Efficient methods of modulating NMDA receptor mediated toxicity

Abstract

The present invention relates to compounds that inhibit the toxic activity of the extrasynaptic NMDA receptor, in particular by inhibiting the formation of the NMDA receptor / TRPM4 complex. In particular, the present invention relates to diamino compounds according to general formula I and their use in medicine, in particular for the treatment of nervous system diseases, such as neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to the field of neurodegenerative processes and protection against such processes. In particular, the present invention relates to compounds that inhibit the toxic activity of extrasynaptic NMDA receptors, in particular by inhibiting the formation of NMDA receptor / TRPM4 complexes. More specifically, the present invention relates to diamine compounds according to general formula I and their use in medicine, in particular for the treatment of diseases of the nervous system, such as neurodegenerative diseases. Background Art

[0002] Neurodegenerative diseases are destructive disorders involving the progressive loss of neuronal structure or function and the eventual death of neurons. Neurodegeneration may be acute or slowly progressive, but both types of neurodegeneration generally involve increased death signaling by extrasynaptic NMDA receptors caused by elevated extracellular glutamate concentrations or relocalization of NMDA receptors to extrasynaptic sites. NMDA receptors are glutamate- and voltage-gated ion channels that are permeable to calcium. They can be divided into synaptic and extrasynaptic NMDA receptors based on their subcellular location. The subunit composition of receptors inside and outside synaptic contacts is similar, but in addition to carrying the common glutamate ion channel receptor NMDA-type subunit 1 (GRIN1) subunit, extrasynaptic NMDA receptors preferentially contain GRIN2B subunits, while GRIN2A is the major subunit of synaptic NMDA receptors. The cellular consequences of synaptic and extrasynaptic NMDA receptor stimulation are distinct. Synaptic NMDA receptors induce physiological changes in the efficacy of synaptic transmission. They also trigger calcium signaling pathways to the nucleus that activate gene expression responses that are critical for the long-term implementation of nearly all behavioral adaptations. Most importantly, synaptic NMDA receptors, acting via nuclear calcium, are strong activators of neuronal structural protective genes and survival-promoting genes. In stark contrast, extrasynaptic NMDA receptors trigger cell death pathways. Within minutes of extrasynaptic NMDA receptor activation, mitochondrial membrane potential is disrupted, followed by mitochondrial permeability transition. Extrasynaptic NMDA receptors also strongly antagonize excitation-transcription coupling and disrupt nuclear calcium-driven adaptive genomics because they trigger the cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) shutdown pathway, inactivate extracellular signal-regulated kinase (ERK)-MAPK signaling, and lead to nuclear import of class IIa histone deacetylases (HDACs) and the proapoptotic transcription factor Foxo3A. This affects the regulation of the activity of many genes, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor D (VEGFD), which are essential for maintaining complex dendritic architecture and synaptic connectivity and establishing a neuroprotective barrier. Furthermore, because activated ERK1 / 2 have a short range of action, shutting down ERK1 / 2 by extrasynaptic NMDA receptors disrupts important local signaling events, including dendritic mRNA translation and trafficking of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, which controls the efficacy of synaptic transmission. Thus, extrasynaptic NMDA receptor signaling is characterized by the initiation of a pathological triad of mitochondrial dysfunction, transcriptional dysregulation, and loss of neuronal structural and connectivity integrity.

[0003] Some attempts have been made to treat neurological disorders using blockers of NMDA receptors. In general, the results of clinical studies have been disappointing, mainly due to serious side effects caused by blockers interfering with the physiological functions of synaptic NMDA receptors (Ogden and Traynelis, 2011). A notable exception is the NMDA receptor antagonist memantine (Bormann, 1989). Beneficial effects of low-dose memantine treatment have been observed in several neurodegenerative animal models, including experimental autoimmune encephalomyelitis (EAE) models of Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and MS. In addition, memantine has been approved by the European Medicines Agency and the U.S. Food and Drug Administration (FDA) for the treatment of AD since 2002. The finding that memantine preferentially blocks toxic extrasynaptic NMDA receptors over a range of concentrations explains why it is effective in a wide range of neurodegenerative disorders that share toxic extrasynaptic NMDA receptor signaling as a pathogenic mechanism (Bading, J Exp Med. 2017 Mar 6;214(3):569-578).

[0004] It has recently been discovered that excitotoxicity requires physical coupling of the NMDA receptor and TRPM4, a transient receptor potential channel (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 that is located just below the plasma membrane. Yan et al. also found that this interaction could be inhibited by various methods and provided protection against excitotoxic cell death in cultured neurons and in vivo in a mouse model of neurodegeneration. The methods proposed by Yan et al. include peptide-derived inhibitors of the NMDA receptor / TRPM4 interaction as well as small molecule compounds.

