An effective means of modulating NMDA receptor-mediated toxicity

Abstract

The present invention relates to compounds that inhibit the toxic activity of extrasynaptic NMDA receptors, particularly by inhibiting the formation of the NMDA receptor / TRPM4 complex. In particular, the present invention relates to diamine compounds according to general formula I and their use in medicine, especially in the treatment of neurological disorders such as neurodegenerative disorders.

Description

[Technical Field]

[0001] The present invention relates to the field of neurodegenerative processes and protective measures thereagainst.In particular, the present invention relates to compounds that inhibit the toxic activity of extrasynaptic NMDA receptors, in particular compounds that inhibit the formation of the NMDA receptor / TRPM4 complex.More specifically, the present invention relates to diamine compounds according to general formula I and their use in medicine for the treatment of neurological disorders, in particular neurodegenerative disorders. [Background technology]

[0002] Neurodegenerative diseases are devastating conditions that result in the gradual loss of neuronal structure and function, ultimately leading to neuronal death. Neurodegeneration can be acute or slowly progressive. Both types of neurodegeneration are often accompanied by increased death signaling by extrasynaptic NMDA receptors, triggered by elevated extracellular glutamate concentrations and relocalization of NMDA receptors to extrasynaptic sites. NMDA receptors are calcium-permeable glutamate- and voltage-gated ion channels. Based on their intracellular location, they can be classified as synaptic or extrasynaptic NMDA receptors. While the subunit composition of receptors within and outside synaptic junctions is similar, in addition to the common glutamate ionotropic receptor NMDA type 1 subunit (GRIN1), extrasynaptic NMDA receptors primarily contain the GRIN2B subunit, whereas GRIN2A is the predominant subunit in synaptic NMDA receptors. The cellular effects of synaptic and extrasynaptic NMDA receptor stimulation are significantly different. Synaptic NMDA receptors induce physiological changes in the efficacy of synaptic transmission. Synaptic NMDA receptors also trigger calcium signaling pathways to the cell nucleus, activating gene expression responses essential for the long-term implementation of virtually all behavioral adaptations. Most importantly, synaptic NMDA receptors act through nuclear calcium and are potent activators of genes that protect neuronal structure and promote survival. In contrast, extrasynaptic NMDA receptors trigger cell death pathways. Within minutes of extrasynaptic NMDA receptor activation, mitochondrial membrane potential collapses, followed by mitochondrial permeability transition (MTT). Extrasynaptic NMDA receptors trigger the cyclic adenosine monophosphate (cAMP)-responsive element-binding protein (CREB) blockade pathway, inactivating extracellular signal-regulated kinase (ERK)-MAPK signaling, and triggering the nuclear import of class IIa histone deacetylases (HDACs) and the pro-apoptotic transcription factor Foxo3A, thereby strongly disrupting excitation-transcription coupling and inhibiting nuclear calcium-driven adaptogenomics.This affects the activity regulation of many genes, such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor D (VEGF), which are essential for maintaining complex dendritic structures and synaptic connections and for building a neuroprotective shield. Furthermore, due to the short reach of activated ERK1 / 2, their blockade by extrasynaptic NMDA receptors disrupts important local signaling events, such as dendritic mRNA translation and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor trafficking, which controls the efficacy of synaptic transmission. Therefore, extrasynaptic NMDA receptor signaling is characterized by the initiation of a pathological triad involving mitochondrial dysfunction, transcriptional dysregulation, and loss of integrity of neuronal structure and connectivity.

[0003] Several attempts have been made to use NMDA receptor blockers to treat neurological disorders. Clinical trial results have generally been disappointing, primarily due to severe side effects caused by blockers interfering with the physiological function of synaptically localized NMDA receptors (Ogden and Traynelis, 2011). One notable exception is the NMDA receptor antagonist memantine (Bormann, 1989). Beneficial effects of low-dose memantine treatment have been observed in several animal models of neurodegeneration, including Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and the experimental autoimmune encephalomyelitis (EAE) model of MS. Furthermore, memantine has been approved by the European Medicines Agency and the US Food and Drug Administration (FDA) for the treatment of AD since 2002. The discovery that memantine preferentially blocks toxic extrasynaptic NMDA receptors within a specific concentration range explains why memantine is effective in a wide range of neurodegenerative diseases that share toxic extrasynaptic NMDA receptor signaling as a pathological mechanism (Bading, J Exp Med. 2017 Mar 6;214(3):569-578).

[0004] It has recently been discovered that excitotoxicity requires physical binding of the NMDA receptor and the transient receptor potential channel TRPM4 (Yan et al., Science, 2020 Oct. 9;370(6513):eaay3302; see also WO2020 / 079244). The NMDA receptor / TRPM4 interaction is mediated by a 57-amino acid intracellular domain of TRPM4 located just beneath the plasma membrane. Yan et al. also found that this interaction can be inhibited in various ways, providing protection against excitotoxic cell death in cultured neurons and in mouse models of neurodegeneration. The methods proposed by Yan et al. included peptide-derived inhibitors of the NMDA receptor / TRPM4 interaction and small molecule compounds. Summary of the Invention [Problem to be solved by the invention]

[0005] However, although the compounds identified by Yan et al. exhibit inhibitory activity, there remains a need in the art for additional means to selectively inhibit NMDA receptor / TRPM4 interaction, thereby specifically attenuating toxic extrasynaptic NMDA receptor activity. Accordingly, the problem addressed by the present invention was to provide new, preferably improved, means for attenuating toxic extrasynaptic NMDA receptor activity. [Means for solving the problem]

[0006] This problem is solved by the subject matter set forth in the appended claims and in the following description.

[0007] As shown below, the inventors of the present invention have surprisingly identified new compounds that highly effectively inhibit NMDA receptor-mediated toxicity and therefore are particularly useful candidates for the treatment and prevention of diseases involving NMDA receptor-mediated cellular toxicity.

[0008] Thus, the present invention relates in a first aspect to compounds according to the following general formula I:

[0009] [ka]

[0010] Here, R7 is

[0011] [ka]

[0012] is selected from, where: R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and at least one of R1, R2, R3 and R4 is selected from F, Cl, Br, I, -CN and ethynyl; R5 is selected from H, unsubstituted branched or straight chain C1-C4 alkyl, fluorine-substituted branched or straight chain C1-C4 alkyl, unsubstituted propenyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl; R6 is selected from unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, R5 is methyl and R7 is

[0013] [ka]

[0014] and when one of R2 and R3 is H and the other is Cl, and R1 and R4 are H, then R6 is selected from unsubstituted straight chain C3-C6 alkyl, unsubstituted branched C4-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C4-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, R5 is methyl and R7 is

[0015] [ka]

[0016] wherein one of R2 and R3 is H and the other is F, Cl or CN, and R1 and R4 are H, then R6 is selected from unsubstituted straight chain C3-C6 alkyl, unsubstituted branched C4-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C4-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, R5 is methyl and R7 is

[0017] [ka]

[0018] wherein two of R1, R2, R3, and R4 are Cl and the other two are H, and when any of R1 and R2, R3 and R4, R1 and R3, or R2 and R4 is Cl, then R6 is selected from unsubstituted branched or straight chain C3-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, R5 is methyl and R7 is

[0019] [ka]

[0020] wherein one of R1 and R4 is H and the other is F or Br, and R2 and R3 are H, then R6 is selected from unsubstituted straight chain C3-C6 alkyl, unsubstituted branched C4-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C4-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, R5 is ethyl and R7 is

[0021] [ka]

[0022] wherein one of R2 and R3 is H and the other is Cl, and R1 and R4 are H, then R6 is selected from unsubstituted straight chain C3-C6 alkyl, unsubstituted branched C3-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, R5 is H and R7 is

[0023] [ka]

[0024] then the compound has one of the following formulas:

[0025] [ka]

[0026] [ka]

[0027] and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers, hydrates, and / or isotopes of any of these compounds. Most preferred are pharmaceutically acceptable salts of any of the above compounds.

[0028] The terms "unsubstituted alkyl" or "alkyl," when used without the "substituted" modifier, refer to a monovalent saturated aliphatic group having a carbon atom as the point of attachment, a straight or branched acyclic structure, and containing no atoms other than carbon and hydrogen. -CH(Me), -CHCH(Et), -CHCHCH(nPr or propyl), -CH(CH)(iPr, iPr or isopropyl), -CHCHCHCH(nBu), -CH(CH)CHCH(sec-butyl), -CHCH(CH)(isobutyl), -C(CH)(tert-butyl, tButyl, tBu or tBu), and -CHC(CH)(neopentyl) groups are non-limiting examples of alkyl groups. When "alkyl" is used with the "substituted" modifier, unless otherwise specified, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -OCH, -SCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)CH, or -S(O)NH. Preferably, only one hydrogen atom is replaced. Most preferably, only one hydrogen atom on the terminal carbon atom is replaced. A "fluorine-substituted" alkyl refers to an alkyl group in which one or more hydrogen atoms are independently replaced with -F. In the case of a fluorine-substituted alkyl, it is preferred that one or more hydrogen atoms be replaced with -F. More preferably, two or more hydrogen atoms are replaced by -F. Particularly preferred embodiments of fluorine-substituted alkyl are -CF3, -CHF2, -CH2CF3, -CF2CH3, and -CF2CF3.

[0029] The terms "unsubstituted alkenyl" or "alkenyl," when used without the "substituted" modifier, refer to a monovalent unsaturated aliphatic group having a carbon atom as the point of attachment, a straight or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2 (allyl), -CH2CH=CHCHCH3, and -CH=CHCH=CH2. Preferably, the structure contains only one non-aromatic carbon-carbon double bond, such as in allyl, at a terminal end of the structure. When "alkenyl" is used with the "substituted" modifier, unless otherwise specified, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -OCH, -SCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)CH, or -S(O)NH. Preferably, only one hydrogen atom is replaced. Most preferably, only one hydrogen atom on the terminal carbon atom is replaced. In the case of fluorine-substituted alkenyl, it is preferred that one or more hydrogen atoms are replaced with -F. Even more preferably, two or more hydrogen atoms (e.g., three) are replaced with -F.

[0030] As used herein, the terms "unsubstituted cycloalkyl" or "cycloalkyl," when used without the "substituted" modifier, refer to a monovalent saturated aliphatic group having a carbon atom as the point of attachment, said carbon atom forming part of a single non-aromatic ring structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include -CH(CH)(cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl. When "cycloalkyl" is used with the "substituted" modifier, unless otherwise specified, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -OCH, -SCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)CH, or -S(O)NH. Preferably, only one hydrogen atom is replaced. A "fluorine-substituted" cycloalkyl refers to a cycloalkyl group in which one or more hydrogen atoms are independently replaced with -F. In the case of a fluorine-substituted cycloalkyl, one or more hydrogen atoms are preferably replaced with -F. More preferably, two or more hydrogen atoms (eg, three) are replaced with -F.

[0031] As used herein, the terms "unsubstituted bicycloalkyl" or "bicycloalkyl," when used without the "substituted" modifier, refer to a monovalent saturated aliphatic group having a carbon atom as the point of attachment, said carbon atom being part of two non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. A non-limiting example is bicyclo[1.1.1]pentanyl. When "bicycloalkyl" is used with the "substituted" modifier, unless otherwise specified, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -OCH, -SCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)CH, or -S(O)NH. Preferably, only one hydrogen atom is replaced. When the cycloalkyl is substituted with -F, it is preferred that one or more hydrogen atoms are replaced with -F. More preferably, two or more hydrogen atoms (e.g., three) are replaced with -F.

[0032] As used herein, the terms "unsubstituted alkylcycloalkyl" or "alkylcycloalkyl," when used without the "substituted" modifier, refer to an alkyl group, as defined above, having at least two carbon atoms with the first carbon atom as the point of attachment, and the additional terminal carbon atom of the alkyl group forming part of a single non-aromatic ring structure. Non-limiting examples include -CH-CH(CH) (cyclopropylmethyl), cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl. When "alkylcycloalkyl" is used with the "substituted" modifier, unless otherwise specified, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -OCH, -SCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)CH, or -S(O)NH. Preferably, only one hydrogen atom is replaced. Most preferably, only one hydrogen atom of a carbon atom of a non-aromatic ring structure is replaced. When alkylcycloalkyl is substituted with -F, it is preferred that one or more hydrogen atoms be replaced with -F. More preferably, two or more hydrogen atoms (eg, three) are replaced with -F.

[0033] Examples of compounds of formula I include compounds of formula Ia or Ib:

[0034] [ka]

[0035] wherein R1, R2, R3, R4, R5 and R6 are as defined above for Formula I or more specifically below for Formula I, Ia and / or Ib; and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers, hydrates, and / or isotopes of any of these compounds.

[0036] In preferred embodiments of the present invention, R1, R2, R3, and R4 of the compounds of the present invention according to Formula I, Ia, or Ib are each independently selected from H, F, Cl, Br, I, and -CN. Those skilled in the art will understand that when "R1, R2, R3, and R4" are referred to herein, they are interpreted as a reference to "R1 and R2" in the context of Formula Ib, since there is no R3 or R4 in Formula Ib. In the context of the foregoing embodiment, this means that R1 and R2 of Formula Ib are each independently selected from H, F, Cl, Br, I, and -CN. In some embodiments of the compounds of the present invention according to Formula I, Ia, or Ib, at least one of R1, R2, R3, and R4 is ethynyl, and preferably, R2 is ethynyl. In other embodiments of Formula I, Ia, or Ib, two of R1, R2, R3, and R4, respectively, are independently selected from H, F, Cl, Br, I, -CN, and ethynyl. In some embodiments of Formula Ia, one of R2 and R3 is selected from H, F, Cl, Br, I, -CN, and ethynyl, and the other is H. In further embodiments of Formula Ia, at least two of R1, R2, R3, and R4 are H, and one of R2 and R3 is Cl. In some embodiments, R1 is H or F, preferably F, and R2 is selected from F, Cl, Br, I, CN, and ethynyl, preferably Cl, Br, CN, and ethynyl. In some embodiments of Formula Ia, R4 is H or F, preferably F, and R3 is selected from F, Cl, Br, I, CN, and ethynyl, preferably Cl, Br, CN, and ethynyl. In some embodiments of Formula Ia, R1 is F, R2 is Cl, and R3 and R4 are H, or R1 and R2 are H, R3 is Cl, and R4 is F.

[0037] R5 of the compounds of the invention according to Formula I, Ia, or Ib can be selected from H, unsubstituted branched or straight-chain C1-C4 alkyl, fluorine-substituted branched or straight-chain C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl. In preferred embodiments of the invention, R5 of the compounds of the invention according to Formula I, Ia, or Ib is selected from unsubstituted branched or straight-chain C1-C4 alkyl, fluorine-substituted branched or straight-chain C1-C4 alkyl, unsubstituted propenyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl. In some embodiments of the compounds of the invention according to Formula I, Ia, or Ib, R5 is H. In some embodiments of the compounds of the invention according to Formula I, Ia, or Ib, R5 is methyl. In some embodiments of the compounds of the present invention according to Formula I, Ia, or Ib, R5 is selected from ethyl, isopropyl, -CH2CF3, -CF2CF3, -CF2CH3, CHF2, CF3, cyclopropyl, fluorine-substituted isopropyl, propenyl, cyclopropyl, cyclobutyl, fluorine-substituted cyclobutyl, and cyclopentyl. In particular, in the case where R5 is not H, R1, R2, R3, and R4 are preferably each independently selected from H, F, Cl, Br, and -CN, and optionally ethynyl. Similarly, particularly when R5 is not H, it is also contemplated that at least two of R1, R2, R3, and R4 are H, and one or two, preferably one, of R2 and R3 are Cl or Br. For example, R1 is F, R2 is Cl, and R3 and R4 are H. Another example is when R1 and R2 are H, R3 is Cl, and R4 is F. In particularly preferred embodiments, R5 is selected from unsubstituted branched or straight-chain C1-C4 alkyl, fluorine-substituted branched or straight-chain C1-C4 alkyl, and unsubstituted propenyl.

[0038] Preferably, R6 in compounds of the invention according to formula I, Ia or Ib is not unsubstituted ethyl, i.e., is selected from unsubstituted straight chain C3-C6 alkyl, unsubstituted branched C4-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C4-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl and substituted C3-C6 alkenyl. When R6 of the compounds of the present invention according to Formula I, Ia, or Ib is selected from substituted branched or straight-chain C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 bicycloalkyl, substituted C4-C7 alkylcycloalkyl, and substituted C3-C6 alkenyl, the substituents of the substituted branched or straight-chain C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted bicycloalkyl, substituted C4-C7 alkylcycloalkyl, and substituted C3-C6 alkenyl are each independently selected from halogen, CN, OH, alkylthio, and alkoxy. Preferably, the substituents of the substituted branched or straight-chain C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted bicycloalkyl, substituted C4-C7 alkylcycloalkyl, and substituted C3-C6 alkenyl are each independently selected from F, Cl, CN, —SCH3, and OH.

[0039] Particularly preferred embodiments of the compounds according to the invention are characterized in that R6 is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl-, allyl, -CH2CH2-S-CH3, CH2CF2H, -CH2CF3, and -CH2CH2CN. Most preferably, R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl-, and allyl. Preferably, no substituent is present on the carbon atom forming the point of attachment of R6 to the nitrogen of formula I (or Ia or Ib, respectively).

[0040] Particularly preferred combinations of R5 and R6 are those in which R5 is not H (e.g., substituted C1-C4 alkyl or propenyl) and R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl, and allyl.

[0041] Examples of compounds of the invention where R5 is H include compounds having one of the following formulae:

[0042] [ka]

[0043] [ka]

[0044] and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers, hydrates, and / or isotopes of any of these compounds. Most preferred are pharmaceutically acceptable salts of any of the above compounds.

[0045] Examples of compounds of the invention where R5 is not H include compounds having one of the following formulae:

[0046] [ka]

[0047] [ka]

[0048] [ka]

[0049] and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers, hydrates, and / or isotopes of any of these compounds. Most preferred are pharmaceutically acceptable salts of any of the above compounds.

[0050] In some embodiments, the compound according to the first aspect of the invention is of formula Ia:

[0051] [ka]

[0052] wherein R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, in particular H, F, Cl, Br, I and -CN, and at least one of R1, R2, R3 and R4 is selected from F, Cl, Br, I, -CN and ethynyl, in particular F, Cl, Br, I and -CN; R5 is selected from H, unsubstituted branched or straight chain C1-C4 alkyl, fluorine-substituted branched or straight chain C1-C4 alkyl, unsubstituted propenyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl, in particular H, unsubstituted branched or straight chain C1-C4 alkyl, fluorine-substituted branched or straight chain C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl; R6 is selected from unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; with the proviso that if R5 is methyl, one of R2 and R3 is H and the other is Cl, and R1 and R4 are H, then R6 is selected from unsubstituted straight chain C3-C6 alkyl, unsubstituted branched C4-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C4-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; with the proviso that if R5 is methyl, two of R1, R2, R3 and R4 are Cl and the other two are H, and any of R1 and R2, R3 and R4, R1 and R3, or R2 and R4 is Cl, then R6 is selected from unsubstituted branched or straight chain C3-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; with the proviso that if R5 is ethyl, one of R2 and R3 is H and the other is Cl, and R1 and R4 are H, then R6 is selected from unsubstituted straight chain C3-C6 alkyl, unsubstituted branched C3-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, when R5 is H, the compound has one of the following formulas:

[0053] [ka]

[0054] [ka]

[0055] and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers, hydrates, and / or isotopes of any of these compounds. Most preferred are pharmaceutically acceptable salts of any of the above compounds.

[0056] In a preferred embodiment of the present invention, R5 in the compound of the present invention according to Formula Ia is selected from unsubstituted branched or straight-chain C1-C4 alkyl, fluorine-substituted branched or straight-chain C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl. Particularly in such a scenario, R1, R2, R3, and R4 are preferably each independently selected from H, F, Cl, Br, and -CN. Similarly (particularly when R5 is not H), it is also preferred that at least two of R1, R2, R3, and R4 are H, and one or two, preferably one, of R2 and R3 are Cl or Br. For example, R1 is F, R2 is Cl, and R3 and R4 are H. Another example is when R1 and R2 are H, R3 is Cl, and R4 is F. In a particularly preferred embodiment, R5 is selected from unsubstituted branched or straight-chain C1-C4 alkyl, fluorine-substituted branched or straight-chain C1-C4 alkyl. More preferably, R5 of the compounds of the present invention is selected from unsubstituted branched C3-C4 or straight chain C1-C4 alkyl, preferably straight chain C1-C4 alkyl. In some embodiments, R5 is methyl.

[0057] R6 in the compounds of the invention according to Formula Ia can be selected from substituted branched or straight-chain C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 bicycloalkyl, substituted C4-C7 alkylcycloalkyl, and substituted C3-C6 alkenyl, where the substituents of the substituted branched or straight-chain C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted bicycloalkyl, substituted C4-C7 alkylcycloalkyl, and substituted C3-C6 alkenyl are each independently selected from halogen, CN, OH, alkylthio, and alkoxy. Preferably, the substituents of the substituted branched or straight-chain C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted bicycloalkyl, substituted C4-C7 alkylcycloalkyl, and substituted C3-C6 alkenyl are each independently selected from F, Cl, CN, —SCH3, and OH. Particularly preferred embodiments of the compounds according to the invention are characterized in that R6 is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl-, allyl, -CH2CH2-S-CH3, CH2CF2H, -CH2CF3, and -CH2CH2CN. Most preferably, R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl-, and allyl. Preferably, no substituent is present on the carbon atom forming the point of attachment of R6 to the nitrogen of formula I, Ia, or Ib.

[0058] Possible combinations of R5 and R6 in the compounds of formula Ia of the present invention are those in which R5 is methyl and R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl, and allyl.

[0059] In an embodiment in which the compound according to the present invention is a pharmaceutically acceptable salt, the pharmaceutically acceptable salt is preferably a salt formed with an inorganic acid or an organic acid. The pharmaceutically acceptable salt of the compound according to the present invention may be a salt of the compound according to the first aspect of the present invention with a mineral acid, a carboxylic acid, or a sulfonic acid. Particularly preferred are salts with, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid, or benzoic acid. Preferred salts are selected from halides, formates, and trifluoroacetates.

[0060] Examples of enantiomers of the present invention include compounds selected from the following structures:

[0061] [ka]

[0062] or a pharmaceutically acceptable salt, hydrate, and / or isotope of any of these compounds.

[0063] The compound according to the first aspect of the present invention is preferably capable of inhibiting extrasynaptic toxic NMDA receptor activity. Suitable tests for assessing NMDA receptor activity are described in the Examples section of this application. A preferred test for assessing the inhibition of extrasynaptic toxic NMDA receptor activity is to study said activity in primary neuronal cultures, as further described below. Preferably, at a concentration of 10 μM, the compound of the present invention achieves the same level of inhibitory activity (i.e., the same index rating) as at least 10 μM of (2-aminoethyl)[(3-chlorophenyl)methyl]ethylamine (compound P401 of WO2020 / 079244). Preferably, the inhibitory activity is even greater than that of compound P401. This is particularly the case when the compound of the first aspect of the present invention achieves the same inhibitory activity at a lower concentration than compound P401 (e.g., 3.0 μM or less, e.g., 1.0 μM, 0.3 μM, 0.1 μM, or 0.03 μM). It is also preferred that the compounds according to the first aspect of the invention disrupt the formation of the NMDA receptor / TRPM4 complex. Suitable methods for assessing the ability to disrupt the complex are the co-immunoprecipitation and Western blot detection methods described in the Examples section of this application.

[0064] The compounds according to the invention may be part of a composition according to the invention, which comprises at least one compound according to the first aspect of the invention and a suitable pharmaceutical carrier, excipient or diluent.

[0065] In a second aspect, the present invention relates to a compound for use in a method for treating or preventing a disease of the human or animal body, the compound being a compound according to the following general formula I:

[0066] [ka]

[0067] Here, R7 is

[0068] [ka]

[0069] is selected from, where: R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, —CN and ethynyl; R5 is selected from H, unsubstituted branched or straight chain C1-C4 alkyl, fluorine-substituted branched or straight chain C1-C4 alkyl, unsubstituted propenyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl; R6 is selected from unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; provided that when one of R1 and R4 is H and the other is Cl, and R2, R3 and R5 are H, then R6 is selected from unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; provided that when one of R2 and R3 is H and the other is Br, Cl or I, and R1, R4 and R5 are H, then R6 is selected from unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; Alternatively, the compound is a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer of a compound of Formula I.

[0070] The compound used according to the second aspect of the invention may be a compound of formula Ia or Ib,

[0071] [ka]

[0072] wherein R1, R2, R3, R4, R5, and R6 are as defined herein for Formula I, Ia, or Ib, respectively.

[0073] In some embodiments, when the compound used in the second aspect of the invention is a compound of formula Ia:

[0074] [ka]

[0075] The following applies: R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I and -CN; R5 is selected from H, unsubstituted branched or straight chain C1-C4 alkyl, fluorine-substituted branched or straight chain C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl; R6 is selected from unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; provided that when one of R1 and R4 is H and the other is Cl, and R2, R3 and R5 are H, then R6 is selected from unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; provided that when one of R2 and R3 is H and the other is Cl or I, and R1, R4 and R5 are H, then R6 is selected from unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; or wherein the compound is a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer, hydrate, and / or isotope of a compound of formula I. Most preferred are pharmaceutically acceptable salts of a compound of formula I.

[0076] In a third aspect, the present invention relates to a method of treating a disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound, the compound being according to the following general formula I:

[0077] [ka]

[0078] Here, R7 is

[0079] [ka]

[0080] is selected from, where: R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, —CN and ethynyl; R5 is selected from H, unsubstituted branched or straight chain C1-C4 alkyl, fluorine-substituted branched or straight chain C1-C4 alkyl, unsubstituted propenyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl; R6 is selected from unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; provided that when one of R1 and R4 is H and the other is Cl, and R2, R3 and R5 are H, then R6 is selected from unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; provided that when one of R2 and R3 is H and the other is Br, Cl or I, and R1, R4 and R5 are H, then R6 is selected from unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; Alternatively, the compound is a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer of a compound of Formula I.

[0081] The compound used in the method of the third aspect of the present invention is a compound of formula Ia or Ib, i.e.

[0082] [ka]

[0083] where R1, R2, R3, R4, R5 and R6 are as defined herein for Formula I, Ia and / or Ib.

[0084] In some embodiments, the compound used in the method of the third aspect of the invention may be a compound of formula Ia:

[0085] [ka]

[0086] wherein R1, R2, R3, and R4 are each independently selected from H, F, Cl, Br, I, and —CN; R5 is selected from H, unsubstituted branched or straight chain C1-C4 alkyl, fluorine-substituted branched or straight chain C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl; R6 is selected from unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; provided that when one of R1 and R4 is H and the other is Cl, and R2, R3, and R5 are H, then R6 is selected from unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; provided that when one of R2 and R3 is H and the other is Cl or I, and R1, R4 and R5 are H, then R6 is selected from unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; or wherein the compound is a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer, hydrate, and / or isotope of any of these compounds. Most preferred are pharmaceutically acceptable salts of compounds of formula I.

[0087] The compound used in accordance with the second aspect of the invention, as well as the compound used in the method of the third aspect of the invention, can be a compound of Formula I (or a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer thereof), wherein R7 is

[0088] [ka]

[0089] Alternatively, R7 is

[0090] [ka]

[0091] In some embodiments, R1, R2, R3, and R4 are each independently selected from H, F, Cl, Br, and -CN. In some embodiments, at least one of R1, R2, R3, and R4 is ethynyl, and preferably, R2 is ethynyl. In some embodiments, two of R1, R2, R3, and R4 are each independently selected from H, F, Cl, Br, I, -CN, and ethynyl. R7 is

[0092] [ka]

[0093] In some embodiments, one of R2 and R3 is selected from H, F, Cl, Br, I, —CN, and ethynyl, and the other is H.

[0094] [ka]

[0095] In other embodiments of Formula Ia, at least two of R1, R2, R3, and R4 are H and one of R2 and R3 is Cl. In some embodiments, R1 is H or F, preferably F, and R2 is selected from F, Cl, Br, I, CN, and ethynyl, preferably Cl, Br, CN, and ethynyl. In some embodiments of Formula Ia, R4 is H or F, preferably F, and R3 is selected from F, Cl, Br, I, CN, and ethynyl, preferably Cl, Br, CN, and ethynyl. R7 is

[0096] [ka]

[0097] In other embodiments, R1 is F, R2 is Cl, and R3 and R4 are H, or R1 and R2 are H, R3 is Cl, and R4 is F.

[0098] The compound used according to the second aspect of the invention or the compound used in the method of the third aspect of the invention can be a compound according to Formula I, Ia, or Ib (or a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer thereof), where R5 is selected from unsubstituted branched or straight-chain C1-C4 alkyl, fluorine-substituted branched or straight-chain C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl. In some embodiments, as exemplified in the Examples, R5 is H or methyl. In other embodiments, R5 is selected from ethyl, isopropyl, -CH2CF3, -CF2CF3, CF2CH3, -CHF2, -CF3, cyclopropyl, fluorine-substituted isopropyl, propenyl, cyclopropyl, cyclobutyl, fluorine-substituted cyclobutyl, and cyclopentyl, as exemplified in the Examples.

[0099] The compound used according to the second aspect of the invention, or the compound used in the method of the third aspect of the invention, can be a compound according to Formula I, Ia, or Ib (or a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer thereof), wherein R6 is selected from substituted branched or straight-chain C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 bicycloalkyl, substituted C4-C7 alkylcycloalkyl, and substituted C3-C6 alkenyl, and the substituents of the substituted branched or straight-chain C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted bicycloalkyl, substituted C4-C7 alkylcycloalkyl, and substituted C3-C6 alkenyl are each independently selected from F, Cl, CN, OH, alkylthio, and alkoxy, preferably each independently selected from F, Cl, CN, SCH3, and OH. In particularly preferred embodiments, R6 is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl, allyl, -CH2CH2-S-CH3, CH2CF2H, -CH2CF3, and -CH2CH2CN. Most preferably, R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl, and allyl.

[0100] A possible combination of R5 and R6 in the second and third aspects of the present invention is that R5 is methyl and R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl, and allyl.

[0101] For example, a compound according to the first aspect of the invention is a compound that qualifies as a compound for use according to the second aspect of the invention, or a compound that can be used in the method of the third aspect of the invention. Other suitable examples include:

[0102] [ka]

[0103] and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers, hydrates, and / or isotopes of any of these compounds. Most preferred are pharmaceutically acceptable salts of any of these compounds.

[0104] As already mentioned above for the compounds according to the first aspect of the invention, in embodiments in which the compounds for use according to the second aspect of the invention or the compounds used in the methods of the third aspect of the invention are pharmaceutically acceptable salts, the pharmaceutically acceptable salts are preferably salts formed with inorganic or organic acids. The pharmaceutically acceptable salts of the compounds of the invention may be salts of the compounds according to the first aspect of the invention with mineral acids, carboxylic acids, or sulfonic acids. Particularly preferred are salts with, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid, or benzoic acid. Most preferably, the salts are selected from halides, formates, and trifluoroacetates.

[0105] As with the compounds according to the first aspect of the invention, the compounds used according to the second aspect of the invention, or any compounds used in the methods of the third aspect of the invention, are preferably capable of inhibiting extrasynaptic toxic NMDA receptor activity and / or disrupting the formation of the NMDA receptor / TRPM4 complex. For suitable tests, see the corresponding section above regarding the compounds according to the first aspect of the invention.

