.627 mL, 7.16 mmol). The reaction mixture was stirred overnight at rt, diluted with more DCM and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluent 5 then 10% MeOH (with 2% ammonia) in DCM to afford title compound 141 (748 mg, 91% yield) as a honey-like material that contains ca 0.6 M of DCM per 1M of the product The material was taken to the next step as is.
1H NMR: 500 MHz, CD3OD, δ (ppm): 7.26-7.23 (m, 2H), 7.16-7.10 (m, 3H), 3.72-3.68 (m, 1H), 3.67-3.62 (m, 4H), 3.57-3.53 (m, 4H), 3.05-2.98 (m, 2H), 2.69-2.66 (m, 2H), 2.62-2.56 (m, 3H), 2.13-2.09 (m, 4H), 2.02-1.94 (m, 1H), 1.82-1.79 (m, 1H), 1.75-1.72 (m, 1H), 1.41 (s, 9H), 1.40-1.38 (m, 1H), 1.25-1.21 (m, 1H). MS: 457.6 (calcd.), 458.4 (M+H+, found).
Step 4. 1-Morpholino-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one di-hydrochloride (142)
[0277] To a solution of compound 141 (748 mg, 1.635 mmol) in dioxane (7.0 mL) at rt was added a 4M HCl solution of in dioxane (12.0 ml, 48 mmol). The mixture was stirred at ambient temperature for 3 hrs, evaporated to dryness in vacuum. The resultant white precipitate was triturated with acetone to afford title compound 142 (637 mg, 91% yield) as a white solid (Example 48).
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 10.71 and 10.52 (two bs, 1H, mixture of rotamers), 10.18 and 10.02 (2 bs, 2H, mixture of rotamers), 7.32-7.29 (m, 2H), 7.24-7.17 (m, 3H), 3.61-3.59 (m, 4H), 3.56-3.54 (m, 2H), 3.45-3.44 (m, 5H), 3.24 (bt, 2H), 3.03-2.94 (m, 3H), 2.89 (t, J = 7.6 Hz, 2H), 2.68-2.65 and 2.59-2.55 (two m, 1H, mixture of rotamers), 2.32-2.21 (bs, 2H), 2.11-2.01 (m, 2H), 1.66 and 1.60-1.56 (bs and m, 1H, mixture of rotamers), 1.31-1.27 (m, 1H). MS: 357.5 (calcd.), 358.7 (M+H+, found).
[0278] Following the general teachings of the Reaction Schemes and specific synthetic routes set forth herein, the additional following compounds were prepared:
| Further Exemplary Compounds of the Invention | ||||
| Ex. # | Structure | Method | LCMS [M+1] Observed | 1H NMR |
| 49 |
|
Scheme 2b | 409.4 | (400 MHz, methanol-d4) δ 7.38 - 7.30 (m, 2H), 7.29 - 7.18 (m, 5H), 6.91 (d, J = 8.8 Hz, 2H), 4.13 (t, J = 5.4 Hz, 2H), 3.89 - 3.68 (m, 3H), 3.60 - 3.52 (m, 2H), 3.40 - 331 (m, 2H), 3.26 - 3.12 (m, 2H), 3.07 - 3.04 (m, 1H), 2.67 - 2.42 (m, 3H), 2.34 - 2.09 (m, 4H), 1.65 - 1.56 (m, 1H), 1.52 - 1.46 (m, 1H). |
| 2-(4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acetic acid | ||||
| 50 |
|
Example 20 | 433.3 | (400 MHz, deuterium oxide) δ 7.28 - 7.21 (m, 2H), 7.20 - 7.14 (m, 3H), 7.13 - 7.03 (m, 4H), 3.70 - 3.57 (m, 5H), 3.50 - 3.47 (m, 2H), 3.40 - 3.36 (m, 2H), 3.19 - 3.02 (m, 2H), 2.89 - 2.85 (m, 1H), 2.45 - 2.28 (m, 5H), 2.00 - 1.72 (m, 6H), 1.45 - 1.29 (m, 2H) |
| 1-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)piperidin-2-one | ||||
| 51 |
|
Example 20 | 435.4 | (400 MHz, deuterium oxide) δ 7.32 - 7.17 (m, 5H), 7.10 (d, J = 7.6 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 4.35 (t, J = 5.2 Hz, 2H), 3.74 - 3.54 (m, 7H), 3.44 - 3.34 (m, 2H), 3.13 - 3.04 (m, 2H), 2.93 - 2.86 (m, 1H), 2.48 - 2.31 (m, 3H), 2.15 - 1.85 (m, 4H), 1.50 - 1.32 (m, 2H) |
| 3-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-one | ||||
| 52 |
|
Example 20 | 435.2 | (400 MHz, deuterium oxide) δ 7.38 - 7.04 (m, 7H), 7.00 - 6.76 (m, 2H), 4.24 (s, 2H), 4.05 - 3.91 (m, 2H), 3.74 - 3.51 (m, 7H), 3.42 - 3.28 (m, 2H), 3.20 - 3.09 (m, 2H), 2.94 - 2.86 (m, 1H), 2.51 - 2.25 (m, 3H), 2.02 - 1.84 (m, 2H), 1.51 - 1.30 (m, 2H) |
| 4-(4-((2-(4-(((1R2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)morpholin-3-one | ||||
| 53 |
|
Example 20 | 419.3 | (400 MHz, deuterium oxide) δ 7.36 - 7.26 (m, 4H), 7.25 - 7.17 (m, 1H), 7.12 - 7.10 (m, 2H), 6.78 - 6.75 (m, 2H), 3.79 - 3.58 (m, 3H), 3.57 - 3.39 (m, 6H), 3.35 - 3.26 (m, 2H), 3.20 - 2.99 (m, 2H), 2.93 - 2.91 (m, 1H), 2.54 - 2.29 (m, 3H), 2.06 - 1.70 (m, 7H), 1.60 - 1.32 (m, 3H) |
| N-((1R,2S)-2-phenylcyclopropyl)-1-(2-((4-(piperidin-1-yl)phenyl)amino)ethyl)piperidin-4-amine | ||||
| 54 |
|
Example 20 | 421.2 | (400 MHz, deuterium oxide) δ 7.33 (d, J = 8.8 Hz, 2H), 7.28 - 7.12 (m, 3H), 7.08 - 7.02 (m, 2H), 6.77 (d, J=8.0 Hz, 2H), 4.02 - 3.92 (m, 4H), 3.72 - 3.45 (m, 9H), 3.29 - 3.24 (m., 2H), 3.12 - 3.06 (m, 2H), 2.94 - 2.82 (m, 1H), 2.48 - 2.23 (m, 3H), 2.04 - 1.85 (m, 2H), 1.49 - 1.28 (m, 2H) |
| 1-(2-((4-morpholinophenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 55 |
|
Example 20 | 434.3 | (400 MHz, deuterium oxide) δ 7.40 - 6.99 (m, 9H), 3.95 - 3.54 (m, 9H), 3.51 - 3.05 (m, 8H), 3.00 - 2.86 (m, 4H), 2.51 - 2.29 (m, 3H), 2.05 - 1.88 (m, 2H), 1.52 - 1.33 (m, 2H) |
| 1-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 56 |
|
Example 20 | 419.3 | (400 MHz, deuterium oxide) δ 7.42 (d, J = 8.4 Hz, 2H), 7.29 - 7.10 (m, 5H), 7.09 - 6.99 (m, 2H), 3.83 - 3.54 (m, 7H), 3.42 - 3.38 (m, 2H), 3.14 - 3.08 (m, 2H), 2.89 - 2.72 (m, 1H), 2.53 - 2.27 (m, 5H), 2.08 - 1.82 (m, 4H), 1.45 - 1.26 (m, 2H) |
| 1-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)pyrrolidin-2-one | ||||
| 57 |
|
Example 20 | 421.2 | (400 MHz, deuterium oxide) δ 7.36 (d, J = 8.8 Hz, 2H), 7.29 - 7.23 (m, 2H), 7.22 - 7.16 (m, 1H), 7.08 - 7.03 (m, 4H), 4.40 (t, J = 8.2 Hz, 2H), 3.98 (t, J = 8.2 Hz, 2H), 3.71 - 3.57 (m, 5H), 3.42 - 3.33 (m, 2H), 3.16 - 3.04 (m, 2H), 2.90 - 2.88 (m, 1H), 2.47 - 2.29 (m, 3H), 2.02 - 1.85 (m, 2H), 1.50 - 1.31 (m, 2H). |
| 3-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)oxazolidin-2-one | ||||
| 58 |
|
Example 20 | 434.2 | (400 MHz, deuterium oxide) δ 7.57 - 7.33 (m, 2H), 7.33 - 7.04 (m, 7H), 3.91 - 3.55 (m, 7H), 3.52 - 3.34 (m, 4H), 3.21 - 3.06 (m, 2H), 2.92 - 2.90 (m, 4H), 2.48 - 2.32 (m, 3H), 2.05 - 1.85 (m, 2H), 1.50 - 1.33 (m, 2H). |
| 1-methyl-3-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-l)ethyl)amino)phenyl)imidazolidin-2-one | ||||
| 59 |
|
Scheme 3b | 338.1 | (400 MHz, methanol-d4) δ, 7.37 - 7.31 (m, 2H), 7.29 - 7.24 (m, 1H), 7.22 (d, J = 7.6 Hz, 2H), 3.86 (d, J = 12.0 Hz, 2H), 3.79 - 3.64 (m, 1H), 3.61 - 3.47 (m, 2H), 3.39 - 3.34 (m, 2H), 3.28 - 3.15 (m, 2H), 3.10-3.00 (m, 4H), 2.60 - 2.54 (m, 1H), 2.48 (t, J = 12.4 Hz, 2H), 2.20 - 2.05 (m, 2H), 1.65 - 1.56 (m, 1H), 1.50 - 1.43 (m, 1H) |
| N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)methanesulfonamide | ||||
| 60 |
|
Scheme 3b | 400.2 | (400 MHz, methanol-d4) δ, 7.93 (d, J = 7.2 Hz, 2H), 7.73 - 7.67 (m, 1H), 7.67 - 7.60 (m, 2H), 7.39 - 7.30 (m, 2H), 7.30 - 7.24 (m, 1H), 7.22 (d, J = 7.6 Hz, 2H), 3.84 (d, J = 12.8 Hz, 2H), 3.77 - 3.67 (m, 1H), 3.50 (br. s., 1H), 3.30 - 3.18 (m, 4H), 3.09 - 3.04 (m, 1H), 2.62 - 2.55 (m, 1H), 2.49 (t, J = 12.8 Hz, 2H), 2.35 (br. s., 1H), 2.23 - 2.13 (m, 2H), 1.73 - 1.58 (m, 1H), 1.50 - 1.42 (q, J = 7.1 Hz, 1H). |
| N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)benzenesulfonamide | ||||
| 61 |
|
Scheme 2b | 395.2 | (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 10.24 - 9.59 (m, 3H), 7.91 (d, J = 8.4 Hz, 2H), 7.37 - 7.28 (m, 2H), 7.27 - 7.16 (m, 3H), 7.03 (d, J = 8.8 Hz, 2H), 4.14 (t, J = 5.8 Hz, 2H), 3.65 - 3.53 (m, 2H), 3.54 - 3.46 (m, 1H), 3.21 - 3.09 (m, 2H), 3.07 - 2.92 (m, 3H), 2.39 - 1.95 (m, 7H), 1.63 - 1.52 (m, 1H), 1.33 - 1.29 (m, 1H). |
| 4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)benzoic acid | ||||
| 62 |
|
Example 34 | 421.2 | (400 MHz, DMSO-d6) δ 12.27 (br. s., 1H), 10.59 (br. s., 1H), 9.98 (br. s., 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 16.0 Hz, 1H), 7.40 - 7.28 (m, 2H), 7.27 - 7.15 (m, 3H), 6.98 (d, J = 8.0 Hz, 2H), 6.39 (d, J = 16.0 Hz, 1H), 4.11 (t, J = 5.6 Hz, 2H), 3.66 - 3.55 (m, 2H), 3.20 - 3.08 (m, 3H), 3.02 - 2.96 (m, 3H), 2.41 - 1.95 (m, 7H), 1.64 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H) |
| (E)-3-(4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylic acid | ||||
| 63 |
|
Example 20 | 462.2 | (400 MHz, deuterium oxide) δ 7.28 (d, J = 8.8 Hz, 2H), 7.19 - 7.10 (m, 3H), 7.05 - 6.96 (m, 2H), 6.78 - 6.75 (m, 2H), 3.88 - 3.73 (m, 4H), 3.68 - 3.51 (m, 5H), 3.39 - 3.36 (m, 4H), 3.27 - 3.22 (m, 2H), 3.04 - 2.98 (m, 2H), 2.84 - 2.80 (m, 1H), 2.42 - 2.22 (m, 3H), 2.01 (s, 3H), 1.98 - 1.82 (m, 2H), 1.43 - 1.22 (2, 2H) |
| 1-(4-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)piperazin-1-yl)ethan-1-one | ||||
| 64 |
|
Example 12 | 403.1 | (400 MHz, Methanol-d4) δ7.46 (d, J = 9.2 Hz, 2H), 7.38 - 7.29 (m, 2H), 7.29 - 7.18 (m, 3H), 6.96 (d, J = 9.2 Hz, 2H), 4.50 - 4.41 (m, 2H), 4.36 - 4.20 (m, 4H), 3.82 - 3.57 (m, 4H), 3.48 - 3.37 (m, 1H), 3.07 - 2.96 (m, 1H), 2.64 - 2.58 (m, 1H), 1.64 - 1.59 (m, 1H), 1.46 - 1.41 (m, 1H) |
| (1R,2S)-N-((1-(2-(4-bromophenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine | ||||
| 65 |
|
Scheme 2b | 405.1 | (400 MHz, Methanol-d4) δ7.50 (d, J=2.8 Hz, 1H), 7.39 - 7.31 (m, 3H), 7.30 - 7.16 (m, 4H), 4.61 - 4.50 (m, 2H), 4.01 - 3.95 (m, 2H), 3.84 - 3.66 (m, 3H), 3.42 - 3.36 (m, 2H), 3.08 - 3.04 (m, 1H), 2.63 - 2.40 (m, 3H), 2.24 - 2.18 (m, 2H), 1.71 - 1.57 (m, 1H), 1.52 - 1.46 (m, 1H) |
| 1-(2-(2,4-dichlorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 66 |
|
Example 11 | 391.0 | (400 MHz, deuterium oxide) δ7.49 (d, J = 2.8 Hz, 1H), 7.39 - 7.29 (m, 3H), 7.29 - 7.18 (m, 3H), 7.15 (d, J = 8.8 Hz, 1H), 4.61 - 4.48 (m, 2H), 4.42 - 4.26 (m., 4H), 3.83 - 3.76 (m, 2H), 3.73 - 3.60 (m, 2H), 3.43 - 3.34 (m, 1H), 3.06 - 2.98 (m, 1H), 2.62 - 2.55 (m, 1H), 1.64 - 1.56 (m, 1H), 1.47 - 1.41 (m, 1H). |
| (1R,2S)-N-((1-(2-(2,4-dichlorophenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine | ||||
| 67 |
|
Scheme 2b | 373.2 | (400 MHz, deuterium oxide) δ7.31 - 7.23 (m, 2H), 7.22 - 7.16 (m, 1H), 7.09 (d, J = 7.2 Hz, 2H), 7.04 - 7.00 (m, 1H), 6.95 - 6.91 (m, 1H), 6.86 - 6.77 (m, 1H), 4.37 - 4.26 (m, 2H), 3.83 - 3.59 (m, 3H), 3.57 - 3.48 (m., 2H), 3.21 - 3.13 (m, 2H), 2.94 - 2.87 (m, 1H), 2.49 - 2.30 (m, 3H), 2.06 - 1.88 (m, 2H), 1.50 - 1.33 (m, 2H) |
| 1-(2-(2,4-difluorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 68 |
|
Example 11 | 359.2 | (400 MHz, deuterium oxide) δ7.26 - 7.19 (m, 2H), 7.17 - 7.11 (m, 1H), 7.07 (d, J = 7.2 Hz, 2H), 7.02 - 6.88 (m, 2H), 6.85 - 6.77 (m, 1H), 4.42 - 4.28 (m, 2H), 4.21 - 3.98 (m, 4H), 3.68 - 3.42 (m, 4H), 3.39 - 3.25 (m, 1H), 2.94 - 2.83 (m, 1H), 2.44 - 2.38 (m, 1H), 1.47 - 1.38 (m, 1H), 1.36 - 1.28 (m, 1H). |
| (1R,2S)-N-((1-(2-(2,4-difluorophenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine | ||||
| 69 |
|
Example 35 | 514.3 | (400 MHz, deuterium oxide) δ 7.57 (d, J = 15.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.34 - 7.19 (m, 3H), 7.12 (d, J = 7.6 Hz, 2H), 6.98 - 6.88 (m, 2H), 6.29 (d, J = 16 Hz, 1H), 4.49 - 4.42 (m, 1H), 4.12 - 3.98 (m, 2H), 3.84 - 3.61 (m, 3H), 3.43 - 3.25 (m, 5H), 3.24 - 3.00 (m, 2H), 2.94 - 2.92 (m, 1H), 2.51 - 2.31 (m, 3H), 2.12 - 1.92 (m, 2H), 1.53 - 1.36 (m, 2H). |
| (E)-3-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)-N-(methylsulfonyl)acrylamide | ||||
| 70 |
|
Example 10 | 337.2 | (400 MHz, METHANOL-d4) δ = 7.31 - 7.29 (d, J = 7.6 Hz, 2H), 7.25 - 7.18 (m, 3H), 7.12 - 7.10 (d, J = 8.4 Hz, 2H), 6.88 -6.85 (d, J = 8.4 Hz, 2H), 4.50 - 4.38 (m, 2H), 4.20 (m, 4H), 3.69 (m, 4H), 3.40 (br s, 1H), 3.01 (br s, 1H), 2.61 -2.56 (m, 1H), 2.27 (s, 3H), 1.60 - 1.57 (m, 1H), 1.43 - 1.39 (q, J = 6.8 Hz, 1H) |
| (1R,2S)-2-phenyl-N-((1-(2-(p-tolyloxy)ethyl)azetidin-3-yl)methyl)cyclopropan-1-amine | ||||
| 71 |
|
Example 10 | 324.2 | (400 MHz, METHANOL-d4) δ = 8.36 - 8.35 (br d, J = 5.2 Hz, 1H), 8.25 (br s, 1H), 7.40 - 7.38 (br d, J = 6.4 Hz, 2H), 7.31 - 7.29 (m, 2H), 7.24 - 7.19 (m, 3H), 4.70 (br s, 2H), 4.50 - 4.47 (m, 2H), 4.32 - 4.30 (m, 2H), 3.84 (br s, 2H), 3.73 (br s, 1H), 3.61 - 3.59 (br d, J = 5.2 Hz, 1H), 3.41 (br s, 1H), 3.02 (br s, 1H), 2.64 - 2.59 (m, 1H), 1.65 - 1.59(m, 1H), 1.41 - 1.39 (m, 1H) |
| (1R,2S)-2-phenyl-N-((1-(2-(pyridin-2-yloxy)ethyl)azetidin-3-yl)methyl)cyclopropan-1-amine | ||||
| 72 |
|