[0106] Compounds according to the first aspect of the invention, or for use according to the second aspect of the invention, or for use in the context of the third aspect of the invention, can be prepared, for example, but not limited to, as shown in the examples and figures of the present application. For example, tert-butyl-N-[2-(alkylamino)ethyl]carbamates F, such as tert-butyl N-[2-(cyclopropylamino)ethyl]carbamate (CAS 578706-31-7), are known from the literature and can be prepared by known methods, for example, by alkylating alkylamines with 2-(tert-butoxycarbonylamino)ethyl bromide (see WO2013062065), by reductive amination of N-Boc-2-aminoacetaldehyde (CAS 89711-08-0) analogous to WO2003066621, or by reductive amination of ketones or aldehydes with tert-butyl-N-(2-aminoethyl)carbamate (CAS 57260-73-8) analogous to JP2010064982. Tertiary amines C are obtained by reductive amination of ketones A with the resulting secondary amines F. Aldehyde R 6c -CHO or Ketone R 6a (R 6b) CO can be converted to N-substituted benzylamine B by reductive amination with benzylamine E (Figure 1C). The order of the reaction sequence can also be reversed; in this case, E first generates D and then C (Figure 1C). N-substituted benzylamine B can also be obtained by reductive amination of aryl ketone A with amine R6-NH2 (Figure 1A). A new reductive amination with N-Boc-2-aminoacetaldehyde (CAS 89711-08-0), for example, in a manner analogous to WO 2003066621, or alkylation with halides such as tert-butyl (2-bromoethyl)carbamate (CAS 39684-80-5) or with reagents such as tert-butyl 2,2-dioxo-1,2λ6,3-oxathiazolidine-3-carboxylate, gives the tertiary amine C, from which, after removal of the BOC protecting group, compounds of formula I, in particular Ia, according to the present invention are obtained (Figure 1A). The order of the reaction sequence can also be reversed: A first generates D, which then generates C (Figure 1A). All common methods are suitable for removing the BOC group, such as HCl / MeOH, HCl / ethyl acetate, TFA / DCM, hexafluoroisopropanol, or other acids. Reducing agents and catalysts for reductive amination include NaBH4, NaBH3CN, NaBH(OAc)3 / TFA, PMHS / SnCl2x2H2O, Pd / C / Et3SiH, PhSiH3 / Bu2SnCl2, Ph2SiH2 / [RuCl2(p-cymene)]2 / MS4A, PhSiH3 / Cu(OAc)2, Et3SiH / InCl3, NaBH4 / Ti(i-PrO)4, HCOOH / Pd-C, H2 / Pd-C, or B 10 H 14Solvents that can be used include ethers such as THF, 2-methyl-THF, dioxane, BuO, MeOH, EtOH, trifluoroethanol, ethylene glycol, TAME, diglyme, alcohols such as propanol and isopropanol, acetonitrile, butyronitrile, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetic acid, DMF, DMAC, water, or mixtures thereof. Alkylation can be carried out, for example, with mesylates, tosylates, trifluoromesylates, or halides, such as 1-chloro-2-methylsulfanylethane, or tert-butyl(ethyl)carbamate, preferably tert-butyl(2-bromoethyl)carbamate, or tert-butyl 2,2-dioxo-1,2λ6,3-oxathiazolidine-3-carboxylate, in solvents such as THF, 2-methyl-THF, dioxane, DMF, acetonitrile, butyronitrile, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, DMF, DMAC, diglyme, and the like, optionally in the presence of a base such as NaH, sodium carbonate, potassium carbonate, sodium methylate, KOtBut, triethylamine, or DIPEA. Acylation can be carried out using the appropriate acid chloride and an inorganic or organic base, the corresponding acid anhydride, or an organic acid and a dehydrating agent such as EDCI / DMAP / DCM. Instead of BOC, all other known protecting groups for amino groups that can be cleaved by known methods are also contemplated, such as Cbz, Fmoc, Alloc, or phthalimide. These include, for example, H2 / Pd-C, HBr / AcOH, piperidine / DMF, Pd(PPh3)4 / morpholine / DCM, or hydrazine hydrate. Further synthetic routes for compounds according to the invention are shown in Figure 1D.The required ketone A (Figure 1E) can be prepared from the corresponding aldehyde O by Grignard reaction with R-magnesium halides in ethers such as diethyl ether, THF, 2-methyl-THF, dioxane, or MTBE to give alcohol P, followed by oxidation to aryl ketone A with common oxidants such as Dess-Martin periodinane (DMP), pyridinium chlorochromate, or activated MnO in solvents such as DCM, toluene, DMF, or DMAC. Ketone A can also be prepared by orthometalation of substituted aryl compounds S, preferentially substituted with R = F, R = Cl, Br, or CN, using strong bases such as LDA or TMP (2,2,6,6-tetramethylpiperidyl)MgCl*LiCl in solvents such as THF, 2-methyl-THF, or 1,4-dioxane (see Santos et al., Org. Lett. 2021, 23, 7396), followed by reaction of the resulting anion with an R5-ester (R5-CO2Et). Alternatively, these intermediate anions can be reacted with an R5-aldehyde (R5-CHO) to give carbinol P. A trifluoromethyl group can be introduced into benzaldehyde by reaction with TMSCF3 / TBAF to give trimethylsilylated carbinol T, which can be hydrolyzed to the free carbinol P (R = CF3), which can then be oxidized to ketone A (R = CF3) as described above. The trifluoromethyl group can be introduced onto acetophenone by first converting it to the respective triethylsilyl enol ether U using TESCl / DIEA / n-BuLi in an ethereal solvent such as THF, followed by reaction with Togni reagent II in the presence of CuSCN in a solvent such as DMF, DMAC, or NMP to give the trifluoroethyl phenyl ketone A (R5 = CH2CF3).Acetophenone A (R5 = CH3) can be obtained by the reaction of the corresponding aryl halide R with tributyl(1-ethoxyvinyl)stannane. This reaction is catalyzed by a Pd catalyst such as Pd(PPh3)4, palladium diacetate / 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl / TEA, tris(dibenzylideneacetone)dipalladium / tri-tert-butylphosphine / cesium fluoride, or Pd(PPh3)2Cl2 in solvents such as dioxane, THF, 2-methyl-THF, toluene, benzene, or NMP. Amine B can be prepared from benzaldehyde O by first reacting it with amine R6-NH2 in a solvent such as MeOH using an acid catalyst such as AcOH to give Schiff base imine V, which can then be used to introduce the R5 group via reaction with the corresponding Grignard reagent such as R5-MgBr or other suitable organometallics. Amine B can be reacted with a halogenoacetamide, such as acetamide bromide, in a solvent such as MeCN, butyronitrile, DMF, DMAC, or TAME in the presence of a base such as potassium hydroxide, sodium hydroxide, TEA, or DIPEA to give the substituted aminoacetamide G, which can be reduced with a suitable reducing agent, such as LiAlH4, BH3*Me2S, or BH3*THF in a solvent such as THF or 2-methyl-THF to give the desired compound (I). Alternatively, amine B can be reacted with a haloacyl halide, such as acetyl bromide or acetyl chloride, to give the haloacetamide H. These can be aminated using potassium phthalamide to generate protected amines K, which can be deprotected with hydrazine hydrate or methylamine in methanol, ethanol, and / or water to give substituted aminoacetamides M, or using NaBH4 / 2-propanol followed by acetic acid (J.O. Osby, M.G. Martin, B. Ganem, Tetrahedron Lett., 1984, 25, 2093-2096). Haloacetamides H can also be converted to the corresponding azidoacetamides L using sodium azide in DMF or DMAC. Azides L can then be reduced to acetamides M using triphenylphosphine in THF / water.These compounds M can be reduced to the desired compounds (I) using a suitable reducing reagent such as LiAlH, BH*MeS, BH*THF in a solvent such as THF or 2-methyl-THF. While Figure 1 shows a synthetic route for compounds of formula Ia, it is understood that such procedures can be used in a similar manner to produce compounds of formula Ib as used herein.

[0107] The disease that is treated according to the second or third aspect of the present invention is preferably neurological disease, particularly neurodegenerative disease, or the disease that may lead to neurodegenerative events or that is accompanied by neurodegenerative events, for example, infectious disease that leads to neurodegenerative events, especially in the brain.In some embodiments, neurological disease or neurodegenerative disease may have inflammatory components, i.e., is a neuroinflammatory disease.Neurodegenerative disease may be a progressive neurodegenerative disease. Preferably, the disease or disorder is stroke, particularly ischemic stroke and hemorrhagic stroke, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), traumatic brain injury, post-traumatic brain injury, absent-mindedness, age-associated memory loss, age-associated memory decline, progressive nuclear palsy, multiple sclerosis, thalamic degeneration, glutamate-induced excitotoxicity, dystonia, epilepsy, optic nerve disease, diabetic retinopathy, glaucoma, pain, particularly neuropathic pain, anti-NMDA receptor encephalitis, dementia, e.g. post-stroke dementia, HIV dementia, Creutzfeldt-Jakob dementia, dementia with Lewy bodies (DLB), dementia with frontal lobar degeneration including Pick's disease, corticobasal ganglia degeneration. The disease may be selected from the group consisting of dementia with dementia, vascular dementia, microangiopathy, Binswanger's disease, cerebral ischemia, hypoxia, Parkinson's disease, Batten disease, schizophrenia, particularly schizophrenia with dementia, Korsakoff's psychosis, depression, cerebral malaria, toxoplasmosis (due to the risk of toxoplasmosis-associated encephalopathy), HIV infection / AIDS-associated encephalopathy (due to the risk of HIV), and Zika virus infection (due to the possibility of Zika virus-associated encephalopathy), or other viral infections that may cause neurodegenerative events and associated neuronal or brain damage, such as viral encephalopathy, viral meningitis, and SARS-CoV2 virus-induced encephalitis. In a further embodiment, the disease may be brain tumor, particularly glioblastoma. Three recent articles published in Nature (see Nature, 2019, Vol. 573, pp. 499-501) indicate that glioblastoma cells express NMDA receptors and that their growth is promoted / stimulated by NMDA receptor activation. Thus, blocking NMDA receptor signaling, for example, by the compounds described herein, can inhibit the growth of glioblastoma cells.In contrast, conventional NMDA receptor blockers cannot be used in this case because they interfere with the physiological role of NMDA receptors in normal synaptic transmission and cognitive functions such as memory. Due to the general relevance of extrasynaptic NMDA receptor signaling, the compounds disclosed herein are also suitable for treating central nervous system disorders such as anxiety, tension, and depression, as well as sexual dysfunction and sleep disorders. They can also be used to control pathological disorders caused by the ingestion of food, stimulants, and addictive substances.

[0108] Typically, therapeutic methods (in the context of the second or third aspect of the present invention) focus on halting or slowing the progression of the disorder. Alternatively, such compounds can be administered prophylactically, for example, in situations where the subject is at (high) risk of suffering from a neurological and / or neurodegenerative disease. This includes (increased) acute risk (e.g., post-operative thrombotic stroke) and persistent risk (e.g., due to genetic and / or familial predisposition to a particular neurological and / or neurodegenerative disease).

[0109] The subject to be treated is preferably a mammal, preferably selected from the group consisting of humans, mice, rats, dogs, cats, cows, monkeys, horses, hamsters, guinea pigs, pigs, sheep, goats, rabbits, etc. Most preferably, the subject is a human.

[0110] For the purposes of the second and third aspects of the present invention, those skilled in the art can easily select an appropriate administration route depending on the specific disease to be treated or prevented and / or the body part to be treated. The administration route may be, for example, oral, topical, intranasal, parenteral, intravenous, rectal, pulmonary, sublingual, lingual, buccal, transdermal, conjunctival, or other route suitable for the particular situation. The compound may also be administered using an implant that releases the compound over time. For example, when the disease is a cerebrovascular disease, such as stroke, intranasal administration is a preferred administration route. Those skilled in the art know that intranasal administration is particularly suitable for administering neuroprotective compounds in general, for example, in the context of treating stroke and stroke-induced brain damage. For oral administration, known dosage forms that deliver active substances rapidly and / or in a modified form are suitable, such as tablets (uncoated and coated tablets, e.g., enteric-coated or film-coated tablets), capsules, granules, pellets, powders, emulsions, suspensions, solutions, and aerosols. Parenteral administration can be carried out without the absorption step (intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with absorption (intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). For parenteral administration, suitable dosage forms include injections and infusions in the form of solutions, suspensions, emulsions, lyophilizates, and sterile powders. For other administration routes, suitable dosage forms include inhalants (powder inhalers, nebulizers, etc.), nasal drops / solutions, sprays, lingual, sublingual, or buccal tablets or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, pastes, powders, or implants such as stents. The active substance can be transferred into the above application forms by methods known per se. This is done using inert, nontoxic, and pharmaceutically suitable excipients. These include excipients (e.g., microcrystalline cellulose), solvents (e.g., polyethylene glycol), emulsifiers (e.g., sodium dodecyl sulfate), dispersants (e.g., polyvinylpyrrolidone), synthetic and natural biopolymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), colorants (e.g., inorganic pigments such as iron oxide), or taste and / or odor correctors.The active ingredient may, if desired, be present in microencapsulated form in one or more of the excipients listed above. In general, in both human and veterinary medicine, administration of the active ingredient of the present invention in a total amount of about 0.001 to about 60, or 0.001 to 40 mg / kg body weight per 24 hours, optionally in the form of several single doses, has proven advantageous for achieving desirable results. A single dose preferably contains the active ingredient of the present invention in an amount of about 0.001 to about 30 mg / kg body weight, particularly 0.001 to 20 mg / kg body weight.

[0111] In a fourth aspect, the present invention relates to compounds (intermediates) according to the following general formula II:

[0112] [ka]

[0113] Here, R7 is

[0114] [ka]

[0115] is selected from R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and at least one of R1, R2, R3 and R4 is selected from F, Cl, Br, I, -CN and ethynyl; R5 is selected from H, unsubstituted branched or straight chain C1-C4 alkyl, fluorine-substituted branched or straight chain C1-C4 alkyl, unsubstituted propenyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl; R6 is selected from H, unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, R5 is methyl and R7 is

[0116] [ka]

[0117] wherein one of R2 and R3 is H and the other is Cl, and R1 and R4 are H, then R6 is selected from unsubstituted straight chain C3-C6 alkyl, unsubstituted branched C4-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C4-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, R5 is methyl and R7 is

[0118] [ka]

[0119] and two of R1, R2, R3 and R4 are Cl and the other two are H, and when any of R1 and R2, R3 and R4, R1 and R3, or R2 and R4 is Cl, then R6 is selected from unsubstituted branched or straight chain C3-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; Further optionally, R5 is methyl and R7 is

[0120] [ka]

[0121] and R1 and R4 are Cl, one of R2 and R3 is H, and the other is F, then R6 is selected from unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, R5 is methyl and R7 is

[0122] [ka]

[0123] and one of R1 and R4 is H and the other is F, and R2 and R3 are Cl, then R6 is selected from unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; further optionally, when R5 is methyl, one of R1 and R4 is H and the other is Cl, and R2 and R3 are H, then R6 is selected from unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; with the proviso that if R5 is ethyl, one of R2 and R3 is H and the other is Cl, and R1 and R4 are H, then R6 is selected from unsubstituted straight chain C3-C6 alkyl, unsubstituted branched C3-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, R5 is H and R7 is

[0124] [ka]

[0125] then the compound has one of the following formulas:

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] [ka]

[0130] and salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes of these compounds.

[0131] Compounds according to the fourth aspect of the invention are compounds according to formula IIa or IIb, i.e.

[0132] [ka]

[0133] where R1, R2, R3, R4, R5, and R6 are as defined herein for Formula II, or Formula I, Ia, or Ib, respectively.

[0134] In some embodiments, the compounds according to the fourth aspect of the invention may be the corresponding Boc-protected compounds shown in the Examples section as direct precursors to compounds according to the first aspect of the invention, or for use according to the second or third aspects of the invention.

[0135] In some embodiments, the compound according to the fourth aspect of the invention is a compound according to Formula IIa:

[0136] [ka]

[0137] wherein R1, R2, R3, and R4 are each independently selected from H, F, Cl, Br, I, and —CN, and at least one of R1, R2, R3, and R4 is selected from F, Cl, Br, I, and —CN; R5 is selected from H, unsubstituted branched or straight chain C1-C4 alkyl, fluorine-substituted branched or straight chain C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl; R6 is selected from H, unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; with the proviso that if R5 is methyl, one of R2 and R3 is H and the other is Cl, and R1 and R4 are H, then R6 is selected from unsubstituted straight chain C3-C6 alkyl, unsubstituted branched C4-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C4-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; with the proviso that if R5 is methyl, two of R1, R2, R3 and R4 are Cl and the other two are H, and any of R1 and R2, R3 and R4, R1 and R3, or R2 and R4 is Cl, then R6 is selected from unsubstituted branched or straight chain C3-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; with the proviso that if R5 is methyl, one of R1 and R4 is H and the other is F, and R2 and R3 are Cl, then R6 is selected from unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; with the proviso that if R5 is ethyl, one of R2 and R3 is H and the other is Cl, and R1 and R4 are H, then R6 is selected from unsubstituted straight chain C3-C6 alkyl, unsubstituted branched C3-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, and substituted C3-C6 alkenyl; However, when R5 is H, the compound has one of the following formulas:

[0138] [ka]

[0139] [ka]

[0140] [ka]

[0141] and salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes of these compounds.

[0142] The above compounds according to general formula II, IIa, and IIb (intermediates in the preparation of compounds of general formula I, Ia, and Ib) are particularly useful for the preparation of compounds according to the first aspect of the invention or for the preparation of compounds for use according to the second aspect of the invention (or the process according to the third aspect of the invention). As mentioned above, all conventional methods are suitable for removing the BOC group, such as HCl / MeOH, HCl / ethyl acetate, TFA / DCM, hexafluoroisopropanol, or any other acid. The preferred embodiments exemplified above for the compounds of the invention according to the first aspect of the invention apply equally to the compounds of the fourth aspect of the invention. Particularly preferred embodiments are those in which R5 is selected from unsubstituted branched or linear C1-C4 alkyl, preferably linear C1-C4 alkylalkyl. Most preferably, R5 in the intermediate is methyl. A particularly preferred embodiment of the intermediate according to the present invention is characterized in that R6 is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl, allyl, -CH2CH2-S-CH3, CH2CF2H, -CH2CF3, and -CH2CH2CN. Most preferably, R6 of the intermediate is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl, and allyl. In the intermediate, R1, R2, R3, and R4 are each preferably independently selected from H, F, Cl, and -CN. It is also preferred that at least two of R1, R2, R3, and R4 are H, and one or two, preferably one, of R2 and R3 are Cl. A particularly preferred combination of R5 and R6 is where R5 is methyl and R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl, and allyl.

[0143] In a preferred embodiment, the intermediate compound according to the fourth aspect of the invention is selected from one of the following formulae:

[0144] [ka]

[0145] [ka]

[0146] and salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes of these compounds.

[0147] In a fifth aspect, the present invention relates to further compounds (intermediates) which are not Boc-protected compounds according to formula II, IIa or IIb, but compounds according to the following general formula III:

[0148] [ka]

[0149] Here, R7 is

[0150] [ka]

[0151] wherein R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and at least one of R1, R2, R3 and R4 is selected from F, Cl, Br, I, -CN and ethynyl; R5 is selected from H, unsubstituted branched or straight chain C1-C4 alkyl, fluorine-substituted branched or straight chain C1-C4 alkyl, unsubstituted propenyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl; R6 is selected from H, unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl and substituted C3-C6 alkenyl; and salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes thereof.

[0152] Compounds according to the fifth aspect of the invention are compounds according to formula IIIa or IIIb, i.e.

[0153] [ka]

[0154] where R1, R2, R3, R4, R5, and R6 are as defined herein for Formula III, or Formula I, Ia, or Ib, respectively.

[0155] In a sixth aspect, the present invention relates to yet another intermediate which does not fall within formula II or III, but is a compound according to the following general formula IV:

[0156] [ka]

[0157] Here, R7 is

[0158] [ka]

[0159] is selected from R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and at least one of R1, R2, R3 and R4 is selected from F, Cl, Br, I, -CN and ethynyl; R5 is selected from H, unsubstituted branched or straight chain C1-C4 alkyl, fluorine-substituted branched or straight chain C1-C4 alkyl, unsubstituted propenyl, unsubstituted C3-C6 cycloalkyl, and fluorine-substituted C3-C6 cycloalkyl; R6 is selected from H, unsubstituted branched or straight chain C2-C6 alkyl, substituted branched or straight chain C2-C6 alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7 alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl and substituted C3-C6 alkenyl; and salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes thereof.

[0160] A compound according to the sixth aspect of the present invention is a compound according to formula IVa or IVb, i.e.

[0161] [ka]

[0162] where R1, R2, R3, R4, R5, and R6 are as defined herein for Formula IV, or Formula I, Ia, or Ib, respectively.

[0163] The Examples section of this invention describes in more detail various immediate precursors in the synthesis of compounds according to the first aspect of the invention or compounds used according to the second or third aspects of the invention, i.e. compounds according to Formula III or IV. All of these intermediates of Formula III and IV are specifically contemplated as preferred embodiments of the fifth and sixth aspects of the invention, respectively.

[0164] The term "comprising" as used herein should not be construed as being limited to the meaning of "consisting of" (i.e., excluding the presence of additional other substances). Rather, "comprising" means that additional substances may optionally be present. The term "comprising" encompasses, with the former being more preferred, "consisting of" (i.e., excluding the presence of additional other substances) and "comprising, but not consisting of" (i.e., requiring the presence of additional other substances), as particularly contemplated embodiments within its scope. [Brief explanation of the drawings]

[0165] A brief description of the accompanying drawings follows, which serve to more fully illustrate aspects of the present invention, but are not intended to limit the scope of the present invention. [Figure 1] Various general reaction schemes are presented to illustrate the synthesis of compounds used in this application. Various educts lead to tert-butyloxycarbonyl-protected compounds (intermediate C), which are converted to the final products (formula I), where R6a and R6b are chain or ring members that form part of R6 after reductive amination; similarly, R6c-CHO forms the R6 moiety. 1A) Methods for obtaining compounds of the invention starting from aryl ketones or benzaldehydes. 1B) Convergent routes to compounds of formula I, particularly Ia. 1C) Methods for obtaining compounds of the invention starting from benzylamines. 1D) Further possible synthetic routes for compounds of the invention. 1E) Synthesis of ketones A and alcohols P. 1F) Introduction of trifluoromethyl groups into benzaldehydes and acetophenones. [Figure 2] Quantification of cell survival after glutamate / NMDA treatment in primary cultured neurons is shown. The areas above the curve (shaded areas of the AAC, vehicle, and compound P401 groups) were quantified to determine the protective index of other compounds. Compound P401 (10 μM) in WO2020 / 079244 provided approximately 60% protection, with a protective index of 6.0. [Figure 3]Quantification of cell survival after HO treatment in primary cultured neurons. A) Compound P401 (see WO2020 / 079244) provides superior protection against HO injury compared to the FDA-approved ALS drugs riluzole and edaravone. B) Compound 220 provides superior protection against HO injury compared to 10 μM P401, which is equivalent to 0.1 μM of compound 220. [Figure 4] Quantification of cell survival (%) after glutamate / NMDA treatment in human iPSC-derived prefrontal cortical organoids. Compound 120 provided better protection than compound P401 (see WO2020 / 079244). [Figure 5] Co-immunoprecipitation of TRPM4 and NMDA receptor subunits is shown. Lysates from human iPSC-derived brain organoids were precipitated with anti-TRPM4. Both the input (5%) and immunoprecipitates were separated by SDS-PAGE, transferred, and blotted with antibodies against GluN2A, GluN2B, GluA2, TRPM4, and tubulin. In the presence of compound 120, the NMDAR / TRPM4 complex was disrupted. DETAILED DESCRIPTION OF THE INVENTION

[0166] Below are presented specific examples illustrating embodiments and aspects of the present invention. However, the present invention is not limited in scope by the specific examples described herein. Indeed, various modifications of the present invention in addition to those described herein will be readily apparent to those skilled in the art from the foregoing description and examples below. All such modifications are within the scope of the appended claims. [Example]

[0167] [General Procedure] The compounds used in the present invention to attenuate extrasynaptic toxic NMDA receptor activity are generally prepared as follows.

[0168] <Reductive amination - preparation of BOC-protected intermediate C> To a solution of tert-butyl N-(2-aminoethyl)carbamate (100 mg, 624.2 μmol, 98 μL, 1 equiv.) in MeOH (3 mL) was added the appropriate benzaldehyde or acetophenone (compound 109 for description) derivative (1 equiv.). The mixture was stirred at 65°C for 12 h. NaBHCN (196 mg, 3.1 mmol, 5 equiv.) was then added, and the mixture was stirred at 65°C for 2 h. Acetaldehyde (344 mg, 3.1 mmol, 438 μL, 40% purity, 5 equiv.) (see compounds 91, 92, 94, 95, and 109 for description) or the appropriate cyclopropanecarbaldehyde derivative (see compounds 153 and 157 for description) was then added, and the mixture was stirred at 65°C for 4 h. The reaction mixture was concentrated, diluted with 5 mL of ethyl acetate, and washed with water (5 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a residue (Intermediate C).

[0169] <Removal of the BOC group> A solution of intermediate C (637 μmol, 1 equiv.) in HCl / ethyl acetate (2 mL, 4 M) was stirred at 20° C. for 0.5 h, and LC-MS indicated consumption of the starting material. The reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC (HCl condition, column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: [water (HCl)-ACN], B%: 1%-1%, 8 min) to give the final product (compound of Formula I) shown in the table after evaporation in vacuo.

[0170] Following the general procedure, the following compounds were prepared:

[0171] [Table 1-1]

[0172] [Table 1-2]

[0173] [Table 1-3] [Example]

[0174] [Synthesis of N1-(3-chlorobenzyl)-N1-cyclobutylethane-1,2-diamine hydrochloride (Compound 123)] 1) tert-Butyl N-[2-[(3-chlorophenyl)methylamino]ethyl]carbamate

[0175] [ka]

[0176] To a solution of tert-butyl N-(2-aminoethyl)carbamate (2.28 g, 14.23 mmol, 2.23 mL, 1 equiv.) in MeOH (30 mL) was added 3-chlorobenzaldehyde (2 g, 14.23 mmol, 1.61 mL, 1 equiv.). The mixture was stirred at 25 °C for 12 h. NaBH CN (4.47 g, 71.14 mmol, 5 equiv.) was added to the mixture. The mixture was stirred at 25 °C for 12 h. LC-MS showed that the desired compound was detected. The reaction mixture was concentrated to dryness. The reaction was quenched by the cold addition of 100 mL of aqueous NH Cl solution. The residue was partitioned between H O (100 mL) and ethyl acetate (100 mL). The mixture was extracted with ethyl acetate (100 mL × 3). The separated organic layer was washed with brine (100 mL × 3), dried over Na SO , and evaporated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient, 150 mL / min) to give the compound tert-butyl N-[2-[(3-chlorophenyl)methylamino]ethyl]carbamate (2.3 g) as a yellow oil. 1 H NMR (400 MHz, chloroform-d₆) δ = 7.60 (dd, J = 1.1, 2.1 Hz, 5H), 4.11 (q, J = 7.2 Hz, 6H), 2.03 (s, 9H), 1.24 (t, J = 7.2 Hz, 13H).

[0177] 2) tert-Butyl N-[2-[(3-chlorophenyl)methylcyclobutylamino]ethyl]carbamate

[0178] [ka]

[0179] To a solution of tert-butyl N-[2-[(3-chlorophenyl)methylamino]ethyl]carbamate (100 mg, 351 μmol, 1 equiv.) in EtOH (2 mL) was added dropwise at 20 °C. Then, CH₃COOH was added to adjust the pH to 4–5, and the mixture was stirred at this temperature for 1 h. NaBH₃CN (66.20 mg, 1.05 mmol, 3 equiv.) was then added dropwise. The resulting mixture was stirred at 40 °C for 12 h. LCMS indicated complete consumption of the starting material and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with HO (3 mL) and extracted with ethyl acetate (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[(3-chlorophenyl)methyl-cyclobutyl-amino]ethyl]carbamate (100 mg, crude) as a colorless oil.

[0180] 3) N1-(3-chlorobenzyl)-N1-cyclobutylethane-1,2-diamine hydrochloride (Compound 123)

[0181] [ka]

[0182] A solution of tert-butyl N-[2-[(3-chlorophenyl)methyl-cyclobutyl-amino]ethyl]carbamate (100 mg, 295 μmol, 1 equiv.) in HCl / ethyl acetate (2 mL, 4 M) was stirred at 20° C. for 1 h. LCMS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (HCl condition, column: Phenomenex Luna 80×30 mm×3 μm, mobile phase: [water (HCl)-ACN], B%: 1%-1%, 8 min) to give compound N. 1 -(3-chlorobenzyl)-N 1 -Cyclobutylethane-1,2-diamine hydrochloride (compound 123, 29 mg, 103 μmol, 35% yield, 98.7% purity, HCl) was obtained as a white solid. MS (ESI): m / z = 239.1 [M+H] + , retention time: 1.542 minutes, method: A, 1 HNMR (400MHz, METHANOL-d4) δ=7.65(br s, 1H), 7.54(br d, J=4.0Hz, 1H), 7.39(br s, 2H), 4.31(br s, 2H), 3.99-3.78(m, 1H), 3.20(br s, 1H), 2.59(br s, 2H), 2.52-1.86(m, 4H), 1.82-1.56(m, 2H). [Example]

[0183] [Synthesis of compounds 124, 134, and 135] The following compounds were further prepared in a similar manner as described above for compound 123 (Example 2):

[0184] [Table 2-1]

[0185] [Table 2-2] [Example]

[0186] [Synthesis of N-(2-aminoethyl)-N-[(3-chlorophenyl)methyl]but-3-enamide hydrochloride (Compound 137)] 1) tert-Butyl N-[2-[but-3-enoyl-[(3-chlorophenyl)methyl]amino]ethyl]carbamate

[0187] [ka]

[0188] To a solution of tert-butyl N-[2-[(3-chlorophenyl)methylamino]ethyl]carbamate (100 mg, 351.2 μmol, 1 equiv.) in DCM (2 mL) was added EDCI (87.5 mg, 456.5 μmol, 1.3 equiv.) and DMAP (5.6 mg, 45.7 μmol, 0.13 equiv.). The mixture was stirred at 20 °C for 20 min. Then, but-3-enoic acid (39.3 mg, 456.5 μmol, 1.3 equiv.) was added, and the mixture was stirred at 20 °C for 12 h. LCMS showed that the starting material was completely consumed and the desired product was obtained. The reaction mixture was partitioned between DCM (2 mL) and HO (3 mL × 2). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl N-[2-[but-3-enoyl-[(3-chlorophenyl)methyl]amino]ethyl]carbamate (60 mg, crude) as a colorless oil.

[0189] 2) N-(2-aminoethyl)-N-[(3-chlorophenyl)methyl]but-3-enamide hydrochloride (Compound 137)

[0190] [ka]

[0191] A solution of tert-butyl N-[2-[but-3-enoyl[(3-chlorophenyl)methyl]amino]ethyl]carbamate (60 mg, 170 μmol, 1 equivalent) in HCl / ethyl acetate (2 mL, 4 M) was stirred at 20° C. for 1 hour. LCMS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HCl condition, column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: [water (HCl) ACN], B%: 10%-45%, 8 min) to give the compound N-(2-aminoethyl)-N-[(3-chlorophenyl)methyl]but-3-enamide hydrochloride (19 mg, 62.4 μmol, yield 37%, purity 97.5%, HCl) as a white solid. MS (ESI): m / z = 253.1 [M+H] + , retention time: 11.778, method: B, 1 H NMR (400MHz, DMSO-d6) δ=8.25-7.95(m, 2H), 7.43-7.28(m, 3H), 7.22(br d, J=7.3Hz, 1H), 6.02-5.84(m, 1H), 5.23-5.03(m, 2H), 4.69-4.48(m, 5H), 3.63-3.51(m, 2H), 2.96(br s, 2H). [Example]

[0192] [Synthesis of N1-(3-chloro-2-fluorobenzyl)-N1-(2,2-difluoroethyl)ethane-1,2-diamine (Compound 118)] 1) N-[(3-chloro-2-fluorophenyl)methyl]-2,2-difluoroethanamine

[0193] [ka]

[0194] To a solution of 3-chloro-2-fluorobenzaldehyde (500 mg, 3.15 mmol, 1 equiv.) and 2,2-difluoroethanamine (384 mg, 4.7 mmol, 1.5 equiv.) in MeOH (15 mL), the pH was adjusted to 4-5 with the addition of AcOH. After the addition, the mixture was stirred at 25 °C for 2 h, and then NaBH3CN (793 mg, 12.6 mmol, 4 equiv.) was added at 25 °C. The resulting mixture was stirred at 25 °C for 12 h. LC-MS showed that the desired compound was detected. The reaction mixture was quenched at 25 °C by the addition of saturated NaHCO3 solution (10 mL) and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (15 mL×2), dried over NaSO, filtered, and concentrated under reduced pressure to give compound N-[(3-chloro-2-fluorophenyl)methyl]-2,2-difluoroethanamine (712 mg, crude) as a yellow liquid.

[0195] 2) N-[2-[(3-chloro-2-fluorophenyl)methyl-(2,2-difluoroethyl)amino]ethyl]carbamate

[0196] [ka]

[0197] N-[(3-chloro-2-fluorophenyl)methyl]-2,2-difluoroethanamine (200 mg, 894.4 μmol, 1 equiv.) and tert-butyl N-(2-oxoethyl)carbamate (142.37 mg, 894.37 μmol, 1 equiv.) were dissolved in CHCl (10 mL), and the pH was adjusted to 4–5 with AcOH. The mixture was stirred at 25 °C for 2 h. NaBH(OAc) (190 mg, 894.4 μmol, 1 equiv.) was then added. The final mixture was stirred for 12 h. LC-MS showed that the desired compound was detected. The reaction mixture was quenched with saturated brine, washed with NaHCO solution (15 mL) at 25 °C, and extracted with CHCl (10 mL × 3). The combined organic layers were washed with brine (15 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give compound N-[2-[(3-chloro-2-fluorophenyl)methyl-(2,2-difluoroethyl)amino]ethyl]carbamate (283 mg, crude) as a colorless oil.

[0198] 3) N1-(3-chloro-2-fluorobenzyl)-N1-(2,2-difluoroethyl)ethane-1,2-diamine (Compound 118)

[0199] [ka]

[0200] A mixture of tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methyl-(2,2-difluoroethyl)amino]ethyl]carbamate (160 mg, 436.5 μmol, 1 equivalent) and HCl / ethyl acetate (3 mL, 4 M) was stirred at 25 °C for 1 hour. LC-MS showed that the target compound was detected. The residue was purified by preparative HPLC (HCl conditions, column: Phenomenex Luna C18 100 × 30 mm × 5 μm, mobile phase: [water (HCl)-ACN], B%: 45%-75%, 10 min) to obtain compound N1 (3-chloro-2-fluorobenzyl)-N1-(2,2-difluoroethyl)ethane-1,2-diamine hydrochloride (15 mg, 49.5 μmol, 11% yield, HCl) as a yellow liquid. MS (ESI): m / z = 267.1 [M+H] + , retention time: 1.899 minutes, method: A, 1 H NMR (400MHz, DMSO-d6) δ=8.11-7.78(m, 3H), 7.51(q, J=7.7Hz, 2H), 7.23(t, J=7.8Hz, 1H), 6.32-5.96(m, 1H), 3.87(s, 2H), 3.00-2.78(m, 6H). [Example]

[0201] [Synthesis of N1-(3-chloro-2-fluorobenzyl)-N1-(2,2,2-trifluoroethyl)ethane-1,2-diamine (Compound 119)] The following compounds were further prepared in a similar manner as described above for compound 118 (Example 5):

[0202] [Table 3] [Example]

[0203] [Synthesis of N1-(3-chloro-2-fluorobenzyl)-N1-(2-(methylthio)ethyl)ethane-1,2-diamine hydrochloride (Compound 168)] 1) tert-Butyl N-[2-[(3-chloro-2-fluorophenyl)methylamino]ethyl]carbamate

[0204] [ka]

[0205] To a solution of 3-chloro-2-fluorobenzaldehyde (10 g, 63 mmol, 1 equiv.) in MeOH (150 mL) was added tert-butyl N-(2-aminoethyl)carbamate (10.1 g, 63 mmol, 9.91 mL, 1 equiv.). The mixture was stirred at 65 °C for 12 h. Then, NaBH3CN (19.82 g, 315.3 mmol, 5 equiv.) was added at 20 °C. The mixture was stirred at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 150 mL of HO and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with HO (100 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent 0–36% ethyl acetate / petroleum ether gradient, 120 mL / min) to give the compound tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methylamino]ethyl]carbamate (10 g, 33 mmol, 52.4% yield) as a yellow oil.

[0206] 2) N-[2-[(3-chloro-2-fluorophenyl)methyl-(2-methylsulfanylethyl)amino]ethyl]carbamate

[0207] [ka]

[0208] A mixture of tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methylamino]ethyl]carbamate (500 mg, 1.65 mmol, 1 equiv.), 1-chloro-2-methylsulfanylethane (182 mg, 1.65 mmol, 163 μL, 1 equiv.), and KCO (685 mg, 4.95 mmol, 3 equiv.) in CHCN (10 mL) was stirred at 80 °C for 12 h. LC-MS showed that the desired compound was detected. The mixture was filtered to remove KCO, and then the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent 0 to 100% ethyl acetate / petroleum ether gradient, 80 mL / min) to give the compound N-[2-[(3-chloro-2-fluorophenyl)methyl-(2-methylsulfanylethyl)amino]ethyl]carbamate (200 mg, 500.7 μmol, 30% yield, 94.4% purity) as a colorless oil.

[0209] 3) N1-(3-chloro-2-fluorobenzyl)-N1-(2-(methylthio)ethyl)ethane-1,2-diamine hydrochloride (Compound 168)

[0210] [ka]

[0211] A solution of tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methyl-(2-methylsulfanylethyl)amino]ethyl]carbamate (50 mg, 133 μmol, 1 equivalent) in HCl / ethyl acetate (1 mL, 4 M) was stirred at 25 °C for 1 hour. LC-MS showed that the target compound was detected. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (HCl condition, column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: [water (HCl)-ACN], B%: 1%-20%, 8 min) to obtain the compound N1-(3-chloro-2-fluorobenzyl)-N1-(2-(methylthio)ethyl)ethane-1,2-diamine hydrochloride (7.5 mg, 26.7 μmol, 20% yield, 98.5% purity) as a white solid. MS (ESI): m / z = 277.1 [M+H] + , retention time: 1.777 minutes, method: A, 1 H NMR (400MHz, DMSO-d6) δ = 8.20 (br s, 3H), 7.79-7.62 (m, 2H), 7.32 (br t, J = 7.8Hz, 1H), 4.60-4.07 (m, 2H), 3.27-2.80 (m, 8H), 2.09 (s, 3H). [Example]

[0212] [Synthesis of compounds 126, 136, and 160] The following compounds were further prepared in a similar manner as described above for compound 168 (Example 7):

[0213] [Table 4-1]

[0214] [Table 4-2] [Example]

[0215] [Synthesis of 3-(((2-aminoethyl)(ethyl)amino)methyl)-2-fluorobenzonitrile TFA salt (Compound 175)] 1) tert-Butyl N-[2-[(3-bromo-2-fluorophenyl)methylamino]ethyl]carbamate

[0216] [ka]

[0217] To a solution of 3-bromo-2-fluorobenzaldehyde (400 mg, 1.97 mmol, 1 equiv.) and tert-butyl N-(2-aminoethyl)carbamate (316 mg, 2 mmol, 310 μL, 1 equiv.) in MeOH (5 mL), AcOH was added to adjust the pH to 4–5. The mixture was stirred at 40 °C for 12 h. NaBHCN (372 mg, 5.9 mmol, 3 equiv.) was then added, and the mixture was stirred at 25 °C for 2 h. The mixture was concentrated to give a residue, which was poured into water and extracted with ethyl acetate (5 mL × 3). The combined organic layers were then washed with brine (5 mL × 2), dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give compound tert-butyl N-[2-[(3-bromo-2-fluorophenyl)methylamino]ethyl]carbamate (600 mg, crude) as a colorless oil.

[0218] 2) tert-Butyl N-[2-[(3-bromo-2-fluorophenyl)methylethylamino]ethyl]carbamate

[0219] [ka]

[0220] To a solution of tert-butyl N-[2-[(3-bromo-2-fluorophenyl)methylamino]ethyl]carbamate (600 mg, 1.73 mmol, 1 equiv.) and acetaldehyde (761 mg, 6.9 mmol, 970 μL, 40% purity, 4 equiv.) in MeOH (5 mL), AcOH was added to adjust the pH to 4-5, and the mixture was stirred at 25 °C for 12 h. NaBHCN (326 mg, 5.18 mmol, 3 equiv.) was then added and the mixture was stirred at 25 °C for 12 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the compound tert-butyl N-[2-[(3-bromo-2-fluorophenyl)methyl-ethyl-amino]ethyl]carbamate (300 mg, 799.4 μmol, 46% yield) as a colorless oil.

[0221] tert-Butyl N-[2-[(3-cyano-2-fluorophenyl)methylethylamino]ethyl]carbamate

[0222] [ka]

[0223] A mixture of tert-butyl N-[2-[(3-bromo-2-fluorophenyl)methyl-ethyl-amino]ethyl]carbamate (200 mg, 533 μmol, 1 equiv.), Zn(CN) (188 mg, 1.6 mmol, 101.5 μL, 3 equiv.), Pd(dba) (49 mg, 53.3 μmol, 0.1 equiv.), and dppf (59 mg, 106.6 μmol, 0.2 equiv.) in DMF (3 mL) was degassed and purged with N three times. The mixture was stirred under N at 100 °C for 12 h. The mixture was filtered, and the filtrate was poured into water and extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed with brine (3 mL × 2), then dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give compound tert-butyl N-[2-[(3-cyano-2-fluorophenyl)methyl-ethyl-amino]ethyl]carbamate (150 mg, crude) as a colorless oil.

[0224] 4) 3-(((2-aminoethyl)(ethyl)amino)methyl)-2-fluorobenzonitrile TFA salt (Compound 175)

[0225] [ka]

[0226] To a solution of tert-butyl N-[2-[(3-cyano-2-fluoro-phenyl)methyl-ethyl-amino]ethyl]carbamate (150 mg, 467 μmol, 1 equiv.) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 29 equiv.) The mixture was stirred at 25° C. for 12 h, and the mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (TFA conditions, column: C18-1 150 x 30 mm x 5 μm, mobile phase: [water (TFA)-ACN], B%: 1%-25%, 8 min), followed by preparative HPLC (TFA conditions, column: C18-1 150 x 30 mm x 5 μm, mobile phase: [water (TFA)-ACN], B%: 1%-25%, 8 min) to give compound 3-[[2-aminoethyl(ethyl)amino]methyl]-2-fluorobenzonitrile TFA salt (145 mg, 413.4 μmol, 88.6% yield, 95.5% purity, TFA) as a colorless gum. MS (ESI): m / z = 222.1 [M+H] + , Retention time: 0.497 minutes, Method: I, 1 H NMR (400MHz, DMSO-d6) δ = 8.00-7.85 (m, 4H), 7.47 (t, J = 7.8Hz, 1H), 4.24-3.85 (m, 2H), 3.12-2.67 (m, 6H), 1.13 (br s, 3H). [Example]

[0227] [Synthesis of compound 175A] Compound 175A was prepared in a similar manner as described above for compound 175 (Example 9), except step 3 was omitted and HCl was used instead of TFA in the deprotection step.

[0228] [Table 5] [Example]

[0229] [Synthesis of N1-(3-chloro-2-fluorobenzyl)-N1-cyclobutylethane-1,2-diamine hydrochloride (Compound 159)] 1) tert-Butyl (2-((3-chloro-2-fluorobenzyl)(cyclobutyl)amino)ethyl)carbamate

[0230] [ka]

[0231] To a solution of tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methylamino]ethyl]carbamate (150 mg, 495.4 μmol, 1 equiv.) and cyclobutanone (69.5 mg, 991 μmol, 74 μL, 2 equiv.) in MeOH (2 mL) was added AcOH to adjust the pH to 4–5. The mixture was stirred at 25 °C for 1 h, and then NaBHCN (93.4 mg, 1.49 mmol, 3 equiv.) was added. The mixture was stirred at 25 °C for 12 h. The mixture was poured into 5 mL of water and then extracted with ethyl acetate (3 mL × 3). The organic layer was then washed with brine (2 mL × 2), filtered, and the filtrate was concentrated under vacuum to obtain compound tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methyl-cyclobutyl-amino]ethyl]carbamate (170 mg, crude) as a white solid.

[0232] N1-(3-chloro-2-fluorobenzyl)-N1-cyclobutylethane-1,2-diamine dihydrochloride (Compound 159)

[0233] [ka]

[0234] To a solution of tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methyl-cyclobutyl-amino]ethyl]carbamate (170 mg, 476 μmol, 1 equiv.) in HCl / ethyl acetate (1 mL, 4 M) was added ethyl acetate (2 mL), and the mixture was stirred at 25° C. for 12 hours. The mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC (HCl condition, column: Phenomenex Luna C18 80*40 mm*3 μm, mobile phase: [water (HCl)-ACN], B%: 1%-30%, 7 min) to give N1-(3-chloro-2-fluorobenzyl)-N1-cyclobutylethane-1,2-diamine dihydrochloride (99 mg, 337.3 μmol, 71% yield, 100% purity, 2HCl) as a white gum. MS (ESI): m / z = 257.0 [M+H] + , Retention time: 1.337 minutes, Method: A, 1 H NMR (400MHz, DMSO-d6) δ=12.20-11.89(m, 1H), 8.66-8.27(m, 3H), 7.89-7.67(m, 2H), 7.32(t, J=7.9Hz, 1H), 4.52-4.30(m , 2H), 4.19-3.70(m, 4H), 3.49-3.32(m, 1H), 2.62-2.51(m, 1H), 2.47-2.30(m, 1H), 2.26-1.93(m, 2H), 1.78-1.56(m, 2H). [Example]

[0235] [Synthesis of (R)-N1-(1-(3-chlorophenyl)ethyl)-N1-ethylethane-1,2-diamine dihydrochloride (Compound 176)] 1) (R)-tert-Butyl (2-((1-(3-chlorophenyl)ethyl)amino)ethyl)carbamate

[0236] [ka]

[0237] To a solution of tert-butyl N-(2-oxoethyl)carbamate (198.89 mg, 1.25 mmol, 1.2 equiv) and (1R)-1-(3-chlorophenyl)ethanamine hydrochloride (200 mg, 1.04 mmol, 1 equiv) in MeOH (3 mL) was added AcOH (420 mg, 7 mmol, 400 μL, 6.72 equiv) and NaOAc (85.4 mg, 1.04 mmol, 1 equiv), followed by NaBHCN (78.5 mg, 1.25 mmol, 1.2 equiv). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with saturated NaHCO (3 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give (R)-tert-butyl (2-((1-(3-chlorophenyl)ethyl)amino)ethyl)carbamate (300 mg, 1 mmol, 96.4% yield) as a colorless oil.

[0238] 2) (R)-tert-butyl(2-((1-(3-chlorophenyl)ethyl)(ethyl)amino)ethyl)carbamate

[0239] [ka]

[0240] To a solution of tert-butyl N-[2-[[(1R)-1-(3-chlorophenyl)ethyl]amino]ethyl]carbamate (260 mg, 870 μmol, 1 equiv.) and acetaldehyde (192 mg, 4.35 mmol, 244 μL, 5 equiv.) in DCM (4 mL), AcOH was added to adjust the pH to 4–5. The mixture was stirred at 20 °C for 2 h. NaBH(OAc) (369 mg, 1.74 mmol, 2 equiv.) was then added and the mixture was stirred at 20 °C for 2 h. LC-MS showed that reactant 2 was completely consumed, with approximately 49% of the desired compound detected. The mixture was concentrated to give a residue. The reaction mixture was quenched with saturated brine. The pH was adjusted to 8 with NaHCO solution, followed by extraction with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous NaSO. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 1 / 1, Rf = 0.44) to give (R)-tert-butyl(2-((1-(3-chlorophenyl)ethyl)(ethyl)amino)ethyl)carbamate (100 mg, 306 μmol, 35% yield) as a colorless oil.

[0241] 3) (R)-N1-(1-(3-chlorophenyl)ethyl)-N1-ethylethane-1,2-diamine dihydrochloride (Compound 176)

[0242] [ka]

[0243] A solution of tert-butyl N-[2-[[(1R)-1-(3-chlorophenyl)ethyl]-ethyl-amino)ethyl]carbamate (70 mg, 214 μmol, 1 equiv.) in hexafluoroisopropanol (0.5 mL) was stirred at 80 °C for 3 h. LC-MS showed complete consumption of reactant 3, with approximately 94% of the desired compound detected. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (HCl conditions, column: Phenomenex Luna C18 80 × 40 mm × 3 μm, mobile phase: [water (HCl)-ACN], B%: 1%-30%, 7 min) to give (R)-N1-(1-(3-chlorophenyl)ethyl)-N1-ethylethane-1,2-diamine dihydrochloride (13 mg, 48 μmol, 22% yield, 97.3% purity, 2HCl) as a white solid. MS (ESI): m / z = 227.1 [M+H] + , retention time: 1.799 minutes, method: K, 1 H NMR (400MHz, DMSO-d6)δ 10.99-12.28(m, 1H), 8.26-8.86(m, 3H), 7.87(s, 1H), 7.67-7.77(m, 1H), 7.41-7.53(m, 2H), 4.69(q, J=6.72Hz, 1H), 3.77(br s, 3H), 3.48(br s, 1H), 2.82-3.22(m, 2H), 1.74(d, J=6.85Hz, 3H), 1.17-1.41(m, 3H). [Example]

[0244] [Synthesis of (S)-N1-(1-(3-chlorophenyl)ethyl)-N1-ethylethane-1,2-diamine dihydrochloride (Compound 177)] Compound 177 was prepared in a similar manner as described above for compound 176 (Example 12).

[0245] [Table 6] [Example]

[0246] [Synthesis of N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopentylethane-1,2-diamine dihydrochloride (Compound 184)] 1) N-(1-(3-chloro-2-fluorophenyl)ethyl)cyclopentanamine

[0247] [ka]

[0248] A solution of 1-(3-chloro-2-fluorophenyl)ethanone (500 mg, 2.90 mmol, 1 equiv.) and cyclopentanamine (493 mg, 5.79 mmol, 571.7 μL, 2 equiv.) in tetraisopropoxytitanium (1.07 g, 3.8 mmol, 1.1 mL, 1.3 equiv.) was stirred at 20 °C for 1 h. Then, MeOH (10 mL) and NaBH (186 mg, 4.93 mmol, 1.7 equiv.) were added at 0 °C, and the mixture was stirred at 20 °C for 2 h. LC-MS showed complete consumption of reactant 1, with approximately 70% of the desired compound remaining. The reaction mixture was diluted with 10 mL of HO and extracted three times with 10 mL of HO. The combined organic phase was dried over anhydrous Na2SO4, the mixture was filtered, and the filtrate was concentrated in vacuo to give N-(1-(3-chloro-2-fluorophenyl)ethyl)cyclopentanamine (400 mg, crude) as a yellow oil.

[0249] 2) tert-Butyl (2-((1-(3-chloro-2-fluorophenyl)ethyl)(cyclopentyl)amino)ethyl)carbamate

[0250] [ka]

[0251] To a solution of N-(1-(3-chloro-2-fluorophenyl)ethyl)cyclopentanamine (280 mg, 1.16 mmol, 1 equiv.) and tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate (259 mg, 1.16 mmol, 1 equiv.) in THF (6 mL) was added NaH (56 mg, 1.39 mmol, 60% purity, 1.2 equiv.) at 0 °C, and the mixture was stirred at 80 °C for 2 h under a N atmosphere. LC-MS revealed that approximately 42% of reactant 2 remained, and approximately 21% of the desired compound was detected. The reaction mixture was diluted with 10 mL HO and extracted with ethyl acetate (8 mL × 3). The combined organic phase was dried over anhydrous NaSO, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (HCl condition, column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: [water (HCl)-ACN], B%: 20%-45%, 8 min) to obtain tert-butyl (2-((1-(3-chloro-2-fluorophenyl)ethyl)(cyclopentyl)amino)ethyl)carbamate (240 mg, 624 μmol, yield 54%) as a white solid.

[0252] 3) N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopentylethane-1,2-diamine dihydrochloride (Compound 184)

[0253] [ka]

[0254] A solution of tert-butyl (2-((1-(3-chloro-2-fluorophenyl)ethyl)(cyclopentyl)amino)ethyl)carbamate (40 mg, 103.9 μmol, 1 equiv.) and HCl / ethyl acetate (4 M, 1.5 mL, 57.74 equiv.) in ethyl acetate (1 mL) was stirred at 20° C. for 2 h. LC-MS showed that reactant 3 was completely consumed and approximately 23% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl conditions, Phenomenex Luna 80 x 30 mm x 3 μm column, mobile phase: [water (HCl)-ACN], B%: 5%-25%, 8 min) to obtain N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopentylethane-1,2-diamine dihydrochloride (10.24 mg, 33.19 μmol, 31.9% yield, 92.3% purity, 2HCl) as a colorless gum. MS (ESI): m / z = 285.1 [M+H] + , retention time: 1.641 minutes, method: A, 1 H NMR (400MHz, DMSO-d6) δ11.2-11.8(m, 1H), 8.3-8.7(m, 3H), 8.0-8.2(m, 1H), 7.7-7.8(m, 1H), 7.3-7.4(m, 1H), 4.9-5.1(m, 1H), 3.5-3.8(m, 3H), 3.0-3.4(m, 2H), 1.9-2.2(m, 2H), 1.6-1.9(m, 7H), 1.4-1.6(m, 2H). [Example]

[0255] [Synthesis of N'-[1-(3-chloro-2-fluorophenyl)ethyl]-N'-cyclopropylethane-1,2-diamine hydrochloride (Compound 220) and its enantiomer] 1) N-(1-(3-chloro-2-fluorophenyl)ethyl)cyclopropanamine

[0256] [ka]

[0257] A solution of 1-(3-chloro-2-fluorophenyl)ethanone (200 mg, 1.16 mmol, 1 equiv.) and cyclopropanamine (99.3 mg, 1.74 mmol, 120.4 μL, 1.5 equiv.) in MeOH (2 mL) was adjusted to pH 4–5 with AcOH and stirred at 40 °C for 12 h. NaBH CN (218.47 mg, 3.48 mmol, 3 equiv.) was then added, and the mixture was stirred at 40 °C for 2 h. The mixture was concentrated to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1–3 / 1) to give the compound N-[1-(3-chloro-2-fluorophenyl)ethyl]cyclopropanamine (200 mg, 936 μmol, 81% yield) as a colorless oil.

[0258] 2) tert-Butyl (2-((1-(3-chloro-2-fluorophenyl)ethyl)(cyclopropyl)amino)ethyl)carbamate

[0259] [ka]

[0260] To a solution of N-[1-(3-chloro-2-fluorophenyl)ethyl]cyclopropanamine (200 mg, 936 μmol, 1 equiv.) and tert-butyl N-(2-oxoethyl)carbamate (149 mg, 936 μmol, 1 equiv.) in MeOH (3 mL), AcOH was added to adjust the pH to 4-5, and the mixture was stirred at 40 °C for 2 h. NaBHCN (177 mg, 2.8 mmol, 3 equiv.) was then added, and the mixture was stirred at 40 °C for 12 h. The mixture was concentrated in vacuo to give the compound tert-butyl N-[2-[1-(3-chloro-2-fluorophenyl)ethyl-cyclopropyl-amino]ethyl]carbamate (250 mg, crude) as a white solid.

[0261] 3) N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 220)

[0262] [ka]

[0263] To a solution of tert-butyl N-[2-[1-(3-chloro-2-fluorophenyl)ethyl-cyclopropyl-amino]ethyl]carbamate (200 mg, 560.4 μmol, 1 equivalent) in ethyl acetate (2 mL) was added HCl / ethyl acetate (1 mL, 4 M). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated to give a residue, which was purified by preparative HPLC (HCl condition, column: Phenomenex Luna 80 * 30 mm * 3 μm, mobile phase: [water (HCl)-ACN], B%: 5%-30%, 8 min) to give the compound N'-[1-(3-chloro-2-fluorophenyl)ethyl]-N'-cyclopropylethane-1,2-diamine hydrochloride (117 mg, 399 μmol, yield 71%, purity 100%, HCl) as a white solid. MS (ESI): m / z = 257.0 [M + H] + , retention time: 1.744 minutes, method: K, 1 H NMR (400MHz, DMSO-d6) δ=8.44-8.17(m, 3H), 7.75-7.65(m, 1H), 7.60(br t, J=7.4Hz, 1H), 7.29(t, J=7.9Hz, 1H), 4.91-4.65(m, 1H), 3.47-3.29(m, 1H), 3.15(br d, J=2.0Hz, 3H), 2.43-2.26(m, 1H), 1.67(br d, J=6.7Hz, 3H), 1.03-0.80(m, 2H), 0.69(br t, J=6.1Hz, 2H).

[0264] 4) Enantiomer of N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopropylethane-1,2-diamine 200 mg of compound 220 was further separated by SFC (instrument: Waters SFC80 preparative SFC, column: Daicel ChiralPak IH, 250*30 mm, 10 μm, flow rate: 60 g / min, wavelength: 220 nm, column temperature: 40 °C, system back pressure: 100 bar, mobile phase: A: CO2, B: [0.1% NH3*H2O in MeOH], B%: 30%-30%, 3 min) (P1 retention time = 1.245, P2 retention time = 1.506), and then the product with retention time = 1.245 was separated by preparative HPLC (neutral conditions, column: Waters Xbridge Prep OBD C18 Purification with 150*40 mm*10 μm, mobile phase: A: water (NH3 * H2O + NH4HCO3), B: MeCN, B%: 5%-70%, 8 min) gave compound 220A (+)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopropylethane-1,2-diamine (retention time = 1.245, 20.2 mg, 76.88 μmol, 20% yield, 97.72% purity) as a brown oil ((+) rotation in DMSO at 589 nm / 19.9 °C, ee% = 100%). MS (ESI): m / z = 257.0 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ=7.50-7.45(m, 1H), 7.43-7.37(m, 1H), 7.26-7.15(m, 1H), 4.34(q, J=7.0Hz, 1H), 2.71- 2.53(m, 3H), 2.42-2.28(m, 1H), 1.80-1.66(m, 1H), 1.38(d, J=7.0Hz, 3H), 0.48-0.41(m, 2H), 0.40-0.24(m, 2H). The second fraction yielded compound 220B (-)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopropylethane-1,2-diamine (retention time = 1.506, 26.8 mg, 101.79 μmol, 27% yield, 97.52% purity) as a brown oil ((-)-rotation in DMSO at 589 nm / 19.9 °C, ee% = 97.86%). MS (ESI): m / z = 257.0 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ=7.54-7.48(m, 1H), 7.45-7.38(m, 1H), 7.22(t, J=7.9Hz, 1H), 6.35-5.65(m, 2H), 4.36(q, J=7.0Hz, 1H), 2.86-2.68(m, 3H), 2.48-2.41(m, 1H), 1.78-1.67(m, 1H), 1.41(d, J=7.0Hz, 3H), 0.54-0.38(m, 3H), 0.33-0.25(m, 1H). [Example]

[0265] Synthesis of N'-[1-(2-chloro-3,5-difluorophenyl)ethyl]-N'-cyclopropylethane-1,2-diamine hydrochloride (Compound 188) Compound 188 was prepared in a similar manner as described above for compound 220 (Example 15).

[0266] [Table 7] [Example]

[0267] [Synthesis of N1-(bicyclo[1.1.1]pentan-1-yl)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (Compound 182)] 1) N-(1-(3-chloro-2-fluorophenyl)ethyl)bicyclo[1.1.1]pentan-1-amine

[0268] [ka]

[0269] A solution of 1-(3-chloro-2-fluorophenyl)ethanone (400 mg, 2.3 mmol, 1 equiv.) and bicyclo[1.1.1]pentan-1-amine (289 mg, 3.48 mmol, 1.5 equiv.) in MeOH (5 mL) was adjusted to pH 4-5 with AcOH and stirred at 40 °C for 12 h. NaBH3CN (437 mg, 7 mmol, 3 equiv.) was then added at 20 °C. The mixture was stirred at 40 °C for 2 h. LC-MS showed complete consumption of reactant 1, with approximately 30% of the desired compound detected. The reaction mixture was quenched with saturated brine. A NaHCO3 solution (10 mL) was heated to pH 7 at 0 °C, diluted with H2O (5 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent: 0–7% ethyl acetate / petroleum ether gradient, 90 mL / min) (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.62) to give N-(1-(3-chloro-2-fluorophenyl)ethyl)bicyclo[1.1.1]pentan-1-amine (300 mg, 1.25 mmol, 54% yield) as a colorless oil.

[0270] 2) tert-Butyl N-[2-[1-bicyclo[1.1.1]pentanyl-[1-(3-chloro-2-fluorophenyl)ethyl]amino]ethyl]carbamate

[0271] [ka]

[0272] A solution of N-[1-(3-chloro-2-fluorophenyl)ethyl]bicyclo[1.1.1]pentan-1-amine (270 mg, 1.13 mmol, 1 equiv.) and tert-butyl N-(2-oxoethyl)carbamate (179 mg, 1.13 mmol, 1 equiv.) in MeOH (4 mL) was adjusted to pH 4-5 with AcOH and stirred at 40 °C for 2 h. NaBH CN (212 mg, 3.38 mmol, 3 equiv.) was then added, and the mixture was stirred at 40 °C for 12 h. LC-MS showed that approximately 15% of reactant 2 remained, and approximately 37% of the desired compound was detected. The reaction mixture was quenched at 0 °C with saturated NaHCO solution (5 mL), diluted with HO (10 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1, Rf = 0.54) to give tert-butyl N-[2-[1-bicyclo[1.1.1]pentanyl-[1-(3-chloro-2-fluorophenyl)ethyl]amino]ethyl]carbamate (100 mg, 261 μmol, 23% yield) as a colorless oil.

[0273] 3) N1-(bicyclo[1.1.1]pentan-1-yl)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (Compound 182)

[0274] [ka]

[0275] A solution of tert-butyl N-[2-[1-bicyclo[1.1.1]pentanyl-[1-(3-chloro-2-fluorophenyl)ethyl]amino]ethyl]carbamate (50 mg, 130.6 μmol, 1 equiv.) in ethyl acetate (1 mL) and HCl / ethyl acetate (0.5 mL, 4 M) was stirred at 20 °C for 1 h. LC-MS showed complete consumption of reactant 1, approximately 64% of the desired compound. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (HCl conditions, Phenomenex Luna 80 x 30 mm x 3 μm column, mobile phase: [water (HCl)-ACN], B%: 1%-40%, 8 min) to obtain N1-(bicyclo[1.1.1]pentan-1-yl)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (33.5 mg, 118.5 μmol, 91% yield, 100% purity, HCl) as a white solid. MS (ESI): m / z = 283.0 [M+H] + , retention time: 2.127 minutes, method: A, 1 H NMR (400MHz, DMSO-d6) δ8.16(br s, 3H), 7.44-7.65(m, 2H), 7.21(t, J=7.76Hz, 1H), 4.51(q, J=6.93Hz, 1H), 3.01-3.25(m, 2H), 2.66-2.90(m, 2H), 2.38(s, 1H), 1.83-1.90(m, 3H), 1.77-1.82(m, 3H), 1.47(d, J=6.97Hz, 3H). [Example]

[0276] [Synthesis of N1-(cyclobutyl)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (Compound 180) and N1-(cyclopropyl)-N1-(1-(2,5-dichlorophenyl)ethyl)ethane-1,2-diamine hydrochloride (Compound 185)] The following compounds were further prepared in a similar manner as described above for compound 182 (Example 17):

[0277] [Table 8] [Example]

[0278] [Synthesis of N1-allyl-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (Compound 172)] 1) tert-Butyl (2-((1-(3-chloro-2-fluorophenyl)ethyl)amino)ethyl)carbamate

[0279] [ka]

[0280] A solution of 1-(3-chloro-2-fluorophenyl)ethanone (2 g, 11.59 mmol, 1 equiv.) and tert-butyl N-(2-aminoethyl)carbamate (1.86 g, 11.59 mmol, 1.82 mL, 1 equiv.) in MeOH (20 mL) was adjusted to pH 4-5 with AcOH. The mixture was stirred at 70 °C for 12 h, then NaBH3CN (2.18 g, 34.77 mmol, 3 equiv.) was added, and the mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, giving a residue that was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give compound tert-butyl N-[2-[1-(3-chloro-2-fluorophenyl)ethylamino]ethyl]carbamate (1.8 g, 5.68 mmol, yield 49%) as a red oil.