Example 15 | 381.1 | (400 MHz, Deuterium oxide) δ 7.89 - 7.81 (m, 2H), 7.32 - 7.18 (m, 3H), 7.10 (d, J=7.2 Hz, 2H), 6.99 - 6.91 (m, 2H), 4.43 - 4.29 (m, 2H), 3.82 - 3.60 (m, 3H), 3.58 - 3.52 (m, 2H), 3.34 - 3.08 (m, 2H), 2.94 - 2.89 (m, 1H), 2.50 - 2.31 (m, 3H), 2.06 - 1.89 (m, 2H), 1.50 - 1.34 (m, 2H) |
| 4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzoic acid | ||||
| 73 |
|
Example 16 | 484.2 | 1H NMR: 500 MHz, DMSO-d6, δ (ppm): 11.93 (bs, 1H), 10.93 (bs, 1H), 10.01 (bs, 2H), 7.96 (d, J = 9.0 Hz, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 7.12 (d, J = 9.0 Hz, 2H), 4.50 (bt, 2H), 3.69-3.67 (m, 2H), 3.50-3.49 (m, 4H), 3.18-3.10 (m, 3H), 2.97 (bs, 1H), 2.57 (bs, 1H), 2.31 (bs, 2H), 2.12 (bs, 1H), 1.59 (bs, 1H), 1.31-1.29 (m, 1H), 1.17-1.08 (m, 4H). |
| N-(cyclopropylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamide | ||||
| 74 |
|
Example 16 | 520.2 | 1H NMR: 500 MHz, DMSO-d6, δ (ppm): 12.40 (bs, 1H), 10.88 (bs, 1H), 9.99 (bs, 2H), 8.00-7.99 (m, 2H), 7.89 (d, J = 9.0 Hz, 2H), 7.73-7.70 (m, 1H), 7.66-7.62 (m, 2H), 7.32-7.29 (m, 2H), 7.24-7.17 (m, 3H), 7.08 (d, J = 9.0 Hz, 2H), 4.48 (bt, 2H), 3.68-3.65 (m, 2H), 3.48 (bs, 4H), 3.13 (bs, 2H), 2.97 (bs, 1H), 2.57 (bs, 1H), 2.30 (bs, 2H), 2.10 (bs, 1H), 1.59 (bs, 1H), 1.31-1.28 (m, 1H). |
| 4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-N-(phenylsulfonyl)benzamide | ||||
| 75 |
|
Example 16 | 498.3 | (400 MHz, deuterium oxide) □ 7.53 - 7.45 (m, 3H), 7.32 - 7.24 (m, 2H), 7.24 - 7.18 (m, 1H), 7.10 (d, J = 7.2 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.20 (d, J = 16.0 Hz, 1H), 4.07 (t, J = 5.4 Hz, 2H), 3.77 - 3.58 (m, 3H), 3.33 - 3.21 (m, 5H), 3.11 - 2.96 (m, 2H), 2.93 - 2.85 (m, 1H), 2.50 - 2.32 (m, 3H), 2.20 - 2.10 (m, 2H), 1.96 - 1.82 (m, 2H), 1.51 - 1.34 (m, 2H) |
| (E)-N-(methylsulfonyl)-3-(4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylamide | ||||
| 76 |
|
Examples 10 and 20 | 422.2 | (400 MHz, deuterium oxide) □ 7.28 - 7.21 (m, 2H), 7.20 - 7.13 (m, 3H), 7.08 (d, J = 7.6 Hz, 2H), 6.93 - 6.85 (m, 2H), 4.38 - 4.25 (m, 4H), 4.20 - 3.99 (m, 4H), 3.66 - 3.50 (m, 5H), 3.48 - 3.44 (m, 1H), 3.39 - 3.26 (m, 1H), 2.92 - 2.81 (m, 1H), 2.47 - 2.38 (m, 1H), 2.10 - 2.05 (m, 2H), 1.49 - 1.38 (m, 1H), 1.36 - 1.25 (m, 1H). |
| 3-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one | ||||
| 77 |
|
Examples 10 and 20 | 422.2 | (400 MHz, deuterium oxide) □ 7.26 - 7.19 (m, 2H), 7.19 - 7.12 (m, 3H), 7.07 (d, J = 7.6 Hz, 2H), 6.95 - 6.87 (m, 2H), 4.36 - 4.25 (m, 2H), 4.23 - 4.20 (m, 2H), 4.19 - 4.07 (m, 3H), 4.06 - 3.99 (m, 1H), 3.95 (t, J = 5.0 Hz, 2H), 3.64 - 3.60 (m, 3H), 3.55 - 3.52 (m, 2H), 3.48 - 3.44 (m, 1H), 3.42 - 3.30 (m, 1H), 2.91 - 2.79 (m, 1H), 2.49 - 2.36 (m, 1H), 1.49 - 1.37 (m, 1H), 1.35 - 1.25 (m, 1H) |
| 4-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)morpholin-3-one | ||||
| 78 |
|
Examples 10 and 20 | 420.2 | (400 MHz, deuterium oxide) □ 7.29 - 7.20 (m, 2H), 7.19 - 7.13 (m, 1H), 7.12 - 7.04 (m, 4H), 6.94 - 6.86 (m, 2H), 4.37 - 4.24 (m, 2H), 4.20 - 3.99 (m, 4H), 3.65 - 3.43 (m, 6H), 3.38 - 3.26 (m, 1H), 2.92 - 2.81 (m, 1H), 2.47 - 2.33 (m, 3H), 1.86 - 1.73 (m, 4H), 1.48 - 1.38 (m, 1H), 1.37 - 1.27 (m, 1H) |
| 1-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)piperidin-2-one | ||||
| 79 |
|
Examples 10 and 20 | 421.2 | (400 MHz, deuterium oxide) δ 7.29 - 7.20 (m, 2H), 7.19 - 7.13 (m, 1H), 7.12 - 7.04 (m, 4H), 6.94 - 6.86 (m, 2H), 4.37 - 4.24 (m, 2H), 4.20 - 3.99 (m, 4H), 3.65 - 3.43 (m, 6H), 3.38 - 3.26 (m, 1H), 2.92 - 2.81 (m, 1H), 2.47 - 2.33 (m, 3H), 1.86 - 1.73 (m, 4H), 1.48 - 1.38 (m, 1H), 1.37 - 1.27 (m, 1H) |
| 3-(4-((2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-one | ||||
| 80 |
|
Examples 10 and 20 | 407.2 | (400 MHz, deuterium oxide) □ 7.31 -7.23 (m, 2H), 7.22 - 7.05 (m, 5H), 6.81 (d, J = 7.6 Hz, 2H), 4.42 - 4.08 (m, 5H), 4.02 - 3.89 (m, 1H), 3.61 - 3.24 (m, 9H), 2.85 - 2.78 (m, 1H), 2.44 - 2.40 (m, 1H), 2.11 - 2.06 (m, 2H), 1.46 - 1.37 (m, 1H), 1.32 - 1.29 (m, 1H) |
| (1R,2S)-2-phenyl-N-((1-(2-(4-(piperazin-1-yl)phenoxy)ethyl)azetidin-3-yl)methyl)cyclopropan-1-amine | ||||
| 81 |
|
Examples 10 and 20 | 421.2 | (400 MHz, deuterium oxide) □ 7.33 - 7.20 (m, 4H), 7.18 - 7.11 (m, 1H), 7.08 (d, J = 7.2 Hz, 2H), 7.02 - 6.92 (m, 2H), 4.41 - 4.24 (m, 2H), 4.23 - 4.00 (m, 4H), 3.86 - 3.66 (m, 4H), 3.65 - 3.27 (m, 9H), 2.93 (s, 3H), 2.91 - 2.81 (m, 1H), 2.45 - 2.41 (m, 1H), 1.48 - 1.39 (m, 1H), 1.36 - 1.26 (m, 1H) |
| (1R,2S)-N-((1-(2-(4-(4-methylpiperazin-1-y])phenoxy)ethy])azetidin-3-y])methy])-2-phenylcyclopropan-1-amine | ||||
| 82 |
|
Examples 10 and 20 | 449.3 | (400 MHz, deuterium oxide) □ 7.48 (d, J = 9.2 Hz, 2H), 7.26 - 7.18 (m, 2H), 7.16 - 7.10 (m, 1H), 7.08 (d, J = 7.2 Hz, 2H), 7.05 - 6.98 (m, 2H), 4.37 - 4.26 (m, 2H), 4.21 - 4.01 (m, 4H), 3.98 - 3.82 (m, 4H), 3.71 - 3.52 (m, 7H), 3.49 - 3.47 (m, 1H), 3.39 - 3.28 (m, 1H), 2.91 - 2.81 (m, 1H), 2.44 - 2.41 (m, 1H), 2.09 (s, 3H), 1.49 - 1.39 (m, 1H), 1.33 - 1.30 (m, 1H) |
| 1-(4-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethan-1-one | ||||
| 83 |
|
Example 11 | 365.2 | (400MHz, METHANOL-d4) δ = 7.96 - 7.95 (d, J = 3.2 Hz, 1H), 7.28 - 7.25 (m, 3H), 7.17 - 7.15 (m, 2H), 7.11 - 7.09 (m, 2H), 3.61 - 3.59 (m, 2H), 3.26 (m, 2H), 3.12 (m, 1H), 2.97 (s, 3H), 2.86 (m, 2H), 2.63 - 2.61 (m, 3H), 2.42 (s, 3H), 2.17 - 2.11 (m, 3H), 1.70 - 1.67 (m, 2H), 1.30 - 1.22 (m, 2H). |
| N,6-dimethyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)pyridin-3-amine | ||||
| 84 |
|
Scheme 2b | 352.3 | (400MHz, METHANOL+D2O-d4) δ = 8.10 (s, 1H), 8.05 - 8.03 (br d, J = 8.4 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.25 - 7.19 (m, 4H), 4.76 - 4.74 (m, 2H), 3.88 - 3.85 (br d, J = 12.4 Hz, 2H), 3.76 - 3.72 (m, 3H), 3.42 - 3.34 (m, 2H), 3.01 - 2.99 (m, 1H), 2.57 - 2.47 (m, 3H), 2.36 (s, 3H), 2.20 - 2.17 (m, 2H), 1.61 - 1.58 (m, 1H), 1.47 - 1.45 (m, 1H) |
| 1-(2-((5-methylpyridin-2-yl)oxy)ethyl)-N-((lR,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 85 |
|
Scheme 2b | 352.1 | (400 MHz, D2O) δ = 8.31 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0, 1H), 7.76 - 7.74 (d, J = 8.8 Hz, 1H), 7.36 - 7.34 (m, 2H), 7.32 - 7.26 (m, 1H), 7.17 - 7.15 (br d, J = 7.6 Hz, 2H), 4.55 - 4.53 (m, 2H), 3.82 - 3.69 (m, 5H), 3.28 - 3.25 (m, 2H), 2.99 - 2.97 (m, 1H), 2.65 (s, 3H), 2.50 - 2.43 (m, 3H), 2.05 (br s, 2H), 1.52 - 1.44 (m, 2H) |
| 1-(2-((6-methylpyridin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 86 |
|
Scheme 2b | 428.0; 430.0 | (400 MHz, Methanol-d4) δ 7.46 (d, J = 8.8 Hz, 2H), 7.37 - 7.30 (m, 2H), 7.29 - 7.19 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 3.96 - 3.91 (m, 2H), 3.85 - 3.67 (m, 3H), 3.43 - 3.37 (m, 2H), 3.34 - 3.26 (m, 2H), 3.12 - 3.04 (m, 4H), 2.62 - 2.58 (m, 1H), 2.49 - 2.43 (m, 2H), 2.31 - 2.12 (m, 2H), 1.67 - 1.58 (m, 1H), 1.48 - 1.45 (m, 1H) |
| 1-(2-((4-bromophenyl)(methyl)amino)ethyl)-N-((lR,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 87 |
|
Scheme 3b | 458.1 | 1H NMR: 500 MHz, DMSO-d6, δ (ppm): 11.98 (bs, 1H), 10.82 (bs, 1H), 9.93 (bs, 2H), 7.97 (d, J = 9.0 Hz, 2H), 7.33-7.29 (m, 2H), 7.25-7.18 (m, 3H), 7.12 (d, J = 9.0 Hz, 2H), 4.49 (bt, 2H), 3.68-3.66 (m, 2H), 3.50 (bs, 4H), 3.36 (s, 3H), 3.14 (bs, 2H), 2.98 (bs, 1H), 2.56 (bs, 1H), 2.30 (bs, 2H), 2.11 (bs, 1H), 1.58 (bs, 1H), 1.32-1.28 (m, 1H). |
| N-(methylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamide | ||||
| 88 |
|
Scheme 3b | 472.2 | 1H NMR: 500 MHz, DMSO-d6, δ (ppm): 11.87 (bs, 1H), 10.94 (bs, 1H), 10.01 (bs, 2H), 7.97 (d, J = 8.9 Hz, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 7.12 (d, J = 9.0 Hz, 2H), 4.50 (bt, 2H), 3.68-3.66 (m, 2H), 3.53-3.48 (m, 6H), 3.14 (bs, 2H), 2.97 (bs, 1H), 2.58 (bs, 1H), 2.31 (bs, 2H), 2.12 (bs, 1H), 1.59 (bs, 1H), 1.31-1.27 (m, 1H), 1.25 (t, J = 7.4 Hz, 3H). |
| N-(ethylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamide | ||||
| 89 |
|
Example 20 | 422.3 | (400 MHz, METHANOL-d4) δ = 7.79 - 7.77 (m, 1H), 7.74 (br d, J = 8.4 Hz, 1H), 7.33 - 7.29 (m, 2H), 7.25 - 7.21 (m, 3H), 7.09 - 7.06 (br d, J = 9.2 Hz, 1H), 4.56 (br s, 2H), 4.44 - 4.24 (m, 4H), 3.80 - 3.77 (m, 5H), 3.64 - 3.61 (m, 3H), 3.39 (m, 1H), 3.33 (m, 1H), 3.28 (m, 1H), 3.17 - 3.14 (m, 2H), 3.03 (m, 1H), 2.97 (s, 3H), 2.61 - 2.57 (m, 1H), 1.63 - 1.58 (m, 1H), 1.42 - 1.39 (q, J=6.8 Hz, 1H). |
| (1S,2R)-N-((1-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine | ||||
| 90 |
|
Scheme 2a | 381.2 | (400 MHz, deuterium oxide) δ 7.31 - 7.18 (m, 5H), 7.12 (d, J = 7.6 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.42 - 4.30 (m, 2H), 4.22 - 4.02 (m, 4H), 3.68 - 3.53 (m, 5H), 3.52 - 3.49 (m, 1H), 3.42 - 3.31 (m, 1H), 2.93 - 2.85 (m, 1H), 2.47 - 2.44 (m, 1H), 1.50 - 1.43 (m, 1H), 1.40 - 1.33 (m, 1H). |
| 2-(4-(2-(3-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)acetic acid | ||||
| 91 |
|
Example 20 | 449.3 | (400 MHz, Deuterium oxide) δ 7.34 - 7.28 (m, 4H), 7.27 - 7.20 (m, 1H), 7.19 -7.10 (m, 4H), 4.39 (t, J = 5.4 Hz, 2H), 3.83 (t, J = 7.4 Hz, 2H)), 3.72 - 3.53 (m, 5H), 3.39 - 3.28 (m, 2H), 3.20 - 3.00 (m, 5H), 2.96 - 2.90 (m, 1H), 2.49 - 2.32 (m, 3H), 2.17 - 2.09 (m, 2H), 2.04 - 1.88 (m, 2H), 1.50 - 1.37 (m, 2H) |
| 3-(4-(methyl(2-(4-(((lR,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-one | ||||
| 92 |
|
Scheme 2a | 367.0 | (400 MHz, Deuterium Oxide) δ = 7.99 - 7.97 (m, 2H), 7.32 - 7.24 (m, 3H), 7.17 - 7.15 (m, 2H), 7.01 - 6.98 (d, J = 8.8 Hz, 2H), 4.42 - 4.37 (m, 2H), 4.27 - 4.11 (m, 4H), 3.77 - 3.70 (m, 1H), 3.69 - 3.60 (m, 2H), 3.56 - 3.54 (d, J = 6.8 Hz, 1H), 3.43 - 3.41 (m, 1H), 2.94 - 2.92 (m, 1H), 2.53 - 2.48 (m, 1H), 1.52 - 1.43 (m, 1H), 1.41 - 1.40 (m, 1H) |
| 4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)benzoic acid | ||||
| 93 |
|
Scheme 3a | 520.3 | (400 MHz, deuterium oxide) δ 7.83 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.26 - 7.20 (m, 2H), 7.16 - 7.06 (m, 3H), 7.00 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 4.35 - 4.25 (m, 2H), 4.17 - 3.98 (m, 4H), 3.62 - 3.45 (m, 6H), 3.37 - 3.28 (m, 1H), 2.90 - 2.82 (m, 1H), 2.44 - 2.41 (m, 1H), 1.48 - 1.41 (m, 1H), 1.37 - 1.31 (m, 1H) |
| 2-(4'-(2-(3-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)-[1,1'-biphenyl]-4-yl)-N-(phenylsulfonyl)acetamide | ||||
| 94 |
|
Example 20 | 437.2 | (400 MHz, D2O) δ 8.11 (d, J = 2.8 Hz, 1H) 7.80 - 7.78 (m, 1H), 7.36 - 7.32 (m, 2H), 7.28 - 7.27 (m, 1H), 7.17 - 7.15 (d, J = 8.8 Hz, 1H), 4.62 - 4.60 (m, 2H), 446 - 4.43 (t, J = 5.2 Hz, 2H), 3.85 - 3.82 (br d, J = 12.0 HZ, 2h), 3.68 - 3.62 (m, 5H), 3.26 - 3.15 (m, 2H), 2.98- 2.96 (m, 1H), 2.49 - 2.43 (m, 3H), 2.19 - 2.16 (m, 2H),, 2.01 (m, 2H), 1.50 - 1.43 (m, 2H) |
| 3-(6-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)pyridin-3-yl)-1,3-oxazinan-2-one | ||||
| 95 |
|
Example 11 | 351.3 | (400 MHz, deuterium oxide) δ 7.36 - 7.26 (m, 2H), 7.26 - 7.18 (m, 1H), 7.17 - 7.09 (m, 4H), 6.89 - 6.81 (m, 2H), 4.27 (t, J = 4.8 Hz, 2H), 3.80 - 3.57 (m, 3H), 3.56 - 3.48 (m, 2H), 3.23 - 3.08 (m, 2H), 3.02 - 2.89 (m, 1H), 2.49 - 2.31 (m, 3H), 2.23 - 2.14 (m, 3H), 2.07 - 1.86 (m, 2H), 1.50 - 1.36 (m, 2H) |
| N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(p-tolyloxy)ethyl)piperidin-4-amine | ||||
| 96 |
|
Example 20 | 450.3 | (400 MHz, D2O) δ = 7.34 - 7.29 (m, 2H), 7.27 - 7.23 (m, 3H), 7.16 (br s, 2H), 7.02 - 7.00 (m, 2H), 4.41 - 4.35 (m, 4H), 3.81 (m, 2H), 3.63 - 3.55 (m, 5H), 3.20 - 3.15 (m, 3H), 3.02 (s, 3H), 2.60 (m, 3H), 2.16 - 2.11 (m, 4H), 1.55 - 1.54 (m, 2H). |
| 3-(4-(2-(4-(methyl((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one | ||||
| 97 |
|
Example 20 | 437.2 | (400 MHz, D2O) δ = 8.20 - 8.19 (d, J = 3.2 Hz, 1H), 7.81 - 7.78 (m, 1H), 7.58 - 7.56 (d, J = 9.2 Hz, 1H), 7.32 - 7.25 (m, 3H), 7.16 - 7.14 (d, J = 7.2 Hz, 2H), 4.51 - 4.45 (br s, 4H), 3.83 - 3.63 (m, 7H), 3.22 - 3.20 (m, 2H), 2.98 - 2.97 (m, 1H), 2.48 - 2.46 (m, 3H), 2.22 - 2.19 (m, 2H), 2.03 (m, 2H), 1.51 - 1.42 (m, 2H). |
| 3-(5-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)pyridin-2-yl)-1,3-oxazinan-2-one | ||||
| 98 |
|