[0281] 2) tert-Butyl (2-(allyl(1-(3-chloro-2-fluorophenyl)ethyl)amino)ethyl)carbamate

[0282] [ka]

[0283] To a solution of tert-butyl N-[2-[1-(3-chloro-2-fluorophenyl)ethylamino]ethyl]carbamate (200 mg, 631.3 μmol, 1 equiv.) in MeCN (2 mL) was added KCO (262 mg, 1.89 mmol, 3 equiv.) and 3-bromoprop-1-ene (115 mg, 947 μmol, 1.5 equiv.). The mixture was stirred at 70° C. for 12 hours. The mixture was then filtered, and the filtrate was concentrated to give compound tert-butyl N-[2-[allyl-[1-(3-chloro-2-fluorophenyl)ethyl]amino]ethyl]carbamate (200 mg, crude) as a yellow oil.

[0284] 3) N1-Allyl-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (Compound 172)

[0285] [ka]

[0286] To a solution of tert-butyl N-[2-[allyl-[1-(3-chloro-2-fluorophenyl)ethyl]amino]ethyl]carbamate (100 mg, 280.2 μmol, 1 equivalent) in ethyl acetate (2 mL) was added HCl / ethyl acetate (1 mL, 4 M). The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (HCl condition, column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: [water (HCl)-ACN], B%: 15%-45%, 8 min) to give compound N1-allyl-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (58 mg, 196.4 μmol, yield 70%, purity 99.5%, HCl) as a colorless oil. MS (ESI): m / z = 257.0 [M+H] + , retention time: 1.607 minutes, method: K, 1H NMR (400MHz, DMSO-d6) δ=8.43-8.07(m, 3H), 7.86-7.73(m, 1H), 7.62(br t, J=7.5Hz, 1H), 7.32(t, J=7.9Hz, 1H), 6.10-5.92(m, 1H), 5.48-5.35(m, 2H), 4.75-4.54(m, 1H), 3.84-2.96(m, 6H), 1.66(br d, J=4.8Hz, 3H). [Example]

[0287] [Synthesis of N1-(2-(methylthio)ethyl)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine (Compound 169)] The following compounds were further prepared in a similar manner as described above for compound 172 (Example 19):

[0288] [Table 9] [Example]

[0289] [Synthesis of N1-(3-chloro-2-fluorobenzyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 120)] 1) N-(3-chloro-2-fluorobenzyl)cyclopropanamine

[0290] [ka]

[0291] To a solution of 3-chloro-2-fluorobenzaldehyde (500 mg, 3.15 mmol, 1 equiv.) and cyclopropanamine (360 mg, 6.31 mmol, 437 μL, 2 equiv.) in methanol (20 mL), acetic acid was added to adjust the pH to 4–5, and the mixture was stirred at 25 °C for 12 h. NaBHCN (595 mg, 9.46 mmol, 3 equiv.) was then added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched at 25 °C by the addition of 5 mL of saturated NaHCO solution and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give compound N-[(3-chloro-2-fluorophenyl)methyl]cyclopropanamine (600 mg, crude) as a colorless oil.

[0292] 2) tert-Butyl (2-((3-chloro-2-fluorobenzyl)(cyclopropyl)amino)ethyl)carbamate

[0293] [ka]

[0294] To a solution of N-[(3-chloro-2-fluorophenyl)methyl]cyclopropanamine (200 mg, 1 mmol, 1 equiv) in DCM (3 mL) was added tert-butyl N-(2-oxoethyl)carbamate (160 mg, 1 mmol, 1 equiv), and the mixture was adjusted to pH 4-5 by the addition of AcOH and stirred at 25 °C for 1 h. Next, NaBH(OAc) (637 mg, 3 mmol, 3 equiv) was added, and the mixture was stirred at 25 °C for 12 h. The mixture was concentrated in vacuo to give the crude product tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methyl-cyclopropyl-amino]ethyl]carbamate (160 mg, crude) as a pale yellow oil.

[0295] 3) N1-(3-chloro-2-fluorobenzyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 120)

[0296] [ka]

[0297] A mixture of tert-butyl N-[2-[(3-chloro-2-fluoro-phenyl)methyl-cyclopropyl-amino]ethyl]carbamate (160 mg, 467 μmol, 1 equivalent) in HCl / ethyl acetate (2 mL, 4 M) was stirred at 25 °C for 30 minutes. The mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC (HCl condition, column: Phenomenex Luna C18 80 * 40 mm * 3 μm, mobile phase: [water (HCl)-ACN], B%: 1%-20%, 7 min) to give compound N1-(3-chloro-2-fluorobenzyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (59 mg, 210 μmol, yield 45%, purity 99.7%, HCl) as a white solid. MS (ESI): m / z = 243.0 [M + H] + , retention time: 1.654 minutes, method: A, 1 H NMR (400MHz, DMSO-d6)δ=8.16(br s, 3H), 7.44-7.65(m, 2H), 7.21(t, J=7.76Hz, 1H), 4.51(q, J=6.93Hz, 1H), 3.01-3.25(m, 2H), 2.66-2.90(m, 2H), 2.38(s, 1H), 1.83-1.90(m, 3H), 1.77-1.82(m, 3H), 1.47(d, J=6.97Hz, 3H). [Example]

[0298] [Synthesis of Compound 130] Compound 130 was prepared in a similar manner as described above for compound 120 (Example 21).

[0299] [Table 10] [Example]

[0300] [Synthesis of N1-(1-(3-bromo-2-fluorophenyl)ethyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 191)] 1) N-(1-(3-bromo-2-fluorophenyl)ethyl)cyclopropanamine

[0301] [ka]

[0302] To a solution of 1-(3-bromo-2-fluorophenyl)ethenone (CAS 161957-61-5) (500 mg, 2.3 mmol, 1 equiv) in MeOH (5 mL) was added cyclopropanamine (197.3 mg, 3.5 mmol, 239.4 μL, 1.5 equiv). The reaction was then stirred at 60 °C for 12 h. NaBH CN (579.1 mg, 9.2 mmol, 4 equiv) was then added at 20 °C, and the mixture was stirred at 60 °C for 2 h. LC-MS showed that reactant 1 was consumed and the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 6 mL of HO and extracted with ethyl acetate (4 mL × 3). The combined organic layers were washed with HO (8 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate=5 / 1) to obtain the compound N-[1-(3-bromo-2-fluorophenyl)ethyl]cyclopropanamine (320 mg, 1.2 mmol, 53.8% yield) as a white solid.

[0303] 2) 2-((1-(3-bromo-2-fluorophenyl)ethyl)(cyclopropyl)amino)acetamide

[0304] [ka]

[0305] To a solution of N-[1-(3-bromo-2-fluorophenyl)ethyl]cyclopropanamine (290 mg, 1.1 mmol, 1 equiv.) in ACN (4 mL) was added 2-bromoacetamide (372.0 mg, 2.7 mmol, 2.4 equiv.) and K2CO3 (465.81 mg, 3.37 mmol, 3 equiv.). The mixture was stirred at 80 °C for 12 h. LC-MS showed approximately 50% of 2 remaining and approximately 24% of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 6 mL of H2O and extracted with ethyl acetate (4 mL × 3). The combined organic layers were washed with H2O (8 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1). The compound 2-[1-(3-bromo-2-fluorophenyl)ethyl-cyclopropyl-amino]acetamide (58 mg, 184.0 μmol, 16.4% yield) was obtained as a yellow oil.

[0306] 3) N1-(1-(3-Bromo-2-fluorophenyl)ethyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 191)

[0307] [ka]

[0308] To a solution of 2-[1-(3-bromo-2-fluorophenyl)ethyl-cyclopropyl-amino]acetamide (58 mg, 184.0 μmol, 1 equiv.) in THF (1 mL) was added BH3.THF (1 M, 736.1 μL, 4 equiv.). The mixture was stirred at 70 °C for 12 h. LC-MS showed that the desired compound was detected. The residue was diluted with 5 mL of MeOH and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl condition, column: Phenomenex Luna C18 80 × 40 mm × 3 μm, mobile phase: [water (HCl)-ACN], B%: 5%-35%, 7 min). The compound N1-(1-(3-bromo-2-fluorophenyl)ethyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (4.3 mg, 14.3 μmol, 7.8% yield, HCl, 100% purity) was obtained as a colorless oil. MS (ESI): m / z = 301.3 [M+H] + , retention time: 1.838 minutes, method: B, 1 H NMR (400MHz, DMSO-d6) δ=8.41-7.91(m, 3H), 7.90-7.56(m, 2H), 7.31-7.16(m, 1H), 5.2 4-4.52(m, 1H), 3.31-2.98(m, 4H), 2.54(s, 1H), 1.76-1.51(m, 3H), 1.14-0.44(m, 4H). [Example]

[0309] [Synthesis of compounds 242, 243, 244, and 245] The following compounds were further prepared in a similar manner as described above for compound 191 (Example 23):

[0310] [Table 11-1]

[0311] [Table 11-2] [Example]

[0312] [Synthesis of N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 224)] 1) 1-(3-chloro-2-fluorophenyl)propan-1-ol

[0313] [ka]

[0314] To a solution of 3-chloro-2-fluorobenzaldehyde (1 g, 6.3 mmol, 1 equiv.) in THF (5 mL) was added (ethyl)magnesium bromide (3 M, 2.5 mL, 1.2 equiv.) at 0 °C under N2. The mixture was stirred at 20 °C for 12 h. TLC showed that reactant 1 was completely consumed and one new spot had formed. The reaction mixture was quenched at 20 °C by addition to saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with NaCl (20 mL × 2), dried over Na2SO4, and concentrated under reduced pressure to give the crude product, 1-(3-chloro-2-fluorophenyl)propan-1-ol (1 g, 5.3 mmol, 84.1% yield), as a yellow oil.

[0315] 2) 1-(3-chloro-2-fluorophenyl)propan-1-one

[0316] [ka]

[0317] To a solution of 1-(3-chloro-2-fluorophenyl)propan-1-ol (1 g, 5.3 mmol, 1 equiv.) in DCM (20 mL) was added DMP (3.4 g, 8.0 mmol, 1.5 equiv.). The mixture was stirred at 20 °C for 12 h. TLC showed that 2 was consumed and one major new spot with greater polarity was detected. The residue was quenched with 20 mL of saturated Na2SO3 and extracted with 30 mL of DCM (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (silica flash column, eluent: 0–20% ethyl acetate / petroleum ether gradient, 120 mL / min) to give compound 1-(3-chloro-2-fluorophenyl)propan-1-one (790 mg, 4.23 mmol, 79.85% yield) as a colorless oil.

[0318] 3) N-(1-(3-chloro-2-fluorophenyl)propyl)cyclopropanamine

[0319] [ka]

[0320] To a solution of 1-(3-chloro-2-fluorophenyl)propan-1-one (390 mg, 2.1 mmol, 1 equiv) in MeOH (2 mL) was added cyclopropanamine (179.0 mg, 3.1 mmol, 217.2 μL, 1.5 equiv). The reaction was then stirred at 60 °C for 12 h. NaBH CN (525.3 mg, 8.4 mmol, 4 equiv) was then added, and the mixture was stirred at 60 °C for 2 h. LC-MS showed that the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 6 mL of HO and extracted with ethyl acetate (4 mL × 3). The combined organic layers were washed with HO (8 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=3:1) to obtain the compound N-(1-(3-chloro-2-fluorophenyl)propyl)cyclopropanamine (250 mg, 805.2 μmol, yield 38.5%, purity 73.3%) as a yellow oil.

[0321] 4) 2-((1-(3-chloro-2-fluorophenyl)propyl)(cyclopropyl)amino)acetamide

[0322] [ka]

[0323] To a solution of 2-bromoacetamide (455.3 mg, 3.3 mmol, 3 equiv.) in ACN (5 mL) was added K2CO3 (456.09 mg, 3.30 mmol, 3 equiv.) and N-[1-(3-chloro-2-fluorophenyl)propyl]cyclopropanamine (250 mg, 1.1 mmol, 1 equiv.). The mixture was stirred at 80 °C for 12 h. LC-MS showed that the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 50 mL of H2O and extracted with 150 mL of ethyl acetate (50 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 0:1). The residue was purified by preparative HPLC (HCl conditions) (column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: [water (HCl)-ACN], B%: 10%-45%, 8 min) to obtain the compound 2-((1-(3-chloro-2-fluorophenyl)propyl)(cyclopropyl)amino)acetamide (110 mg, 353.6 μmol, yield 32.2%, purity 91.6%) as a white solid.

[0324] 5) N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 224)

[0325] [ka]

[0326] To a solution of 2-[1-(3-chloro-2-fluoro-phenyl)propyl-cyclopropyl-amino]acetamide (110 mg, 386.3 μmol, 1 eq) in THF (3 mL) was added BH3.THF (1 M, 2.4 mL, 6 eq). The mixture was stirred at 70° C. for 12 hours. LC-MS showed that the desired compound was detected. To the reaction was added 2 mL MeOH. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl conditions, column: Phenomenex Luna 80 x 30 mm x 3 μm, mobile phase: [water (HCl)-ACN], B%: 5%-35%, 8 min) to obtain the compound N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (37 mg, 136.7 μmol, yield 35.4%, purity 100%, HCl) as a colorless oil. MS (ESI): m / z = 271.1 [M+H] + , retention time: 1.558 minutes, method: M, 1 H NMR (400MHz, DMSO-d6) δ=8.01(br dd, J=1.8, 3.3Hz, 3H), 7.61-7.50(m, 2H), 7.33-7.24(m, 1H), 4.33(br dd, J=1.0, 2.0Hz, 1H), 3.29-3.14(m, 1H), 3.13-2.98(m, 2H), 2.96-2.77( m, 1H), 2.26-2.13(m, 1H), 2.11-1.92(m, 2H), 0.88-0.70(m, 5H), 0.63(br d, J=4.0Hz, 2H). [Example]

[0327] [Synthesis of N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-propylethane-1,2-diamine hydrochloride (Compound 262)] 1) 1-(3-chloro-2-fluorophenyl)propan-1-ol

[0328] [ka]

[0329] To a solution of 3-chloro-2-fluorobenzaldehyde (1 g, 6.3 mmol, 1 equiv.) in THF (5 mL) was added (ethyl)magnesium bromide (3 M, 2.5 mL, 1.2 equiv.) at 0 °C under N2. The mixture was stirred at 20 °C for 12 h. TLC showed that reactant 1 was completely consumed and one new spot had formed. The reaction mixture was quenched at 20 °C by addition to saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with NaCl (20 mL × 2), dried over Na2SO4, and concentrated under reduced pressure to give the crude product, 1-(3-chloro-2-fluorophenyl)propan-1-ol (1 g, 5.3 mmol, 84.1% yield), as a yellow oil.

[0330] 2) 1-(3-chloro-2-fluorophenyl)propan-1-one

[0331] [ka]

[0332] To a solution of 1-(3-chloro-2-fluorophenyl)propan-1-ol (1 g, 5.3 mmol, 1 equiv.) in DCM (20 mL) was added DMP (3.4 g, 8.0 mmol, 1.5 equiv.). The mixture was stirred at 20 °C for 12 h. TLC detected one major new spot with greater polarity. The residue was diluted with 200 mL of saturated Na2SO3 and extracted with 300 mL of DCM (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (silica flash column, eluent: 0-20% ethyl acetate / petroleum ether gradient, 120 mL / min) to give the compound 1-(3-chloro-2-fluorophenyl)propan-1-one (790 mg, 4.23 mmol, 79.85% yield) as a colorless oil.

[0333] 3) 1-(3-chloro-2-fluorophenyl)-N-propylpropan-1-amine

[0334] [ka]

[0335] To a solution of 1-(3-chloro-2-fluorophenyl)propan-1-one (200 mg, 1.1 mmol, 1 equiv.) in MeOH (3 mL), propan-1-amine (95.0 mg, 1.6 mmol, 132.2 μL, 1.5 equiv.) and Ti(i-PrO) (913.8 mg, 3.2 mmol, 948.9 μL, 3 equiv.) were added. The mixture was stirred at 60 °C for 12 h. NaBHCN (269.4 mg, 4.3 mmol, 4 equiv.) was added to the reaction mixture at 20 °C and stirred at 60 °C for 2 h. LC-MS showed complete consumption of 3, with one main peak of the desired m / z. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 15 mL of H2O, extracted with 30 mL of ethyl acetate (10 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product 1-(3-chloro-2-fluorophenyl)-N-propylpropan-1-amine (210 mg, crude) as a yellow oil.

[0336] 4) tert-Butyl (2-((1-(3-chloro-2-fluorophenyl)propyl)(propyl)amino)ethyl)carbamate

[0337] [ka]

[0338] To a solution of 1-(3-chloro-2-fluoro-phenyl)-N-propyl-propan-1-amine (150 mg, 653.0 μmol, 1 equiv.) in MeOH (2 mL), tert-butyl N-(2-oxoethyl)carbamate (727.6 mg, 4.6 mmol, 7 equiv.) and AcOH were added to adjust the pH to 5, and the mixture was stirred at 60 °C for 12 h. Then, NaBH CN (164.1 mg, 2.6 mmol, 4 equiv.) was added at 20 °C. The mixture was stirred at 60 °C for 2 h. LC-MS showed that 4 was completely consumed, and one main peak of the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 mL of HO, extracted with 30 mL of ethyl acetate (10 mL × 3), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate=3 / 1) to obtain the compound tert-butyl (2-((1-(3-chloro-2-fluorophenyl)propyl)(propyl)amino)ethyl)carbamate (73 mg, 195.8 μmol, yield 30.0%) as a white solid.

[0339] 5) N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-propylethane-1,2-diamine hydrochloride (Compound 262)

[0340] [ka]

[0341] A solution of tert-butyl N-[2-[1-(3-chloro-2-fluoro-phenyl)propyl-propyl-amino]ethyl]carbamate (73 mg, 195.8 μmol, 1 equiv.) in HCl / ethyl acetate (5 mL) was stirred at 20° C. for 1 h. LC-MS showed complete consumption of 5, with one main peak of the desired m / z. The reaction mixture was concentrated under reduced pressure to remove the solvent. 2 mL of MeOH was added to the reaction mixture. The residue was purified by preparative HPLC (HCl conditions, column: Phenomenex Luna 80 x 30 mm x 3 μm, mobile phase: [water (HCl)-ACN], gradient: 10%-35% B over 8 min) to give the compound N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-propylethane-1,2-diamine hydrochloride (28.03 mg, 90.64 μmol, 46.30% yield, 100% purity, HCl) as a yellow oil. MS (ESI): m / z = 273.3 [M+H] + , retention time: 1.368 minutes, method: M, special 1 H NMR (400MHz, DMSO-d6) δ=8.81-8.22(m, 3H), 7.95-7.79 (m, 1H), 7.67(br t, J=7.5Hz, 1H), 7.36(t, J=7.9Hz, 1H), 4.70-4.44(m, 1H), 3.34-3.09(m, 4H), 3.05(br s, 2H), 2.41-2.07(m, 2H), 1.85-1.61(m, 2H), 0.87(br t, J=6.9Hz, 3H), 0.72(t, J=7.3Hz, 3H). [Example]

[0342] [Synthesis of compounds 190, 258, and 248] The following compounds were further prepared in a similar manner as described above for compound 262 (Example 26):

[0343] [Table 12-1]

[0344] [Table 12-2] [Example]

[0345] [Synthesis of Compounds 218 and 227] The following compounds were prepared following the method described for the synthesis of compound 262 (Example 26), starting from 3-acetyl-2-fluorobenzonitrile (CAS 112279-89-7) instead of intermediate 3 in step 3 and using cyclopropylamine or cyclobutylamine, respectively.

[0346] [Table 13] [Example]

[0347] [N 1 -(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N 1 Synthesis of -cyclopropylethane-1,2-diamine hydrochloride (compound 275) 1) 1-(3-chloro-2-fluorophenyl)-2,2-difluoroethan-1-one

[0348] [ka]

[0349] A solution of 1-chloro-2-fluorobenzene (3 g, 23.0 mmol, 1 equiv.) in THF (30 mL) was degassed and purged with N2 three times. LDA (2 M, 23.0 mL, 2 equiv.) was then added to the reaction mixture at -78 °C, and the mixture was stirred at -78 °C for 15 min under N2 atmosphere. Ethyl 2,2-difluoroacetate (3.1 g, 25.3 mmol, 1.1 equiv.) was then added to the reaction mixture at -78 °C, and the mixture was stirred at 25 °C under N2 atmosphere for 12 h. TLC showed that reactant 1 was completely consumed and many new spots had formed. The reaction mixture was quenched by the addition of saturated sodium chloride. The mixture was stirred with 10 mL of NH4Cl at 0 °C and then extracted with 30 mL of ethyl acetate (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (10 g silica flash column, eluent 0–10% ethyl acetate / petroleum ether gradient, 80 mL / min) to give the compound 1-(3-chloro-2-fluorophenyl)-2,2-difluoroethanone (pure 0.4 g, crude 2.5 g) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.55-7.49 (m, 1H), 7.37-7.32 (m, 1H), 7.08 (t, J = 7.9 Hz, 1H), 6.68 (s, 1H).

[0350] 2) N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)cyclopropanamine

[0351] [ka]

[0352] To a solution of 1-(3-chloro-2-fluorophenyl)-2,2-difluoroethanone (2.5 g, 11.8 mmol, 1 equiv.) in MeOH (2 mL) was added cyclopropanamine (1.0 g, 17.6 mmol, 1.2 mL, 1.5 equiv.) and Ti(i-PrO) (10.0 g, 35.2 mmol, 10.4 mL, 3 equiv.). The mixture was stirred at 60 °C for 12 h. NaBHCN (3.0 g, 47.0 mmol, 4 equiv.) was then added, and the resulting mixture was stirred at 60 °C for 3 h. LC-MS indicated that the desired compound was detected in approximately 29%. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g silica flash column, eluent 0–5% ethyl acetate / petroleum ether gradient, 80 mL / min) to obtain the compound N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)cyclopropanamine (2.0 g, 2.8 mmol, 23.9% yield, 35% purity) as a white solid.

[0353] 3) 2-Bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide

[0354] [ka]

[0355] To a solution of N-[1-(3-chloro-2-fluorophenyl)ethyl]-3,3-difluoroprop-2-en-1-amine (1.8 g, 7.4 mmol, 1 equiv.) in DCM (20 mL) was added a solution of KCO (2.0 g, 14.7 mmol, 2 equiv.) in HO (20 mL). 2-Bromoacetyl bromide (1.8 g, 8.8 mmol, 768.1 μL, 1.2 equiv.) was added to the reaction mixture at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed that reactant 3 was completely consumed, with approximately 65% of the desired mass detected. The reaction mixture was extracted with 60 mL of DCM (20 mL × 3). The combined organic layers were washed with saturated sodium chloride. 20 mL of NaCl was added, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (10 g silica flash column, eluent 0–10% ethyl acetate / petroleum ether gradient, 80 mL / min) to give the compound 2-bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide (1.5 g, 4.0 mmol, 54.0% yield) as a yellow oil.

[0356] 4) N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide

[0357] [ka]

[0358] To a solution of 2-bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide (1.5 g, 4.0 mmol, 1 equiv.) in DMF (15 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (952.8 mg, 5.1 mmol, 1.3 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed that reactant 4 was completely consumed, and approximately 20% of the desired mass was detected. The reaction mixture was quenched at 25 °C by the addition of 20 mL of water and then extracted with 60 mL of ethyl acetate (20 mL × 3). The combined organic layers were washed with 20 mL of saturated NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (10 g silica flash column, eluent 0–80% ethyl acetate / petroleum ether gradient, 80 mL / min) to give the compound N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (0.6 g, 1.3 mmol, 33.8% yield) as an off-white solid.

[0359] 5) 2-Amino-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide

[0360] [ka]

[0361] To a solution of N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (0.6 g, 1.3 mmol, 1 equiv.) in EtOH (10 mL) was added N2H4-HO (83.6 mg, 1.3 mmol, 81.0 μL, 80% purity, 1 equiv.). The mixture was stirred at 80 °C for 12 h. LC-MS showed complete consumption of reactant 5, approximately 27% of the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g silica flash column, eluent 0–8% ethyl acetate / petroleum ether gradient, 40 mL / min) to give the compound 2-amino-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide (0.4 g, 1.3 mmol, 97.7% yield) as a yellow oil.

[0362] 6) N1-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 275)

[0363] [ka]

[0364] A mixture of 2-amino-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide (0.4 g, 1.1 mmol, 1 equiv.) in THF (10 mL) was degassed and purged with N2 three times. Then, BH3.THF (1 M, 11.4 mL, 10 equiv.) was added to the reaction at 0 °C and stirred at 0 °C for 30 min. The mixture was then stirred at 60 °C under a N2 atmosphere for 12 h. LC-MS showed that reactant 6 was completely consumed, with approximately 66% of the desired mass. The reaction mixture was quenched at 0 °C with 2 mL of MeOH, diluted with 5 mL of water, and extracted with 15 mL of ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated sodium chloride, purified with 10 mL of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (0.04% HCl condition, column: Phenomenex Luna C18 75 × 30 mm × 3 μm, mobile phase: [HO (0.04% HCl)-ACN], gradient: 15%-45% B over 8.0 min) to give compound N. 1 -(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride (0.2 g, 616.4 μmol, 54.0% yield, 99.2% purity, HCl) was obtained as a white solid. MS (ESI): m / z = 293.2 [M+H] + , Holding time: 1.600 minutes, Method: M, 1 H NMR (400MHz, DMSO-d6) δ=8.09-7.84(m, 3H), 7.67-7.61(m, 1H), 7.58-7.52(m, 1H), 7.30(t, J=7.9Hz, 1H), 6.91-6.5 9(m, 2H), 4.49(dt, J=6.0, 12.4Hz, 1H), 3.09-2.81(m, 3H), 2.73-2.63(m, 1H), 1.85-1.77(m, 1H), 0.68-0.40(m, 4H). [Example]

[0365] [Synthesis of compounds 225 and 274] The following compounds were further prepared in a similar manner as described above for compound 275 (Example 30):

[0366] [Table 14] [Example]

[0367] Synthesis of N'-[1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl]-N'-cyclopropylethane-1,2-diamine hydrochloride (Compound 247) 1) ((1-(3-chloro-2-fluorophenyl)vinyl)oxy)triethylsilane

[0368] [ka]

[0369] A solution of DIEA (1.9 g, 19.1 mmol, 2.7 mL, 1.1 equiv) in THF (10 mL) was stirred at -78 °C, and n-BuLi (2.5 M, 7.7 mL, 1.1 equiv) was added dropwise, and the solution was stirred for 30 min. To this solution was added 1-(3-chloro-2-fluorophenyl)ethanone (3 g, 17.4 mmol, 1 equiv), followed by chloro(triethyl)silane (2.9 g, 19.1 mmol, 3.3 mL, 1.1 equiv), and the reaction mixture was stirred at 20 °C for 12 h. TLC showed complete consumption of 1 and the formation of many new spots. The reaction mixture was quenched at 0 °C with 2 mL of HO, diluted with 20 mL of HO, extracted with 45 mL of ethyl acetate (15 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g silica flash column, eluent 0–0% ethyl acetate / petroleum ether gradient, 80 mL / min) to obtain the compound ((1-(3-chloro-2-fluorophenyl)vinyl)oxy)triethylsilane (2.0 g, 7.0 mmol, 40.1% yield) as a colorless oil.

[0370] 2) 1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropan-1-one

[0371] [ka]

[0372] 1-(Trifluoromethyl)-1λ3,2-benziodoxol-3-one (2.5 g, 7.8 mmol, 1.5 equiv.) and CuSCN (65.7 mg, 522.9 μmol, 0.1 equiv.) were mixed under a N atmosphere. To the mixture was added ((1-(3-chloro-2-fluorophenyl)vinyl)oxy)triethylsilane (1.5 g, 5.23 mmol, 1 equiv.) and DMF (15 mL). The mixture was stirred at 20 °C for 12 h. TLC showed complete consumption of 2 and the formation of one large new spot. The reaction mixture was diluted with 25 mL of HO and extracted with 75 mL of ethyl acetate (25 mL × 3). The combined organic layers were washed with 20 mL of brine (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g silica flash column, eluent 0–0% ethyl acetate / petroleum ether gradient, 80 mL / min) to give the compound 1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropan-1-one (0.8 g, 3.4 mmol, 64.4% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.85-7.79 (m, 1H), 7.70-7.64 (m, 1H), 7.27-7.22 (m, 1H), 3.85 (dq, J = 2.6, 9.8 Hz, 2H).

[0373] 3) N-(1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)cyclopropanamine

[0374] [ka]

[0375] 1-(3-Chloro-2-fluorophenyl)-3,3,3-trifluoropropan-1-one (300 mg, 1.3 mmol, 1 equiv.) and cyclopropanamine (106.8 mg, 1.9 mmol, 129.6 μL, 1.5 equiv.) were dissolved in dry DCM (6 mL) under a nitrogen atmosphere. AlMe3 (2 M, 935.2 μL, 1.5 equiv.) was added dropwise to the reaction mixture via syringe. The solution was stirred at 20 °C for 15 h. BH3-Me2S (10 M, 249.4 μL, 2 equiv.) was added dropwise to the reaction mixture. The mixture was stirred at 20 °C for 2 h. LC-MS showed one main peak with the desired m / z. The reaction mixture was quenched by adding 20% aqueous NaOH solution dropwise. The aqueous layer was extracted with CHCl2 (3 × 30 mL). The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=5 / 1) to obtain the compound N-(1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)cyclopropanamine (170 mg, 603.5 μmol, yield 48.4%) as a yellow oil.

[0376] 4) 2-((1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)(cyclopropyl)amino)acetamide

[0377] [ka]

[0378] To a solution of N-(1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)cyclopropanamine (170 mg, 603.5 μmol, 1 equiv.) in ACN (3 mL) was added K2CO3 (417.06 mg, 3.02 mmol, 5 equiv.) and 2-bromoacetamide (499.59 mg, 3.62 mmol, 6 equiv.). The mixture was stirred at 80 °C for 12 h. LC-MS showed complete consumption of 4 and one main peak of the desired m / z. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 15 mL of HO and extracted with 30 mL of ethyl acetate (10 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate=5 / 1) to give the compound 2-((1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)(cyclopropyl)amino)acetamide (101 mg, 298.2 μmol, yield 49.4%) as a yellow oil.

[0379] ≪5) N 1 -(1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride (Compound 247)

[0380] [ka]

[0381] To a solution of 2-[[1-(3-chloro-2-fluoro-phenyl)-3,3,3-trifluoro-propyl]-cyclopropyl-amino]acetamide (101 mg, 298.2 μmol, 1 equiv.) in THF (10 mL) was added BH3.THF (1 M, 3.0 mL, 10 equiv.). The mixture was stirred at 70 °C for 12 h. LC-MS showed complete consumption of 5 and one peak of the desired m / z was detected. The residue was diluted with 5 mL of NH4Cl, extracted with 15 mL of ethyl acetate (5 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HCl conditions, column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm, mobile phase: [water (HCl)-ACN], B%: 25%-55%, 8 min) to obtain the compound N'-[1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl]-N'-cyclopropylethane-1,2-diamine hydrochloride (11 mg, 30.2 μmol, 10.1% yield, 99% purity, HCl) as a colorless oil. MS (ESI): m / z = 325.3 [M+H] + , retention time: 1.790 minutes, method: M, 1 H NMR (400MHz, DMSO-d6) δ=8.08-7.89(m, 3H), 7.63-7.54(m, 2H), 7.28(br t, J=7.8Hz, 1H), 4.60-4.52(m, 1H), 3.22-2.94(m, 4H), 2.89(br s, 2H), 1.68-1.57(m, 1H), 0.65-0.40(m, 4H). [Example]

[0382] [N 1 -((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)-N 1 Synthesis of -cyclopropylethane-1,2-diamine hydrochloride (compound 267) 1) (3-chloro-2-fluorophenyl)(cyclobutyl)methanol

[0383] [ka]

[0384] A solution of 1-chloro-2-fluorobenzene (1 g, 7.7 mmol, 1 equiv) in THF (10 mL) was degassed and purged with N2 three times. Then, LDA (2 M, 7.7 mL, 2 equiv) was added to the reaction mixture at -78 °C. The mixture was stirred at -78 °C for 15 min. Then, cyclobutanecarbaldehyde (708.8 mg, 8.4 mmol, 1.1 equiv) was added to the reaction mixture, and the reaction mixture was stirred at 25 °C for 12 h. TLC showed complete consumption of reactant 1 and a new spot was detected. The reaction mixture was quenched at 0 °C by the addition of 10 mL of saturated NH4Cl and extracted with 30 mL of ethyl acetate (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (10 g silica flash column, eluent: 0–5% ethyl acetate / petroleum ether gradient, 80 mL / min) to obtain the compound (3-chloro-2-fluorophenyl)(cyclobutyl)methanol (1.0 g, 4.8 mmol, 63.3% yield) as a yellow oil. H NMR (400 MHz, chloroform-d) δ = 7.35–7.28 (m, 2H), 7.11–7.01 (m, 1H), 4.96 (dd, J = 2.7, 7.4 Hz, 1H), 2.75–2.63 (m, 1H), 2.07–2.01 (m, 2H), 1.89–1.81 (m, 4H).

[0385] 2) (3-Chloro-2-fluorophenyl)(cyclobutyl)methanone

[0386] [ka]

[0387] To a solution of (3-chloro-2-fluorophenyl)(cyclobutyl)methanol (1.0 g, 4.8 mmol, 1 equiv.) in DCM (10 mL) was added DMP (2.5 g, 5.8 mmol, 1.8 mL, 1.2 equiv.). The mixture was stirred at 25 °C for 12 h. TLC showed that 2 was completely consumed and a new spot had formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (10 g silica flash column, eluent 0–8% ethyl acetate / petroleum ether gradient, 80 mL / min) to give the compound (3-chloro-2-fluorophenyl)(cyclobutyl)methanone (0.5 g, 2.3 mmol, 46.7% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.74 (ddd, J = 1.8, 6.3, 7.9 Hz, 1H), 7.59-7.53 (m, 1H), 7.18 (t, J = 7.9 Hz, 1H), 3.90 (dquin, J = 2.8, 8.3 Hz, 1H), 2.40-2.27 (m, 4H), 2.12-1.99 (m, 1H), 1.95-1.84 (m, 1H).

[0388] 3) N-((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)cyclopropanamine

[0389] [ka]

[0390] To a solution of (3-chloro-2-fluorophenyl)(cyclobutyl)methanone (0.5 g, 2.3 mmol, 1 equiv.) in MeOH (5 mL), cyclopropanamine (193.9 mg, 3.4 mmol, 235.3 μL, 1.5 equiv.) and Ti(i-PrO) (1.9 g, 6.8 mmol, 2.0 mL, 3 equiv.) were added. The mixture was stirred at 60 °C for 12 h. NaBHCN (569.0 mg, 9.0 mmol, 4 equiv.) was then added. The resulting mixture was stirred at 60 °C for 3 h. LC-MS indicated that 3 was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g silica flash column, eluent 0–5% ethyl acetate / petroleum ether gradient, 40 mL / min) to obtain the compound N-((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)cyclopropanamine (0.3 g, 1.2 mmol, 52.2% yield) as a yellow oil.

[0391] 4) N-((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)cyclopropanamine

[0392] [ka]

[0393] To a solution of N-((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)cyclopropanamine (0.1 g, 512.3 μmol, 1 equiv.) in MeOH (1 mL) was added tert-butyl N-(2-oxoethyl)carbamate (489.3 mg, 3.1 mmol, 6 equiv.). The mixture was stirred at 60 °C for 12 h, and then NaBHCN (128.8 mg, 2.1 mmol, 4 equiv.) was added to the reaction. The mixture was stirred at 60 °C for 3 h. LC-MS showed that 4 was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product, tert-butyl (2-(((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)(cyclopropyl)amino)ethyl)carbamate (0.2 g, 378.6 μmol, 73.8% yield, 37.5% purity), was obtained as a yellow oil.

[0394] ≪5) N 1 -((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride (Compound 267)

[0395] [ka]

[0396] A solution of tert-butyl (2-(((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)(cyclopropyl)amino)ethyl)carbamate (0.2 g, 377.9 μmol, 1 equiv.) in HCl / ethyl acetate (3 mL) was stirred at 25° C. for 1 h. LC-MS indicated that approximately 3% of reactant 5 remained. LC-MS showed several new peaks, with approximately 40% of the desired compound detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (0.04% HCl condition, column: Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: [HO(0.04% Cl)-ACN], gradient: 15%-45% B, 8.0 min) to give compound N. 1 -((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)-N1 -Cyclopropylethane-1,2-diamine hydrochloride (0.08 g, 271.7 μmol, 71.9% yield, 99.6% purity, HCl) was obtained as a yellow oil. MS (ESI): m / z = 297.1 [M+H] + , retention time: 2.021 minutes, method: M, 1 H NMR (400MHz, DMSO-d6) δ=8.07-7.75(m, 3H), 7.52(t, J=7.4Hz, 1H), 7.43(br s, 1H), 7.27-7.20(m, 1H), 4.35-4.23(m, 1H), 3.20-2.91(m, 4H), 2.81-2.6 4(m, 1H), 2.28-2.16(m, 1H), 2.03-1.66(m, 5H), 1.44-1.30(m, 1H), 0.60(br d, J=5.4Hz, 4H). [Example]

[0397] [Synthesis of compounds 268 and 273] The following compounds were further prepared in a similar manner as described above for compound 267 (Example 32):

[0398] [Table 15] [Example]

[0399] [Synthesis of 3-(1-((2-aminoethyl)(cyclopropyl)amino)propyl)-2-fluorobenzonitrile hydrochloride (Compound 257)] 1) 2-Fluoro-3-(1-hydroxypropyl)benzonitrile

[0400] [ka]

[0401] A dry round-bottom flask flushed with N2 was charged with the desired 2-fluorobenzonitrile (1.5 g, 12.4 mmol, 1.3 mL, 1 equiv) and THF (20 mL). Lithium chloride (1 M, 16.1 mL, 1.3 equiv) was added dropwise, and the reaction was maintained at 20 °C for 1 h. The resulting organomagnesium species were trapped with propanal (791.3 mg, 13.6 mmol, 991.6 μL, 1.1 equiv), and the mixture was allowed to react at 20 °C for 12 h. TLC indicated complete consumption of reactant 1 and the formation of one large new spot. The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g silica flash column, eluent 0–5% ethyl acetate / petroleum ether gradient, 60 mL / min) to obtain the compound 2-fluoro-3-(1-hydroxypropyl)benzonitrile (876.9 mg, 4.9 mmol, 39.5% yield) as a yellow oil.

[0402] ≪2) 2-Fluoro-3-propionylbenzonitrile≫

[0403] [ka]

[0404] To a solution of 2-fluoro-3-(1-hydroxypropyl)benzonitrile (800 mg, 4.5 mmol, 1 equiv.) in DCM (35 mL) was added DMP (2.3 g, 5.36 mmol, 1.2 equiv.). The mixture was stirred at 20 °C for 12 h. TLC showed that 2 was completely consumed and one large new spot had formed. The reaction mixture was diluted with 6 mL of HO, extracted with 15 mL of DCM (5 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g silica flash column, eluent: 0–3% ethyl acetate / petroleum ether gradient, 60 mL / min) to give compound 2-fluoro-3-propionylbenzonitrile (468 mg, 2.6 mmol, 59.2% yield) as a white solid.

[0405] 3) 3-(1-(cyclopropylamino)propyl)-2-fluorobenzonitrile

[0406] [ka]

[0407] To a solution of 2-fluoro-3-propanoylbenzonitrile (200 mg, 1.1 mmol, 1 equiv.) in MeOH (3 mL) was added cyclopropanamine (96.7 mg, 1.7 mmol, 117.3 μL, 1.5 equiv.) and Ti(i-PrO) (962.5 mg, 3.4 mmol, 999.5 μL, 3 equiv.). The mixture was stirred at 60 °C for 12 h. NaBHCN (283.6 mg, 4.5 mmol, 4 equiv.) was added to the reaction mixture at 20 °C and stirred at 60 °C for 2 h. LC-MS showed one main peak at the desired m / z. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 15 mL of H2O, extracted with 30 mL of ethyl acetate (10 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 3-(1-(cyclopropylamino)propyl)-2-fluorobenzonitrile (263 mg, crude) as a yellow oil.

[0408] 4) tert-Butyl (2-((1-(3-cyano-2-fluorophenyl)propyl)(cyclopropyl)amino)ethyl)carbamate

[0409] [ka]

[0410] To a solution of 3-[1-(cyclopropylamino)propyl]-2-fluorobenzonitrile (150 mg, 687.2 μmol, 1 equiv.) in MeOH (3 mL), tert-butyl N-(2-oxoethyl)carbamate (656.4 mg, 4.1 mmol, 6 equiv.) and AcOH were added to adjust the pH to 5, and the mixture was stirred at 60 °C for 12 h. NaBH CN (172.8 mg, 2.8 mmol, 4 equiv.) was then added at 20 °C. The mixture was stirred at 60 °C for 2 h. LC-MS showed that 4 was completely consumed and one main peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 mL of HO, extracted with 30 mL of ethyl acetate (10 mL × 3), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate=5 / 1) to obtain the compound tert-butyl (2-((1-(3-cyano-2-fluorophenyl)propyl)(cyclopropyl)amino)ethyl)carbamate (220 mg, 608.7 μmol, yield 88.6%) as a yellow oil.

[0411] 5) 3-(1-((2-aminoethyl)(cyclopropyl)amino)propyl)-2-fluorobenzonitrile hydrochloride (Compound 257)

[0412] [ka]

[0413] A solution of tert-butyl N-[2-[1-(3-cyano-2-fluoro-phenyl)propyl-cyclopropyl-amino]ethyl]carbamate (220 mg, 608.7 μmol, 1 equiv.) in HCl / ethyl acetate (5 mL) was stirred at 20 °C for 3 h. LC-MS showed complete consumption of 5, with one main peak of the desired m / z. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl conditions, column: Phenomenex Luna C18 75 x 30 mm x 3 μm, mobile phase: [HO (0.04% HCl)-ACN], gradient: 10% to 40% B over 8.0 min) to give compound 3-(1-((2-aminoethyl)(cyclopropyl)amino)propyl)-2-fluorobenzonitrile hydrochloride (91.2 mg, 306.3 μmol, 50.3% yield, 100% purity, HCl) as a yellow oil. MS (ESI): m / z = 262.4 [M+H] + , retention time: 1.496 minutes, method: M, special 1 H NMR (400MHz, DMSO-d6) δ=8.36(br s, 3H), 8.09(br t, J=7.1Hz, 1H), 7.94(ddd, J=1.5, 6.3, 7.7Hz, 1H), 7.52-7.45(m, 1H), 4.56(br dd. [Example]

[0414] [Synthesis of Compound 259] The following compounds were further prepared in a similar manner as described above for compound 257 (Example 34):

[0415] [Table 16] [Example]

[0416] [Synthesis of 3-(((2-aminoethyl)(cyclopropyl)amino)methyl)-2-fluorobenzonitrile hydrochloride (Compound 219)] 1) 3-((cyclopropylamino)methyl)-2-fluorobenzonitrile

[0417] [ka]

[0418] To a solution of 2-fluoro-3-formylbenzonitrile (500 mg, 3.4 mmol, 1 equiv) in MeOH (3 mL) was added cyclopropanamine (287.2 mg, 5.0 mmol, 348.5 μL, 1.5 equiv). The mixture was stirred at 60 °C for 12 h. NaBH3CN (842.8 mg, 13.4 mmol, 4 equiv) was added to the reaction mixture at 20 °C and stirred at 60 °C for 2 h. LC-MS showed complete consumption of reactant 2, with one main peak of the desired m / z. The reaction mixture was concentrated under reduced pressure. The residue was diluted with 15 mL of H2O, extracted with 45 mL of ethyl acetate (15 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=10 / 1) to give the compound 3-((cyclopropylamino)methyl)-2-fluorobenzonitrile (363.0 mg, 1.9 mmol, yield 56.9%) as a yellow oil.

[0419] 2) tert-Butyl (2-((3-cyano-2-fluorobenzyl)(cyclopropyl)amino)ethyl)carbamate

[0420] [ka]

[0421] To a solution of 3-((cyclopropylamino)methyl)-2-fluorobenzonitrile (200.0 mg, 1.1 mmol, 1 equiv.) in MeOH (3 mL) was added tert-butyl N-(2-oxoethyl)carbamate (1.0 g, 6.3 mmol, 6 equiv.). The mixture was stirred at 60 °C for 12 h. NaBH CN (264.3 mg, 4.2 mmol, 4 equiv.) was added to the reaction at 20 °C and stirred at 60 °C for 2 h. LC-MS showed complete consumption of reactant 3, with one main peak of the desired m / z. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 15 mL of HO and extracted with 45 mL of ethyl acetate (15 mL × 3). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate=3 / 1) to obtain the compound tert-butyl (2-((3-cyano-2-fluorobenzyl)(cyclopropyl)amino)ethyl)carbamate (262.6 mg, 787.6 μmol, yield 74.9%) as a yellow oil.

[0422] 3) 3-(((2-aminoethyl)(cyclopropyl)amino)methyl)-2-fluorobenzonitrile hydrochloride (Compound 219)

[0423] [ka]

[0424] A solution of tert-butyl (2-((3-cyano-2-fluorobenzyl)(cyclopropyl)amino)ethyl)carbamate (262.6 mg, 787.6 μmol, 1 equiv.) in HCl / ethyl acetate (3 mL) was stirred at 20 °C for 1 h. LC-MS showed complete consumption of reactant 4. LC-MS showed several new peaks, with 18% of the desired compound detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (HCl condition, column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: [water (HCl)-ACN], B%: 1%-25%, 8 min) to give compound 3-(((2-aminoethyl)(cyclopropyl)amino)methyl)-2-fluorobenzonitrile hydrochloride (25.1 mg, 107.6 μmol, yield 13.7%, purity 100%, HCl) as a dark brown oil. MS (ESI): m / z = 234.3 [M+H] + , retention time: 1.253 minutes, method: M, 1 H NMR (400MHz, DMSO-d6) δ=8.42(br s, 3H), 8.13-7.92(m, 2H), 7.42(t, J=7.8Hz, 1H), 4.44(br s, 2H), 3.46-3.24(m, 4H), 2.71(br s, 1H), 0.99-0.59(m, 4H). [Example]

[0425] [Synthesis of compounds 186, 187, 219B, 227B, and 246] The following compounds were further prepared in a similar manner as described above for compound 219 (Example 39):

[0426] [Table 17-1]

[0427] [Table 17-2] [Example]

[0428] Synthesis of 3-(1-((2-aminoethyl)(cyclopropyl)amino)-2-methylpropyl)-2-fluorobenzonitrile TFA salt (Compound 264) 1) 2-Fluoro-3-(1-hydroxy-2-methylpropyl)benzonitrile

[0429] [ka]

[0430] A dry round-bottom flask flushed with N2 was charged with the desired 2-fluorobenzonitrile (2 g, 16.51 mmol, 1.76 mL, 1 equiv) and THF (25 mL). Lithium chloride (1 M, 21.47 mL, 1.3 equiv) was added dropwise, and the reaction was maintained at 20 °C for 1 h. The resulting organomagnesium species were trapped with 2-methylpropanal (1.31 g, 18.17 mmol, 1.66 mL, 1.1 equiv), and the mixture was allowed to react at 20 °C for 12 h. TLC indicated complete consumption of reactant 1 and the formation of one large new spot. The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica flash column, eluent 0-6% ethyl acetate / petroleum ether gradient, 60 mL / min) to obtain the compound 2-fluoro-3-(1-hydroxy-2-methylpropyl)benzonitrile (1.2 g, 6.21 mmol, yield 37.61%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.77-7.69 (m, 1H), 7.55-7.48 (m, 1H), 7.26-7.22 (m, 1H), 4.81 (d, J = 6.3 Hz, 1H), 2.00-1.92 (m, 1H), 0.95 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H).

[0431] ≪2) 2-Fluoro-3-isobutyrylbenzonitrile≫

[0432] [ka]

[0433] To a solution of 2-fluoro-3-(1-hydroxy-2-methylpropyl)benzonitrile (1.2 g, 6.21 mmol, 1 equiv.) in DCM (30 mL) was added DMP (3.16 g, 7.45 mmol, 2.31 mL, 1.2 equiv.). The mixture was stirred at 20 °C for 12 h. TLC showed that reactant 2 was completely consumed and one large new spot had formed. The reaction mixture was diluted with 10 mL of HO, extracted with 30 mL of DCM (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (silica flash column, eluent: 0–5% ethyl acetate / petroleum ether gradient, 60 mL / min) to give compound 2-fluoro-3-isobutyrylbenzonitrile (840 mg, 4.39 mmol, 70.74% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 8.07-8.00 (m, 1H), 7.80 (ddd, J = 1.8, 5.9, 7.6 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 3.42-3.32 (m, 1H), 1.22 (dd, J = 0.8, 6.9 Hz, 6H).

[0434] 3) 3-(1-(cyclopropylamino)-2-methylpropyl)-2-fluorobenzonitrile

[0435] [ka]

[0436] To a solution of 2-fluoro-3-(2-methylpropanoyl)benzonitrile (840 mg, 4.39 mmol, 1 equiv.) in MeOH (8 mL), cyclopropanamine (376.25 mg, 6.59 mmol, 456.61 μL, 1.5 equiv.) and Ti(i-PrO) (3.75 g, 13.18 mmol, 3.89 mL, 3 equiv.) were added. The mixture was stirred at 60 °C for 12 h. NaBHCN (1.10 g, 17.57 mmol, 4 equiv.) was added to the reaction mixture at 20 °C and stirred at 60 °C for 2 h. LC-MS showed one main peak of the desired m / z. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 mL of HO, extracted with 30 mL of ethyl acetate (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (silica flash column, eluent 0-7% ethyl acetate / petroleum ether gradient, 80 mL / min) to obtain the compound 3-(1-(cyclopropylamino)-2-methylpropyl)-2-fluorobenzonitrile (577 mg, 2.48 mmol, yield 56.54%) as a colorless oil.

[0437] 2-Bromo-N-(1-(3-cyano-2-fluorophenyl)-2-methylpropyl)-N-cyclopropylacetamide

[0438] [ka]

[0439] To a stirred, cooled solution of KCO (686.60 mg, 4.97 mmol, 2 equiv.) in HO (5 mL) was added a solution of 3-[1-(cyclopropylamino)-2-methylpropyl]-2-fluorobenzonitrile (577 mg, 2.48 mmol, 1 equiv.) in DCM (5 mL), followed by 2-bromoacetyl bromide (601.63 mg, 2.98 mmol, 259.66 μL, 1.2 equiv.). The reaction mixture was stirred at 20 °C for 1 h. LC-MS showed complete consumption of reactant 4, with one main peak of the desired m / z. The reaction mixture was diluted with 10 mL of HO, extracted with 30 mL of DCM (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product 2-bromo-N-[1-(3-cyano-2-fluorophenyl)-2-methylpropyl]-N-cyclopropylacetamide (820 mg, crude yellow oil).

[0440] 5) N-(1-(3-cyano-2-fluorophenyl)-2-methylpropyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide

[0441] [ka]

[0442] To a solution of 2-bromo-N-[1-(3-cyano-2-fluoro-phenyl)-2-methyl-propyl]-N-cyclopropyl-acetamide (820 mg, 2.32 mmol, 1 equiv.) in DMF (20 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (515.98 mg, 2.79 mmol, 1.2 equiv.). The mixture was stirred at 20 °C for 12 h. LC-MS showed complete consumption of reactant 5, with one main peak of the desired m / z. The reaction mixture was diluted with 15 mL of HO and extracted with 45 mL of ethyl acetate (15 mL × 3). The combined organic layers were washed with 20 mL of aqueous NaCl (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (silica flash column, eluent 0–20% ethyl acetate / petroleum ether gradient, 80 mL / min) to give the crude product N-(1-(3-cyano-2-fluorophenyl)-2-methylpropyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (1.08 g, crude) as a yellow oil.

[0443] 6) 2-Amino-N-(1-(3-cyano-2-fluorophenyl)-2-methylpropyl)-N-cyclopropylacetamide

[0444] [ka]

[0445] To a solution of N-[1-(3-cyano-2-fluoro-phenyl)-2-methyl-propyl]-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (200 mg, 476.82 μmol, 1 equiv.) in EtOH (20 mL) was added N2H4.HO (59.67 mg, 953.64 μmol, 57.82 μL, 80% purity, 2 equiv.). The mixture was stirred at 80 °C for 3 h. LC-MS showed complete consumption of reactant 6, with one main peak of the desired m / z. The mixture was cooled to 4 °C, and the phthalyl hydrazide was removed by filtration. The ethanol was removed under vacuum. The solution was extracted with 30 mL of ethyl acetate (10 mL × 3). The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product, 2-amino-N-[1-(3-cyano-2-fluorophenyl)-2-methylpropyl]-N-cyclopropylacetamide (146 mg crude) was a yellow oil.

[0446] 7) 3-(1-((2-aminoethyl)(cyclopropyl)amino)-2-methylpropyl)-2-fluorobenzonitrile TFA salt

[0447] [ka]

[0448] A dry, N-flushed round-bottom flask was charged with the desired 2-amino-N-[1-(3-cyano-2-fluoro-phenyl)-2-methyl-propyl]-N-cyclopropyl-acetamide (96 mg, 331.78 μmol, 1 equiv.) and THF (5 mL). BH3-Me2S (10 M, 66.36 μL, 2 equiv.) was added to the reaction mixture at 0 °C and stirred at 20 °C for 4 h. LC-MS showed complete consumption of 7, with one main peak of the desired m / z. The reaction mixture was quenched with 2 mL of MeOH at 0 °C and stirred at 60 °C for 2 h. The mixture was then diluted with 10 mL of HO, extracted with 30 mL of ethyl acetate (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 75*30 mm*3 μm, mobile phase: [HO(0.1% TFA)-ACN], gradient: 15%-45% B over 8.0 min) to give compound 264 (3-(1-((2-aminoethyl)(cyclopropyl)amino)-2-methylpropyl)-2-fluorobenzonitrile TFA salt) (10.85 mg, 26.75 μmol, yield 8.06%, purity 95.99%, TFA) as a yellow oil. MS (ESI): m / z = 276.3 [M+H] + , Retention time: 1.702 minutes, Method: B. 1 H NMR (400MHz, DMSO-d6) δ=7.90(dt, J=1.5, 6.9Hz, 1H), 7.81-7.61(m, 4H), 7.46(t, J=7.8Hz, 1H), 3.71(d, J=11.1Hz, 1H) , 3.06-2.83(m, 3H), 2.40-2.23(m, 2H), 1.39-1.29(m, 1H), 1.01(d, J=6.4Hz, 3H), 0.67-0.54(m, 5H), 0.53-0.34(m, 2H). [Example]

[0449] [N 1 -(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N 1 Synthesis of -cyclopropylethane-1,2-diamine hydrochloride (compound 263) 1) 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethan-1-ol

[0450] [ka]

[0451] To a solution of 3-chloro-2-fluorobenzaldehyde (4 g, 25.2 mmol, 1 equiv.) in DMF (20 mL) was added TMSCF3 (4.7 g, 32.8 mmol, 1.3 equiv.) and stirred at 0 °C for 15 min. After that, TBAF (1 M, 252.3 μL, 0.01 equiv.) was added to the reaction mixture. The mixture was stirred at 25 °C for 12 h. Next, HCl (2 M, 25.2 mL, 2 equiv.) was added to the mixture, and the mixture was stirred at 25 °C for 3 h. TLC showed that reactant 1 was completely consumed and many new spots had formed. The reaction mixture was partitioned between 20 mL of ethyl acetate and the reaction mixture. The organic phase was separated and washed with saturated sodium chloride. It was diluted with 20 mL of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g silica flash column, eluent 0–5% ethyl acetate / petroleum ether gradient, 80 mL / min) to obtain the compound 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethan-1-ol (5.1 g, 22.2 mmol, 88.1% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.54 (t, J = 6.9 Hz, 1H), 7.50-7.44 (m, 1H), 7.22-7.16 (m, 1H), 5.49-5.41 (m, 1H).

[0452] 2) 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethan-1-one

[0453] [ka]

[0454] To a solution of 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethan-1-ol (2.5 g, 10.9 mmol, 1 equiv.) in DCM (10 mL) was added DMP (5.6 g, 13.1 mmol, 4.1 mL, 1.2 equiv.). The mixture was stirred at 25 °C for 12 h. TLC showed that reactant 3 was completely consumed and two new spots had formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (10 g silica flash column, eluent: 0-10% ethyl acetate / petroleum ether gradient, 80 mL / min) to give the compound 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethan-1-one (1.3 g, 5.9 mmol, 54.1% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.76-7.62 (m, 2H), 7.27-7.16 (m, 1H).

[0455] 3)(E)-1-(3-chloro-2-fluorophenyl)-N-cyclopropyl-2,2,2-trifluoroethan-1-imine

[0456] [ka]

[0457] Dissolve 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethan-1-one (1.3 g, 5.9 mmol, 1 equiv.) and cyclopropanamine (506.5 mg, 8.9 mmol, 614.7 μL, 1.5 equiv.) in DCM (5 mL) under N2. Add AlMe3 (2 M, 4.4 mL, 1.5 equiv.) dropwise to the reaction mixture. Stir the solution at 20 °C for 5 h. LC-MS showed that approximately 23% of the desired compound was detected. Quench the reaction mixture by adding 20% aqueous NaOH solution dropwise. Extract the aqueous layer with CHCl2 (3 × 30 mL). Dry the organic layer with NaSO4. Remove the solvent under reduced pressure. The residue was purified by flash silica gel chromatography (10 g silica flash column, eluent 0–10% ethyl acetate / petroleum ether gradient, 80 mL / min) to obtain compound (E)-1-(3-chloro-2-fluorophenyl)-N-cyclopropyl-2,2,2-trifluoroethan-1-imine (0.58 g, 1.3 mmol, 22.5% yield, 61.4% purity) as a yellow oil.

[0458] 4) N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)cyclopropanamine

[0459] [ka]

[0460] A mixture of (E)-1-(3-chloro-2-fluorophenyl)-N-cyclopropyl-2,2,2-trifluoroethan-1-imine (0.58 g, 2.2 mmol, 1 equiv.) in THF (6 mL) was degassed and purged with N2 three times. LAH (2.5 M, 1.7 mL, 2.0 equiv.) was then added to the reaction at 0 °C, and the mixture was stirred under N2 atmosphere at 0 °C for 2 h. LC-MS showed that reactant 5 was completely consumed and the desired mass was detected. The reaction mixture was quenched at 0 °C by the addition of 10 mL of saturated MgSO4, followed by extraction with 30 mL of ethyl acetate (10 mL × 3). The combined organic layers were washed with 30 mL of water, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (10 g silica flash column, eluent 0–10% ethyl acetate / petroleum ether gradient, 80 mL / min) to obtain the compound N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)cyclopropanamine (0.5 g, 805.5 μmol, 37.1% yield, 41.5% purity) as a yellow oil.

[0461] 5) 2-Bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide

[0462] [ka]

[0463] To a solution of N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)cyclopropanamine (0.5 g, 1.9 mmol, 1 equiv.) in DCM (6 mL) was added a solution of KCO (537.0 mg, 3.9 mmol, 2 equiv.) in HO (6 mL), and 2-bromoacetyl bromide (470.6 mg, 2.3 mmol, 203.1 μL, 1.2 equiv.) was added to the reaction mixture at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed that reactant 6 was completely consumed, with approximately 48% of the desired mass being detected. The reaction mixture was extracted with 15 mL of dichloromethane (5 mL × 3). The combined organic layers were washed with saturated sodium chloride. Added 10 mL of NaCl, dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product 2-bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide (0.56 g, 682.6 μmol, 35.1% yield, 47.5% purity) as a yellow oil.

[0464] 6) 2-Azido-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide

[0465] [ka]

[0466] To a solution of 2-bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide (0.5 g, 1.2 mmol, 1 equiv.) in DMSO (1 mL) was added NaN (82.8 mg, 1.3 mmol, 1.1 equiv.). The mixture was stirred at 20 °C for 12 h. LC-MS showed that reactant 7 was completely consumed, with approximately 16% of the desired mass being detected. The reaction mixture was quenched at 0 °C by the addition of 10 mL of water and then extracted with 15 mL of ethyl acetate (5 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (0.1% NH₃·H₂O, column: Waters Xbridge BEH C18 100*30mm*10μm, mobile phase: [H₂O (10mM NH₄HCO₃)-ACN], gradient: 50%-80% B over 8.0 min) to give the compound 2-azido-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide (90.4 mg, 245.1 μmol, yield 21.2%, purity 95.1%) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=7.75-7.69(m, 1H), 7.66-7.60(m, 1H), 7.38-7.32(m, 1 H), 6.46-6.38(m, 1H), 4.52-4.41(m, 2H), 2.48-2.41(m, 1H), 0.95-0.60(m, 4H).

[0467] 7) 2-Amino-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide

[0468] [ka]

[0469] To a solution of 2-azido-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide (0.08 g, 228.1 μmol, 1 equiv.) in THF (1.5 mL) and water (0.5 mL) was added PPh3 (89.8 mg, 342.2 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed that reactant 8 was completely consumed, with approximately 49% of the desired mass being detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=10 / 1) to obtain the compound 2-amino-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide (0.02 g, 61.6 μmol, 27.0% yield) as a colorless oil.