Scheme 3a | 472.2 | (400 MHz, deuterium oxide) δ 7.38 - 7.31 (m, 2H), 7.30 - 7.19 (m, 5H), 7.00 (d, J = 8.8 Hz, 2H), 4.71 - 4.63 (m, 2H), 4.50 - 4.40 (m, 4H), 4.00 - 3.93 (m, 2H), 3.77 - 3.68 (m, 1H), 3.67 - 3.60 (m, 2H), 3.41 - 3.37 (m, 2H), 3.35 (s, 3H), 3.23 (s, 3H), 3.05 - 3.00 (m, 1H), 2.65 - 2.59 (m, 1H), 1.66 - 1.60 (m, 1H), 1.45 - 1.41 (m, 1H) |
| 2-(4-(2-(1-methyl-3-((((1R,2S)-2-phenylcyclopropyl(amino(methyl)- 4-azetidin-1-yl)ethoxy)phenyl)-N-(methylsulfonyl)acetamide | ||||
| 99 |
|
Example 11 | 366.2 | (400 MHz, D2O) δ = 8.31 (d, J = 2.8 Hz, 1H), 8.06 - 8.03 (m, 1H), 7.77 - 7.75 (d, J = 8.8 Hz, 1H), 7.35 - 7.34 (m, 2H), 7.30 - 7.28 (m, 1H), 7.18 - 7.16 (m, 2H), 4.55 - 4.53 (m, 2H), 3.84 - 3.81 (m, 3H), 3.69 - 3.67 (m, 2H), 3.26 (m, 2H), 3.16 - 3.15 (m, 1H), 3.04 (s, 3H), 2.65 (s, 3H), 2.62 - 2.39 (m, 3H), 2.20 - 2.16 (m, 2H), 1.62 - 1.55 (m, 2H). |
| N-methyl-1-(2-((6-methylpyridin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 100 |
|
Example 39 | 316.1 | (400 MHz, CD3OD) δ = 7.25 - 7.18 (m, 2H), 7.15 - 7.08 (m, 1H), 7.03 (m, J = 7.6 Hz, 2H), 3.53 - 3.44 (m, 2H), 3.05 (s, 2H), 3.00 - 2.90 (m, 3H), 2.70 - 2.59 (m, 1H), 2.56 - 2.46 (m, 2H), 2.33 - 2.27 (m, 1H), 2.22 - 2.00 (d, 6H), 1.98 - 1.81 (m, 3H), 1.50 - 1.38 (m, 2H), 1.09 - 0.97 (m, 2H). |
| N-methyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)acetamide | ||||
| 101 |
|
Example 11 | 338.1 | (400 MHz, METHANOL-d4) δ = 8.08 (d, J = 2.8 Hz, 1H), 7.31 - 7.30 (m, 1H), 7.24 - 7.20 (m, 3H), 7.17 - 7.13 (m, 1H), 7.06 - 7.04 (m, 2H), 4.09 - 4.07 (t, J = 5.2 Hz, 2H), 3.77 - 3.73 (t, J = 8.4 Hz, 2H), 3.34 - 3.31 (s, 2H), 3.08 - 3.05 (t, J = 5.2 Hz, 2H), 2.96 - 2.94 (d, J = 7.2 Hz, 2H), 2.82 - 2.81 (m, 1H), 2.45 (s, 3H), 2.33 - 2.32 (m, 1H), 1.91 - 1.90 (m, 1H), 1.09 - 1.01 (m, 2H). |
| (1R,2S)-N-((1-(2-((6-methylpyridin-3-yl)oxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine | ||||
| 102 |
|
Scheme 3a | 458.1 | (400 MHz, deuterium oxide) □ 7.29 - 7.20 (m, 2H), 7.19 - 7.13 (m, 1H), 7.12 - 7.04 (m, 4H), 6.94 - 6.86 (m, 2H), 4.37 - 4.24 (m, 2H), 4.20 - 3.99 (m, 4H), 3.65 - 3.43 (m, 6H), 3.38 - 3.26 (m, 1H), 2.92 - 2.81 (m, 1H), 2.47 - 2.33 (m, 3H), 1.86 - 1.73 (m, 4H), 1.48 - 1.38 (m, 1H), 1.37 - 1.27 (m, 1H) |
| 4-(2-(1-methyl-3-((((1R,2S)-2-phenylcyclopropyl(amino(methyl)- 4-azetidin-1-yl)ethoxy)-N-(methylsulfonyl)benzamide | ||||
| 103 |
|
Example 20 | 423.1 | (400 MHz, D2O) δ = 8.05 - 8.03 (m, 1H), 7.51 (m, 1H), 7.43 - 7.41 (d, J = 8.8 Hz, 1H), 7.26 - 7.24 (m, 2H), 7.18 - 7.16 (m, 1H), 7.10 - 7.08 (m, 2H), 4.43 - 4.40 (m, 2H), 4.33 - 4.42 (m, 6H), 3.72 - 3.69 (m, 3H), 3.60 - 3.55 (m, 2H), 3.49 -3.47 (m, 1H), 3.34 (m, 1H), 2.86 - 2.85 (m, 1H), 2.43 (m, 1H), 2.18 - 2.14 (m, 2H), 1.44 - 1.43 (m, 1H), 1.35 - 1.33 (q, J = 7.2 Hz, 1H) |
| 3-(5-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)pyridin-2-yl)-1,3-oxazinan-2-one | ||||
| 104 |
|
Example 11 | 406.0 | (400 MHz, Deuterium oxide) δ 7.34 - 7.28 (m, 2H), 7.27 - 7.21 (m, 1H), 7.13 (d, J = 7.2 Hz, 2H), 6.86 - 6.77 (m, 3H), 4.29 - 4.24 (m, 2H), 3.50 - 3.48 (m, 1H), 3.85 - 3.48 (m, 4H), 3.26 - 3.07 (m, 2H), 2.97 - 2.93 (m, 1H), 2.89 - 2.81 (m, 2H), 2.53 - 2.33 (m, 5H), 2.09 - 1.90 (m, 2H), 1.52 - 1.37 (m, 2H) |
| 6-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one | ||||
| 105 |
|
Example 11 | 392.2 | (400 MHz, methanol-d4) δ, 7.39 - 7.29 (m, 2H), 7.28 - 7.17 (m, 3H), 7.04 (d, J = 2.0 Hz, 1H), 6.97 - 6.88 (m, 1H), 6.87 - 6.81 (m, 1H), 4.42 - 4.35 (m, 2H), 3.88 (br d, J = 12.4 Hz, 2H), 3. 82 - 3.73 (m, 1H), 3.67 - 3.59 (m, 2H), 3.34 (br s, 2H), 3.31 (br s, 2H), 3.09 - 3.01 (m, 1H), 2.60 (br s, 1H), 2.50 (brt, J = 11.6 Hz, 2H), 2.37 - 2.15 (m, 2H), 1.67 - 1.58 (m, 1H), 1.49 - 1.43 (m, 1H) |
| 5-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)indolin-2-one | ||||
| 106 |
|
Example 11 | 369.1 | (400MHz, methanol-d4) δ, 7.38 - 7.29 (m, 2H), 7.30 - 7.27 (m, 1H), 7.24 - 7.19 (m, 2H), 7.18 - 7.16 (m, 1H), 6.81 - 6.71 (m, 2H), 4.43 - 4.34 (m, 2H), 3.85 (br d, J = 11.6 Hz, 2H), 3.73 (br s, 1H), 3.62 (br s, 2H), 3.30 - 3.22 (m, 2H), 3.03 (td, J = 4.0, 7.6 Hz, 1H), 2.56 (br s, 1H), 2.47 (br s, 2H), 2.25 - 2.16(m, 5H), 1.60 (br s, 1H), 1.47 - 1.42 (m, 1H) |
| 1-(2-(3-fluoro-4-methylphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 107 |
|
Example 36 | 389.5 | (400 MHz, METHANOL-d4) δ = 8.74 (s, 1H), 8.27 -8.25 (d, J=8.0 Hz, 1H), 7.94 - 7.90 (m, 2H), 7.69 - 7.67 (m, 1H), 7.23 -7.19 (m, 2H), 7.12 - 7.10 (m, 1H), 7.03 - 7.02 (d, J=7.2 Hz, 2H), 4.79 - 4.76 (t, J=5.2 Hz, 2H), 3.10 - 2.96 (m, 2H), 2.94 - 2.93 (m, 2H), 2.74 - 2.59 (m, 1H), 2.30 - 2.28 (m, 3H), 1.94 - 1.88 (m, 3H), 1.51 - 1.48 (m, 2H), 1.06 - 1.00 (m, 2H). |
| N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(quinazolin-4-yloxy)ethyl)piperidin-4-amine | ||||
| 108 |
|
Example 36 | 388.2 | (400 MHz, Methanol-d4) δ 8.69 (d, J=5.2 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.26 - 7.21 (m, 2H), 7.15 - 7.10 (m, 1H), 7.09 - 7.00 (m, 3H), 4.44 (t, J=5.2 Hz, 2H), 3.16 - 3.08 (m, 2H), 3.01 (t, J=5.4 Hz, 2H), 2.78 - 2.64 (m, 1H), 2.42 - 2.26 (m, 3H), 2.07 - 1.78 (m, 3H), 1.62 - 1.47 (m, 2H), 1.14 - 1.00 (m, 2H) |
| N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(quinolin-4-yloxy)ethyl)piperidin-4-amine | ||||
| 109 |
|
Example 11 | 339.1 | (400 MHz, CHLOROFORM-d) δ = 8.87 (s, 1H), 8.44 (s, 2H), 7.37 - 7.13 (m, 4H), 7.04 (d, J=7.0 Hz, 2H), 4.21 (t, J=5.7 Hz, 2H), 2.96 (br d, J=11.4 Hz, 2H), 2.89 - 2.78 (m, 2H), 2.73 - 2.61 (m, 1H), 2.41 - 2.33 (m, 1H), 2.21 (br t, J=11.4 Hz, 2H), 2.01 - 1.84 (m, 3H), 1.54 - 1.38 (m, 2H), 1.14 - 0.96 (m, 2H) |
| N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(pyrimidin-5-yloxy)ethyl)piperidin-4-amine | ||||
| 110 |
|
Example 11 | 372.9 | (400 MHz, deuterium oxide) δ 7.34 - 7.27 (m, 2H), 7.26 - 7.20 (m, 1H), 7.13 (d, J=7.6 Hz, 2H), 6.60 - 6.52 (m, 3H), 4.31 (t, J=4.6 Hz, 2H)), 3.80 - 3.60 (m, 3H), 3.57 - 3.53 (m, 2H), 3.26 - 3.07 (m, 2H), 2.94 - 2.92 (m, 1H), 2.50 - 2.32 (m, 3H), 2.02 - 1.87 (m, 2H), 1.52 - 1.36 (m, 2H) |
| 1-(2-(3,5-difluorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 111 |
|
Example 11 | 406.9 | (400 MHz, deuterium oxide) δ 7.35 - 7.28 (m, 2H), 7.27 - 7.20 (m, 1H), 7.17 - 7.07 (m, 3H), 6.94 (d, J=1.6 Hz, 2H), 4.31 (t, J=4.6 Hz, 2H), 3.79 - 3.62 (m, 3H), 3.62 - 3.54 (m, 2H), 3.24 - 3.10 (m, 2H), 2.95 - 2.92 (m, 1H), 2.50 - 2.33 (m, 3H), 2.06 - 1.89 (m, 2H), 1.50 - 1.37 (m, 2H) |
| 1-(2-(3,5-dichlorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 112 |
|
Example 36 | 353.2 | (400MHz, CD3OD) δ = 7.51-7.47 (m, 1H), 7.24-7.20 (m, 2H), 7.13-7.09 (m, 2H), 7.04-7.02 (m, 2H), 4.58-4.55 (t, J = 5.6 Hz, 2H), 3.04-3.01 (m, 2H), 2.84-2.01 (t, J = 5.6 Hz, 2H),2.69-2.60 (m, 1H), 2.56 (s, 3H), 2.32-2.28 (m, 1H), 2.21-2.15 (m, 2H), 1.94-1.87 (m,3H), 1.53-1.41 (m, 2H), 1.08-0.99 (m, 2H). |
| 1-(2-((6-methylpyridazin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 113 |
|
Example 11 | 355.1 | (400 MHz, CHLOROFORM-d) δ = 7.36 - 7.22 (m, 6H), 6.88 - 6.78 (s, 3H), 4.45 - 4.42 (t, J=4.8 Hz, 2H), 3.88 - 3.65 (m, 5H), 3.36 - 3.27 (m, 2H), 3.06 - 3.03 (m, 1H), 2.57 - 2.48 (m, 3H), 2.20 - 2.17 (m, 2H), 1.61 - 1.47 (m, 2H). |
| 1-(2-(3-fluorophenoxy)ethyl)-N-((1R,2S)-2-phenyl cyclopropyl)piperidin-4-amine | ||||
| 114 |
|
Example 36 | 352.2 | (400 MHz, CD3OD) δ = 7.64-7.60 (t, J = 7.6 Hz, 1H), 7.33-7.17 (m, 5H), 6.89 (d, J = 7.2 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 4.69-4.67 (m, 2H), 3.88-3.85 (m, 2H), 3.73-3.61 (m, 3H), 2.29-3.23 (m, 2H), 3.03-2.99 (m, 1H), 2.53-2.43 (m, 6H), 2.16-2.07 (m,2H), 1.57-1.52 (m, 1H), 1.77-1.42 (m, 1H). |
| 1-(2-((6-methylpyridin-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 115 |
|
Example 11 | 353.1 | (400 MHz, D2O) δ = 8.69 - 8.68 (d, J = 2.8 Hz, 2H), 7.35 - 7.24 (m, 3H), 7.16 - 7.14 (d, J = 7.6 Hz, 2H), 4.57 - 4.55 (t, J = 4.4 Hz, 2H), 3.83 - 3.68 (m, 5H), 3.23 (m, 2H), 2.98 - 2.96 (m, 1H), 2.70 (s, 3H), 2.50 - 2.43 (m, 3H), 2.04 (br s, 2H), 1.51 - 1.41 (m, 2H). |
| 1-(2-((2-methylpyrimidin-5-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 116 |
|
Example 41 | 338.1 | (400 MHz, CD3OD) δ = 7.25-7.03 (m, 5H), 3.51-3.45 (m, 2H), 3.11-3.06 (m, 2H), 2.97-2.94 (m, 2H), 2.89-2.87 (m, 2H), 2.85-2.82 (m, 6H), 2.69-2.62 (m, 3H), 2.29-2.26 (m, 1H), 1.90-1.85 (m, 1H), 1.97-0.97 (m, 2H). |
| N-methyl-N-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)methanesulfonamide | ||||
| 117 |
|
Example 36 | 261.3 | (400 MHz, METHANOL-d4) δ = 7.25 - 7.22 (m, 2H), 7.14 - 7.06 (m, 1H), 7.06 - 7.04 (m, 2H), 3.69 -3.66 (t, J=6.4 Hz, 2H), 2.99 - 2.96 (m, 2H), 2.66 (m, 1H), 2.54 - 2.51 (t, J=6.4 Hz, 2H), 2.32 (m, 1H), 2.13 - 2.12 (m, 2H), 1.92 - 1.90 (m, 3H), 1.57 - 1.40 (m, 2H), 1.08 - 1.02 (m, 2H). |
| 2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethan-1-ol | ||||
| 118 |
|
Example 20 | 478.1 | (400 MHz, METHANOL-d4) δ = 7.33 - 7.29 (m, 4H), 7.20 - 7.18 (m, 3H), 7.09 - 7.06 (d, J = 8.8 Hz, 2H), 4.46 - 4.41 (m, 4H), 4.14 (m, 1H), 3.75 - 3.69 (m, 4H), 3.61 - 3.59 (m, 2H), 3.25 (m, 2H), 3.02 (br s, 1H), 2.78 - 2.61 (m, 1H), 2.58 - 2.44 (m, 1H), 2.37 (m, 1H), 2.24 - 2.18 (m, 5H), 2.07 - 2.03 (m, 2H), 1.62 - 1.61 (m, 1H), 1.46 -1.45 (m, 1H). |
| N-(1-(2-(4-(2-oxo-1,3-oxazinan-3-yl)phenoxy)ethyl)pipendin-4-yl)-N-((1R,2S)-2-phenylcyclopropyl)acetamide | ||||
| 119 |
|
Example 36 | 275.2 | (400 MHz, Methanol-d4) δ 7.28 - 7.21 (m, 2H), 7.17 - 7.10 (m, 1H), 7.09 - 6.99 (m, 2H), 3.57 - 3.49 (m, 2H), 3.34 - 3.32 (m, 3H), 3.07 - 2.92 (m, 2H), 2.69 - 2.52 (m, 3H), 2.34 - 2.30 (m, 1H), 2.20 - 2.03 (m, 2H), 1.98 - 1.85 (m, 3H), 1.56 - 1.43 (m, 2H), 1.13 - 1.00 (m, 2H). |
| 1-(2-methoxyethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 120 |
|
Example 11 | 355.2 | (400 MHz, Methanol-d4) δ 7.29 - 7.18 (m, 2H), 7.16 - 7.09 (m, 1H), 7.08 - 7.01 (m, 2H), 5.48 (s, 1H), 4.18 (t, J=5.4 Hz, 2H), 3.53 (s, 3H), 3.02 - 2.96 (m, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.73 - 2.55 (m, 1H), 2.34 - 2.29 (m, 1H), 2.21 - 2.13 (m, 5H), 2.00 - 1.85 (m, 3H), 1.65 - 1.42 (m, 2H), 1.11 - 1.00 (m, 2H) |
| 1-(2-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 121 |
|
Example 11 | 341.2 | (400 MHz, Methanol-d4) δ 7.34 (d, J=2.0 Hz, 1H), 7.28 - 7.19 (m, 2H), 7.17 - 7.09 (m, 1H), 7.09 - 7.01 (m, 2H), 5.66 (d, J=2.4 Hz, 1H), 4.21 (t, J=5.6 Hz, 2H), 3.72 (s, 3H), 3.03 - 3.00 (m, 2H), 2.76 (t, J=5.4 Hz, 2H), 2.71 - 2.53 (m, 1H), 2.34 - 2.29 (m, 1H), 2.21 - 2.15 (m, 2H), 1.99 - 1.74 (m, 3H), 1.65 - 1.43 (m, 2H), 1.11 - 1.00 (m, 2H) |
| 1-(2-((1-methyl-1H-pyrazol-3-yl)oxy)ethyl)-N-((lR,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 122 |
|
Example 41 | 324.1 | (400 MHz, methanol-d4) δ = 7.27 - 7.21 (m, 2H), 7.16 - 7.11 (m, 1H), 7.08 - 7.04 (m, 2H), 3.51 (t, J = 8.0 Hz, 2H), 3.04 (t, J = 6.8 Hz, 2H), 2.99 (br t, J = 6.4 Hz, 2H), 2.95 (s, 3H), 2.91 (d, J = 7.6 Hz, 2H), 2.70 (td, J = 7.2, 14.4 Hz, 1H), 2.62 (t, J = 6.8 Hz, 2H), 2.30 (td, J = 3.6, 7.2 Hz, 1H), 1.90 (ddd, J = 3.2, 6.0, 9.2 Hz, 1H), 1.10 - 0.98 (m, 2H). |
| N-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)methanesulfonamide | ||||
| 123 |
|
Example 20 | 423.0 | (400 MHz, METHANOL-d4) δ = 8.18 (d, J = 2.4 Hz, 1H), 7.76 - 7.74 (dd, J = 2.8, 8.8 Hz, 1H), 7.34 - 7.18 (m, 5H), 6.91 - 6.88 (d, J = 9.2 Hz, 1H), 4.59 - 4.56 (m, 2H), 4.49 - 4.46 (m, 4H), 4.21 (br s, 2H), 3.74 - 3.69 (m, 4H), 3.60 - 3.58 (br d, J = 6.8 Hz, 2H), 3.44 - 3.35 (m, 1H), 2.99 - 2.97(m, 1H), 2.53 (m, 1H), 2.25 - 2.2 (m, 2H), 1.56 - 1.52 (m, 1H), 1.43 - 1.40 (q, J=6.8 Hz, 1H). |
| 3-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one | ||||
| 124 |
|
Example 36 | 303.1 | (400 MHz, CD3OD) □ = 7.27 - 7.20 (m, 2H), 7.16 - 7.10 (m, 1H), 7.08 - 7.02 (m, 2H), 3.63 - 3.56 (m, 3H), 2.98 (d, J=12.4 Hz, 2H), 2.70 - 2.61 (m, 1H), 2.56 (t, J=6.0 Hz, 2H), 2.32 (m, 1H), 2.13 (tt, J=2.8, 12.0 Hz, 2H), 1.98 - 1.86 (m, 3H), 1.57 - 1.42 (m, 2H), 1.16 (d, J=6.0 Hz, 6H), 1.10 - 1.00 (m, 2H). |
| 1-(2-isopropoxyethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 125 |
|
Example 11 | 387.1 | (400 MHz, METHANOL-d4) δ = 7.40 - 7.18 (m, 5H), 6.74 - 6.63 (m, 2H), 4.48 - 4.32 (m, 2H), 3.92 - 3.58 (m, 5H), 3.31 - 3.08 (m, 2H), 2.94 - 2.91 (t, J = 7.6 Hz, 1H), 2.45 - 2.35 (m, 3H), 2.04 - 1.91 (m, 5H), 1.53 - 1.42 (m, 2H) |