[0470] <8)N 1 -(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride≫

[0471] [ka]

[0472] A mixture of 2-amino-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide (0.02 g, 61.6 μmol, 1 equiv.) in THF (5 mL) was degassed and purged with N2 three times. Then, BH3.THF (1 M, 616.0 μL, 10 equiv.) was added to the reaction at 0 °C and stirred at 0 °C for 30 min. The mixture was then stirred at 60 °C under a N2 atmosphere for 12 h. LC-MS indicated that reactant 9 was completely consumed, with approximately 41% of the desired mass detected. The reaction mixture was quenched at 0 °C with 2 mL of MeOH, diluted with 5 mL of water, and extracted with 15 mL of ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated sodium chloride, purified with 10 mL of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (0.04% HCl condition, column: Phenomenex luna C18 8*30 mm*3 μm, mobile phase: [HO (0.04% HCl)-ACN], gradient: 20%-50% B over 8.0 min) to give compound 263 (N 1 -(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N 1 -cyclopropylethane-1,2-diamine hydrochloride) (0.02 g, 47.3 μmol, 76.7% yield, 97.93% purity, HCl) was obtained as a white solid. MS (ESI): m / z = 311.2 [M+H] + , retention time: 1.706 minutes, method: M, 1 H NMR (400MHz, DMSO-d6)δ=7.80-7.64(m, 4H), 7.53-7.46(m, 1H), 7.39-7.33(m, 1H), 5.18-5.07(m, 1H), 3.06-2.67(m, 4H), 2.00- 1.92(m, 1H), 0.68-0.44(m, 4H). [Example]

[0473] [Synthesis of N'-[1-(3-chloro-2-fluorophenyl)but-3-enyl]-N'-cyclopropylethane-1,2-diamine TFA salt (Compound 271A)] 1) (Z)-1-(3-chloro-2-fluorophenyl)-N-cyclopropylmethanimine

[0474] [ka]

[0475] To a solution of 3-chloro-2-fluorobenzaldehyde (5 g, 31.5 mmol, 1 equiv.) in MeOH (70 mL), cyclopropanamine (2.70 g, 47.30 mmol, 3.28 mL, 1.5 equiv.) and AcOH (5.68 g, 94.60 mmol, 5.42 mL, 3 equiv.) were added. The mixture was stirred at 60 °C for 12 h. LCMS showed that the desired compound was formed. The reaction mixture was concentrated under reduced pressure to give compound (Z)-1-(3-chloro-2-fluoro-phenyl)-N-cyclopropyl-methanimine (6 g, crude) as a yellow oil.

[0476] 2) N-(1-(3-chloro-2-fluorophenyl)but-3-en-1-yl)cyclopropanamine

[0477] [ka]

[0478] To a mixture of (Z)-1-(3-chloro-2-fluoro-phenyl)-N-cyclopropyl-methanimine (6 g, 30.36 mmol, 1 equiv.) in THF (150 mL) was added allylmagnesium bromide (1 M, 45.54 mL, 1.5 equiv.). After the mixture was degassed and purged with N2 three times, the mixture was stirred under N2 atmosphere at -78 °C for 3 h. LCMS showed that the desired compound was formed. The reaction mixture was quenched by the addition of NH4Cl (100 ml), diluted with H2O (100 mL), and extracted with 150 mL (50 mL*3) of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (40 g silica flash column, eluent 0–3% ethyl acetate / petroleum ether gradient, 80 mL / min) to obtain the compound N-[1-(3-chloro-2-fluorophenyl)but-3-enyl]cyclopropanamine (2.5 g, 10.43 mmol, 34.35% yield) as a yellow oil.

[0479] 3) tert-Butyl (2-((1-(3-chloro-2-fluorophenyl)but-3-en-1-yl)(cyclopropyl)amino)ethyl)carbamate

[0480] [ka]

[0481] To a solution of N-[1-(3-chloro-2-fluoro-phenyl)but-3-enyl]cyclopropanamine (1 g, 4.17 mmol, 1 equiv.) in MeOH (20 mL) was added tert-butyl N-(2-oxoethyl)carbamate (3.98 g, 25.03 mmol, 6 equiv.). The mixture was stirred at 60 °C for 12 h. Then, NaBH CN (1.05 g, 16.6 mmol, 4 equiv.) was added at 25 °C. The mixture was stirred at 60 °C for 2 h. LCMS showed that the desired compound was formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 mL of H O and extracted with 15 mL of EtOAc (5 mL × 3). The combined organic layers were dried over [Na SO ], filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g, silica flash column, eluent 0–15% ethyl acetate / petroleum ether gradient, 120 mL / min) to obtain the compound tert-butyl N-[2-[1-(3-chloro-2-fluoro-phenyl)but-3-enyl-cyclopropyl-amino]ethyl]carbamate (314 mg, 820.06 μmol, 19.66% yield) as a yellow solid.

[0482] <4) N1-(1-(3-chloro-2-fluorophenyl)but-3-en-1-yl)-N1-cyclopropylethane-1,2-diamine TFA salt>

[0483] [ka]

[0484] A solution of tert-butyl N-[2-[1-(3-chloro-2-fluoro-phenyl)but-3-enyl-cyclopropyl-amino]ethyl]carbamate (20 mg, 52.23 μmol, 1 equiv.) in TFA (1 mL) and DCM (1 mL) was stirred at 25° C. for 0.5 h. LCMS showed the formation of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 100*40mm*3μm, mobile phase: [HO (0.1% TFA)-ACN], gradient: 15%-45% B, 8.0 min) to obtain compound N'-[1-(3-chloro-2-fluorophenyl)but-3-enyl]-N'-cyclopropylethane-1,2-diamine TFA salt (21.4 mg, 53.43 μmol, yield 51.15%, purity 99.08%, TFA) as a yellow oil. MS (ESI): m / z = 282.13 [M+H] + , retention time: 1.773 minutes, method: M, 1 H NMR (400MHz, DMSO-d6)δ=7.60(br s, 3H), 7.55-7.49(m, 1H), 7.41(t, J=6.5Hz, 1H), 7.27-7.20(m, 1H), 5.64(tdd, J=6.8, 10.2, 17.0Hz, 1H), 5.1 0-4.88(m, 2H), 4.26(dd, J=6.7, 9.1Hz, 1H), 2.98-2.82(m, 3H), 2.77-2.59(m, 2H), 2.49-2.42(m, 1H), 1.66(br d, J=2.9Hz, 1H), 0.60-0.27(m, 4H). [Example]

[0485] [Synthesis of N'-[1-(4-chloro-2-thienyl)ethyl]-N'-cyclopropylethane-1,2-diamine hydrochloride (Compound 279)] 1) N-(1-(4-chlorothiophen-2-yl)ethyl)cyclopropanamine

[0486] [ka]

[0487] To a solution of cyclopropanamine (266.6 mg, 4.7 mmol, 323.5 μL, 1.5 equiv.), 1-(4-chloro-2-thienyl)ethanone (500 mg, 3.1 mmol, 1 equiv.) in MeOH (20 mL) was added Ti(i-PrO) (2.6 g, 9.3 mmol, 2.8 mL, 3 equiv.) and AcOH (373.9 mg, 6.2 mmol, 356.4 μL, 2 equiv.). The mixture was stirred at 60 °C for 12 h. NaBHCN (782.5 mg, 12.5 mmol, 4 equiv.) was added. The mixture was stirred at 60 °C for 2 h. LC-MS showed that the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 15 mL of HO and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (15 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound N-(1-(4-chlorothiophen-2-yl)ethyl)cyclopropanamine (300 mg, crude) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.06 (d, J = 1.3 Hz, 1H), 6.96 (s, 1H), 4.25 (q, J = 6.7 Hz, 1H), 2.26-2.18 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H), 0.70-0.53 (m, 5H).

[0488] 2) tert-Butyl (2-((1-(4-chlorothiophen-2-yl)ethyl)(cyclopropyl)amino)ethyl)carbamate

[0489] [ka]

[0490] To a solution of tert-butyl N-(2-oxoethyl)carbamate (1.2 g, 7.4 mmol, 6 equiv.) and N-[1-(4-chloro-2-thienyl)ethyl]cyclopropanamine (250 mg, 1.2 mmol, 1 equiv.) in MeOH (10 mL) was added AcOH (89.31 mg, 1.5 mmol, 85.1 μL, 1.2 equiv.) to adjust the pH to 5. The mixture was stirred at 60 °C for 12 h. NaBH CN (311.5 mg, 5.0 mmol, 4 equiv.) was then added. The mixture was stirred at 60 °C for 2 h. LC-MS showed that the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 mL of HO and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 5:1) to give compound tert-butyl (2-((1-(4-chlorothiophen-2-yl)ethyl)(cyclopropyl)amino)ethyl)carbamate (purity 66.23%, 500 mg) as a white solid.

[0491] 3) N1-(1-(4-chlorothiophen-2-yl)ethyl)-N1-cyclopropylethane-1,2-diamine hydrochloride

[0492] [ka]

[0493] A solution of tert-butyl N-[2-[1-(4-chloro-2-thienyl)ethyl-cyclopropyl-amino]ethyl]carbamate (200 mg, 579.9 μmol, 1 equiv.) in HCl / ethyl acetate (4 mL, 4 M) was stirred at 20 °C for 2 hours. LC-MS showed that the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl condition, column: Phenomenex Luna C18 75*30 mm*3 μm, mobile phase: [HO (0.04% HCl)-ACN], gradient: 5%-35% B over 8.0 min) to give compound N′-[1-(4-chloro-2-thienyl)ethyl]-N′-cyclopropylethane-1,2-diamine hydrochloride (20.0 mg, 71.2 μmol, yield 12.3%, purity 100%, HCl) as a white solid. MS (ESI): m / z = 245.1 [M+H] + , Retention time: 1.441 min, Method: M. 1 H NMR (400MHz, DMSO-d6) δ=8.03-7.70(m, 3H), 7.47(s, 1H), 7.06(br s, 1H), 4.48-4.31(m, 1H), 3.08-2.73(m, 4H), 2.08(br s, 1H), 1.53(br d, J=6.4Hz, 3H), 0.62(br d, J=5.5Hz, 4H). [Example]

[0494] Synthesis of 3-[1-[2-aminoethyl(cyclopropyl)amino]-2-fluoro-2-methylpropyl]-2-fluorobenzonitrile TFA salt (Compound 287) 1) 2-Fluoro-3-(2-fluoro-2-methylpropanoyl)benzonitrile

[0495] [ka]

[0496] To a solution of 2-fluorobenzonitrile (5.50 g, 45.41 mmol, 4.83 mL, 1 equiv.) in THF (50 mL) was added lithium chloro-(2,2,6,6-tetramethyl-1-piperidyl)magnesium chloride (1 M, 59.03 mL, 1.3 equiv.). The mixture was stirred at −78 °C for 1 h, and then methyl 2-fluoro-2-methylpropanoate (12 g, 99.90 mmol, 2.2 equiv.) was added. The mixture was stirred at 20 °C for 11 h. TLC showed that 1 was completely consumed and many new spots had formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 100 mL of H2O and extracted with ethyl acetate (80 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (silica flash column, eluent 0-3% ethyl acetate / petroleum ether gradient, 120 mL / min) to give 2-fluoro-3-(2-fluoro-2-methylpropanoyl)benzonitrile (1.7 g, 8.13 mmol, 17.90% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.83-7.70 (m, 2H), 7.42-7.34 (m, 1H), 1.74-1.69 (m, 3H), 1.68-1.63 (m, 3H).

[0497] 2) 3-[(E)-N-cyclopropyl-C-(1-fluoro-1-methylethyl)carbonimidoyl]-2-fluorobenzonitrile

[0498] [ka]

[0499] To a solution of 2-fluoro-3-(2-fluoro-2-methylpropanoyl)benzonitrile (500 mg, 2.39 mmol, 1 equiv.) in MeOH (4 mL) was added cyclopropanamine (204.70 mg, 3.59 mmol, 248.42 μL, 1.5 equiv.) and Ti(i-PrO) (2.04 g, 7.17 mmol, 2.12 mL, 3 equiv.). The mixture was stirred at 60 °C for 12 h. LC-MS showed that 2 was consumed, with approximately 66% of the desired compound detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 5 mL of HO and extracted with ethyl acetate (4 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (silica flash column, eluent: 0–3% ethyl acetate / petroleum ether gradient, 60 mL / min) to give 3-[(E)-N-cyclopropyl-C-(1-fluoro-1-methylethyl)carbonimidoyl]-2-fluorobenzonitrile (380 mg, 1.30 mmol, 54.44% yield, 85.01% purity) as a yellow oil.

[0500] 3) 3-[1-(cyclopropylamino)-2-fluoro-2-methylpropyl]-2-fluorobenzonitrile

[0501] [ka]

[0502] To a solution of 3-[(E)-N-cyclopropyl-C-(1-fluoro-1-methyl-ethyl)carbonimidoyl]-2-fluorobenzonitrile (360 mg, 1.45 mmol, 1 equiv.) in MeOH (3 mL) was added TFA (181.87 mg, 1.60 mmol, 118.48 μL, 1.1 equiv.) and NaBHCN (364.49 mg, 5.80 mmol, 4 equiv.). The mixture was stirred at 20 °C for 12 h. LC-MS showed approximately 36% of 3 remaining and approximately 46% of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 5 mL of HO and extracted with ethyl acetate (4 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (silica flash column, eluent: 0-3% ethyl acetate / petroleum ether gradient, 40 mL / min). The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 100*40 mm*5 μm, mobile phase: [HO (0.1% TFA)-ACN], gradient: 1% to 35% B over 7.0 min) to give 3-[1-(cyclopropylamino)-2-fluoro-2-methylpropyl]-2-fluorobenzonitrile (230 mg, 748.48 μmol, yield 51.62%, purity 81.45%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 8.22-8.08 (m, 1H), 7.78-7.67 (m, 1H), 7.44 (t, J = 7.9 Hz, 1H), 4.67 (d, J = 17.4 Hz, 1H), 2.27-2.15 (m, 1H), 1.62-1.47 (m, 3H), 1.41-1.28 (m, 3H), 0.99-0.84 (m, 2H), 0.68-0.51 (m, 2H).

[0503] 4) tert-Butyl N-[2-[[1-(3-cyano-2-fluorophenyl)-2-fluoro-2-methylpropyl]cyclopropylamino]ethyl]carbamate

[0504] [ka]

[0505] A solution of 3-[1-(cyclopropylamino)-2-fluoro-2-methylpropyl]-2-fluorobenzonitrile (200 mg, 799.08 μmol, 1 equiv.) and tert-butyl N-(2-oxoethyl)carbamate (763.20 mg, 4.79 mmol, 6 equiv.) in MeOH (3 mL) was adjusted to pH 6 with AcOH, and the mixture was stirred at 20 °C for 1 h. NaBH CN (200.86 mg, 3.20 mmol, 4 equiv.) was then added, and the mixture was stirred at 20 °C for 1 h. LC-MS showed approximately 74% of 4 remaining, with approximately 18% of the desired compound remaining. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 5 mL of HO and extracted with ethyl acetate (4 mL × 3). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (SepaFlash® silica flash column, eluent 0–10% ethyl acetate / petroleum ether gradient, 40 mL / min) to afford tert-butyl N-[2-[[1-(3-cyano-2-fluorophenyl)-2-fluoro-2-methylpropyl]-cyclopropylamino]ethyl]carbamate (30 mg, 72.26 μmol, 9.04% yield, 94.77% purity) as a white solid.

[0506] 5) 3-[1-[2-aminoethyl(cyclopropyl)amino]-2-fluoro-2-methylpropyl]-2-fluorobenzonitrile TFA salt

[0507] [ka]

[0508] To a solution of tert-butyl N-[2-[[1-(3-cyano-2-fluoro-phenyl)-2-fluoro-2-methyl-propyl]-cyclopropyl-amino]ethyl]carbamate (30 mg, 76.24 μmol, 1 equiv.) in DCM (1 mL) was added TFA (335.01 mg, 2.94 mmol, 218.25 μL, 38.54 equiv.). The mixture was stirred at 20 °C for 0.5 h. LC-MS showed 4% of 5 remaining and approximately 82% of the desired compound. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex luna C18 100*40 mm*5 μm, mobile phase: [HO (0.1% TFA)-ACN], gradient: 25%-55% B over 8.0 min) to give 3-[1-[2-aminoethyl(cyclopropyl)amino]-2-fluoro-2-methylpropyl]-2-fluorobenzonitrile TFA salt (10.13 mg, 24.87 μmol, 32.61% yield, 100% purity, TFA) as a white solid. MS (ESI): m / z = 293.17 [M+H] + , Retention time: 1.603 min, Method: Bhalo. 1 H NMR (400 MHz, chloroform-d) δ = 7.98-7.92 (m, 1H), 7.92-7.72 (m, 2H), 7.68-7.58 (m, 1H), 7.36-7.29 (m, 1H), 4.34-4.20 (m, 1H), 3.46-3.06 (m, 3H), 2.50-2.39 (m, 1H), 1.76-1.66 (m, 1H), 1.62-1.48 (m, 3H), 1.27-1.12 (m, 3H), 0.53 (s, 4H). [Example]

[0509] Synthesis of N'-[1-(3-chloro-2-fluorophenyl)-2-methylpropyl]-N'-(2,2-difluoroethyl)ethane-1,2-diamine TFA salt (Compound 282) 1) 1-(3-chloro-2-fluorophenyl)-2-methylpropan-1-ol

[0510] [ka]

[0511] To a solution of 3-chloro-2-fluorobenzaldehyde (10 g, 63.07 mmol, 1 equiv.) in THF (100 mL) was added chloro(isopropyl)magnesium (2 M, 47.30 mL, 1.5 equiv.) under a nitrogen atmosphere at −78°C. The mixture was then stirred under a nitrogen atmosphere at 25°C for 1 h. LC-MS showed no 1 remaining and approximately 33% of the desired compound was detected. The reaction was quenched under a nitrogen atmosphere by the slow addition of 30 mL of NH4Cl over 10 min. The aqueous phase was extracted with ethyl acetate (200 mL*3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (20 g silica flash column, eluent 0–2% ethyl acetate / petroleum ether gradient, 100 mL / min) to give 1-(3-chloro-2-fluorophenyl)-2-methylpropan-1-ol (3.5 g, 17.27 mmol, 27.38% yield) as a yellow oil.

[0512] 2) 1-(3-chloro-2-fluorophenyl)-2-methylpropan-1-one

[0513] [ka]

[0514] To a solution of 1-(3-chloro-2-fluoro-phenyl)-2-methyl-propan-1-ol (2 g, 9.87 mmol, 1 equiv.) in DCM (20 mL) was added DMP (12.56 g, 29.61 mmol, 9.17 mL, 3 equiv.) at 0 °C (under N2). The mixture was stirred at 25 °C for 1 h. LC-MS showed no 2 remaining and approximately 30% of the desired compound was detected. The reaction mixture was diluted with 100 mL of H2O and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 1), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was washed with petroleum ether (20 mL) and the liquid was concentrated in vacuo under reduced pressure to give 1-(3-chloro-2-fluorophenyl)-2-methylpropan-1-one (1.5 g, 7.48 mmol, 75.75% yield) as a yellow oil.

[0515] 3) 1-(3-chloro-2-fluorophenyl)-N-(2,2-difluoroethyl)-2-methylpropan-1-amine

[0516] [ka]

[0517] To a solution of 2,2-difluoroethanamine (4.85 g, 59.81 mmol, 8 equiv.) and 1-(3-chloro-2-fluorophenyl)-2-methylpropan-1-one (1.50 g, 7.48 mmol, 1 equiv.) in MeOH (10 mL) was added titanium tetraisopropoxide (17.00 g, 59.81 mmol, 17.65 mL, 8 equiv.). The mixture was stirred at 60 °C for 12 h. Sodium cyanoboronide (2.82 g, 44.86 mmol, 6 equiv.) was added to the reaction mixture and stirred at 60 °C for 2 h. LC-MS showed approximately 10% of 3 remaining and approximately 55% of the desired compound. The reaction mixture was diluted with 50 mL of HO and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by pre-HPLC (column: Phenomenex luna C18 250*150 mm*15 μm, mobile phase: [HO (0.1% TFA)-ACN], gradient: 30%-60% B in 20.0 min) to give 1-(3-chloro-2-fluoro-phenyl)-N-(2,2-difluoroethyl)-2-methyl-propan-1-amine (1.4 g, 5.27 mmol, 70.48% yield) as a yellow oil.

[0518] 4) tert-Butyl N-[2-[[1-(3-chloro-2-fluorophenyl)-2-methylpropyl]-(2,2-difluoroethyl)amino]ethyl]carbamate

[0519] [ka]

[0520] To a solution of 1-(3-chloro-2-fluorophenyl)-N-(2,2-difluoroethyl)-2-methylpropan-1-amine (500 mg, 1.65 mmol, 1 equiv., HCl), TEA (167.44 mg, 1.65 mmol, 230.32 μL, 1 equiv.), and tert-butyl N-(2-oxoethyl)carbamate (1.05 g, 6.62 mmol, 4 equiv.) in MeOH (4 mL) was added AcOH until the pH reached 6. After stirring the mixture at 20 °C for 1 h, NaBHCN (415.93 mg, 6.62 mmol, 4 equiv.) was added, and the mixture was stirred at 20 °C for 11 h. LC-MS showed approximately 86% of 4 remaining, with approximately 10% of the desired compound remaining. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA condition, column: Phenomenex luna C18 100*40 mm*5 μm, mobile phase: [HO(0.1% TFA)-ACN], gradient: 45%-100% B over 8.0 min) to give tert-butyl N-[2-[[1-(3-chloro-2-fluorophenyl)-2-methylpropyl]-(2,2-difluoroethyl)amino]ethyl]carbamate (40 mg, 84.09 μmol, yield 5.08%, purity 85.96%) as a white solid.

[0521] 5) N'-[1-(3-chloro-2-fluorophenyl)-2-methylpropyl]-N'-(2,2-difluoroethyl)ethane-1,2-diamine

[0522] [ka]

[0523] To a solution of tert-butyl N-[2-[[1-(3-chloro-2-fluoro-phenyl)-2-methyl-propyl]-(2,2-difluoroethyl)amino]ethyl]carbamate (40 mg, 97.83 μmol, 1 equiv.) in DCM (2 mL) was added TFA (429.84 mg, 3.77 mmol, 280.02 μL, 38.54 equiv.). The mixture was stirred at 20° C. for 1 h. LC-MS showed no 4A remaining and approximately 82% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 100*40mm*5μm, mobile phase: [HO (0.1% TFA)-ACN], gradient: 15%-65% B, 7.0 min) to obtain N'-[1-(3-chloro-2-fluorophenyl)-2-methylpropyl]-N'-(2,2-difluoroethyl)ethane-1,2-diamine TFA salt (41 mg, 96.97 μmol, yield 99.13%, purity 100%, TFA) as a colorless oil. MS (ESI): m / z = 308.13 [M+H] + , Retention time: 1.726 min, Method: Bhalo. 1 H NMR (400MHz, chloroform-d) δ=8.12-7.71(m, 3H), 7.45-7.31(m, 1H), 7.20-7.04(m, 2H), 5.90(br t, J=55.7Hz, 1H), 3.67(br d, J=11.0Hz, 1H), 3.12(br s, 2H), 3.05-2.84(m, 2H), 2.77-2.55(m, 2H), 2.26(tt, J=5.9, 11.6Hz, 1H), 1.15(br d, J=6.4Hz, 3H), 0.89-0.61(m, 3H). [Example]

[0524] [Synthesis of N'-cyclopropyl-N'-[1-(3-ethynyl-2-fluorophenyl)ethyl]ethane-1,2-diamine TFA salt (Compound 295)] 1) N-[1-(3-bromo-2-fluorophenyl)ethyl]cyclopropanamine

[0525] [ka]

[0526] To a solution of 1-(3-bromo-2-fluorophenyl)ethanone (5 g, 23.04 mmol, 1 equiv.) in MeOH (50 mL) was added cyclopropanamine (1.97 g, 34.56 mmol, 2.39 mL, 1.5 equiv.) and Ti(i-PrO) (19.64 g, 69.11 mmol, 20.40 mL, 3 equiv.). The mixture was stirred at 60 °C for 12 h, and then NaBHCN (5.79 g, 92.15 mmol, 4 equiv.) was added, and the mixture was stirred at 60 °C for 2 h. LC-MS showed no 1 remaining, and approximately 86% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 50 mL of HO and extracted with ethyl acetate (40 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g silica flash column, eluent 0–2% ethyl acetate / petroleum ether gradient, 100 mL / min) to obtain the compound N-[1-(3-bromo-2-fluorophenyl)ethyl]cyclopropanamine (3.8 g, 14.54 mmol, 63.10% yield, 98.75% purity) as a pale yellow oil.

[0527] 2) tert-Butyl N-[2-[1-(3-bromo-2-fluorophenyl)ethyl-cyclopropylamino]ethyl]carbamate

[0528] [ka]

[0529] To a solution of N-[1-(3-bromo-2-fluorophenyl)ethyl]cyclopropanamine (1 g, 3.87 mmol, 1 equiv.) and tert-butyl N-(2-oxoethyl)carbamate (1.54 g, 9.69 mmol, 2.5 equiv.) in MeOH (10 mL) was added NaBHCN (486.89 mg, 7.75 mmol, 2 equiv.) and ZnCl (1.06 g, 7.75 mmol, 363.27 μL, 2 equiv.). The mixture was stirred at 20 °C for 12 h. LC-MS showed no 2 remaining, with approximately 95% of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 mL of HO and extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[1-(3-bromo-2-fluorophenyl)ethyl-cyclopropyl-amino]ethyl]carbamate (2 g, crude) as a white solid.

[0530] 3) tert-Butyl N-[2-[cyclopropyl-[1-[2-fluoro-3-(2-trimethylsilylethynyl)phenyl]ethyl]amino]ethyl]carbamate

[0531] [ka]

[0532] To a solution of tert-butyl N-[2-[1-(3-bromo-2-fluorophenyl)ethyl-cyclopropyl-amino]ethyl]carbamate (1 g, 2.49 mmol, 1 equiv.) and ethynyl(trimethyl)silane (1.22 g, 12.46 mmol, 1.73 mL, 5 equiv.) in dioxane (10 mL) was added CuI (47.46 mg, 249.18 μmol, 0.1 equiv.), Pd(PPh3)2Cl2 (174.90 mg, 249.18 μmol, 0.1 equiv.), and TEA (1.26 g, 12.46 mmol, 1.73 mL, 5 equiv.). The mixture was stirred at 80 °C under a N2 atmosphere for 6 h. LC-MS showed approximately 13% of 3 remaining and approximately 11% of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 15 mL of HO and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex luna C18 100*40 mm*3 μm, mobile phase: [HO (0.1% TFA)-ACN], gradient: 40%-70% B over 8.0 min) to give tert-butyl N-[2-[cyclopropyl-[1-[2-fluoro-3-(2-trimethylsilylethynyl)phenyl]ethyl]amino]ethyl]carbamate (300 mg, 701.31 μmol, yield 28.14%, purity 97.86%) as a pale yellow oil.

[0533] 4) tert-Butyl N-[2-[cyclopropyl-[1-(3-ethynyl-2-fluorophenyl)ethyl]amino]ethyl]carbamate

[0534] [ka]

[0535] To a solution of tert-butyl N-[2-[cyclopropyl-[1-[2-fluoro-3-(2-trimethylsilylethynyl)phenyl]ethyl]amino]ethyl]carbamate (185 mg, 441.93 μmol, 1 equiv.) in THF (2 mL) was added TBAF (1 M, 662.89 μL, 1.5 equiv.). The mixture was stirred at 20 °C for 1 h. LC-MS showed no 4 remaining, and approximately 93% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 4 mL of HO and extracted with ethyl acetate (3 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give tert-butyl N-[2-[cyclopropyl-[1-(3-ethynyl-2-fluorophenyl)ethyl]amino]ethyl]carbamate (200 mg, crude) as a yellow oil.

[0536] 5) N'-Cyclopropyl-N'-[1-(3-ethynyl-2-fluorophenyl)ethyl]ethane-1,2-diamine TFA salt

[0537] [ka]

[0538] To a solution of tert-butyl N-[2-[cyclopropyl-[1-(3-ethynyl-2-fluorophenyl)ethyl]amino]ethyl]carbamate (180 mg, 519.57 μmol, 1 equiv) in DCM (2 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 12.96 equiv). The mixture was stirred at 20 °C for 1 h. LC-MS showed no 5 remaining and approximately 86% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 100*40mm*5μm, mobile phase: [HO (0.1% TFA)-ACN], gradient: 1%-40% B, 8.0 min) to obtain N'-cyclopropyl-N'-[1-(3-ethynyl-2-fluorophenyl)ethyl]ethane-1,2-diamine TFA salt (70.09 mg, 193.98 μmol, yield 37.33%, purity 99.73%, TFA) as a pale yellow oil. MS (ESI): m / z = 246.15 [M+H] + , Retention time: 1.360 minutes, Method: Bhalo. 1 H NMR (400MHz, chloroform-d) δ=9.18-8.08(m, 3H), 7.62-7.42(m, 2H), 7.25-7.18(m, 1H), 4. 94(q, J=6.7Hz, 1H), 3.79-3.64(m, 1H), 3.62-3.41(m, 2H), 3.39-3.25(m, 2H), 2.26(br s, 1H), 1.73(br d, J=7.0Hz, 3H), 1.07(br s, 2H), 0.94-0.74(m, 2H). [Example]

[0539] Synthesis of 5-[1-[2-aminoethyl(cyclopropyl)amino]ethyl]-4-fluorothiophene-3-carbonitrile TFA salt and N'-[1-(4-bromo-3-fluoro-2-thienyl)ethyl]-N'-cyclopropylethane-1,2-diamine TFA salt (Compounds 297 and 297A) 1) 4-Bromo-3-fluorothiophene-2-carboxylic acid

[0540] [ka]

[0541] To a solution of methyl 4-bromo-3-fluoro-thiophene-2-carboxylate (0.7 g, 2.93 mmol, 1 equiv.) in THF (10 mL) and HO (10 mL) was added LiOH.HO (245.75 mg, 5.86 mmol, 2 equiv.), and the mixture was stirred at 20 °C for 1 h. LC-MS showed that 1 was completely consumed and one main peak was detected. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was acidified with HCl (1 M) to adjust the pH to approximately 3, then extracted with ethyl acetate (5 mL * 2). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 4-bromo-3-fluoro-thiophene-2-carboxylic acid (0.69 g, crude) as a white solid.

[0542] 2) 4-Bromo-3-fluoro-N-methoxy-N-methyl-thiophene-2-carboxamide

[0543] [ka]

[0544] To a solution of 4-bromo-3-fluoro-thiophene-2-carboxylic acid (0.69 g, 3.07 mmol, 1 equiv.) and N-methoxymethanamine (448.63 mg, 4.60 mmol, 1.5 equiv., HCl) in DCM (20 mL) was added HOBt (497.18 mg, 3.68 mmol, 1.2 equiv.), EDCI (705.35 mg, 3.68 mmol, 1.2 equiv.), and TEA (775.66 mg, 7.67 mmol, 1.07 mL, 2.5 equiv.). The mixture was stirred at 20 °C for 2 h. LC-MS showed complete consumption of 1A, with one main peak corresponding to the desired mass. The reaction mixture was quenched with 10 mL of HO at 20 °C and then extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (12 g silica flash column, eluent 0–20% ethyl acetate / petroleum ether gradient, 60 mL / min) to give the compound 4-bromo-3-fluoro-N-methoxy-N-methyl-thiophene-2-carboxamide (0.7 g, 2.61 mmol, 85.15% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.39 (d, J = 4.0 Hz, 1H), 3.75 (s, 3H), 3.35 (s, 3H).

[0545] 3) 1-(4-Bromo-3-fluoro-2-thienyl)ethanone

[0546] [ka]

[0547] To a solution of 4-bromo-3-fluoro-N-methoxy-N-methyl-thiophene-2-carboxamide (0.6 g, 2.24 mmol, 1 equiv.) in THF (10 mL) was added MeMgBr (3 M, 895.18 μL, 1.2 equiv.) at −78 °C, and the mixture was stirred at 20 °C for 1 h. TLC showed that 2 was completely consumed and one new spot was formed. The reaction mixture was quenched by adding 10 mL of NH4Cl at 20 °C, and then extracted with ethyl acetate (10 mL * 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 1-(4-bromo-3-fluoro-2-thienyl)ethanone (0.55 g, crude) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.55-7.48 (m, 1H), 2.61 (d, J=2.88 Hz, 3H).

[0548] 4) 1-(3-Bromo-2-fluorophenyl)-2-methylpropan-1-one

[0549] [ka]

[0550] To a solution of 1-(4-bromo-3-fluoro-2-thienyl)ethanone (500 mg, 2.24 mmol, 1 equiv) in MeOH (5 mL) was added cyclopropanamine (191.97 mg, 3.36 mmol, 232.97 μL, 1.5 equiv) and Ti(i-PrO) (1.91 g, 6.72 mmol, 1.98 mL, 3 equiv). The mixture was stirred at 60 °C for 12 h, followed by the addition of NaBHCN (563.43 mg, 8.97 mmol, 4 equiv). The mixture was stirred at 60 °C for 2 h. LC-MS showed no 3 remaining and approximately 66% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 5 mL of HO and extracted with ethyl acetate (4 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g silica flash column, eluent 0–2% ethyl acetate / petroleum ether gradient, 40 mL / min) to obtain the compound N-[1-(4-bromo-3-fluoro-2-thienyl)ethyl]cyclopropanamine (350 mg, 1.29 mmol, 57.50% yield, 97.27% purity) as a yellow oil.

[0551] 5) tert-Butyl N-[2-[1-(4-bromo-3-fluoro-2-thienyl)ethyl-cyclopropylamino]ethyl]carbamate

[0552] [ka]

[0553] To a solution of N-[1-(4-bromo-3-fluoro-2-thienyl)ethyl]cyclopropanamine (300 mg, 1.14 mmol, 1 equiv.) and tert-butyl N-(2-oxoethyl)carbamate (542.34 mg, 3.41 mmol, 3 equiv.) in MeOH (3 mL) was added NaBHCN (142.73 mg, 2.27 mmol, 2 equiv.) and ZnCl (309.59 mg, 2.27 mmol, 106.50 μL, 2 equiv.). The mixture was stirred at 20 °C for 3 h. LC-MS showed no 4 remaining, with approximately 94% of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 5 mL of HO and extracted with ethyl acetate (3 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g silica flash column, eluent 0–2% ethyl acetate / petroleum ether gradient, 40 mL / min) to obtain the compound tert-butyl N-[2-[1-(4-bromo-3-fluoro-2-thienyl)ethyl-cyclopropyl-amino]ethyl]carbamate (350 mg, 776.40 μmol, yield 68.36%, purity 90.36%) as a yellow oil.

[0554] 6) tert-Butyl N-[2-[1-(4-cyano-3-fluoro-2-thienyl)ethyl-cyclopropylamino]ethyl]carbamate

[0555] [ka]

[0556] To a solution of tert-butyl N-[2-[1-(4-bromo-3-fluoro-2-thienyl)ethyl-cyclopropyl-amino]ethyl]carbamate (200 mg, 490.99 μmol, 1 equiv.) and dppf (108.88 mg, 196.40 μmol, 0.4 equiv.) in DMF (2 mL) was added Zn (16.05 mg, 245.49 μmol, 0.5 equiv.), Zn(CN) (130 mg, 1.11 mmol, 70.27 μL, 2.25 equiv.), and Pd(dba) (89.92 mg, 98.20 μmol, 0.2 equiv.). The mixture was stirred at 80 °C under a N atmosphere for 12 h. LC-MS showed that no 5 remained and approximately 17% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 5 mL of HO and extracted with ethyl acetate (4 mL*3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g silica flash column, eluent: 0–3% ethyl acetate / petroleum ether gradient, 40 mL / min) to give the compound tert-butyl N-[2-[1-(4-cyano-3-fluoro-2-thienyl)ethyl-cyclopropyl-amino]ethyl]carbamate (160 mg, 307.14 μmol, 62.56% yield, 67.85% purity) as a yellow solid.

[0557] <7) 5-[1-[2-aminoethyl(cyclopropyl)amino]ethyl]-4-fluorothiophene-3-carbonitrile TFA salt>

[0558] [ka]

[0559] To a solution of tert-butyl N-[2-[1-(4-cyano-3-fluoro-2-thienyl)ethyl-cyclopropyl-amino]ethyl]carbamate (160 mg, 452.68 μmol, 1 equiv.) in DCM (2 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 14.87 eq.). The mixture was stirred at 20 °C for 1 h. LC-MS showed no 6 remaining and approximately 47% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 100*40mm*5μm, mobile phase: [HO (0.1% TFA)-ACN], gradient: 1%-40% B, 8.0 min) to obtain compound 5-[1-[2-aminoethyl(cyclopropyl)amino]ethyl]-4-fluorothiophene-3-carbonitrile TFA salt (49.6 mg, 134.44 μmol, yield 29.70%, purity 99.57%, TFA) as a colorless oil. MS (ESI): m / z = 253.10 [M+H] + , Retention time: 1.362 minutes, Method: M. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.63-7.95 (m, 2H), 7.88 (d, J = 3.38 Hz, 1H), 4.74-4.61 (m, 1H), 3.48-3.20 (m, 3H), 3.12-2.94 (m, 1H), 2.12-1.99 (m, 1H), 1.76-1.52 (m, 3H), 0.96-0.61 (m, 4H).

[0560] 8) N'-[1-(4-bromo-3-fluoro-2-thienyl)ethyl]-N'-cyclopropylethane-1,2-diamine TFA salt

[0561] [ka]

[0562] To a solution of tert-butyl N-[2-[1-(4-bromo-3-fluoro-2-thienyl)ethyl-cyclopropyl-amino]ethyl]carbamate (110 mg, 270.04 μmol, 1 equiv.) in DCM (1 mL) was added TFA (1.19 g, 10.41 mmol, 772.99 μL, 38.54 equiv.). The mixture was stirred at 20 °C for 1 h. LC-MS showed approximately 5% of 5 remaining and approximately 60% of the target compound. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 100*40mm*5μm, mobile phase: [HO (0.1% TFA)-ACN], gradient: 10%-45% B, 8.0 min) to obtain the compound N'-[1-(4-bromo-3-fluoro-2-thienyl)ethyl]-N'-cyclopropyl-ethane-1,2-diamine TFA salt (16.85 mg, 39.79 μmol, yield 14.74%, purity 99.48%, TFA) as a colorless oil. MS (ESI): m / z = 306.02 [M + H] + , Retention time: 1.535 minutes, Method: B. 1 H NMR (400MHz, chloroform-d) δ ppm 8.94-7.74(m, 3H), 7.32-7.23(m, 1H), 4.85-4.70(m, 1H), 3.48(br d, J=7.25Hz, 2H), 3.41-3.28(m, 1H), 3.15(br dd, J=9.94, 4.57Hz, 1H), 2.19-2.05(m, 1H), 1.65(br d, J=7.00Hz, 3H), 1.07-0.72(m, 4H). [Example]

[0563] Synthesis of 3-[1-[2-aminoethyl(cyclopropyl)amino]-2,2,2-trifluoroethyl]-2-fluorobenzonitrile hydrochloride (Compound 261) 1) tert-Butyl (2-((1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)(cyclopropyl)amino)ethyl)carbamate

[0564] [ka]

[0565] To a solution of N'-[1-(3-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethyl]-N'-cyclopropyl-ethane-1,2-diamine (2 g, 5.63 mmol, 1 equiv.) in THF (40 mL) was added BocO (6.14 g, 28.16 mmol, 6.47 mL, 5 equiv.). The mixture was stirred at 25 °C for 12 h. LCMS showed the formation of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 50 mL of H2O and extracted with 150 mL of DCM (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g silica flash column, eluent 0–5% ethyl acetate / petroleum ether gradient, 80 mL / min) to obtain the compound tert-butyl N-[2-[[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]cyclopropylamino]ethyl]carbamate (750 mg, 1.65 mmol, 29.25% yield) as a white solid.

[0566] 2) tert-Butyl (2-((1-(3-cyano-2-fluorophenyl)-2,2,2-trifluoroethyl)(cyclopropyl)amino)ethyl)carbamate

[0567] [ka]

[0568] A mixture of tert-butyl N-[2-[[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]cyclopropylamino]ethyl]carbamate (200 mg, 439.29 μmol, 1 equiv.), Pd(dba) (40.23 mg, 43.93 μmol, 0.1 equiv.), Zn(CN) (154.75 mg, 1.32 mmol, 83.65 μL, 3 equiv.), and s-Phos (18.03 mg, 43.93 μmol, 0.1 equiv.) in DMF (4 mL) was degassed and purged with N three times. The mixture was then stirred under a N atmosphere at 120 °C for 12 h. LCMS indicated the formation of the desired compound. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was diluted with 10 mL of HO and extracted with 30 mL of EtOAc (10 mL × 3). The combined organic layers were washed with 30 mL of brine (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 3:1) to obtain compound tert-butyl N-[2-[[1-(3-cyano-2-fluorophenyl)-2,2,2-trifluoroethyl]-cyclopropylamino]ethyl]carbamate (110 mg, 274.04 μmol, 62.38% yield) as a yellow oil.

[0569] 3) 3-(1-((2-aminoethyl)(cyclopropyl)amino)-2,2,2-trifluoroethyl)-2-fluorobenzonitrile hydrochloride

[0570] [ka]

[0571] A solution of tert-butyl N-[2-[[1-(3-cyano-2-fluorophenyl)-2,2,2-trifluoroethyl]cyclopropylamino]ethyl]carbamate (110 mg, 274.04 μmol, 1 equiv) in HCl / ethyl acetate (2 mL) was stirred at 25° C. for 0.5 h. LCMS showed the formation of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl conditions, column: Phenomenex Luna C18 75*30 mm*3 μm, mobile phase: [HO (0.04% HCl)-ACN], gradient: 10%-40% B over 8.0 min) to give the compound 3-[1-[2-aminoethyl(cyclopropyl)amino]-2,2,2-trifluoroethyl]-2-fluorobenzonitrile hydrochloride (90.84 mg, 268.69 μmol, yield 98.05%, purity 99.9%, HCl) as a white solid. MS (ESI): m / z = 301.12 [M+H] + , retention time: 1.584 minutes, method: M, 1 H NMR (400MHz, DMSO-d6) δ=8.14-8.01(m, 1H), 7.92-7.81(m, 4H), 7.54(t, J=7.9Hz, 1H), 5.18(q, J=9.3Hz, 1H), 3.10-2.68(m, 4H), 1.99(br d, J=2.1Hz, 1H), 0.69-0.41(m, 4H). [Example]

[0572] [Synthesis of N'-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N'-cyclopropylethane-1,2-diamine hydrochloride (Compound 261A)] 1) 1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethan-1-ol

[0573] [ka]

[0574] To a mixture of 3-bromo-2-fluorobenzaldehyde (10 g, 49.26 mmol, 1 equiv.) in DMF (100 mL), TMSCF3 (9.11 g, 64.04 mmol, 1.3 equiv.) was added, and the mixture was stirred at 0 °C. After 15 min, TBAF (1 M, 492.59 μL, 0.01 equiv.) was added dropwise via syringe. The mixture was degassed and purged with N2 three times. The mixture was then stirred at 20 °C for 12 h under a N2 atmosphere. When the reaction was complete, HCl (2 M, 49.26 mL, 2 equiv.) was added to the solution, and the mixture was stirred at 20 °C for 4 h. TLC showed that reactant 1 was completely consumed and one new spot had formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL of HO and extracted with 90 mL of EtOAc (30 mL × 3). The combined organic layers were washed with 90 mL of brine (30 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (40 g silica flash column, eluent: 0–3% ethyl acetate / petroleum ether gradient, 80 mL / min) to give the compound 1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethanol (9.6 g, 35.16 mmol, 71.38% yield) as a yellow oil.

[0575] 2) 1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethan-1-one

[0576] [ka]

[0577] To a solution of 1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethanol (9.6 g, 35.16 mmol, 1 equiv.) in DCM (200 mL) was added DMP (16.41 g, 38.6 mmol, 11.98 mL, 1.1 equiv.). The mixture was stirred at 25 °C for 12 h. TLC showed that 3 was completely consumed and one new spot had formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel chromatography (40 g silica flash column, eluent 0–2% ethyl acetate / petroleum ether gradient, 80 mL / min) to obtain the compound 1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (6.62 g, 24.43 mmol, 69.47% yield) as a yellow oil.

[0578] 3) (E)-1-(3-bromo-2-fluorophenyl)-N-cyclopropyl-2,2,2-trifluoroethan-1-imine

[0579] [ka]

[0580] 1-(3-Bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (6.6 g, 24.35 mmol, 1 equiv.) and cyclopropanamine (2.09 g, 36.53 mmol, 2.53 mL, 1.5 equiv.) were mixed in DCM (70 mL). AlMe (2 M, 12.18 mL, 1 equiv.) was added under N atmosphere, and the mixture was stirred at 25 °C for 12 h under N atmosphere. LCMS showed the formation of the desired compound. The residue was diluted with 50 mL of NaOH (20%) and extracted with 90 mL of DCM (30 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, affording compound (E)-1-(3-bromo-2-fluorophenyl)-N-cyclopropyl-2,2,2-trifluoroethanimine (8 g, crude) as a yellow oil.

[0581] 4) N-(1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)cyclopropanamine

[0582] [ka]

[0583] To a solution of (E)-1-(3-bromo-2-fluoro-phenyl)-N-cyclopropyl-2,2,2-trifluoro-ethanimine (8 g, 25.80 mmol, 1 equiv.) in MeOH (90 mL) was added TFA (2.94 g, 25.80 mmol, 1.92 mL, 1 equiv.) and NaBH3CN (6.49 g, 103.20 mmol, 4 equiv.). The mixture was stirred at 60 °C for 1 hour. LCMS showed that the desired compound had formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent 0–4% ethyl acetate / petroleum ether gradient, 120 mL / min) to give the compound N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]cyclopropanamine (3.14 g, 9.68 mmol, 37.51% yield, 96.2% purity) as a yellow oil.

[0584] 5) 2-Bromo-N-(1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide

[0585] [ka]

[0586] To a solution of N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]cyclopropanamine (2.4 g, 7.69 mmol, 1 equiv) in DCM (30 mL) and HO (30 mL) was added KCO (2.13 g, 15.38 mmol, 2 equiv) and 2-bromoacetyl bromide (2.79 g, 13.84 mmol, 1.21 mL, 1.8 equiv) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. LCMS showed that the desired compound had formed. The residue was diluted with HO (20 mL) and extracted with DCM (90 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g silica flash column, eluent 0–7% ethyl acetate / petroleum ether gradient, 80 mL / min) to give the compound 2-bromo-N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N-cyclopropylacetamide (3 g, 6.93 mmol, 90.09% yield) as a white solid.

[0587] 6) N-(1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide

[0588] [ka]

[0589] To a solution of 2-bromo-N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N-cyclopropylacetamide (3.18 g, 7.34 mmol, 1 equiv.) in DMF (40 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (1.50 g, 8.08 mmol, 1.1 equiv.). The mixture was stirred at 20 °C for 4 h. LCMS indicated the formation of the desired compound. The residue was diluted with 20 mL of H2O and extracted with 60 mL of ethyl acetate (20 mL × 3). The combined organic layers were washed with 60 mL of brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g silica flash column, eluent 0–20% ethyl acetate / petroleum ether gradient, 100 mL / min) to give the compound N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (4.11 g, 5.66 mmol, 77.01% yield, 68.7% purity) as a white solid.

[0590] 7) 2-Amino-N-(1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide

[0591] [ka]

[0592] To a solution of N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (4.11 g, 8.23 mmol, 1 equiv.) in EtOH (40 mL) was added NH2NH2.HO (841.04 mg, 16.46 mmol, 814.96 μL, 98% purity, 2 equiv.). The mixture was stirred at 80 °C for 3 h. LCMS showed the formation of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The mixture was filtered and concentrated under reduced pressure to give a residue to give the compound 2-amino-N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N-cyclopropylacetamide (2.4 g, crude) as a white solid.

[0593] 8) N1-(1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)-N1-cyclopropylethane-1,2-diamine hydrochloride

[0594] [ka]

[0595] To a solution of 2-amino-N-[1-(3-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethyl]-N-cyclopropyl-acetamide (47 mg, 127.32 μmol, 1 equiv.) in THF (2 mL) was added BH3.THF (1 M, 1.27 mL, 10 equiv.). The mixture was stirred at 70° C. for 12 hours. LCMS showed that the desired compound had formed. The reaction mixture was quenched by the addition of MeOH (5 ml) at 70° C. for 2 hours, and the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl condition, column: Phenomenex luna C18 80*30 mm*3 μm, mobile phase: [HO (0.04% HCl)-ACN], gradient: 22%-52% B over 8.0 min) to obtain the compound N'-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N'-cyclopropylethane-1,2-diamine hydrochloride (16 mg, 40.32 μmol, yield 31.67%, purity 98.68%, HCl) as a white solid. MS (ESI): m / z = 354.04 [M+H] + , retention time: 1.765 minutes, method: M, 1 H NMR (400MHz, DMSO-d6) δ=7.92(br s, 3H), 7.86-7.79(m, 1H), 7.55(br t, J=7.1Hz, 1H), 7.29(t, J=7.9Hz, 1H), 5.11(q, J=9.5Hz, 1H), 3.13-2.71(m, 4H), 2.03-1.90(m, 1H), 0.71-0.40(m, 4H). [Example]

[0596] [Synthesis of N1-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N1-cyclopropylethane-1,2-diamine TFA salt (Compound 270)] 1) 1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropan-1-ol

[0597] [ka]

[0598] A dry round-bottom flask flushed with N2 was charged with the desired 1-chloro-2-fluorobenzene (2 g, 15.3 mmol, 1 equiv.) and THF (45 mL). LDA base (2 M, 8.4 mL, 1.1 equiv.) was added dropwise, and the reaction was maintained at -70 °C for 0.25 h. Ethyl 2,2,3,3,3-pentafluoropropanoate (3.5 g, 18.4 mmol, 1.2 equiv.) was then added, and the mixture was allowed to react at 20 °C for 12 h. TLC showed complete consumption of reactant 1 and the formation of one large new spot. The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 0–0% ethyl acetate / petroleum ether gradient, 60 mL / min) to give 1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropan-1-ol (1.6 g, 5.7 mmol, 37.5% yield) as a yellow oil.

[0599] 2) 1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropan-1-one

[0600] [ka]

[0601] To a solution of 1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropan-1-ol (1.7 g, 6.1 mmol, 1 equiv.) in DCM (30 mL) was added DMP (3.1 g, 7.3 mmol, 1.2 equiv.). The mixture was stirred at 20 °C for 12 h. TLC showed that 2 was completely consumed and one large new spot had formed. The reaction mixture was diluted with 5 mL of HO, extracted with 15 mL of DCM (5 mL * 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 0–0% ethyl acetate / petroleum ether gradient, 60 mL / min) to give 1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropan-1-one (952 mg, 3.4 mmol, 56.4% yield) as a yellow oil.

[0602] 3)(E)-1-(3-chloro-2-fluorophenyl)-N-cyclopropyl-2,2,3,3,3-pentafluoropropan-1-imine

[0603] [ka]

[0604] To a solution of 1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropan-1-one (1 g, 3.6 mmol, 1 equiv.) in MeOH (15 mL) was added cyclopropanamine (309.7 mg, 5.4 mmol, 375.8 μL, 1.5 equiv.) and Ti(i-PrO)4 (3.1 g, 10.9 mmol, 3.2 mL, 3 equiv.). The mixture was stirred at 60 °C for 12 h. LC-MS showed one main peak at the desired m / z. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 100 mL of HO, extracted with 300 mL of ethyl acetate (100 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue to afford (E)-1-(3-chloro-2-fluorophenyl)-N-cyclopropyl-2,2,3,3,3-pentafluoropropan-1-imine (860 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0605] 4) N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)cyclopropanamine

[0606] [ka]

[0607] To a solution of (E)-1-(3-chloro-2-fluoro-phenyl)-N-cyclopropyl-2,2,3,3,3-pentafluoro-propan-1-imine (500 mg, 1.6 mmol, 1 equiv.) in MeOH (15 mL) was added NaBHCN (398.2 mg, 6.3 mmol, 4 equiv.) and TFA (198.7 mg, 1.7 mmol, 129.4 μL, 1.1 equiv.). The mixture was stirred at 20 °C for 12 h. LC-MS showed that 4 was completely consumed and one main peak of the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 8 mL of HO, extracted with 30 mL of ethyl acetate (10 mL * 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=10 / 1) to give N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)cyclopropanamine (360 mg, 1.1 mmol, 71.5% yield) as a white solid.

[0608] 5) 2-Bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N-cyclopropylacetamide

[0609] [ka]

[0610] A solution of K2CO3 (261.1 mg, 1.9 mmol, 2 equiv) in HO (10 mL) was cooled with stirring, and a solution of N-[1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl]cyclopropanamine (300.0 mg, 944.4 μmol, 1 equiv) in DCM (10 mL) was added, followed by 2-bromoacetyl bromide (228.8 mg, 1.1 mmol, 98.7 μL, 1.2 equiv). The reaction mixture was stirred at 20 °C for 1 h. LC-MS showed partial retention of 5. To the reaction mixture was added K2CO3 (261.1 mg, 1.9 mmol, 2 equiv) and 2-bromoacetyl bromide (228.8 mg, 1.1 mmol, 98.7 μL, 1.2 equiv), and the mixture was stirred at 20 °C for 1 h. LC-MS showed that reactant 5 was completely consumed and one main peak of the desired m / z was detected. The reaction mixture was diluted with 10 mL of HO, extracted with 30 mL of DCM (10 mL*3), dried over NaSO, filtered, and concentrated under reduced pressure to give 2-bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N-cyclopropylacetamide (460 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0611] 6) N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide

[0612] [ka]

[0613] To a solution of 2-bromo-N-[1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl]-N-cyclopropyl-acetamide (400 mg, 912.0 μmol, 1 equiv.) in DMF (20 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (202.7 mg, 1.1 mmol, 1.2 equiv.). The mixture was stirred at 20 °C for 12 h. LC-MS showed complete consumption of 6, with one main peak of the desired m / z. The reaction mixture was diluted with 25 mL of HO and extracted with 75 mL of ethyl acetate (25 mL × 3). The combined organic layers were washed with 20 mL of aqueous NaCl (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (750 mg, crude) as a yellow oil.

[0614] 7) 2-Amino-N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N-cyclopropylacetamide

[0615] [ka]

[0616] To a solution of N-[1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl]-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (300 mg, 594.3 μmol, 1 equiv.) in EtOH (15 mL) was added N2H4.HO (74.4 mg, 1.2 mmol, 72.1 μL, 80% purity, 2 equiv.). The mixture was stirred at 80 °C for 2.5 h. LC-MS showed complete consumption of 7, with one main peak of the desired m / z. The mixture was cooled to 4 °C, and the phthalyl hydrazide was removed by filtration. The ethanol was removed under vacuum. The solution was diluted with 20 mL of HO and then extracted with 30 mL of ethyl acetate (10 mL × 3), and the organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give 2-amino-N-[1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl]-N-cyclopropylacetamide (176 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0617] 8) N1-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N1-cyclopropylethane-1,2-diamine

[0618] [ka]

[0619] To a solution of 2-amino-N-[1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl]-N-cyclopropyl-acetamide (176 mg, 469.7 μmol, 1 equiv.) in THF (15 mL) was added BH3.THF (1 M, 2.8 mL, 6 equiv.). The mixture was stirred at 60 °C under a N2 atmosphere for 12 h. LC-MS showed that 8 was completely consumed and one main peak of the desired M / z was detected. The reaction mixture was quenched at 0 °C with 2 mL of MeOH and stirred at 60 °C for 2 h. After that, it was diluted with 10 mL of HO and extracted with 30 mL (10 mL * 3) of ethyl acetate, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 75*30 mm*3 μm, mobile phase: [HO (0.1% TFA)-ACN], gradient: 15%-45% B over 8.0 min) to give N1-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N1-cyclopropylethane-1,2-diamine TFA salt (17.5 mg, 48.1 μmol, 10.2% yield, 99.3% purity) as a yellow oil. MS (ESI): m / z = 361.1 [M+H] + , Retention time: 1.914 minutes, Method: M. 1 H NMR (400MHz, DMSO-d6)δ=7.96-7.66(m, 4H), 7.62(br t, J=7.1Hz, 1H), 7.36(t, J=8.1Hz, 1H), 5.12-4.97(m, 1H), 3.19-3.13(m, 1H), 3.03-2.86(m, 2H), 2.81-2.70(m, 1H), 1.91(br d, J=4.4Hz, 1H), 0.73-0.47(m, 4H). [Example]

[0620] [Synthesis of 3-(1-((2-aminoethyl)(cyclopropyl)amino)-3,3,3-trifluoropropyl)-2-fluorobenzonitrile hydrochloride (Compound 280)] 1) ((1-(3-bromo-2-fluorophenyl)vinyl)oxy)triethylsilane

[0621] [ka]

[0622] A dry round-bottom flask flushed with N2 was charged with the desired 1-(3-bromo-2-fluorophenyl)ethanone (2.5 g, 11.5 mmol, 1 equiv) and THF (15 mL). LDA base (2 M, 6.9 mL, 1.2 equiv) was added dropwise, and the reaction was maintained at -70 °C for 1 h. Chloro(triethyl)silane (2.1 g, 13.8 mmol, 2.4 mL, 1.2 equiv) was added to the reaction at -70 °C and stirred at 20 °C for 12 h. TLC showed complete consumption of reactant 1 with the formation of one new spot. The reaction was quenched with 50 mL of saturated aqueous NH4Cl and extracted with ethyl acetate (3 × 80 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g silica flash column, eluent 0–0% ethyl acetate / petroleum ether gradient, 80 mL / min) to afford ((1-(3-bromo-2-fluorophenyl)vinyl)oxy)triethylsilane (1.0 g, 3.1 mmol, 27.0% yield) as a colorless oil.

[0623] 2) 1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropan-1-one

[0624] [ka]

[0625] 1-(Trifluoromethyl)-1,2-benziodoxol-3-one (1.4 g, 4.5 mmol, 1.5 equiv.) and CuSCN (37.9 mg, 301.9 μmol, 0.1 equiv.) were mixed under a N atmosphere. To the mixture was added 1-(3-bromo-2-fluorophenyl)vinyloxy-triethyl-silane (1.0 g, 3.0 mmol, 1 equiv.) and DMF (20 mL). The mixture was stirred at 20 °C for 12 h. TLC showed complete consumption of 2 and the formation of many new spots. The reaction mixture was diluted with 25 mL of H2O and extracted with 75 mL of ethyl acetate (25 mL × 3). The combined organic layers were washed with 20 mL of brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g silica flash column, eluent 0–3% ethyl acetate / petroleum ether gradient, 80 mL / min) to give 1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropan-1-one (530 mg, 1.9 mmol, 61.6% yield) as a yellow oil.

[0626] 3) N-(1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropyl)cyclopropanamine

[0627] [ka]

[0628] 1-(3-Bromo-2-fluorophenyl)-3,3,3-trifluoropropan-1-one (300 mg, 1.1 mmol, 1 equiv.) and cyclopropanamine (90.1 mg, 1.6 mmol, 109.4 μL, 1.5 equiv.) were dissolved in dry DCM (15 mL) under a nitrogen atmosphere. AlMe3 (2 M, 789.4 μL, 1.5 equiv.) was added dropwise to the reaction mixture via syringe. The solution was stirred at 20 °C for 15 h. BH3-Me2S (10 M, 210.5 μL, 2 equiv.) was added dropwise to the reaction mixture. The mixture was stirred at 20 °C for 2 h. LC-MS showed one main peak with the desired m / z. The reaction mixture was quenched by adding 20% aqueous NaOH solution dropwise. The aqueous layer was extracted with CHCl2 (3 × 30 mL). Dry the organic layer over Na2SO4. Remove the solvent under reduced pressure. Purify the residue by flash silica gel chromatography (12 g silica flash column, eluent: 0-3% ethyl acetate / petroleum ether gradient, 60 mL / min) to give N-(1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropyl)cyclopropanamine (120 mg, 368.0 μmol, 35.0% yield) as a yellow oil.

[0629] 4) tert-Butyl (2-((1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropyl)(cyclopropyl)amino)ethyl)carbamate

[0630] [ka]

[0631] To a solution of N-[1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropyl]cyclopropanamine (120 mg, 368.0 μmol, 1 equiv.) and tert-butyl N-(2-oxoethyl)carbamate (175.7 mg, 1.1 mmol, 3 equiv.) in MeOH (2 mL) was added ZnCl (100.3 mg, 735.9 μmol, 34.5 μL, 2 equiv.) and NaBHCN (92.5 mg, 1.5 mmol, 4 equiv.). The mixture was stirred at 20 °C for 12 h. LC-MS showed 4 remaining, with one main peak at the desired m / z. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 5 mL of HO and extracted with 15 mL of ethyl acetate (5 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 4 / 1) to give tert-butyl (2-((1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropyl)(cyclopropyl)amino)ethyl)carbamate (103 mg, 219.5 μmol, 59.7% yield) as a yellow oil.

[0632] 5) tert-Butyl (2-((1-(3-cyano-2-fluorophenyl)-3,3,3-trifluoropropyl)(cyclopropyl)amino)ethyl)carbamate

[0633] [ka]

[0634] A mixture of tert-butyl N-[2-[[1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropyl]cyclopropylamino]ethyl]carbamate (100 mg, 213.1 μmol, 1 equiv.), Zn(CN) (75.1 mg, 639.2 μmol, 40.6 μL, 3 equiv.), Pd(dba) (19.5 mg, 21.3 μmol, 0.1 equiv.), and s-Phos (8.8 mg, 21.1 μmol, 0.1 equiv.) in DMF (3 mL) was degassed and purged with N three times. The mixture was then stirred under N at 120 °C for 12 h. LC-MS showed that 5 was partially consumed and one main peak of the desired m / z was detected. The reaction mixture was quenched by the addition of 10 mL of water at 0 °C and then extracted with 15 mL of ethyl acetate (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl (2-((1-(3-cyano-2-fluorophenyl)-3,3,3-trifluoropropyl)(cyclopropyl)amino)ethyl)carbamate (35 mg, 84.6 μmol, 39.5% yield) as a yellow oil.

[0635] 6) 3-(1-((2-aminoethyl)(cyclopropyl)amino)-3,3,3-trifluoropropyl)-2-fluorobenzonitrile hydrochloride

[0636] [ka]

[0637] A solution of tert-butyl N-[2-[[1-(3-cyano-2-fluoro-phenyl)-3,3,3-trifluoro-propyl]-cyclopropyl-amino]ethyl]carbamate (35 mg, 84.6 μmol, 1 equiv.) in HCl / ethyl acetate (5 mL) was stirred at 20 °C for 1 h. LC-MS showed complete consumption of 6, with one main peak of the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl condition, column: Phenomenex Luna C18 75*30 mm*3 μm, mobile phase: [HO (0.04% HCl)-ACN], gradient: 10%-40% B over 8.0 min) to give 3-(1-((2-aminoethyl)(cyclopropyl)amino)-3,3,3-trifluoropropyl)-2-fluorobenzonitrile hydrochloride (27.7 mg, 78.4 μmol, 93.0% yield, 99.7% purity, HCl) as a yellow oil. MS (ESI): m / z = 316.2 [M+H] + , Retention time: 1.638 minutes, Method: M. 1 H NMR (400MHz, DMSO-d6) δ=8.19-8.05(m, 3H), 8.00(br t, J=7.1Hz, 1H), 7.97-7.89(m, 1H), 7.51-7.42(m, 1H), 4.59(br dd, J=5.6, 8.6Hz, 1H), 3.30-3.02(m, 3H), 2.90(br d, J=5.5Hz, 2H), 2.61-2.51(m, 1H), 1.78-1.66(m, 1H), 0.72-0.40(m, 4H). [Example]

[0638] [Synthesis of N'-[1-(3-bromo-2-fluorophenyl)-2-methylpropyl]-N'-cyclopropylethane-1,2-diamine TFA salt (Compound 294)] 1) 1-(3-bromo-2-fluorophenyl)-2-methylpropan-1-ol

[0639] [ka]

[0640] To a solution of 3-bromo-2-fluorobenzaldehyde (6.8 g, 33.50 mmol, 1 equiv.) in THF (50 mL), i-PrMgBr (1 M, 40.20 mL, 1.2 equiv.) was added dropwise. The mixture was stirred at 0 °C for 2 h. TLC showed complete consumption of 1 and the formation of one large new spot. The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica flash column, eluent 0–3% ethyl acetate / petroleum ether gradient, 100 mL / min) to give 1-(3-bromo-2-fluoro-phenyl)-2-methyl-propan-1-ol (1.9 g, 6.91 mmol, 20.62% yield, 89.84% purity) as a pale yellow oil. 1 H NMR (400MHz, DMSO-d6) δ=7.61-7.54(m, 1H), 7.49-7.43(m, 1H), 7.16(t, J=7.8Hz, 1H), 5.38(d, J=4 .6Hz, 1H), 4.57(t, J=5.4Hz, 1H), 1.91-1.72(m, 1H), 0.87(d, J=6.8Hz, 3H), 0.79(d, J=6.9Hz, 3H).