| 1-(2-(3,5-difluoro-4-methylphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 126 |
|
Example 11 | 359.1 | (400 MHz, CD3OD) δ = 7.14 - 7.10 (m, 2H), 7.03 - 6.99 (m, 1H), 6.94 - 6.92 (d, J=7.6 Hz, 2H), 4.49-4.46 (t, J=5.4 Hz, 2H), 2.90 - 2.87 (br d, J=11.2 Hz, 2H), 2.73 - 2.62 (t, J=5.4 Hz, 2H), 2.59 - 2.51 (m, 1H), 2.49 (s, 3H), 2.30 (td, J=3.6, 7.6 Hz, 1H), 2.22 - 2.08 (m, 2H), 1.98 - 1.83 (m, 3H), 1.54 - 1.40 (m, 2H), 1.12 - 0.97 (m, 2H). |
| 1-(2-((5-methyl-1,3,4-thiadiazol-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 127 |
|
Example 11 | 382.1 | (400 MHz, METHANOL-d4) δ = 8.14 - 8.13 (m, 1H), 7.40 - 7.39 (d, J = 5.2 Hz, 1H), 7.28 - 7.24 (m, 3H), 7.17 - 7.07 (m, 3H), 4.61 - 4.58 (m, 2H), 3.48 - 3.45 (m, 2H), 3.30 - 3.28 (m, 2H), 3.04 (m, 1H), 2.84 (m, 2H), 2.47 - 2.46 (m, 1H), 2.17 - 2.15 (m, 2H), 2.03 - 2.02(m, 1H), 1.76 - 1.72 (m, 2H), 1.19 - 1.13 (m, 2H). |
| 2-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)isonicotinic acid | ||||
| 128 |
|
Example 39 | 338.1 | (400 MHz, methanol-d4) δ = 7.26 - 7.22 (m, 2H), 7.16 - 7.11 (m, 1H), 7.08 - 7.02 (m, 2H), 3.29 - 3.20 (m, 2H), 2.95 (br d, J = 12.0 Hz, 2H), 2.84 - 2.77 (m, 2H), 2.75 - 2.71 (m, 3H), 2.70 - 2.63 (m, 1H), 2.32 (ddd, J = 3.2, 4.4, 7.2 Hz, 1H), 2.20 - 2.09 (m, 2H), 2.02 - 1.87 (m, 3H), 1.55 - 1.40 (m, 2H), 1.13 - 0.99 (m, 2H). |
| N-methyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethane-1-sulfonamide | ||||
| 129 |
|
Example 39 | 352.1 | (400 MHz, methanol-d4) δ = 7.28 - 7.20 (m, 2H), 7.16 - 7.10 (m, 1H), 7.05 (d, J = 8.0 Hz, 2H), 3.30 (t, J = 6.8 Hz, 2H), 3.02 - 2.94 (m, 2H), 2.89 (d, J = 7.2 Hz, 6H), 2.71 - 2.62 (m, 1H), 2.57 (t, J = 6.8 Hz, 2H), 2.31 (td, J = 3.6, 7.2 Hz, 1H), 2.10 (br t, J = 11.6 Hz, 2H), 1.99 - 1.84 (m, 3H), 1.54 - 1.40 (m, 2H), 1.12 - 0.99 (m, 2H). |
| N-methyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)methanesulfonamide | ||||
| 130 |
|
Example 38 | 364.1 | (400 MHz, methanol-d4) δ = 7.26 - 7.21 (m, 2H), 7.16 - 7.10 (m, 1H), 7.07 - 7.03 (m, 2H), 3.28 - 3.21 (m, 2H), 2.96 (br d, J = 12 Hz, 2H), 2.72 - 2.62 (m, 1H), 2.60 - 2.50 (m, 3H), 2.32 (ddd, J = 3.6, 4.4, 7.6 Hz, 1H), 2.16 - 2.06 (m, 2H), 1.99 - 1.86 (m, 3H), 1.55 - 1.42 (m, 2H), 1.11 - 0 96 (m, 6H). |
| N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)cyclopropanesulfonamide | ||||
| 131 |
|
Example 37 | 331.2 | (400 MHz, Methanol-d4) δ 7.24 (t, J=7.4 Hz, 2H), 7.16 - 7.10 (m, 1H), 7.05 (d, J=7.2 Hz, 2H), 3.32 - 3.28 (m, 2H), 2.30 - 2.96 (m, 2H), 2.89 (s, 6H), 2.70 - 2.62 (m, 1H), 2.49 (t, J=6.8 Hz, 2H), 2.37 - 2.28 (m, 1H), 2.15 - 2.06 (m, 2H), 2.01 - 1.86 (m, 3H), 1.56 - 1.41 (m, 2H), 1.11 - 1.01 (m, 2H) |
| 1,1-dimethyl-3-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)pipendin-1-yl)ethyl)urea | ||||
| 132 |
|
Example 45 | 318.1 | (400 MHz, methanol-d4) δ = 7.29 - 7.21 (m, 2H), 7.16 - 7.09 (m, 1H), 7.08 - 7.00 (m, 2H), 3.75 - 3.66 (m, 3H), 3.00 (q, J = 6.8 Hz, 1H), 2.94 - 2.85 (m, 2H), 2.68 - 2.59 (m, 1H), 2.36 - 2.25 (m, 2H), 2.24 - 2.14 (m, 1H), 2.01 - 1.84 (m, 3H), 1.55 - 1.40 (m, 2H), 1.29 - 1.22 (m, 3H), 1.12 - 0.97 (m, 2H). |
| N-methoxy-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamide | ||||
| 133 |
|
Example 20 | 436.2 | (400 MHz, CHLOROFORM-d) δ = 7.44 - 7.42 (m, 2H), 7.28 - 7.24 (m, 2H), 7.17 (m, 1H), 7.05 - 7.03 (d, J=7.6 Hz, 2H), 6.93 - 6.90 (m, 2H), 4.49 - 4.45 (m, 2H), 4.17 (br t, J = 5.2 Hz, 2H), 4.05 - 4.01 (m, 2H), 3.17 - 3.15(br d, J = 10.8 Hz, 2H), 2.90 (br s, 2H), 2.55 (br s, 1H), 2.43 (s, 3H), 2.28 - 2.26 (m, 2H), 2.08 - 1.99 (m, 2H), 1.98 - 1.87 (m, 2H), 1.86 - 1.73 (m, 2H), 1.19- 1.18 (m, 1H), 1.07 - 1.02 (q, J = 6.0 Hz, 1H). |
| 3-(4-(2-(4-(methyl((1R,2S)-2-phenylcyclopropyl)aminopiperidin-1-yl)ethoxy)phenyl)oxazolidin-2-one | ||||
| 134 |
|
Example 11 | 435.0 | (400 MHz, CD3Cl) δ = 7.21 - 7.04 (m, 5H), 6.95 (d, J = 7.6 Hz, 2H), 6.78 (t, J = 8.8 Hz, 1H), 4.05 (t, J = 6.0 Hz, 2H), 2.86 (d, J = 11.2 Hz, 2H), 2.73 (t, J = 6.0 Hz, 2H), 2.64 - 2.49 (m, 1H), 2.27 (m, J = 3.6,7.2 Hz, 1H), 2.11 (t, J = 11.6 Hz, 2H), 1.91 - 1.74 (m, 3H), 1.45 - 1.29 (m, 2H), 0.99 (m, J = 4.8, 9.2 Hz, 1H), 0.92 (q, J = 6.0 Hz, 1H). |
| 1-(2-(4-bromo-2-fluorophenoxy)ethyl)-N-((lR,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 135 |
|
Example 11 | 338.1 | (400MHz, D2O) δ = 8.48 - 8.47 (d, J = 2.8 Hz, 1H), 8.38 - 8.36 (d, J = 5.6 Hz, 1H), 8.14 - 8.13 (m, 1H), 7.94 - 7.93 (m, 1H), 7.29 - 7.27 (m, 2H), 7.23 - 7.21 (d, J = 7.6 Hz, 1H), 7.13 - 7.10 (m, 2H), 4.57 - 4.55 (m, 2H), 3.97 - 3.66 (m, 5H), 3.23 - 3.21(br d, J = 8.0 Hz, 2H), 2.97 - 2.90 (m, 1H), 2.46 - 2.39 (m, 3H), 2.02 (br s, 2H), 1.48 - 1.39 (m, 2H). |
| N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(pyridin-3-yloxy)ethyl)piperidin-4-amine | ||||
| 136 |
|
Example 11 | 408.1 | (400 MHz, Deuterium oxide) δ 7.34 - 7.26 (m, 2H), 7.25 - 7.18 (m, 1H), 7.11 (d, J=7.6 Hz, 2H), 6.80 (d, J=8.4 Hz, 1H), 6.62 - 6.54 (m, 2H), 4.51 (d, J=1.6 Hz, 2H), 4.25 (t, J=4.4 Hz, 2H), 3.79 - 3.58 (m, 3H), 3.56 - 3.45 (m, 2H), 3.24 - 3.06 (m 2H), 2.94 - 2.90 (m, 1H), 2.48 - 2.33 (m, 3H), 2.06 - 1.90 (m, 2H), 1.49 - 1.36 (m, 2H) |
| 7-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)pipendin-1-yl)ethoxy)-2H-benzo[b][1,4]oxazin-3(4H)-one | ||||
| 137 |
|
Example 11 | 394.1 | (400 MHz, Deuterium oxide) δ 7.37 - 7.18 (m, 3H), 7.12 (d, J=7.6 Hz, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.87 (s, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.32 - 4.24 (m, 2H), 3.92 - 3.63 (m, 3H), 3.58 - 3.49 (m, 2H), 3.23 - 3.12 (m, 2H), 3.03 - 2.86 (m, 1H), 2.55 - 2.32 (m, 3H), 2.06 - 1.92 (m, 2H), 1.56 - 1.34 (m, 2H) |
| 6-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzo[d]oxazol-2(3H)-one | ||||
| 138 |
|
Example 36 | 358.2 | (400 MHz, D2O) δ = 7.32 - 7.29 (m, 2H), 7.25 - 7.21 (m, 1H), 7.14 - 7.12 (m, 2H), 6.94 (s, 1H), 4.75 (m, 2H), 3.78 - 3.66 (m, 5H), 3.19 (br s, 2H), 2.95 - 2.93 (m, 1H), 2.47 - 2.40 (m, 3H), 2.28 (s, 3H), 2.06 (br s, 2H), 1.49 - 1.40 (m, 2H) |
| 1-(2-((5-methylthiazol-2-yl)oxy)ethyl)-N-((lR,2S)-2-phenylcyclopropyl)piperidin-4-amine | ||||
| 139 |
|
Example 48 | 289.1 | (400 MHz, DEUTERIUM OXIDE) δ = 7.40 - 7.18 (m, 3H), 7.16 - 7.11 (m, 2H), 3.74 - 3.57 (m, 3H), 3.38 (br t, J = 6.4 Hz, 2H), 3.19 - 3.01 (m, 2H), 2.93 (td, J = 4.4, 7.7 Hz, 1H), 2.87 - 2.74 (m, 2H), 2.50 - 2.25 (m, 3H), 1.94 (br s, 2H), 1.51 - 1.35 (m, 2H) |
| 3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanoic acid | ||||
| 140 |
|
Example 36 | 382.1 | (400 MHz, D2O) δ = 8.60 (s, 1H), 8.52 - 8.50 (d, J = 5.8 Hz, 1H), 7.90 - 7.88 (d, J = 5.6 Hz, 1H), 7.38 - 7.35 (m, 2H), 7.31 - 7.29 (m, 1H), 7.20 - 7.18 (d, J = 7.2 Hz, 2H), 4.66 - 4.64 (m, 2H), 3.85 - 3.83 (m, 2H), 3.72 (m, 3H), 3.29 - 3.26 (m, 2H), 3.02 - 3.00 (m, 1H), 2.53 - 2.47 (m, 3H), 2.06 (m, 2H), 1.55 - 1.46 (m, 2H). |
| 3-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)isonicotinic acid | ||||
| 141 |
|
Example 36 | 381.1 | (400 MHz, Deuterium oxide) δ 7.90 (d, J=6.4 Hz, 1H), 7.42 (s, 1H), 7.37 - 7.20 (m, 4H), 7.14 (d, J=7.2 Hz, 2H), 3.86 (t, J=6.2 Hz, 2H), 3.80 - 3.64 (m, 3H), 3.47 (t, J=6.2 Hz, 2H), 3.26 - 3.10 (m, 2H), 3.00 - 2.92 (m, 1H), 2.51 - 2.37 (m, 3H), 2.10 - 1.92 (m, 2H), 1.55 - 1.39 (m, 2H) |
| 2-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)isonicotinic acid | ||||
| 142 |
|
Example 36 | 381.1 | (400 MHz, Deuterium oxide) δ 8.17 (s, 1H), 8.11 (d, J=5.6 Hz, 1H), 7.90 (d, J=5.6 Hz, 1H), 7.26 - 7.19 (m, 2H), 7.18 - 7.11 (m, 1H), 7.08 - 7.02 (m, 2H), 3.79 - 3.56 (m, 5H), 3.40 - 3.32 (m 2H), 3.22 - 3.00 (m, 2H), 2.92 - 2.82 (m, 1H), 2.44 - 2.22 (m, 3H), 2.02 - 1.82 (m, 2H), 1.49 - 1.30 (m, 2H) |
| 3-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)isonicotinic acid | ||||
| 143 |
|
Example 48 | 366.1 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 12.03 (bs, 1H), 10.72 (bs, 1H), 9.97 (bs, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 3.57-3.51 (m, 3H), 3.27 (m, 2H), 3.26 (s, 3H), 3.02 (bs, 2H), 2.07 (m, 1H), 2.89 (t, J = 7.3 Hz, 2H), 2.57 (m, 1H), 2.29 (bs, 2H), 2.07 (m, 2H), 1.59 (m, 1H), 1.31-1.27 (m, 1H). |
| N-(methylsulfonyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamide | ||||
| 144 |
|
Example 48 | 357.3 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 10.98 and 10.71 (two bs, 1H, mixture of rotamers), 10.25 and 10.06 (2 bs, 2H, mixture of rotamers), 9.52 and 9.44 (2 bs, 2H, mixture of rotamers), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 3.70 (bs, 4H), 3.60 (bs, 2H), 3.45 (bs, 1H), 3.24 (bt, 2H), 3.15 (bs, 2H), 3.05-3.01 (m, 4H), 2.95-2.93 (m, 3H), 2.67 and 2.58 (two m, 1H, mixture of rotamers), 2.32-2.24 (m, 2H), 2.08 (bs, 2H), 1.67 and 1.60-1.57 (bs and m, 1H, mixture of rotamers), 1.31-1.27 (m, 1H). |
| 3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-(piperazin-1-yl)propan-1-one | ||||
| 145 |
|
Example | 428.2 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 12.51 (bs, 1H), 10.59 (bs, 1H), 9.96 (bs, 2H), 7.94-7.92 (m, 2H), 7.72-7.69 (m, 1H), 7.64-7.61 (m, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 3.42-3.40 (m, 3H), 3.16 (bt, 2H), 2.96-2.93 (m, 3H), 2.85 (t, J = 7.1 Hz, 2H), 2.56 (m, 1H), 2.23 (bs, 2H), 2.02 (m, 2H), 1.59-1.55 (m, 1H), 1.30-1.26 (m, 1H). |
| 3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-N-(phenylsulfonyl)propanamide | ||||
| 146 |
|
Example 48 | 371.3 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 11.42 (bs, 1H,), 11.03 and 10.76 (2 bs, 1H, mixture of rotamers), 10.05 (2 bs, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 4.40 (bs, 1H), 4.03 (bs, 1H), 3.60-3.53 (m, 3H), 3.45 (bs, 1H), 3.43 (bs, 1H), 3.24 (bt, 2H), 3.04 (bs, 4H), 2.96 (bs, 4H), 2.75 (s, 3H), 2.67 and 2.59 (two m, 1H, mixture of rotamers), 2.33 (bs, 1H), 2.30 (bs, 1H), 2.23 (bs, 1H), 2.08 (m, 2H), 1.66 and 1.61-1.57 (bs and m, 1H, mixture of rotamers), 1.31-1.27 (m, 1H). |
| 1-(4-methylpiperazin-1-yl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one | ||||
| 147 |
|
Example 48 | 380.2 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 11.93 (bs, 1H), 10.76 (bs, 1H), 10.02 (bs, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 3.54-3.50 (m, 3H), 3.36 (q, J = 7.4 Hz, 2H), 3.27 (bt, 2H), 3.01-2.90 (m, 5H), 2.67 and 2.57 (two m, 1H, rotamers), 2.29 (bs, 2H), 2.08 (m, 2H), 1.60 (m, 1H), 1.31-1.27 (m, 1H), 1.23 (t, J = 7.4 Hz, 3H). |
| N-(ethylsulfonyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamide | ||||
| 148 |
|
Example 48 | 374.7 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 10.63 and 10.47 (two bs, 1H, mixture of rotamers), 10.15 and 10.00 (two bs, 2H, mixture of rotamers), 7.33-7.30 (m, 2H), 7.24-7.18 (m, 3H), 3.73-3.68 (m, 4H), 3.61 (bt, 2H), 3.45 (bs, 1H), 3.24 (bt, 2H), 3.06-2.93 (m, 3H), 2.89 (t, J = 7.7 Hz, 2H), 2.66-2.64 (m, 2H), 2.59-2.53 (m, 3H), 2.30 and 2.21 (two bs, 2H), 2.11-2.01 (m, 2H), 1.66 and 1.60-1.56 (bs and m, 1H, mixture of rotamers), 1.31-1.27 (m, 1H). |
| 3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-thiomorpholinopropan-1-one | ||||
| 149 |
|
example 48 | 385.3 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 11.33 and 11.19 (two bs, 1H, mixture of rotamers), 11.00 and 10.70 (two bs, 1H, mixture of rotamers), 10.22 and 10.03 (two bs, 2H, mixture of rotamers), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 4.42 (bd, 1H), 4.02 (bd, 1H), 3.57-3.38 3H), 2.66 and 2.59-2.55 (two m, 1H, mixture of rotamers), 2.32 (bs, 1H), 2.29 (bs, 1H), 2.30 (bs, 1H), 2.24-2.23 (m, 1H), 2.15-2.05 (m, 2H), 1.96-1.89 (m, 2H), 1.67 and 1.61-1.57 (two m, 1H, mixture of rotamers), 1.30-1.26 (m, 1H). MS: 384.6 (calcd.), 385.3 (M+H+, found). |
| 1-(4-methylpiperazin-1-yl)-4-(4-((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butan-1-one | ||||
| 150 |
|
Example 48 | 371.3 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 11.00 and 10.69 (two bs, 1H, mixture of rotamers), 10.04 (bs, 2H), 9.48 and 9.41 (two bs, 2H, mixture of rotamers), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 3.69-3.67 (m, 4H), 3.57 (bs, 2H), 3.46 (bs, 1H), 3.12 (bs, 2H), 3.02-2.97 (7H), 2.69-2.64 and 2.60-2.56 (two m, 1H, mixture of rotamers), 2.32 (bs, 1H), 2.30 (bs, 1H), 2.23 (bs, 1H), 2.14-2.05 (m, 1H), 2.14-2.05 (m, 2H), 1.96-1.88 (m, 2H), 1.67 and 1.61-1.57 (two m, 1H, mixture of rotamers), 1.30-1.26 (m, 1H). |
| 4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-(piperazin-1-yl)butan-1-one | ||||
| 151 |
|
Example 48 | 372.3 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 10.78 and 10.52 (two bs, 1H, mixture of rotamers), 10.14 and 10.00 (two bs, 2H, mixture of rotamers), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 3.58-3.53 (m, 6H), 3.44-3.41 (m, 4H), 3.11-3.07 and 3.02-2.94 (two m, 5H, mixture of rotamers), 2.67-2.63 and 2.59-2.55 (two m, 1H, mixture of rotamers), 2.43 (t, J = 7.1 Hz, 2H), 2.32 (bs, 1H), 2.29 (bs, 1H), 2.23-2.20 (m, 1H), 2.13-2.03 (m, 2H), 1.94-1.88 (m, 2H), 1.68-1.64 and 1.61-1.57 (two m, 1H, mixture of rotamers), 1.33-1.27 (m, 1H). |
| 1-morpholino-4-(4-(((1R,2b)-2-phenylcyclopropyl)amino)piperidin-1-yl)butan-1-one | ||||
| 152 |
|
Example | 442.2 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 12.26 (bs, 1H), 10.50 (bs, 1H), 9.97 (bs, 2H), 7.93-7.91 (m, 2H), 7.74-7.70 (m, 1H), 7.65-7.61 (m, 2H), 7.32-7.29 (m, 2H), 7.24-7.19 (m, 3H), 3.50 (bs, 2H), 3.44 (bs, 1H), 2.96-2.91 (m, 4H), 2.56 (bs, 1H), 2.35 (t, J = 7.2 Hz, 2H), 2.25 (bs, 2H), 2.05 (m, 3H), 1.85-1.79 (m, 2H), 1.58 (bs, 1H), 1.30-1.26 (m, 1H). |
| 4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-N-(phenylsulfonyl)butanamide | ||||
| 153 |
|
Example 48 | 303.2 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 12.29 (bs, 1H), 10.88 and 10.56 (two bs, 1H), 10.05 (bs, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 3.56 (bs, 2H), 3.46 (m, 1H), 3.00-2.96 (m, 5H), 2.58 (m, 1H), 2.34-2.22 (m, 4H), 2.08 (m, 2H), 1.94-1.66 (m, 2H), 1.61-1.57 (m, 1H), 1.31-1.27 (m, 1H). |
| 4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)pipendin-1-yl)butanoic acid | ||||
| 154 |
|
Example 48 | 406.6 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 11.77 (bs, 1H), 10.62 (bs, 1H), 10.01 (bs, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 3.56 (bs, 2H), 3.46 (bs, 1H), 2.99-2.91 (m, 6H), 2.57 (bs, 1H), 2.40 (t, J = 7.2 Hz, 2H), 2.31 (bs, 1H), 2.29 (bs, 1H), 2.08 (m, 2H), 1.97-1.91 (m, 2H), 1.59 (bs, 1H), 1.31-1.27 (m, 1H), 1.10-1.07 (m, 4H). MS: 405.6 (calcd.), 406.6 (M+H+, found). |
| N-(cyclopropylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamide | ||||
| 155 |
|
Example 48 | 394.7 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 11.70 (bs, 1H), 10.58 (bs, 1H), 9.99 (bs, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 3.57 (bs, 2H), 3.46 (bs, 1H), 3.35 (q, J = 7.4 Hz, 2H), 2.97 (bs, 4H), 2.57 (m, 1H), 2.41 (t, J = 7.1 Hz, 2H), 2.31 (bs, 1H), 2.28 (bs, 1H), 2.21 (bs, 1H), 2.07 (m, 2H), 1.96-1.90 (m, 2H), 1.60-1.56 (m, 1H), 1.31-1.27 (m, 1H), 1.21 (t, J = 7.3 Hz, 3H). |
| N-(ethylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamide | ||||
| 156 |
|
Example 48 | 380.2 | 1H NMR 500 MHz, DMSO-d6, δ (ppm): 11.83 (bs, 1H), 10.62 (bs, 1H), 10.02 (bs, 2H), 7.33-7.30 (m, 2H), 7.25-7.19 (m, 3H), 3.57 (bs, 2H), 3.51-3.47 (m, 1H), 3.25 (s, 3H), 2.98 (bs, 4H), 2.68 and 2.58 (m and bs, 1H, mixture of rotamers), 2.43 (t, J = 7.1 Hz, 2H), 2.33 (bs, 1H), 2.30 (bs, 1H), 2.23 (bs, 1H), 2.09 (bs, 2H), 1.97-1.91 (m, 2H), 1.62-1.58 (m, 1H), 1.32-1.28 (m, 1H). |
| N-(methylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamide | ||||
| 157 |
|
Example 43 | 429.7 | 1H NMR 500 MHz, DMSO6, δ (ppm): 12.36 (bs, 1H), 10.95 (bs, 1H), 10.00 (bs, 2H), 7.37 (d, J = 2.4 Hz, 1H), 7.32-7.29 (m, 2H), 7.24-7.14 (m, 5H), 4.48 (bt, 2H), 3.72 (bs, 2H), 3.55 (s, 2H), 3.51 (bs, 2H), 3.47 (bs, 1H), 3.19 (bs, 2H), 2.97 (bs, 1H), 2.57 (m, 1H), 2.33 (bs, 2H), 2.11 (bs, 2H), 1.61-1.57 (m, 1H), 1.31-1.27 (m, 1H). MS: 429.0 (calcd.). |
| 2-(3-chloro-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid | ||||
| 158 |
|
Example 43 | 413.7 | 1H NMR 500 MHz, DMSO6, δ (ppm): 12.36 (bs, 1H), 11.18 and 10.93 (two bs, 1H), 10.04 (bs, 2H), 7.32-7.29 (m, 2H), 7.21-7.15 (m, 5H), 7.05 (m, 1H), 4.47 (bt, 2H), 3.68 (bs, 1H), 3.67 (bs, 1H), 3.54 (s, 2H), 3.59 (bs, 3H), 3.15 (bs, 2H), 2.96 (bs, 1H), 2.58 (m, 1H), 2.33 (bs, 2H), 2.10 (bs, 2H), 1.61-1.57 (m, 1H), 1.31-1.26 (m, 1H). MS: 412.5 (calcd.). |
| 2-(3-fluoro-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid | ||||
| 159 |
|
Example 43 | 409.7 | 1H NMR 500 MHz, DMSO6, δ (ppm): 12.20 (bs, 1H), 11.12 and 10.90 (two bs, 1H), 9.98 (bs, 2H), 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 7.06-7.05 (m, 2H), 6.90-6.89 (m, 1H), 4.37 (bt, 2H), 3.67 (bs, 1H), 3.66 (bs, 1H), 3.48 (bs, 2H), 3.46 (s, 2H), 3.17 (bs, 2H), 2.96 (bs, 1H), 2.64 and 2.56 (two m, 1H, rotamers), 2.33 (bs, 2H), 2.16 (s, 3H), 2.11 (bs, 2H), 1.60-1.56 (m, 1H), 1.31-1.27 (m, 1H). |
| 2-(3-methyl-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid | ||||
| 160 |
|
Example 43 | 417.6 | 1H NMR 500 MHz, DMSO6, δ (ppm): 12.69 (bs, 1H), 11.21 and 10.96 (two bs, 1H), 10.12 (bs, 2H), 7.93 (d, J = 8.9 Hz, 2H), 7.40-7.29 (m, 2H), 7.12-7.08 (m, 3H), 4.49 (bt, 2H), 3.69 (bs, 1H), 3.67 (bs, 1H), 3.50-3.43 (m, 3H), 3.15 (bs, 2H), 3.01 (bs, 1H), 2.61 (m, 1H), 2.34 (bs, 1H), 2.32 (bs, 1H), 2.11 (bs, 2H), 1.64-1.60 (m, 1H), 1.35-1.3 1 (m, 1H). |
| 4-(2-(4-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)piperidin-1-yl)ethoxy)benzoic acid | ||||
| 161 |
|
Example 43 | 386.7 | 1H NMR: 500 MHz, D2O, δ (ppm): 7.44-7.40 (m, 2H), 7.37-7.33 (m, 1H), 7.25-7.23 (m, 2H), 4.32-4.29 (m, 1H), 3.82-3.66 (m, 7H), 3.49 (bt, 2H), 3.18 (bs, 2H), 3.07-3.01 (m, 2H), 2.99-2.91 (m, 2H), 2.58-2.49 (m, 4H), 2.06 (bs, 2H), 1.60-1.50 (m, 2H), 1.27-1.21 (m, 6H, mixture of rotamers). |
| 1-(cis-2,6-dimethylmorpholino)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one | ||||
[0279] The compounds of the present invention have two or more chiral centers and are synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures or the individual components/isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer's instructions. Alternatively, compounds of the present invention may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or entantiomers as described, for example, in Examples 7 & 8. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention.
EXAMPLE A
[0280] This Example illustrates that exemplary compounds of the present invention inhibit LSD1 enzymatic activity.
[0281] Ten-point dose-response curves for compounds shown in Table 3 were determined using a fluorescence coupling enzymatic assay using purified N-terminal truncated human LSD1 enzyme (aa 151-852; Genbank Accession No NM015013) containing an N-terminal His-Tag (Reaction Biology Corp). In this assay, hydrogen peroxide is produced by the LSD1 FAD-dependent demethylase activity using a horseradish peroxidase/Amplex Red coupling reaction resulting in the production of highly fluorescent compound, Resorufin, which is detected at 590 nM.
[0282] Briefly, compounds of the present invention were solubilized in DMSO and a series of 10, three-fold serial dilutions were made for each compound in 15% DMSO. The initial starting concentration for the serial dilutions of each compound was 10 µM. Control samples lacking compound, LSD1 enzyme or various reaction components also were prepared and processed in parallel with compound test samples.
[0283] An aliquot of each serial dilution of test compound was added to a 96 well plate containing 50 nM purified N-truncated LSD1 enzyme (RBC Cat# PDM-11-350), 50 mM Tris-HCl, pH 7.5, 0.05% CHAPS and 1% DMSO in a 10 microliter reaction volume. The plate was pre-incubated at room temperature for 30 min to which 10 µM of histone 3.3 peptide (aa 1-21) was added to initiate the enzymatic reaction. The reaction mixture was incubated at room temperature for one hour. After one hour, 10 µl of a detection mixture of horseradish peroxidase (Sigma Cat #P8375) and Amplex Red (InVitrogen A36006) was added and kinetic measurements were read at 5 minute intervals for a period of 30 minutes using an Envision Multiplate Reader (PerkinElmer; excitation at 535 nM and emmission read at 590 nM). The IC50 value for each compound was determined from each 10-point dose-response curve using GraphPad Prism 4 software with a sigmodial dose response. The results for exemplary compounds of the invention are shown in Table 3.
| Inhibition of LSD1 Activity by Exemplary Compounds of the Invention | |||||
| Example Number | IC50 (nM) | Example Number | IC50 (nM) | Example Number | IC50 (nM) |
| 1 | 36 | 55 | 4 | 109 | 24 |
| 2 | 110 | 56 | 5 | 110 | 9 |
| 3 | 33 | 57 | 2 | 111 | 7 |
| 4 | 47 | 58 | 3 | 112 | 35 |
| 5 | 17 | 59 | 8 | 113 | 9 |
| 6 | 28 | 60 | 1 | 114 | 12 |
| 7 | 15 | 61 | 12 | 115 | 14 |
| 8 | 13 | 62 | 8 | 116 | 38 |
| 9 | 110 | 63 | 14 | 117 | 17 |
| 10 | 8 | 64 | 0.9 | 118 | 709 |
| 11 | 10 | 65 | 8 | 119 | 38 |
| 12 | 5 | 66 | 4 | 120 | 18 |
| 13 | 25 | 67 | 8 | 121 | 24 |
| 14 | 16 | 68 | 6 | 122 | 31 |
| 15 | 11 | 69 | 33 | 123 | 8 |
| 16 | 7 | 70 | 8 | 124 | 71 |
| 17 | 4 | 71 | 31 | 125 | 19 |
| 18 | 7 | 72 | 17 | 126 | 19 |
| 19 | 3 | 73 | 5 | 127 | 286 |
| 20 | 5 | 74 | 4 | 128 | 2 |
| 21 | 5 | 75 | 20 | 129 | 10 |
| 22 | 5 | 76 | 11 | 130 | 14 |
| 23 | 4 | 77 | 10 | 131 | 19 |
| 24 | 3 | 78 | 7 | 132 | 232 |
| 25 | 46 | 79 | 31 | 133 | 15 |
| 26 | 50 | 80 | 22 | 134 | 26 |
| 27 | 116 | 81 | 23 | 135 | 25 |
| 28 | 8 | 82 | 39 | 136 | 11 |
| 29 | 4 | 83 | 76 | 137 | 7 |
| 30 | 14 | 84 | 19 | 138 | 18 |
| 31 | 87 | 85 | 6 | 139 | 277 |
| 32 | 22 | 86 | 7 | 140 | 154 |
| 33 | < 1 | 87 | 22 | 141 | 11 |
| 34 | 3 | 88 | 25 | 142 | 127 |
| 35 | 21 | 89 | 4 | 143 | 221 |
| 36 | 33 | 90 | 20 | 144 | 9 |
| 37 | 108 | 91 | 4 | 145 | 21 |
| 38 | 23 | 92 | 123 | 146 | 8 |
| 39 | 25 | 93 | 46 | 147 | 148 |
| 40 | 11 | 94 | 17 | 148 | 15 |
| 41 | 15 | 95 | 5 | 149 | 14 |
| 42 | 10 | 96 | 624 | 150 | 5 |
| 43 | 17 | 97 | 57 | 151 | 9 |
| 44 | 9 | 98 | 13 | 152 | 20 |
| 45 | 225 | 99 | 349 | 153 | 192 |
| 46 | 58 | 100 | 39 | 154 | 440 |
| 47 | 74 | 101 | 319 | 155 | 134 |
| 48 | 10 | 102 | 14 | 156 | 231 |
| 49 | 21 | 103 | 19 | 157 | 3 |
| 50 | 3 | 104 | 5 | 158 | 8 |
| 51 | 6 | 105 | 6 | 159 | 20 |
| 52 | 6 | 106 | 14 | 160 | 15 |
| 53 | 12 | 107 | 27 | 161 | 17 |
| 54 | 7 | 108 | 11 | ||
EXAMPLE B
[0284] This Example illustrates that exemplary compounds of the present invention inhibit the growth of tumor cell lines that express LSD1.
[0285] The MV4-11 cell line cell line was established from the blast cells of a 10-year-old male with biphenotypic B-myelomonocytic leukemia. This cell line expresses a leukemic fusion protein (MLL-AF9+), LSD1 and has been shown to be sensitive to inhibitors of LSD1.
[0286] Inhibition of LSD1-mediated cellular proliferation by compounds of Formula (I) or Formula (II) was measured in a CellTiter Glo luminescence assay (Promega Corp), which determines the number of viable cells by quantitating the amount of ATP, using a BMG LabTech CLARIOStar instrument in accordance with the manufacturer's instructions. Briefly, MV4-11 cells were plated at a density of 1000 cells/90µl/well in 96 well culture plates and cultured in IMDM medium (Gibco) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin and 1% streptomycin at 37°C. A series of 3-fold serial dilutions of each test compound of Formula (I) was prepared in IMDM medium lacking FBS and added to the cells at final concentrations ranging from 1µM to 0.01 nM. Control samples lacking test compound or cells were processed in parallel. The plates were incubated at 37°C for four days and thereafter 50 µl fresh medium containing the same concentration of test compound was added. The plates were incubated for an additional three days (Day 7). A baseline measurement, as described below, was taken for a time zero point at Day 0.