[0641] 2) 1-(3-bromo-2-fluorophenyl)-2-methylpropan-1-one

[0642] [ka]

[0643] To a solution of 1-(3-bromo-2-fluorophenyl)-2-methyl-propan-1-ol (1.9 g, 7.69 mmol, 1 equiv.) in DCM (20 mL) was added Dess-Martin HCl (6.52 g, 15.38 mmol, 4.76 mL, 2 equiv.). The mixture was stirred at 20 °C for 2 h. LC-MS showed no 2 remaining, with approximately 20% of the desired compound detected. The reaction mixture was filtered to remove insoluble material and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g silica flash column, eluent: 0–0% ethyl acetate / petroleum ether gradient, 80 mL / min) to give 1-(3-bromo-2-fluorophenyl)-2-methyl-propan-1-one (1.3 g, 5.09 mmol, 66.16% yield, 95.91% purity) as a yellow solid.

[0644] 3) N-[1-(3-bromo-2-fluorophenyl)-2-methylpropyl]cyclopropanamine

[0645] [ka]

[0646] To a solution of 1-(3-bromo-2-fluorophenyl)-2-methyl-propan-1-one (1.2 g, 4.90 mmol, 1 equiv.) in MeOH (10 mL) was added cyclopropanamine (419.32 mg, 7.34 mmol, 508.88 μL, 1.5 equiv.) and Ti(i-PrO) (4.17 g, 14.69 mmol, 4.34 mL, 3 equiv.). The mixture was stirred at 60 °C for 12 h, and then NaBHCN (1.23 g, 19.58 mmol, 4 equiv.) was added, and the mixture was stirred at 60 °C for 2 h. LC-MS showed no 3 remaining, and approximately 47% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL of HO and extracted with ethyl acetate (15 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (12 g silica flash column, eluent: 0–3% ethyl acetate / petroleum ether gradient, 80 mL / min) to give N-[1-(3-bromo-2-fluorophenyl)-2-methylpropyl]cyclopropanamine (1.2 g, 3.69 mmol, 75.45% yield, 88.10% purity) as a colorless oil.

[0647] 4) tert-Butyl N-[2-[[1-(3-bromo-2-fluorophenyl)-2-methylpropyl]cyclopropylamino]ethyl]carbamate

[0648] [ka]

[0649] To a solution of N-[1-(3-bromo-2-fluorophenyl)-2-methyl-propyl]cyclopropanamine (600 mg, 2.10 mmol, 1 equiv.) and tert-butyl N-(2-oxoethyl)carbamate (1.33 g, 8.39 mmol, 4 equiv.) in MeOH (8 mL) was added NaBHCN (263.50 mg, 4.19 mmol, 2 equiv.) and ZnCl (571.52 mg, 4.19 mmol, 196.60 μL, 2 equiv.). The mixture was stirred at 20 °C for 12 h. LC-MS showed no 4 remaining, with approximately 84% of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 mL of HO and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl N-[2-[[1-(3-bromo-2-fluorophenyl)-2-methylpropyl]cyclopropylamino]ethyl]carbamate (300 mg, crude) as a colorless oil.

[0650] 5) N'-[1-(3-bromo-2-fluorophenyl)-2-methylpropyl]-N'-cyclopropylethane-1,2-diamine TFA salt

[0651] [ka]

[0652] To a solution of tert-butyl N-[2-[[1-(3-bromo-2-fluoro-phenyl)-2-methyl-propyl]-cyclopropyl-amino]ethyl]carbamate (150 mg, 349.35 μmol, 1 equiv.) in DCM (2 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 38.54 equiv.). The mixture was stirred at 20 °C for 1 h. LC-MS showed no 5 remaining and approximately 60% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 100*40mm*5μm, mobile phase: [HO (0.1% TFA)-ACN], gradient: 25%-55% B, 8.0 min) to obtain N'-[1-(3-bromo-2-fluorophenyl)-2-methylpropyl]-N'-cyclopropylethane-1,2-diamine TFA salt (32.96 mg, 74.27 μmol, yield 21.26%, purity 99.88%, 1 TFA) as a colorless oil. MS (ESI): m / z = 328.1 [M+H] + , Retention time: 1.878 min, Method: Bhalo. 1 H NMR (400MHz, chloroform-d) δ=8.44-7.77(m, 3H), 7.55(t, J=7.0Hz, 1H), 7.30(br t, J=6.6Hz, 1H), 7.09(t, J=7.8Hz, 1H), 3.97(br d, J=10.5Hz, 1H), 3.40(br s, 1H), 3.26(br s, 2H), 2.89-2.75(m, 1H), 2.48-2.32(m, 1H), 1.70-1.60(m, 1H), 1.13-0.97(m, 3H), 0.88(br s, 1H), 0.79-0.59(m, 6H). [Example]

[0653] [LCMS method explanation] The LCMS method specified above is as follows:

[0654] [Table 18-1]

[0655] [Table 18-2]

[0656] [Table 18-3]

[0657] [Table 18-4]

[0658] [Table 18-5]

[0659] [Table 18-6]

[0660] [Table 18-7] [Example]

[0661] [Primary neuronal culture and excitotoxic cell death] Mouse hippocampal primary neurons were prepared as previously described (Bading & Greenberg, Science, 1991; 253:912-914; Zhang et al., Neuron, 2007, 53:549-562), maintained in Neurobasal-A medium supplemented with 2% B27, 5 mM L-Glutamax, and 0.5% penicillin / streptomycin, and stimulated with NMDA at day in vitro (DIV) 10. Glutamate-induced cell death was analyzed in real time by monitoring nuclear-localized mCherry using an IncuCyte® S3 live cell analysis system (Sartorius AG, Germany). Primary neurons seeded in 24-well plates were infected with rAAV-hSyn-mCherry at DIV 3 and stimulated with 10 μM or 20 μM glutamate at DIV 10. All compounds were added to the culture medium 30 min before glutamate / NMDA stimulation. Images were acquired at 2-h intervals for 24 h after glutamate application, with 9–16 images acquired for each condition at each time point using a 20x objective. Cell death was quantified by analyzing the presence of nuclear-localized mCheery using the Basic Analyzer with Incucyte® 2021 software, with size and mean intensity used as exclusion criteria.

[0662] <Compound evaluation> To evaluate the protective effects of various compounds, we developed a quantification method to determine the protective index for each compound. Cell viability was normalized to time 0, and the protective index (0.0–10.0) was calculated by the area under the curve (AAC) during 24 h of excitotoxic stimulation according to the following formula (Figure 2).

[0663]

number

[0664] Here, AAC represents the case of each compound, and AAC basal represents the basal condition without excitotoxicity damage, and AAC Vehrepresents the case of the solvent control with excitotoxicity damage. Based on this formula, the protection index of the solvent (DMSO) is 0.0, and the protection index of compound P401 of WO2020 / 079244 is 6.0 (10 μM). Thus, the inventors classified the compounds into the following categories: A, B, C, and D. A. Protection index of 7.0, providing significantly better protection at 10 μM than compound P401 (10 μM). B. Protection index is 5.0-7.0, providing protection at 10 μM equivalent to that of compound P401 (10 μM). C. Protection index of 3.0-5.0, providing significantly less protection compared to compound P401 (10 μM) at 10 μM. D. Protection index less than 3.0, no significant protection at 10 μM.

[0665] The inventors also performed experiments with Group A compounds at three-fold dilutions (μM: 3.0, 1.0, 0.3, 0.1, 0.03) and were able to achieve similar protective effects as 10 μM of compound P401 at lower concentrations. These compounds were classified as A+, A++, A+++, and A++++ compounds. A+ Protection index of 5.0-7.0, providing protection at 3.0 μM equivalent to that of compound P401 (10 μM). A++ Protection Index: 5.0-7.0, providing protection at 1.0 μM equivalent to that of compound P401 (10 μM). A+++ Protection index of 5.0-7.0, providing protection at 0.3 μM equivalent to that of compound P401 (10 μM). A++++ Protection index of 5.0-7.0, providing protection at 0.1 μM equivalent to that of compound P401 (10 μM). [Example]

[0666] [Biological activities of various compounds] Using the above assay for excitotoxic cell death in primary neuronal cultures, the initial subset of compounds evaluated showed the following results:

[0667] [Table 19]

[0668] In a further series of experiments, a second subset of compounds was evaluated (using the method for assaying excitotoxic cell death in primary neuronal cultures described above) with the following results:

[0669] [Table 20]

[0670] In a further series of experiments, a third subset of compounds was evaluated (using the method for assaying excitotoxic cell death in primary neuronal cultures described above) with the following results:

[0671] [Table 21-1]

[0672] [Table 21-2]

[0673] In this third series of experiments, the biological activity ratings of compounds rated A++++ or better correlate with IC50 (μM) as follows:

[0674] [Table 22] [Example]

[0675] [Neuron death caused by reactive oxygen species (ROS)] ROS are a common cause of neuronal damage, and their accumulation in the brain can lead to neuronal death and neurodegenerative diseases (Barnham et al., Nat Rev Drug Discov, 2004, 3: 205-214; Singh et al., Molecules, 2019, 24(8), 1583). Previous studies have shown that NMDAR mediates ROS-induced neuronal damage (Avshalumov & Rice, J Neurophysiol, 2002, 87: 2896-2903). Therefore, we tested whether an NMDA receptor / TRPM4 interaction inhibitor could provide neuroprotection against ROS toxicity.

[0676] Primary neurons seeded in 24-well plates were infected with rAAV-hSyn-mCherry on DIV3 and stimulated with 300 μM HO on DIV10. All compounds were added to the culture medium 30 min before HO stimulation. Images were acquired at 2-h intervals for 24 h after glutamate application, with 9–16 images acquired for each condition at each time point using a 20x objective. Cell death was quantified by analyzing the presence of nuclear-localized mCherry using the Basic Analyzer with Incucyte® 2021 software, with size and mean intensity used as exclusion criteria.

[0677] Using this assay, the inventors demonstrated that the prior art compound P401 (WO2020 / 079244) provides superior protection against HO injury than the FDA-approved ALS drugs riluzole and edaravone. Furthermore, the compound of the present invention (compound 220) provides even better protection than the prior art compound P401. [Example]

[0678] [Co-immunoprecipitation and disruption of NMDAR / TRPM4 complex formation] Co-immunoprecipitation All co-immunoprecipitation procedures were performed at 4°C. Human iPSC-derived brain organoids were cultured for up to 25 weeks in Falcon® 6-well TC-treated cell culture plates as described (Bauersachs HG et al., Neuroscience, 2022;484:83-97) to abundantly express both luN2A, GluN2B, and TRPM4. Six brain organoids were incubated with 10 μM Compound 120 for 30 minutes, washed twice with ice-cold PBS, and then lysed in 500 μL of immunoprecipitation buffer (10 mM Tris, pH 8.0, 150 mM NaCl, 1 mM EDTA, 1% NP-40, 10% glycerol, EDTA-free protease inhibitor cocktail (Roche)). The lysate was incubated for 60 minutes with rotation and centrifuged at 1,200 × g for 12 minutes to remove cell debris and nuclei. Ten percent of the supernatant was boiled in Laemmli buffer and used for analysis of the input sample. The remainder of the supernatant was mixed overnight with anti-TRPM4 antibody (1:200). The mixture was then incubated with Pierce™ Protein A magnetic beads for an additional 12 hours to pull down the antibody complex and washed with immunoprecipitation buffer to remove nonspecific binding. After the final wash, the supernatant was carefully removed, and the precipitated pellet was boiled in Laemmli buffer. Both the input and precipitated samples were stored at -20°C until analyzed by Western blot.

[0679] Western Blot Input samples and / or immunoprecipitates were separated on 7.5% sodium dodecyl sulfate and polyacrylamide gels (SDS-PAGE), transferred to 0.45 μm nitrocellulose membranes, and finally blotted with the indicated antibodies. Running buffer (mM: 190 glycine, 25 Tris, 0.1% SDS) and transfer buffer (mM: 150 glycine, 20 Tris, 0.1% SDS, 20% methanol) were diluted from 10x stocks.

[0680] Using this co-immunoprecipitation method, the inventors demonstrated that compound 120 disrupts the NMDAR / TRPM4 complex. [Example]

[0681] [Protection of human iPSC-derived organoids] Several human induced pluripotent stem cell (iPSC)-based in vitro models have been used or will be used to investigate the efficacy of the compounds of the present invention in a wide range of neurodegenerative diseases.

[0682] <Human iPSC-derived prefrontal cortex organoids> Prefrontal cortex organoids were generated based on published literature (Bauersachs HG et al., Neuroscience, 2022;484:83-97). At approximately 20 weeks, organoids were preincubated with Compound 120 for 30 minutes and then stimulated with 200 μM NMDA for 24 hours, resulting in 80% neuronal necrosis. Cell death was monitored and analyzed using the RealTime-Glo™ MT Cell Viability Assay (Promega, G9711) according to the manufacturer's instructions, using a plate reader (luciferase). Cell viability (%) can be calculated using the following formula:

[0683]

number

[0684] where F t is the luciferase intensity at each time point, F basal is the basal luciferase intensity before glutamate / NMDA stimulation, and reduces the difference between different organoids. Control and F ControlBasal Since represents the same value in untreated organoids, cell death can be calculated by standardizing to healthy organoids.

[0685] Using this test, the inventors demonstrated that compound 120 improves cell survival after glutamate / NMDA treatment in human iPSC-derived prefrontal cortical organoids compared to the prior art compound P401 (WO2020 / 079244).

[0686] <Human iPSC-derived motor neurons> Human iPSC-derived motor neuron cultures were generated from healthy, sporadic ALS, and SOD1&TDP43&C9orf72 mutation-associated ALS cells based on published studies (Horner SJ et al., Cells, 2021;10(12); Du ZW et al., Nat Commun., 2015;6:6626; Shi Y et al., JCI Insight. 2019;5). iPSCs were cultured and differentiated into motor neurons. They were then treated with 10 μM glutamate on day 17 of differentiation, with or without the compounds of the present invention, to induce glutamate neurotoxicity and cell death. Neuronal viability was tracked using nuclear-expressed mCherry-NLS by Incucyte. Neuronal viability was calculated by the loss of detectable nuclear mCherry fluorescence in the cells. [Example]

[0687] [ALS mouse model] This study uses heterozygous SOD1G93A, C9orf72, and TDP43 transgenic mice (Jackson Laboratory, 004435) on a C57BL / 6 background (Gurney et al., Science, 1994;264(5166):1772-5; Pitzer C et al., Brain, 2008;131(Pt 12):3335-47). Heterozygosity was maintained by mating heterozygous transgenic males with C57BL / 6 wild-type females. Animals are group-housed (maximum of 3 per cage) in standard cages (15 x 21 x 13.5 cm) on a 12:12-h light:dark cycle with free access to food, water, and nesting material. Animals are randomly assigned to treatment groups. The compounds of the present invention are administered to animals at different doses (0.1, 0.3, 1, 3, 10, and 30 mg per kilogram of body weight per day) before and after the onset of disease. The humane endpoint is defined as the inability of the mice to recover on their own within 30 seconds. Mice are examined daily after the onset of paralysis without knowledge of treatment group. [Example]

[0688] [Mouse model of retinal ganglion cell (RGC) degeneration] C57BL / 6J mice were administered vehicle (40% propylene glycol) or the above-described compounds of the present invention (40 mg / kg body weight, dissolved in 40% propylene glycol) by intraperitoneal injection in a volume of 50 μL per injection at -16 h, -3 h, 0 h (intravitreal NMDA / saline injection), +3 h, and +24 h. At 0 h, the left eye of the mice received an intravitreal injection of 20 nmol of NMDA / glutamate (total volume 2.0 μL), and the right eye received saline (total volume 2.0 μL). Seven days after the intravitreal injection, both eyes were enucleated from euthanized mice, and the retinas were dissected and fixed in formalin for 15 minutes before being processed for whole-mount immunohistochemistry. Retinas were incubated in blocking solution (10% normal donkey serum and 1% Triton-X 100 in PBS) for 6 hours, followed by 24 hours of incubation with anti-Brn3a antibody in blocking solution at 4°C. Retinas were then washed three times with PBS and incubated with donkey anti-rabbit Alexa Fluor-594 for 24 hours at room temperature. Retinas were washed again, excised, and mounted on slides. For each retina, images were acquired from eight fields (554 μm × 554 μm) around the peripheral retina (two from each quadrant located approximately 600 μm and 1400 μm from the macular hole), minimizing the impact of location-related variations in RGC density on cell counts. All images were acquired using the HC PL APO 20x objective on a Leica TCS SP8LIA DM6 CFS upright confocal microscope with Las X software. Brn3a-positive cells were identified and counted using a CellProfiler macro. Data analysis will be performed on a single-blind basis without any information being given. [Example]

[0689] [More compounds] In further synthetic rounds, the inventors synthesize the following inventive compounds and evaluate their activity:

[0690]

change

Claims

1. A compound according to the following general formula I, 【Chemistry 1】 Here, R ７ teeth, 【Chemistry 2】 Selected from, R １ 、 R ２ 、 R ３ and R ４ are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, R １ 、 R ２ 、 R ３ and R ４ at least one of which is selected from F, Cl, Br, I, -CN and ethynyl, R ５ This refers to unsubstituted branched or linear C １ -C ４ Alkyl, fluorine-substituted branched or linear C13C1 １ -C ４ Alkyl, unsubstituted propenyl, unsubstituted C ３ -C ６ Cycloalkyl and fluorine-substituted C ３ -C ６ Selected from cycloalkyl groups, R ６ This refers to unsubstituted branched or linear C ２ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, However, R ５ is methyl, R ７ but 【Transformation 3】 And R ２ and R ３ One of them is H, and the other is F, Cl or -CN, and R1 and R ４ If H, then R ６ This is an unsubstituted linear C ３ -C ６ Alkyl, unsubstituted branched C ４ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ４ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, However, R ５ is methyl, R ７ but 【Chemistry 4】 and R １ 、R ２ 、R ３ 、and R ４ two of which are Cl and the other two are H, R １ and R ２ 、R ３ and R ４ 、R １ and R ３ 、or R ２ and R ４ if any of them is Cl, R ６ is unsubstituted branched or straight-chain C ３ -C<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ However, R ５ is methyl, R ７ but 【Transformation 5】 And R １ and R ４ One of them is H, and the other is F or Br, R ２ and R ３ If H, then R ６ This is an unsubstituted linear C ３ -C ６ Alkyl, unsubstituted branched C ４ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ４ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, However, R ５ is ethyl, and R ７ but 【Transformation 6】 And R ２ and R ３ One of them is H, the other is Cl, and R １ and R ４ If H, then R ６ This is an unsubstituted linear C ３ -C ６ Alkyl, unsubstituted branched C ３ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, A substituted alkyl group refers to an alkyl group in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted cycloalkyl refers to a cycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted bicycloalkyl refers to a bicycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted alkylcycloalkyl refers to an alkylcycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted alkenyl refers to an alkenyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. and compounds that are pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers, hydrates, and / or isotopes of any of these compounds.

2. i) R １ , R ２ , R ３ and R ４ Each of these is independently selected from H, F, Cl, Br, I, and -CN. ii) At least one of R1, R2, R3, and R4 is ethynyl, or iii) The compound according to claim 1, wherein two of R1, R2, R3, and R4 are independently selected from H, F, Cl, Br, I, -CN, and ethynyl.

3. R ７ but 【Transformation 7】 i) R ２ and R ３ The compound according to claim 1, wherein one of is selected from H, F, Cl, Br, I, -CN and ethynyl, and the other is H, and / or ii) at least two of R1, R2, R3 and R4 are H, and one of R2 and R3 is Cl.

4. R １ is H or F, R ２ The compound according to claim 1, wherein is selected from F, Cl, Br, I, CN, and ethynyl.

5. R 7 is 【Transformation 8】 And R ４ is H or F, R ３ The compound according to claim 1, wherein is selected from F, Cl, Br, I, CN, and ethynyl.

6. i) R １ F is R ２ Cl is and R ３ and R ４ is H, or ii) R １ and R ２ H is R ３ Cl is and R ４ The compound according to claim 1, wherein F is present.

7. R ５ This refers to unsubstituted branched or linear C １ -C ４ Alkyl, fluorine-substituted branched or linear C13C1 １ -C ４ Alkyl, unsubstituted C ３ -C6 cycloalkyl and fluorine-substituted C ３ -C ６ A compound according to claim 1, selected from cycloalkyl groups.

8. R ５ Methyl, ethyl, isopropyl, -CH ２ CF ３ , -CF ２ CF ３ , -CF ２ CH ３ ,-CHF ２ , -CF ３ The compound according to claim 1, selected from cyclopropyl, fluorine-substituted isopropyl, propenyl, cyclopropyl, cyclobutyl, fluorine-substituted cyclobutyl, and cyclopentyl.

9. R ６ However, unsubstituted branched or linear C ３ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Branched or linear C selected and substituted from alkenyls ２ -C ６ Alkyl, substituted C ３ -C ６ Cycloalkyl, substituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl and substituted C ３ -C ６ The compound according to claim 1, wherein each of the alkenyl substituents is independently selected from F, Cl, CN, OH, alkylthio, and alkoxy.

10. The compound, 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 【Chemistry 9-4】 The compound according to claim 1, selected from the group consisting of a pharmaceutically acceptable salt, racemate, or (R)- or (S)-enantiomer of any of these compounds.

11. The compound according to any one of claims 1 to 10, wherein the pharmaceutically acceptable salt is selected from halides, formates, and trifluoroacetates.

12. A compound for use in methods of treating or preventing diseases of the human or animal body, wherein the compound is a compound of the following general formula I: 【Chemistry 10】 Here, R ７ teeth, 【Chemistry 11】 Selected from, here, R １ , R ２ , R ３ and R ４ Each is independently selected from H, F, Cl, Br, I, -CN and ethynyl, R ５ This refers to unsubstituted branched or linear C １ -C ４ Alkyl, fluorine-substituted branched or linear C13C1 １ -C ４ Alkyl, unsubstituted propenyl, unsubstituted C ３ -C ６ Cycloalkyl and fluorine-substituted C ３ -C ６ Selected from cycloalkyl groups, R ６ This refers to unsubstituted branched or linear C ２ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, A substituted alkyl group refers to an alkyl group in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted cycloalkyl refers to a cycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted bicycloalkyl refers to a bicycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted alkylcycloalkyl refers to an alkylcycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted alkenyl refers to an alkenyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. Alternatively, a compound for use in which the compound is a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer of the compound of formula I.

13. i) R １ , R ２ , R ３ and R ４ Each of these is independently selected from H, F, Cl, Br, I, and -CN. ii) At least one of R1, R2, R3, and R4 is ethynyl, or iii) The compound for use according to claim 12, wherein two of R1, R2, R3, and R4 are each independently selected from H, F, Cl, Br, I, -CN, and ethynyl.

14. R ７ but 【Chemistry 12】 i) R ２ and R ３ The compound for use according to claim 12, wherein one of is selected from H, F, Cl, Br, I, -CN and ethynyl, and the other is H, and / or ii) at least two of R1, R2, R3 and R4 are H, and one of R2 and R3 is Cl.

15. R １ is H or F, R ２ The compound for use according to claim 12, wherein is selected from F, Cl, Br, I, CN, and ethynyl.

16. R 7 is 【Chemistry 13】 And R ４ is H or F, R ３ The compound for use according to claim 12, wherein is selected from F, Cl, Br, I, CN, and ethynyl.

17. i) R １ F is R ２ Cl is and R ３ and R ４ is H, or ii) R １ and R ２ H is R ３ Cl is and R ４ The compound for use according to claim 12, wherein F is present.

18. R ５ However, unsubstituted branched or linear C １ -C ４ Alkyl, fluorine-substituted branched or linear C13C1 １ -C ４ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl and fluorine-substituted C ３ -C ６ A compound for use according to claim 12, selected from cycloalkyl groups.

19. R ５ Methyl, ethyl, isopropyl, -CH ２ CF ３ , -CF ２ CF ３ , -CF ２ CH ３ ,-CHF ２ , -CF ３ A compound for use according to claim 12, selected from cyclopropyl, fluorine-substituted isopropyl, propenyl, cyclopropyl, cyclobutyl, fluorine-substituted cyclobutyl, and cyclopentyl.

20. R ６ However, unsubstituted branched or linear C ３ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Branched or linear C selected and substituted from alkenyls ３ -C ６ Alkyl, substituted C ３ -C ６ Cycloalkyl, substituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl and substituted C ３ -C ６ The compound for use according to claim 12, wherein the substituents of the alkenyl are each independently selected from F, Cl, CN, OH, alkylthio, and alkoxy.

21. The compound is the compound described in claim 1, or the compound is 【Chemistry 14】 The compound for use according to claim 12, which is a pharmaceutically acceptable salt thereof, a racemate, or a (R)- or (S)-enantiomer thereof.

22. The compound, 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 【Chemistry 15-4】 A compound for use according to claim 12, selected from the group of compounds comprising any pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer of these compounds.

23. The compound for use according to claim 12, wherein the pharmaceutically acceptable salt is selected from halides, formates, and trifluoroacetates.

24. The compound for use according to claim 12, wherein the disease is a neurological disease, the disease is a neurodegenerative disease, and / or the disease is treated by inhibiting the formation of an NMDA receptor / TRPM4 complex.

25. Diseases include stroke, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), traumatic brain injury, post-traumatic brain injury, mental fogginess, age-related memory loss, age-related memory decline, progressive nuclear palsy, multiple sclerosis, thalamic degeneration, glutamate-induced excitotoxicity, dystonia, epilepsy, optic nerve disease, diabetic retinopathy, glaucoma, pain, anti-NMDA receptor encephalitis, viral encephalopathy, dementia (e.g., post-stroke dementia, HIV dementia, Creutzfeldt-Jakob dementia, Lewy body dementia (DLB), dementia with frontal lobar degeneration including Pick's disease, corticobasal degeneration, vascular dementia, microvascular disease, Binswanger's disease, cerebral ischemia, hypoxia, Parkinson's disease, and Batten Compounds for use according to any one of claims 12 to 24, selected from the group consisting of diseases, schizophrenia, Korsakoff psychosis, depression, cerebral malaria, toxoplasmosis (due to the risk of toxoplasmosis-related brain damage), HIV infection / AIDS (due to the risk of HIV)-related brain damage, Zika virus infection (due to the possibility of Zika virus-related brain damage), other viral infections that may cause neurodegenerative events and associated neuronal or brain damage, such as viral meningitis and SARS-CoV-2 virus-induced encephalitis, central nervous system disorders such as brain tumors, anxiety, tension and depressive states, sexual dysfunction, sleep disorders, and pathological disorders due to ingestion of food, irritants and toxic substances.

26. The compound for use according to claim 25, i) stroke is selected from ischemic stroke and hemorrhagic stroke, ii) pain is neuropathic pain, iii) schizophrenia is schizophrenia with dementia, and iv) brain tumor is glioblastoma.

27. A compound according to the following general formula II, 【Chemistry 16】 Here, R ７ teeth, 【Chemistry 17】 Selected from, R １ , R ２ , R ３ and R ４ Each is independently selected from H, F, Cl, Br, I, -CN and ethynyl, and R １ , R ２ , R ３ and R ４ At least one of is selected from F, Cl, Br, I, -CN and ethynyl, R ５ This refers to unsubstituted branched or linear C １ -C ４ Alkyl, fluorine-substituted branched or linear C13C1 １ -C ４ Alkyl, unsubstituted propenyl, unsubstituted C ３ -C ６ Cycloalkyl and fluorine-substituted C ３ -C ６ Selected from cycloalkyl groups, R ６ H, unsubstituted branched or linear C ２ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, However, R ５ is methyl, R ７ but [Chemistry 18] And R ２ and R ３ One of them is H, the other is Cl, and R １ and R ４ If H, then R ６ This is an unsubstituted linear C ３ -C ６ Alkyl, unsubstituted branched C ４ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ４ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, However, R ５ is methyl, R ７ but 【Chemistry 19】 And R １ , R ２ , R ３ , and R ４ Two of them are Cl, and the other two are H, R １ and R ２ , R ３ and R ４ , R １ and R ３ , or R ２ and R ４ If either of the following is Cl, then R ６ This refers to unsubstituted branched or linear C ３ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, However, R ５ is methyl, R ７ but 【Chemistry 20】 And R １ and R ４ Cl is and R ２ and R ３ If one of them is H and the other is F, then R ６ This refers to unsubstituted branched or linear C ２ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, However, R ５ is methyl, R ７ but 【Chemistry 21】 And R １ and R ４ One of them is H and the other is F, R ２ and R ３ If Cl, then R ６ This refers to unsubstituted branched or linear C ２ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, R ５ is methyl, R １ and R ４ One of them is H, the other is Cl, and R ２ and R ３ If H, then R ６ This refers to unsubstituted branched or linear C ２ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, However, R ５ is ethyl, and R ２ and R ３ One of them is H, the other is Cl, and R １ and R ４ If H, then R ６ This is an unsubstituted linear C ３ -C ６ Alkyl, unsubstituted branched C ３ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, A substituted alkyl group refers to an alkyl group in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted cycloalkyl refers to a cycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted bicycloalkyl refers to a bicycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted alkylcycloalkyl refers to an alkylcycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted alkenyl refers to an alkenyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. and compounds that are salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes of these compounds.

28. The following compounds are represented by general formula III or general formula IV: 【Chemistry 22】 Here, R ７ teeth, 【Chemistry 23】 Selected from, R １ , R ２ , R ３ and R ４ Each is independently selected from H, F, Cl, Br, I, -CN and ethynyl, and R １ , R ２ , R ３ and R ４ At least one of is selected from F, Cl, Br, I, -CN and ethynyl, R ５ This refers to unsubstituted branched or linear C １ -C ４ Alkyl, fluorine-substituted branched or linear C13C1 １ -C ４ Alkyl, unsubstituted propenyl, unsubstituted C ３ -C ６ Selected from cycloalkyl and fluorine-substituted C3-C6 cycloalkyl groups, R ６ H, unsubstituted branched or linear C ２ -C ６ Alkyl, substituted branched or linear C ２ -C ６ Alkyl, unsubstituted C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, unsubstituted C ４ -C ８ Bicycloalkyl, substituted C ４ -C ８ Bicycloalkyl, unsubstituted C ４ -C ７ Alkylcycloalkyl, substituted C ４ -C ７ Alkylcycloalkyl, unsubstituted C ３ -C ６ Alkenyl and substituted C ３ -C ６ Selected from Alkenil, A substituted alkyl group refers to an alkyl group in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted cycloalkyl refers to a cycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted bicycloalkyl refers to a bicycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted alkylcycloalkyl refers to an alkylcycloalkyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. A substituted alkenyl refers to an alkenyl in which one or more hydrogen atoms are independently substituted with -OH, -F, -Cl, -Br, -I, -NH₂, -NO₂, -CO₂H, -CO₂CH₃, -CN, -OCH₃, -SCH₃, -OCH₂CH₃, -C(O)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -OC(O)CH₃, -NHC(O)CH₃, -S(O)₂CH₃, or -S(O)₂NH₂. Compounds that are salts thereof, racemates, (R)- or (S)-enantiomers, hydrates or isotopes thereof.

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