[0287] At Day 7, the supernatant was removed by aspiration and the plate was allowed to equilibrate to room temperature (∼15 min). The cells were lysed using 45 µl (30 µl for Day 0) of Cell Titer Glo reagent (Promega Corp). The plates were shaken for two minutes and incubated at room temperature for 30 minutes. The degree of inhibition of cell viability was determined using a spectrophotometric readout by measuring the luminescence at 340 nm and the EC50 concentration for each compound was calculated using Graph Pad Prism 4 software. The results are shown in Table 4. Key: N/D = not determined.
| Inhibition of LSD1-mediated Cell Proliferation by Exemplary Compounds of the Invention | |||||
| Example Number | IC50 (nM) | Example Number | IC50 (nM) | Example Number | IC50 (nM) |
| 1 | 13 | 55 | < 1 | 109 | < 1 |
| 2 | 34 | 56 | < 1 | 110 | 5 |
| 3 | 2 | 57 | < 1 | 111 | 13 |
| 4 | 14 | 58 | < 1 | 112 | < 1 |
| 5 | < 1 | 59 | < 1 | 113 | 3 |
| 6 | 14 | 60 | < 1 | 114 | 3 |
| 7 | 2 | 61 | 7 | 115 | 1 |
| 8 | 2 | 62 | 4 | 116 | 6 |
| 9 | 3 | 63 | < 1 | 117 | 2 |
| 10 | < 1 | 64 | 11 | 118 | 23 |
| 11 | < 1 | 65 | 7 | 119 | 5 |
| 12 | < 1 | 66 | 9 | 120 | 3 |
| 13 | 2 | 67 | 4 | 121 | 6 |
| 14 | 2 | 68 | 10 | 122 | 5 |
| 15 | < 1 | 69 | 28 | 123 | < 1 |
| 16 | 33 | 70 | 4 | 124 | 7 |
| 17 | 8 | 71 | 2 | 125 | 29 |
| 18 | < 1 | 72 | 10 | 126 | 4 |
| 19 | 1 | 73 | 3 | 127 | 530 |
| 20 | < 1 | 74 | 3 | 128 | < 1 |
| 21 | < 1 | 75 | 10 | 129 | < 1 |
| 22 | < 1 | 76 | < 1 | 130 | < 1 |
| 23 | < 1 | 77 | < 1 | 131 | 2 |
| 24 | < 1 | 78 | 117 | 132 | 7 |
| 25 | < 1 | 79 | < 1 | 133 | 61 |
| 26 | < 1 | 80 | < 1 | 134 | 3 |
| 27 | < 1 | 81 | < 1 | 135 | 1 |
| 28 | < 1 | 82 | < 1 | 136 | < 1 |
| 29 | < 1 | 83 | 5 | 137 | < 1 |
| 30 | < 1 | 84 | 1 | 138 | 3 |
| 31 | 10 | 85 | < 1 | 139 | 37 |
| 32 | 33 | 86 | 5 | 140 | 30 |
| 33 | < 1 | 87 | 22 | 141 | 60 |
| 34 | < 1 | 88 | 5 | 142 | 38 |
| 35 | 3 | 89 | < 1 | 143 | 10 |
| 36 | 28 | 90 | 34 | 144 | < 1 |
| 37 | 2 | 91 | < 1 | 145 | 3 |
| 38 | < 1 | 92 | 9 | 146 | < 1 |
| 39 | 5 | 93 | 24 | 147 | 9 |
| 40 | < 1 | 94 | < 1 | 148 | 3 |
| 41 | < 1 | 95 | < 1 | 149 | < 1 |
| 42 | 28 | 96 | 67 | 150 | < 1 |
| 43 | 10 | 97 | < 1 | 151 | 2 |
| 44 | 1 | 98 | > 1000 | 152 | 6 |
| 45 | 56 | 99 | 28 | 153 | 13 |
| 46 | 10 | 100 | < 1 | 154 | 1 |
| 47 | 885 | 101 | 3 | 155 | 1 |
| 48 | 3 | 102 | N/D | 156 | 8 |
| 49 | 14 | 103 | < 1 | 157 | 28 |
| 50 | < 1 | 104 | < 1 | 158 | 29 |
| 51 | < 1 | 105 | < 1 | 159 | 10 |
| 52 | < 1 | 106 | 10 | 160 | 10 |
| 53 | < 1 | 107 | < 1 | 161 | 1 |
| 54 | < 1 | 108 | < 1 | ||
[0288] As evidenced in Examples A & B, many of the compounds of formula (I) and formula (II) of the present invention demonstrate at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold or as much as at least 50-fold greater potency than the LSD1 inhibitor GSK2879552
presently in Phase I clinical trials (ClinicalTrials.gov Identifier: NCT02177812).
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is hydrogen, C1-C4 alkyl or C1-C4 acyl;
L is -(CH2)s-CR2R3-(CH2)m-;
R2 and R3 are each independently hydrogen, C1-C4 alkyl, -OR4 or aralkyl;
each R4 is independently hydrogen or C1-C4 alkyl;
X is -W-R5 or Y-R6;
W is -NR4- or -O-;
Y is -C(O)-, -S-, -SO-, -SO2-, -NR4SO2-, -SO2NR4- or -NR4C(O)-;
R5 is acyl, C1-C4 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally independently substituted with one or more R8;
R6 is C1-C6 alkyl, aryl, -NR4R7 or heterocyclyl optionally independently substituted on one or more carbon atoms with C1-C6 alkyl, halogen, cyano, or haloalkyl or optionally independently substituted on one or more nitrogen atoms with -C(O)C1-C6alkyl, -C(O)OC1-C6 alkyl, -C(O)NR4C1-C6alkyl, or -S(O)2NR4C1-C6 alkyl;
R7 is hydroxyl, alkoxy, -SO2C1-C6alkyl, -SO2cycloalkyl, or -SO2aryl, wherein the cycloalkyl or aryl of each of the -SO2cycloalkyl and -SO2aryl is optionally independently substituted with one or more R8;
each R8 is halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, -(CH2)nCOOR4, -(CH2)nC(O)NR4OC1-C6alkyl; -(CH2)nC(O)NR4SO2C1-C6alkyl, -(CH2)nC(O)NR4SO2cycloalkyl, -(CH2)nC(O)NR4SO2aryl, -C2-C6alkenylC(O)OR4, -C2-C6alkenylC(O)NR4SO2C1-C4alkyl, or -C2-C6alkenylC(O)NR4SO2aryl, wherein each of the cycloalkyl, aryl, heteroaryl, heterocyclyl is optionally independently substituted with one or more C1-C3 alkyl or -CH2NR4SO2aryl;
m is 0 or 1;
s is 0 or 1;
each n is 0, 1, or 2;
each p is 0, 1 or 2;
each RA group is independently oxo or C1-C3 alkyl, or two RA groups on different ring atoms together form a C1-C3 bridge in which one of the bridge carbons is optionally replaced with -NH-; and
each Q1, Q2 and Q3 is independently hydrogen, halogen, haloalkyl, C1-C4-alkyl, or C1-C4-alkoxy.
(a) aryl optionally independently substituted with one or more R8;
(b) phenyl optionally independently substituted with one or more R8;
(c) phenyl optionally independently substituted with one or more R8, wherein R8 is heterocyclyl optionally independently substituted with one or more C1-C3 alkyl or C1-C4acyl;
(d) heteroaryl optionally independently substituted with one or more R8;
(e) heteroaryl optionally independently substituted with one or more R8, wherein the heteroaryl is pyridyl, 6-methyl-pyridyl, 4-carboxy-pyridyl, dihydroquinolinone, indolinone, quinazolinyl, quinolinyl, pyrimidinyl, 2-methyl-pyrimidinyl, pyridazinyl, 6-methyl-pyridiazinyl, pyrazolyl, 1-methyl-pyrazolyl, 5-methyl-pyrazolyl, 1,3-dimethylpyrazolyl, thiazolyl, 5-methyl-thiazolyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, thiadiazolyl or 5-methyl-thiadiazolyl;
(f) pyridyl optionally independently substituted with one or more R8; or
(g) pyridyl optionally independently substituted with one or more R8, wherein R8 is heterocyclyl optionally independently substituted with one or more C1-C3 alkyl;
(a) aryl optionally independently substituted with one or more R8;
(b) phenyl optionally independently substituted with one or more R8;
(c) phenyl optionally independently substituted with one or more R8, wherein R8 is heterocyclyl optionally independently substituted with one or more C1-C3 alkyl;
(d) heteroaryl optionally independently substituted with one or more R8;
(e) heteroaryl optionally independently substituted with one or more R8, wherein the heteroaryl is pyridyl, 6-methyl-pyridyl, 4-carboxy-pyridyl, dihydroquinolinone, indolinone, quinazolinyl, quinolinyl, pyrimidinyl, 2-methyl-pyrimidinyl, pyridazinyl, 6-methyl-pyridiazinyl, pyrazolyl, 1-methyl-pyrazolyl, 5-methyl-pyrazolyl, 1,3-dimethylpyrazolyl, thiazolyl, 5-methyl-thiazolyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, thiadiazolyl or 5-methyl-thiadiazolyl;
(f) pyridyl optionally independently substituted with one or more R8; or
(g) pyridyl optionally independently substituted with one or more R8, wherein R8 is heterocyclyl optionally independently substituted with one or more C1-C3 alkyl.
(i) Y is -C(O)-; s is 0; m is 0; R2 is C1-C4 alkyl or aralkyl; R3 is hydrogen; and R6 is heterocyclyl;
(ii) Y is -C(O)-; s is 1; m is 0; R2 and R3 are each independently hydrogen; and R6 is heterocyclyl;
(iii) Y is -C(O)-; s is 1; m is 1; R2 and R3 are each hydrogen; and R6 is heterocyclyl;
(iv) Y is -C(O)-; s is 1; m is 1; R2 and R3 are each hydrogen; and R6 is -NR4R7;
(v) Y is -NR4SO2-; m is 1; R2 and R3 are each hydrogen; and R6 is C1-C6 alkyl, cycloalkyl or aryl, wherein the cycloalkyl or the aryl may be optionally independently substituted with one or more C1-C3 alkyl, halogen, haloalkyl, amino or cyano;
(vi) Y is -SO2NR4-; s is 1; m is 1; R2 and R3 are each independently hydrogen; and R6 is C1-C6 alkyl or aryl, wherein the aryl may be optionally independently substituted with one or more C1-C3 alkyl, halogen, haloalkyl, amino or cyano; or
(vii) Y is -NR4C(O)NR4R4; s is 1; m is 1; R2 and R3 are each hydrogen; and each R4 is independently hydrogen or C1-C3 alkyl or each R4 is C1-C3 alkyl.
1-phenoxy-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol;
1-(2-methoxy-3-phenoxy-propyl)-N-[trans-2-phenylcyclopropyl]piperidin-4-amine;
2-methyl-1-phenoxy-3-(4-(((trans)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol;
1-phenoxy-3-[3-[[[(trans)-2-phenylcyclopropyl]amino]methyl]azetidin-1-yl]propan-2-ol;
(R)-1-phenoxy-3-(4-(((1S,2R)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol;
(S)-1-phenoxy-3-(4-(((1S,2R)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol;
1-phenoxy-3-[(1R,5S)-6-[[(trans)-2-phenylcyclopropyl]amino]-3-azabicyclo[3.1.1]heptan-3-yl]propan-2-ol;
(trans)-N-[[1-(2-phenoxyethyl)azetidin-3-yl]methyl]-2-phenyl-cyclopropanamine;
(trans)-N-[[1-(3-phenoxypropyl)azetidin-3-yl]methyl]-2-phenyl-cyclopropanamine;
1-[2-(4-bromophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine;
1-(3-phenoxypropyl)-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-phenoxyethyl)-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;
2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid;
N-(methylsulfonyl)-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide;
2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-N-(phenylsulfonyl)acetamide;
N,N-dimethyl-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide;
N-methoxy-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamide;
1-[2-(4-morpholinophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine;
1-(2-(4-(4-methylpiperazin-1-yl)phenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)oxazolidin-2-one;
1-methyl-3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)imidazolidin-2-one;
3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one;
4-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)morpholin-3-one;
1-(4-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethan-1-one;
1-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)pyrrolidin-2-one;
1-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)piperidin-2-one;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(4-(piperidin-1-yl)phenoxy)ethyl)piperidin-4-amine;
2-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acetic acid;
4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)benzoic acid;
(E)-3-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylic acid;
2-(4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acetic acid;
4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)benzoic acid;
(E)-3-(4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylic acid;
(1R,2S)-N-((1-(2-(4-bromophenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
1-(2-(2,4-dichlorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
(1R,2S)-N-((1-(2-(2,4-dichlorophenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
1-(2-(2,4-difluorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
(1R,2S)-N-((1-(2-(2,4-difluorophenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
(E)-3-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)-N-(methylsulfonyl)acrylamide;
1-(2-((2-methylpyridin-4-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
(1R,2S)-2-phenyl-N-((1-(2-(p-tolyloxy)ethyl)azetidin-3-yl)methyl)cyclopropan-1-amine;
(1R,2S)-2-phenyl-N-((1-(2-(pyridin-2-yloxy)ethyl)azetidin-3-yl)methyl)cyclopropan-1-amine;
4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzoic acid;
N-(cyclopropylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamide;
4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-N-(phenylsulfonyl)benzamide;
(E)-N-(methylsulfonyl)-3-(4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylamide;
3-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one;
4-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)morpholin-3-one
1-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)piperidin-2-one;
(1R,2S)-2-phenyl-N-((1-(2-(4-(piperazin-1-yl)phenoxy)ethyl)azetidin-3-yl)methyl)cyclopropan-1-amine;
(1R,2S)-N-((1-(2-(4-(4-methylpiperazin-1-yl)phenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
1-(4-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethan-1-one;
1-(2-((5-methylpyridin-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((6-methylpyridin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
N-(methylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamide;
N-(ethylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamide;
(1S,2R)-N-((1-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
2-(4-(2-(3-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)acetic acid;
4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)benzoic acid
2-(4'-(2-(3-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)-[1,1'-biphenyl]-4-yl)-N-(phenylsulfonyl)acetamide;
3-(6-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)pyridin-3-yl)-1,3-oxazinan-2-one;
3-(5-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)pyridin-2-yl)-1,3-oxazinan-2-one;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(p-tolyloxy)ethyl)piperidin-4-amine;
3-(4-(2-(4-(methyl((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one;
2-(4-(2-(1-methyl-3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-
4-azetidin-1-yl)ethoxy)phenyl)-N-(methylsulfonyl)acetamide;
N-methyl-1-(2-((6-methylpyridin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
(1R,2S)-N-((1-(2-((6-methylpyridin-3-yl)oxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amine;
4-(2-(1-methyl-3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-λ4-azetidin-1-yl)ethoxy)-N-(methylsulfonyl)benzamide;
3-(5-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)pyridin-2-yl)-1,3-oxazinan-2-one;
6-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one;
5-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)indolin-2-one;
1-(2-(3-fluoro-4-methylphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(quinazolin-4-yloxy)ethyl)piperidin-4-amine;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(quinolin-4-yloxy)ethyl)piperidin-4-amine;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(pyrimidin-5-yloxy)ethyl)piperidin-4-amine;
1-(2-(3,5-difluorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-(3,5-dichlorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((6-methylpyridazin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
(E)-3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acrylic acid;
1-(2-(3-fluorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((6-methylpyridin-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((2-methylpyrimidin-5-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-(4-bromophenoxy)ethyl)-4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-2-one;
2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethan-1-ol;
N-(1-(2-(4-(2-oxo-1,3-oxazinan-3-yl)phenoxy)ethyl)piperidin-4-yl)-N-((1R,2S)-2-phenylcyclopropyl)acetamide;
1-(2-methoxyethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((1-methyl-1H-pyrazol-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
3-(4-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-one;
1-(2-isopropoxyethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
2-(2-fluoro-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid;
1-(2-(3,5-difluoro-4-methylphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((5-methyl-1,3,4-thiadiazol-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
2-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)isonicotinic acid;
3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)oxazolidin-2-one;
1-(2-(4-bromophenoxy)ethyl)-4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-2,6-dione;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-(pyridin-3-yloxy)ethyl)piperidin-4-amine;
7-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-2H-benzo[b][1,4]oxazin-3(4H)-one;
6-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzo[d]oxazol-2(3H)-one;
1-(2-((5-methylthiazol-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
3-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)isonicotinic acid;
2-(3-chloro-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid;
2-(3-fluoro-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid;
2-(3-methyl-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetic acid;
4-(2-(4-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)piperidin-1-yl)ethoxy)benzoic acid;
1-anilino-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol;
1-(N-methylanilino)-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol;
1-(2-(phenylamino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-(methyl(phenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((4-bromophenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)piperidin-2-one;
3-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-one;
4-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)morpholin-3-one;
N-((1R,2S)-2-phenylcyclopropyl)-1-(2-((4-(piperidin-1-yl)phenyl)amino)ethyl)piperidin-4-amine;
1-(2-((4-morpholinophenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
1-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)pyrrolidin-2-one;
3-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)oxazolidin-2-one;
1-methyl-3-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)imidazolidin-2-one;
1-(4-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)piperazin-1-yl)ethan-1-one;
3-(4-((2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-one;
N,6-dimethyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)pyridin-3-amine;
1-(2-((4-bromophenyl)(methyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
3-(4-(methyl(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-one;
1-methyl-3-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)urea;
N-methyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)acetamide;
N,2-dimethyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)pyridin-4-amine;
1-(2-(4-bromo-2-fluorophenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;
2-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)isonicotinic acid;
3-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)isonicotinic acid;
1-morpholino-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one;
N-methoxy-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamide;
1-morpholino-3-phenyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one;
1-morpholino-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one;
N-(methylsulfonyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamide;
3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-(piperazin-1-yl)propan-1-one;
3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-N-(phenylsulfonyl)propanamide;
1-(4-methylpiperazin-1-yl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one;
N-(ethylsulfonyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamide;
3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-thiomorpholinopropan-1-one;
1-(4-methylpiperazin-1-yl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butan-1-one;
4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-(piperazin-1-yl)butan-1-one;
1-morpholino-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butan-1-one;
4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-N-(phenylsulfonyl)butanamide;
N-(cyclopropylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamide;
N-(ethylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamide;
N-(methylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamide;
1-(cis-2,6-dimethylmorpholino)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one;
N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)methanesulfonamide;
N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)benzenesulfonamide;
N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)propan-2-sulfonamide;
N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propyl)-methanesulfonamide;
N-methyl-N-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)methanesulfonamide;
N-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)methanesulfonamide;
N-methyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)methanesulfonamide;
N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)cyclopropanesulfonamide;
N-phenyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethan-1-sulfonamide;
N-methyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethan-1-sulfonamide; or
1,1-dimethyl-3-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)urea;
or a pharmaceutically acceptable salt thereof.oder ein pharmazeutisch verträgliches Salz davon,
wobei:
R1 Wasserstoffatom, C1-C4-Alkyl oder C1-C4-Acyl ist;
L-(CH2)s-CR2R3-(CH2)m- ist;
R2 und R3 jeweils unabhängig Wasserstoffatom, C1-C4-Alkyl, -OR4 oder Aralkyl sind;
jedes R4 unabhängig Wasserstoffatom oder C1-C4-Alkyl ist;
X -W-R5 oder Y-R6 ist;
W -NR4- oder -O- ist;
Y -C(O)-, -S-, -SO-, -SO2-, -NR4SO2-, -SO2NR4- oder -NR4C(O)- ist;
R5 Acyl, C1-C4-Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl ist, wobei jedes von dem Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert ist;
R6 C1-C6-Alkyl, Aryl, -NR4R7 oder Heterocyclyl, gegebenenfalls unabhängig an einem oder mehreren Kohlenstoffatomen mit C1-C6-Alkyl, Halogenatom, Cyan oder
Halogenalkyl substituiert oder gegebenenfalls unabhängig an einem oder mehreren Stickstoffatomen mit -C(O)C1-C6-Alkyl, -C(O)OC1-C6-Alkyl, -C(O)NR4C1-C6-Alkyl oder -S(O)2NR4C1-C6-Alkyl substituiert, ist;
R7 Hydroxyl, Alkoxy, -SO2C1-C6-Alkyl, -SO2Cycloalkyl oder -SO2Aryl ist, wobei das Cycloalkyl oder Aryl von jedem von dem -SO2Cycloalkyl und -SO2Aryl gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert ist;
jedes R8 Halogenatom, Hydroxyl, Amino, Cyan, C1-C6-Alkyl, C2-C6-Alkenyl, C2-C6-Alkinyl, Halogenalkyl, Alkoxy, Alkylamino, Dialkylamino, Cycloalkyl, Aryl, Heteroaryl, Heterocyclyl, Aralkyl, Heteroarylalkyl, -(CH2)nCOOR4, -(CH2)nC(O)NR4OC1-C6-Alkyl, -(CH2)nC(O)NR4SO2C1-C6-Alkyl, -(CH2)nC(O)NR4SO2Cycloalkyl, -(CH2)nC(O)NR4SO2Aryl, -C2-C6-Alkenyl-C(O)OR4, -C2-C6-Alkenyl-C(O)NR4SO2C1-C4-Alkyl oder -C2-C6-Alkenyl-C(O)NR4SO2Aryl ist, wobei jedes von dem Cycloalkyl, Aryl, Heteroaryl, Heterocyclyl gegebenenfalls unabhängig mit einem oder mehreren C1-C3-Alkyl oder -CH2NR4SO2Aryl substituiert ist;
m 0 oder 1 ist;
s 0 oder 1 ist;
jedes n 0, 1 oder 2 ist;
jedes p 0, 1 oder 2 ist;
jede RA-Gruppe unabhängig Oxo oder C1-C3-Alkyl ist oder zwei RA-Gruppen an unterschiedlichen Ringatomen zusammen eine C1-C3-Brücke bilden, in der eines der Brückenkohlenstoffatome gegebenenfalls durch -NH- ersetzt ist; und
jedes Q1, Q2 und Q3 unabhängig Wasserstoffatom, Halogenatom, Halogenalkyl, C1-C4-Alkyl oder C1-C4-Alkoxy ist.
(a) Aryl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert;
(b) Phenyl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert;
(c) Phenyl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert, wobei R8 Heterocyclyl, gegebenenfalls unabhängig mit einem oder mehreren C1-C3-Alkyl oder C1-C4-Acyl substituiert, ist;
(d) Heteroaryl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert;
(e) Heteroaryl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert, wobei das Heteroaryl Pyridyl, 6-Methylpyridyl, 4-Carboxypyridyl, Dihydrochinolinon, Indolinon, Chinazolinyl, Chinolinyl, Pyrimidinyl, 2-Methylpyrimidinyl, Pyridazinyl, 6-Methylpyridiazinyl, Pyrazolyl, 1-Methylpyrazolyl, 5-Methylpyrazolyl, 1,3-Dimethylpyrazolyl, Thiazolyl, 5-Methylthiazolyl, Benzo[d]oxazol-2(3H)-on, 2H-Benzo[b][1,4]oxazin-3(4H)-on, Thiadiazolyl oder 5-Methylthiadiazolyl ist;
(f) Pyridyl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert; oder
(g) Pyridyl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert, wobei R8 Heterocyclyl, gegebenenfalls unabhängig mit einem oder mehreren C1-C3-Alkyl substituiert, ist.
(a) Aryl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert;
(b) Phenyl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert;
(c) Phenyl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert, wobei R8 Heterocyclyl, gegebenenfalls unabhängig mit einem oder mehreren C1-C3-Alkyl substituiert, ist;
(d) Heteroaryl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert;
(e) Heteroaryl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert, wobei das Heteroaryl Pyridyl, 6-Methylpyridyl, 4-Carboxypyridyl, Dihydrochinolinon, Indolinon, Chinazolinyl, Chinolinyl, Pyrimidinyl, 2-Methylpyrimidinyl, Pyridazinyl, 6-Methylpyridiazinyl, Pyrazolyl, 1-Methylpyrazolyl, 5-Methylpyrazolyl, 1,3-Dimethylpyrazolyl, Thiazolyl, 5-Methylthiazolyl, Benzo[d]oxazol-2(3H)-on, 2H-Benzo[b][1,4]oxazin-3(4H)-on, Thiadiazolyl oder 5-Methylthiadiazolyl ist;
(f) Pyridyl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert; oder
(g) Pyridyl, gegebenenfalls unabhängig mit einem oder mehreren R8 substituiert, wobei R8 Heterocyclyl, gegebenenfalls unabhängig mit einem oder mehreren C1-C3-Alkyl substituiert, ist.
ist.
(i) Y -C(O)- ist; s 0 ist; m 0 ist; R2 C1-C4- Alkyl oder Aralkyl ist; R3 Wasserstoffatom ist; und R6 Heterocyclyl ist;
(ii) Y -C(O)- ist; s 1 ist; m 0 ist; R2 und R3 jeweils unabhängig Wasserstoffatom sind; und R6 Heterocyclyl ist;
(iii) Y -C(O)- ist; s 1 ist; m 1 ist; R2 und R3 jeweils Wasserstoffatom sind; und R6 Heterocyclyl ist;
(iv) Y -C(O)- ist; s 1 ist; m 1 ist; R2 und R3 jeweils Wasserstoffatom sind; und R6 -NR4R7 ist;
(v) Y -NR4SO2- ist; m 1 ist; R2 und R3 jeweils Wasserstoffatom sind; und R6 C1-C6-Alkyl, Cycloalkyl oder Aryl ist, wobei das Cycloalkyl oder das Aryl gegebenenfalls unabhängig mit einem oder mehreren C1-C3-Alkyl, Halogenatomen, Halogenalkyl, Amino oder Cyan substituiert sein kann;
(vi) Y -SO2NR4- ist; s 1 ist; m 1 ist; R2 und R3 jeweils unabhängig Wasserstoffatom sind; und R6 C1-C6-Alkyl oder Aryl ist, wobei das Aryl gegebenenfalls unabhängig mit einem oder mehreren C1-C3-Alkyl, Halogenatomen, Halogenalkyl, Amino oder Cyan substituiert sein kann; oder
(vii) Y -NR4C(O)NR4R4 ist; s 1 ist; m 1 ist; R2 und R3 jeweils Wasserstoffatom sind; und jedes R4 unabhängig Wasserstoffatom oder C1-C3-Alkyl ist oder jedes R4 C1-C3-Alkyl ist.
ist.
1-Phenoxy-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol;
1-(2-Methoxy-3-phenoxy-propyl)-N-[trans-2-phenylcyclopropyl]piperidin-4-amin;
2-Methyl-1-phenoxy-3-(4-(((trans)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol;
1-Phenoxy-3-[3-[[[(trans)-2-phenylcyclopropyllamino]methyl]azetidin-1-yllpropan-2-ol;
(R)-1-Phenoxy-3-(4-(((1S,2R)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol;
(S)-1-Phenoxy-3-(4-(((1S,2R)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-2-ol;
1-Phenoxy-3-[(1R,5S)-6-[[(trans)-2-phenylcyclopropyl]aminol-3-azabicyclo[3.1.1]heptan-3-yl]propan-2-ol;
(trans)-N-[[1-(2-Phenoxyethyl)azetidin-3-yl]methyl]-2-phenyl-cyclopropanamin;
(trans)-N-[[1-(3-Phenoxypropyl)azetidin-3-yl]methyll-2-phenyl-cyclopropanamin;
1-[2-(4-rroniphenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amin;
1-(3-Phenoxypropyl)-N-((trans)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-Phenoxyethyl)-N-((trans)-2-phenylcyclopropyl)piperidin-4-amin;
2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)essigsäure;
N-(Methylsulfonyl)-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamid;
2-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-N-(phenylsulfonyl)acetamid;
N,N-Dimethyl-2-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamid;
N-Methoxy-2-(4-(2-(4-((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acetamid;
1-[2-(4-Morpholinophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amin;
1-(2-(4-(4-Methylpiperazin-1-yl)phenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
3-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)oxazolidin-2-on;
1-Methyl-3-(4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)imidazolidin-2-on;
3-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-on;
4-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)morpholin-3-on;
1-(4-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethan-1-on;
1-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)pyrrolidin-2-on;
1-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)piperidin-2-on;
N-((1R,2S)-2-Phenylcyclopropyl)-1-(2-(4-(piperidin-1-yl)phenoxy)ethyl)piperidin-4-amin;
2-(4-(2-Hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)essigsäure;
4-(2-Hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)benzoesäure;
(E)-3-(4-(2-Hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylsäure;
2-(4-(3-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)essigsäure;
4-(3-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)propoxy)benzoesäure;
(E)-3-(4-(3-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylsäure;
(1R,2S)-N-((1-(2-(4-Bromphenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amin;
1-(2-(2,4-Dichlorphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
(1R,2S)-N-((1-(2-(2,4-Dichlorphenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amin;
1-(2-(2,4-Difluorphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
(1R,2S)-N-((1-(2-(2,4-Difluorphenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amin;
(E)-3-(4-(2-Hydroxy-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)-N-(methylsulfonyl)acrylamid;
1-(2-((2-Methylpyridin-4-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
(1R,2S)-2-Phenyl-N-((1-(2-(p-tolyloxy)ethyl)azetidin-3-yl)methyl)cyclopropan-1-amin;
(1R,2S)-2-Phenyl-N-((1-(2-(pyridin-2-yloxy)ethyl)azetidin-3-yl)methyl)cyclopropan-1-amin;
4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzoesäure;
N-(Cyclopropylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamid;
4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-N-(phenylsulfonyl)benzamid;
(E)-N-(Methylsulfonyl)-3-(4-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propoxy)phenyl)acrylamid;
3-(4-(2-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-on;
4-(4-(2-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)morpholin-3-on;
1-(4-(2-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)piperidin-2-on;
(1R,2S)-2-Phenyl-N-((1-(2-(4-(piperazin-1-yl)phenoxy)ethyl)azetidin-3-yl)methyl)cyclopropan- 1-amin;
(1R,2S)-N-((1-(2-(4-(4-Methylpiperazin-1-yl)phenoxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan- 1-amin;
1-(4-(4-(2-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethan-1-on;
1-(2-((5-Methylpyridin-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-((6-Methylpyridin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
N-(Methylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamid;
N-(Ethylsulfonyl)-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzamid;
(1S,2R)-N-((1-(2-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)oxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan-1-amin;
2-(4-(2-(3-((((1S,2R)-2-Phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)essigsäure;
4-(2-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)benzoesäure;
2-(4'-(2-(3-((((1S,2R)-2-Phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)-[1,1'-biphenyl]-4-yl)-N-(phenylsulfonyl)acetamid;
3-(6-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)pyridin-3-yl)-1,3-oxazinan-2-on;
3-(5-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)pyridin-2-yl)-1,3-oxazinan-2-on;
N-((1R,2S)-2-Phenylcyclopropyl)-1-(2-(p-tolyloxy)ethyl)piperidin-4-amin;
3-(4-(2-(4-(Methyl((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-on;
2-(4-(2-(1-Methyl-3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-λ4-azetidin-1-yl)ethoxy)phenyl)-N-(methylsulfonyl)acetamid;
N-Methyl-1-(2-((6-methylpyridin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
(1R,2S)-N-((1-(2-((6-Methylpyridin-3-yl)oxy)ethyl)azetidin-3-yl)methyl)-2-phenylcyclopropan- 1-amin;
4-(2-(1-Methyl-3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-λ4-azetidin-1-yl)ethoxy)-N-(methylsulfonyl)benzamid;
3-(5-(2-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)pyridin-2-yl)-1,3-oxazinan-2-on;
6-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-3,4-dihydrochinolin-2(1H)-on;
5-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)indolin-2-on;
1-(2-(3-Fluor-4-methylphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
N-((1R,2S)-2-Phenylcyclopropyl)-1-(2-(chinazolin-4-yloxy)ethyl)piperidin-4-amin;
N-((1R,2S)-2-Phenylcyclopropyl)-1-(2-(chinolin-4-yloxy)ethyl)piperidin-4-amin;
N-((1R,2S)-2-Phenylcyclopropyl)-1-(2-(pyrimidin-5-yloxy)ethyl)piperidin-4-amin;
1-(2-(3,5-Difluorphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-(3,5-Dichlorphenoxy)ethyl)-N-(1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-((6-Methylpyridazin-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
(E)-3-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)acrylsäure;
1-(2-(3-Fluorphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-((6-Methylpyridin-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-((2-Methylpyrimidin-5-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-(4-Bromphenoxy)ethyl)-4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-2-on;
2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethan-1-ol;
N-(1-(2-(4-(2-Oxo-1,3-oxazinan-3-yl)phenoxy)ethyl)piperidin-4-yl)-N-((1R,2S)-2-phenylcyclopropyl)acetamid;
1-(2-Methoxyethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-((1,3-Dimethyl-1H-pyrazol-5-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-((1-Methyl-1H-pyrazol-3-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
3-(4-(2-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethoxy)phenyl)-1,3-oxazinan-2-on;
1-(2-Isopropoxyethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
2-(2-Fluor-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)essigsäure;
1-(2-(3,5-Difluor-4-methylphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-((5-Methyl-1,3,4-thiadiazol-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
2-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)isonicotinsäure;
3-(4-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)oxazolidin-2-on;
1-(2-(4-Bromphenoxy)ethyl)-4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-2,6-dion;
N-((1R,2S)-2-Phenylcyclopropyl)-1-(2-(pyridin-3-yloxy)ethyl)piperidin-4-amin;
7-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)-2H-benzo[b][1,4]oxazin-3(4H)-on;
6-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)benzo[d]oxazol-2(3H)-on;
1-(2-((5-Methylthiazol-2-yl)oxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
3-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)isonicotinsäure;
2-(3-Chlor-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)essigsäure;
2-(3-Fluor-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)essigsäure;
2-(3-Methyl-4-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethoxy)phenyl)essigsäure;
4-(2-(4-(((1R,2S)-2-(3,4-Difluorphenyl)cyclopropyl)amino)piperidin-1-yl)ethoxy)benzoesäure;
1-Anilin-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol;
1-(N-Methylanilin)-3-[4-[[trans-2-phenylcyclopropyl]amino]-1-piperidyl]propan-2-ol;
1-(2-(Phenylamino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-(Methyl(phenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-((4-Bromphenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(4-((2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)piperidin-2-on;
3-(4-((2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-on;
4-(4-((2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)morpholin-3-on;
N-((1R,2S)-2-Phenylcyclopropyl)-1-(2-((4-(piperidin-1-yl)phenyl)amino)ethyl)piperidin-4-amin;
1-(2-((4-Morpholinophenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(2-((4-(4-Methylpiperazin-1-yl)phenyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
1-(4-((2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)pyrrolidin-2-on;
3-(4-((2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)oxazolidin-2-on;
1-Methyl-3-(4-((2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)imidazolidin-2-on;
1-(4-(4-((2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)piperazin-1-yl)ethan-1-on;
3-(4-((2-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-on;
N,6-Dimethyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)pyridin-3-amin;
1-(2-((4-Bromphenyl)(methyl)amino)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
3-(4-(Methyl(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)phenyl)-1,3-oxazinan-2-on;
1-Methyl-3-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)harnstoff;
N-Methyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)acetamid;
N,2-Dimethyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)pyridin-4-amin;
1-(2-(4-Brom-2-fluorphenoxy)ethyl)-N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amin;
2-((2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino)isonicotinsäure;
3-((2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethyl)amino) isonicotinsäure;
1-Morpholino-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-on;
N-Methoxy-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamid;
1-Morpholino-3-phenyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-on;
1-Morpholino-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-on;
N-(Methylsulfonyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamid;
3-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)-1-(piperazin-1-yl)propan-1-on;
3-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)-N-(phenylsulfonyl)propanamid;
1-(4-Methylpiperazin-1-yl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-on;
N-(Ethylsulfonyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propanamid;
3-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)-1-thiomorpholinopropan-1-on;
1-(4-Methylpiperazin-1-yl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butan-1-on;
4-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)-1-(piperazin-1-yl)butan-1-on;
1-Morpholino-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butan-1-on;
4-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)-N-(phenylsulfonyl)butanamid;
N-(Cyclopropylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamid;
N-(Ethylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamid;
N-(Methylsulfonyl)-4-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)butanamid;
1-(cis-2,6-Dimethylmorpholino)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-on;
N-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethyl)methansulfonamid;
N-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin- 1-yl)ethyl)benzolsulfonamid;
N-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethyl)propan-2-sulfonamid;
N-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)propyl)methansulfonamid;
N-Methyl-N-(2-(3-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)methansulfonamid;
N-(2-(3-((((1R,2S)-2-Phenylcyclopropyl)amino)methyl)azetidin-1-yl)ethyl)methansulfonamid;
N-Methyl-N-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)methansulfonamid;
N-(2-(4-(((1R,2S)-2-Phenylcyclopropyl)amino)piperidin-1-yl)ethyl)cyclopropansulfonamid;
N-Phenyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethan-1-sulfonamid;
N-Methyl-2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethan-1-sulfonamid; oder
1,1-Dimethyl-3-(2-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)ethyl)harnstoff;
oder ein pharmazeutisch verträgliches Salz davon ist.ou un sel pharmaceutiquement acceptable de celui-ci,
dans lequel :
R1 est un hydrogène, alkyle en C1 à C4 ou acyle en C1 à C4 ;
L est -(CH2)s-CR2R3-(CH2)m- ;
chacun de R2 et R3 est indépendamment un hydrogène, alkyle en C1 à C4, -OR4 ou aralkyle ;
chaque R4 est indépendamment un hydrogène ou alkyle en C1 à C4 ;
X est -W-R5 ou Y-R6 ;
W est -NR4- ou -O- ;
Y est -C(O)-, -S-, -SO-, -SO2-, -NR4SCO2-, -SO2NR4- ou -NR4C(O)- ;
R5 est un acyle, alkyle en C1 à C4, cycloalkyle, hétérocyclyle, aryle ou hétéroaryle, dans lequel chacun desdits cycloalkyle, hétérocyclyle, aryle et hétéroaryle est éventuellement indépendamment substitué par un ou plusieurs R8 ;
R6 est un alkyle en C1 à C6, aryle, -NR4R7 ou hétérocyclyle éventuellement indépendamment substitué sur un ou plusieurs atomes de carbone par alkyle en C1 à C6, halogène, cyano, ou halogénoalkyle, ou éventuellement indépendamment substitué sur un ou plusieurs atomes d'azote par -C(O)-alkyle en C1 à C6, -C(O)O-alkyle en C1 à C6, -C(O)NR4-alkyle en C1 à C6, ou -S(O)2NR4-alkyle en C1 à C6 ;
R7 est un hydroxyle, alcoxy, -SO2-alkyle en C1 à C6, -SO2-cycloalkyle, ou -SO2-aryle, dans lequel le cycloalkyle ou aryle de chacun des -SO2-cycloalkyle et-SO2-aryle est éventuellement indépendamment substitué par un ou plusieurs R8 ;
chaque R8 est un halogène, hydroxyle, amino, cyano, alkyle en C1 à C6, alcényle en C2 à C6, alcynyle en C2 à C6, halogénoalkyle, alcoxy, alkylamino, dialkylamino, cycloalkyle, aryle, hétéroaryle, hétérocyclyle, aralkyle, hétéroarylalkyle, -(CH2)nCOOR4, -(CH2)nC(O)NR4O-alkyle en C1 à C6, -(CH2)nC(O)NR4SO2-alkyle en C1 à C6, -(CH2)nC(O)NR4SO2-cycloalkyle, -(CH2)nC(O)NR4SO2-aryle, -(alcényle en C2 à C6)-C(O)OR4, -(alcényle en C2 à C6)-C(O)NR4SO2-alkyle en C1 à C4, ou -(alcényle en C2 à C6)-C(O)NR4SO2-aryle, dans lequel chacun des cycloalkyle, aryle, hétéroaryle et hétérocyclyle est éventuellement indépendamment substitué par un ou plusieurs alkyle en C1 à C3 ou -CH2NR4SO2-aryle ;
m vaut 0 ou 1 ;
s vaut 0 ou 1 ;
chaque n vaut 0, 1 ou 2 ;
chaque p vaut 0, 1 ou 2 ;
chaque groupe RA est indépendamment un oxo ou alkyle en C1 à C3, ou bien deux groupes RA sur des atomes de cycle différents forment ensemble un pont en C1 à C3 dans lequel l'un des carbones de pont est éventuellement remplacé par -NH- ; et
chaque Q1, Q2 et Q3 est indépendamment un hydrogène, halogène, halogénoalkyle, alkyle en C1 à C4, ou alcoxy en C1 à C4.
(a) un aryle éventuellement indépendamment substitué par un ou plusieurs R8 ;
(b) un phényle éventuellement indépendamment substitué par un ou plusieurs R8 ;
(c) un phényle éventuellement indépendamment substitué par un ou plusieurs R8, où R8 est un hétérocyclyle éventuellement indépendamment substitué par un ou plusieurs alkyle en C1 à C3 ou acyle en C1 à C4 ;
(d) un hétéroaryle éventuellement indépendamment substitué par un ou plusieurs R8 ;
(e) un hétéroaryle éventuellement indépendamment substitué par un ou plusieurs R8, lequel hétéroaryle est pyridyle, 6-méthylpyridyle, 4-carboxypyridyle, dihydroquinolinone, indolinone, quinazolinyle, quinolinyle, pyrimidinyle, 2-méthylpyrimidinyle, pyridazinyle, 6-méthylpyridazinyle, pyrazolyle, 1-méthylpyrazolyle, 5-méthylpyrazolyle, 1,3-diméthylpyrazolyle, thiazolyle, 5-méthylthiazolyle, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, thiadiazolyle ou 5-méthylthiadiazolyle ;
(f) un pyridyle éventuellement indépendamment substitué par un ou plusieurs R8 ; ou
(g) un pyridyle éventuellement indépendamment substitué par un ou plusieurs R8, où R8 est un hétérocyclyle éventuellement indépendamment substitué par un ou plusieurs alkyle en C1 à C3.
(a) un aryle éventuellement indépendamment substitué par un ou plusieurs R8 ;
(b) un phényle éventuellement indépendamment substitué par un ou plusieurs R8 ;
(c) un phényle éventuellement indépendamment substitué par un ou plusieurs R8, où R8 est un hétérocyclyle éventuellement indépendamment substitué par un ou plusieurs alkyle en C1 à C3 ;
(d) un hétéroaryle éventuellement indépendamment substitué par un ou plusieurs R8 ;
(e) un hétéroaryle éventuellement indépendamment substitué par un ou plusieurs R8, lequel hétéroaryle est pyridyle, 6-méthylpyridyle, 4-carboxypyridyle, dihydroquinolinone, indolinone, quinazolinyle, quinolinyle, pyrimidinyle, 2-méthylpyrimidinyle, pyridazinyle, 6-méthylpyridazinyle, pyrazolyle, 1-méthylpyrazolyle, 5-méthylpyrazolyle, 1,3-diméthylpyrazolyle, thiazolyle, 5-méthylthiazolyle, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, thiadiazolyle ou 5-méthylthiadiazolyle ;
(f) un pyridyle éventuellement indépendamment substitué par un ou plusieurs R8 ; ou
(g) un pyridyle éventuellement indépendamment substitué par un ou plusieurs R8, où R8 est un hétérocyclyle éventuellement indépendamment substitué par un ou plusieurs alkyle en C1 à C3.
(i) Y est -C(O)- ; s vaut 0 ; m vaut 0 ; R2 est un aralkyle ou alkyle en C1 à C4 ; R3 est un hydrogène ; et R6 est un hétérocyclyle ;
(ii) Y est -C(O)- ; s vaut 1 ; m vaut 0 ; chacun de R2 et R3 est indépendamment un hydrogène ; et R6 est un hétérocyclyle ;
(iii) Y est -C(O)- ; s vaut 1 ; m vaut 1 ; chacun de R2 et R3 est un hydrogène ; et R6 est un hétérocyclyle ;
(iv) Y est -C(O)- ; s vaut 1 ; m vaut 1 ; chacun de R2 et R3 est un hydrogène ; et R6 est -NR4R7 ;
(v) Y est -NR4SO2- ; m vaut 1 ; chacun de R2 et R3 est un hydrogène ; et R6 est un alkyle en C1 à C6, cycloalkyle ou aryle, dans lequel l'aryle ou cycloalkyle peut être éventuellement indépendamment substitué par un ou plusieurs alkyle en C1 à C3, halogéno, halogénoalkyle, amino ou cyano ;
(vi) Y est -SO2NR4- ; s vaut 1 ; m vaut 1 ; chacun de R2 et R3 est indépendamment un hydrogène ; et R6 est un alkyle en C1 à C6 ou aryle, dans lequel l'aryle peut être éventuellement indépendamment substitué par un ou plusieurs alkyle en C1 à C3, halogène, halogénoalkyle, amino ou cyano ; ou
(vii) Y est -NR4C(O)NR4R4 ; s vaut 1 ; m vaut 1 ; chacun de R2 et R3 est un hydrogène ; et chaque R4 est indépendamment un hydrogène ou alkyle en C1 à C3 ou chaque R4 est un alkyle en C1 à C3.
1-phénoxy-3-[4-[[trans-2-phénylcyclopropyl]amino]-1-pipéridyl]propan-2-ol ;
1-(2-méthoxy-3-phénoxypropyl)-N-[trans-2-phénylcyclopropyl]pipéridin-4-amine ;
2-méthyl-1-phénoxy-3-(4-(((trans)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propan-2-ol ;
1-phénoxy-3-[3-[[[(trans)-2-phénylcyclopropyl]amino]méthyl]azétidin-1-yl]propan-2-ol ;
(R)-1-phénoxy-3-(4-(((1S,2R)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propan-2-ol ;
(S)-1-phénoxy-3-(4-(((1S,2R)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propan-2-ol ;
1-phénoxy-3-[(1R,5S)-6-[[(trans)-2-phénylcyclopropyl]amino]-3-azabicyclo[3.1.1]heptan-3-yl]propan-2-ol ;
(trans)-N-[[1-(2-phénoxyéthyl)azétidin-3-yl]méthyl]-2-phénylcyclopropanamine ;
(trans)-N-[[1-(3-phénoxypropyl)azétidin-3-yl]méthyl]-2-phénylcyclopropanamine ;
1-[2-(4-bromophénoxy)éthyl]-N-[(1R,2S)-2-phénylcyclopropyl]pipéridin-4-amine ;
1-(3-phénoxypropyl)-N-((trans)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-phénoxyéthyl)-N-((trans)-2-phénylcyclopropyl)pipéridin-4-amine ;
acide 2-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)acétique ;
N-(méthylsulfonyl)-2-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)acétamide ;
2-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)-N-(phénylsulfonyl)acétamide ;
N,N-diméthyl-2-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)acétamide ;
N-méthoxy-2-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)acétamide ;
1-[2-(4-morpholinophénoxy)éthyl]-N-[(1R,2S)-2-phénylcyclopropyl]pipéridin-4-amine ;
1-(2-(4-(4-méthylpipérazin-1-yl)phénoxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
3-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)oxazolidin-2-one ;
1-méthyl-3-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)imidazolidin-2-one ;
3-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)-1,3-oxazinan-2-one ;
4-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)morpholin-3-one ;
1-(4-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)pipérazin-1-yl)éthan-1-one ;
1-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)pyrrolidin-2-one ;
1-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)pipéridin-2-one ;
N-((1R,2S)-2-phénylcyclopropyl)-1-(2-(4-(pipéridin-1-yl)phénoxy)éthyl)pipéridin-4-amine ;
acide 2-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propoxy)phényl)acétique ;
acide 4-(2-hydroxy-3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propoxy)benzoïque ;
acide (E)-3-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propoxy)phényl)acrylique ;
acide 2-(4-(3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propoxy)phényl)acétique ;
acide 4-(3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propoxy)benzoïque ;
acide (E)-3-(4-(3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propoxy)phényl)acrylique ;
(1R,2S)-N-((1-(2-(4-bromophénoxy)éthyl)azétidin-3-yl)méthyl)-2-phénylcyclopropan-1-amine ;
1-(2-(2,4-dichlorophénoxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
(1R,2S)-N-(((1-(2-(2,4-dichlorophénoxy)éthyl)azétidin-3-yl)méthyl)-2-phénylcyclopropan-1-amine ;
1-(2-(2,4-difluorophénoxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
(1R,2S)-N-((1-(2-(2,4-difluorophénoxy)éthyl)azétidin-3-yl)méthyl)-2-phénylcyclopropan-1-amine ;
(E)-3-(4-(2-hydroxy-3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propoxy)phényl)-N-(méthylsulfonyl)acrylamide ;
1-(2-((2-méthylpyridin-4-yl)oxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
(1R,2S)-2-phényl-N-((1-(2-(p-tolyloxy)éthyl)azétidin-3-yl)méthyl)cyclopropan-1-amine ;
(1R,2S)-2-phényl-N-((1-(2-(pyridin-2-yloxy)éthyl)azétidin-3-yl)méthyl)cyclopropan-1-amine ;
acide 4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)benzoïque ;
N-(cyclopropylsulfonyl)-4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)benzamide ;
4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)-N-(phénylsulfonyl)benzamide ;
(E)-N-(méthylsulfonyl)-3-(4-(3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propoxy)phényl)acrylamide ;
3-(4-(2-(3-((((1R,2S)-2-phénylcyclopropyl)amino)méthyl)azétidin-1-yl)éthoxy)phényl)-1,3-oxazinan-2-one ;
4-(4-(2-(3-((((1R,2S)-2-phénylcyclopropyl)amino)méthyl)azétidin-1-yl)éthoxy)phényl)morpholin-3-one ;
1-(4-(2-(3-((((1R,2S)-2-phénylcyclopropyl)amino)méthyl)azétidin-1-yl)éthoxy)phényl)pipéridin-2-one ;
(1R,2S)-2-phényl-N-((1-(2-(4-(pipérazin-1-yl)phénoxy)éthyl)azétidin-3-yl)méthyl)cyclopropan-1-amine ;
(1R,2S)-N-((1-(2-(4-(4-méthylpipérazin-1-yl)phénoxy)éthyl)azétidin-3-y))méthyl)-2-phénylcyclopropan-1-amine ;
1-(4-(4-(2-(3-((((1R,2S)-2-phénylcyclopropyl)amino)méthyl)azétidin-1-yl)éthoxy)phényl)pipérazin-1-yl)éthan-1-one ;
1-(2-((5-méthylpyridin-2-yl)oxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-((6-méthylpyridin-3-yl)oxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
N-(méthylsulfonyl)-4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)benzamide ;
N-(éthylsulfonyl)-4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)benzamide ;
(1S,2R)-N-((1-(2-((5-(4-méthylpipérazin-1-yl)pyridin-2-yl)oxy)éthyl)azétidin-3-yl)méthyl)-2-phénylcyclopropan-1-amine ;
acide 2-(4-(2-(3-((((1S,2R)-2-phénylcyclopropyl)amino)méthyl)azétidin-1-yl)éthoxy)phényl)acétique ;
acide 4-(2-(3-((((1R,2S)-2-phénylcyclopropyl)amino)méthy))azétidin-1-yl)éthoxy)benzoïque ;
2-(4'-(2-(3-((((1S,2R)-2-phénylcyclopropyl)amino)méthyl)azétidin-1-yl)éthoxy)-[1,1'-biphényl]-4-yl)-N-(phénylsulfonyl)acétamide ;
3-(6-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)pyridin-3-yl)-1,3-oxazinan-2-one ;
3-(5-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)pyridin-2-yl)-1,3-oxazinan-2-one ;
N-((1R,2S)-2-phénylcyclopropyl)-1-(2-(p-tolyloxy)éthyl)pipéridin-4-amine ;
3-(4-(2-(4-(méthyl((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)-1,3-oxazinan-2-one ;
2-(4-(2-(1-méthyl-3-((((1R,2S)-2-phénylcyclopropyl)amino)méthyl)-4-azétidin-1-yl)éthoxy)phényl)-N-(méthylsulfonyl)acétamide ;
N-méthyl-1-(2-((6-méthylpyridin-3-yl)oxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
(1R,2S)-N-((1-(2-((6-méthylpyridin-3-yl)oxy)éthyl)azétidin-3-yl)méthyl)-2-phénylcyclopropan-1-amine ;
4-(2-(1-méthyl-3-((((1R,2S)-2-phénylcyclopropyl)amino)méthyl)-4-azétidin-1-yl)éthoxy)-N-(méthylsulfonyl)benzamide ;
3-(5-(2-(3-((((1R,2S)-2-phénylcyclopropyl)amino)méthyl)azétidin-1-yl)éthoxy)pyridin-2-yl)-1,3-oxazinan-2-one ;
6-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)-3,4-dihydroquinolin-2(1H)-one ;
5-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)indolin-2-one ;
1-(2-(3-fluoro-4-méthylphénoxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
N-((1R,2S)-2-phénylcyclopropyl)-1-(2-(quinazolin-4-yloxy)éthyl)pipéridin-4-amine ;
N-((1R,2S)-2-phénylcyclopropyl)-1-(2-(quinolin-4-yloxy)éthyl)pipéridin-4-amine ;
N-((1R,2S)-2-phénylcyclopropyl)-1-(2-(pyrimidin-5-yloxy)éthyl)pipéridin-4-amine ;
1-(2-(3,5-difluorophénoxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-(3,5-dichlorophénoxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-aminé ;
1-(2-((6-méthylpyridazin-3-yl)oxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
acide (E)-3-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)acrylique ;
1-(2-(3-fluorophénoxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-((6-méthylpyridin-2-yl)oxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-((2-méthylpyrimidin-5-yl)oxy)éthyl)-N-(((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-(4-bromophénoxy)éthyl)-4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-2-one ;
2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthan-1-ol ;
N-(1-(2-(4-(2-oxo-1,3-oxazinan-3-yl)phénoxy)éthyl)pipéridin-4-yl)-N-((1R,2S)-2-phénylcyclopropyl)acétamide ;
1-(2-méthoxyéthy))-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-((1,3-diméthyl-1H-pyrazol-5-yl)oxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-((1-méthyl-1H-pyrazol-3-yl)oxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
3-(4-(2-(3-((((1R,2S)-2-phénylcyclopropyl)amino)méthyl)azétidin-1-yl)éthoxy)phényl)-1,3-oxazinan-2-one ;
1-(2-isopropoxyéthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
acide 2-(2-fluoro-4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)acétique ;
1-(2-(3,5-difluoro-4-méthylphénoxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-((5-méthy)-1,3,4-thiadiazol-2-yl)oxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
acide 2-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)isonicotinique ;
3-(4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)oxazolidin-2-one ;
1-(2-(4-bromophénoxy)éthyl)-4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridine-2,6-dione ;
N-((1R,2S)-2-phénylcyclopropyl)-1-(2-(pyridin-3-yloxy)éthyl)pipéridin-4-amine ;
7-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)-2H-benzo[b][1,4]oxazin-3(4H)-one ;
6-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)benzo[d]oxazol-2(3H)-one ;
1-(2-((5-méthylthiazol-2-yl)oxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
acide 3-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)isonicotinique ;
acide 2-(3-chloro-4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)acétique ;
acide 2-(3-fluoro-4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)acétique ;
acide 2-(3-méthyl-4-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthoxy)phényl)acétique ;
acide 4-(2-(4-(((1R,2S)-2-(3,4-difluorophényl)cyclopropyl)amino)pipéridin-1-yl)éthoxy)benzoïque ;
1-anilino-3-[4-[[trans-2-phénylcyclopropyl]amino]-1-pipéridyl]propan-2-ol ;
1-(N-méthylanilino)-3-[4-[[trans-2-phénylcyclopropyl]amino]-1-pipéridyi]propan-2-ol ;
1-(2-(phénylamino)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-(méthyl(phényl)amino)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-((4-bromophényl)amino)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(4-((2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)amino)phényl)pipéridin-2-one ;
3-(4-((2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)amino)phényl)-1,3-oxazinan-2-one ;
4-(4-((2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)amino)phényl)morpholin-3-one ;
N-((1R,2S)-2-phénylcyclopropyl)-1-(2-((4-(pipéridin-1-yl)phényl)amino)éthyl)pipéridin-4-amine ;
1-(2-((4-morpholinophényl)amino)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(2-((4-(4-méthylpipérazin-1-yl)phényl)amino)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
1-(4-((2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)amino)phényl)pyrrolidin-2-one ;
3-(4-((2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)amino)phényl)oxazolidin-2-one ;
1-méthyl-3-(4-((2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)amino)phényl)imidazolidin-2-one ;
1-(4-(4-((2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)amino)phényl)pipérazin-1-yl)éthan-1-one ;
3-(4-((2-(3-((((1R,2S)-2-phénylcyclopropyl)amino)méthyl)azétidin-1-yl)éthyl)amino)phényl)-1,3-oxazinan-2-one ;
N,6-diméthyl-N-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)pyridin-3-amine ;
1-(2-((4-bromophényl)(méthyl)amino)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
3-(4-(méthyl(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)amino)phényl)-1,3-oxazinan-2-one ;
1-méthyl-3-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)urée ;
N-méthyl-N-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)acétamide ;
N,2-diméthyl-N-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)pyridin-4-amine ;
1-(2-(4-bromo-2-fluorophénoxy)éthyl)-N-((1R,2S)-2-phénylcyclopropyl)pipéridin-4-amine ;
acide 2-((2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)amino)isonicotinique ;
acide 3-((2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)amino)isonicotinique ;
1-morpholino-2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propan-1-one ;
N-méthoxy-2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propanamide ;
1-morpholino-3-phényl-2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propan-1-one ;
1-morpholino-3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propan-1-one ;
N-(méthylsulfonyl)-3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propanamide ;
3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)-1-(pipérazin-1-yl)propan-1-one ;
3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)-N-(phénylsulfonyl)propanamide ;
1-(4-méthylpipérazin-1-yl)-3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propan-1-one ;
N-(éthylsulfonyl)-3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propanamide ;
3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)-1-thiomorpholinopropan-1-one ;
1-(4-méthylpipérazin-1-yl)-4-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)butan-1-one ;
4-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)-1-(pipérazin-1-yl)butan-1-one ;
1-morpholino-4-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-y))butan-1-one ;
4-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)-N-(phénylsulfonyl)butanamide ;
N-(cyclopropylsulfonyl)-4-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)butanamide ;
N-(éthylsulfonyl)-4-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)butanamide ;
N-(méthylsulfonyl)-4-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)butanamide ;
1-(cis-2,6-diméthylmorpholino)-3-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propan-1-one ;
N-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)méthanesulfonamide ;
N-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)benzènesulfonamide ;
N-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)propane-2-sulfonamide ;
N-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)propyl)méthanesulfonamide ;
N-méthyl-N-(2-(3-((((1R,2S)-2-phénylcyclopropyl)amino)méthyl)azétidin-1-yl)éthyl)méthanesulfonamide ;
N-(2-(3-((((1R,2S)-2-phénylcyclopropyl)amino)méthyl)azétidin-1-yl)éthyl)méthanesulfonamide ;
N-méthyl-N-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)méthanesulfonamide ;
N-(2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)cyclopropanesulfonamide ;
N-phényl-2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthane-1-sulfonamide ;
N-méthyl-2-(4-(((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthane-1-sulfonamide ; et
1,1-diméthyl-3-(2-(4-((1R,2S)-2-phénylcyclopropyl)amino)pipéridin-1-yl)éthyl)urée ;
ou un sel pharmaceutiquement acceptable de celui-ci.REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
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