[0005] However, although the compounds identified by Yan et al. exhibit inhibitory activity, there is still a need in the art for other methods of selectively inhibiting the NMDA receptor / TRPM4 interaction, thereby specifically attenuating the toxic activity of extrasynaptic NMDA receptors. Therefore, the problem to be solved by the present invention is to provide new, preferably improved methods for attenuating extrasynaptic toxic NMDA receptor activity. Summary of the invention

[0006] This problem is solved by the subject matter of the attached claims and the following description.

[0007] As will be shown below, the inventors of the present invention have identified novel compounds which are surprisingly very effective in inhibiting NMDA receptor-mediated toxicity and are therefore particularly useful candidates for the treatment and prevention of diseases involving NMDA receptor-mediated cytotoxicity.

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

[0009]

[0010] in:

[0011] R 7 Selected from

[0012] And among them

[0013] R 1 , R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and wherein R 1 , R 2 , R 3 and R 4 At least one of them is selected from: F, Cl, Br, I, -CN and ethynyl;

[0014] R 5 Selected from H, unsubstituted branched or linear C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted propenyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine substituted C 3 -C 6 Cycloalkyl;

[0015] R 6 Selected from unsubstituted branched or straight chain C 2 -C 6 Alkyl, substituted branched or straight chain 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 -C7 Alkylcycloalkyl, substituted C 4 -C 7 Alkylcycloalkyl, unsubstituted C 3 -C 6 Alkenyl and substituted C 3 -C 6 alkenyl;

[0016] The condition is that if R 5 is methyl, R 7 yes R 2 and R 3 One of them is H, the other is Cl, and R 1 and R 4 is H, then R 6 Selected from unsubstituted straight chain C 3 -C 6 Alkyl, unsubstituted branched C 4 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl; even more preferably: if R 5 is methyl, R 7 yes R 2 and R 3 One of them is H, the other is F, Cl or -CN, and R 1 and R 4 is H, then R 6 Selected from unsubstituted straight chain C 3 -C 6 Alkyl, unsubstituted branched C 4 -C 6 Alkyl, substituted branched or straight chain 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 alkenyl;

[0017] A further condition is that if R 5 is methyl, R 7 yes R 1 , R 2 , R 3 and R 4 Two of them are Cl, and the other two are H, where R 1 and R 2 , R 3 and R 4 , R 1 and R 3 or R 2 and R 4 is Cl, then R 6 Selected from unsubstituted branched or straight chain C 3 -C 6 Alkyl, substituted branched or straight chain 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 alkenyl;

[0018] The optional condition is that if R5 is methyl, R 7 yes R 1 and R 4 One of them is H, the other is F or Br, and R 2 and R 3 is H, then R 6 Selected from unsubstituted straight chain C 3 -C 6 Alkyl, unsubstituted branched C 4 -C 6 Alkyl, substituted branched or straight chain 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 alkenyl;

[0019] A further condition is that if R 5 is ethyl, R 7 yes R 2 and R 3 One of them is H, the other is Cl, and R 1 and R 4 is H, then R 6 Selected from unsubstituted straight chain C 3 -C 6 Alkyl, unsubstituted branched C 3 -C 6 Alkyl, substituted branched or straight chain 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 C4 -C 7 Alkylcycloalkyl, substituted C 4 -C 7 Alkylcycloalkyl, unsubstituted C 3 -C 6 Alkenyl and substituted C 3 -C 6 alkenyl;

[0020] A further condition is that if R 5 Yes H, R 7 yes The compound then has one of the following formulae:

[0021]

[0022]

[0023] 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.

[0024] The term "unsubstituted alkyl" or "alkyl", when used without the "substituted" modifier, refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, having a straight or branched acyclic structure, and having no atoms other than carbon and hydrogen. 3 (Me), -CH 2 CH 3 (Et), -CH 2 CH 2 CH 3 (nPr or propyl), -CH(CH 3 ) 2 (iPr, iPr or isopropyl), -CH 2 CH 2 CH 2 CH 3 (nBu), -CH(CH 3 )CH 2 CH 3 (sec-butyl), -CH 2 CH(CH 3 ) 2 (isobutyl), -C(CH 3 ) 3 (tert-butyl, t-butyl, t-Bu or t-Bu) and -CH 2 C(CH 3 ) 3(neopentyl) is a non-limiting example of an alkyl group. When "alkyl" is used with the "substituted" modifier, unless otherwise indicated, one or more hydrogen atoms are independently replaced by -OH, -F, -Cl, -Br, -I, -NH 2 、-NO 2 , -CO 2 H, -CO 2 CH 3 、-CN、-OCH 3 、-SCH 3 、-OCH 2 CH 3 、-C(O)CH 3 、-NHCH 3 、-NHCH 2 CH 3 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)NHCH 3 、-C(O)N(CH 3 ) 2 、-OC(O)CH 3 、-NHC(O)CH 3 、-S(O) 2 CH 3 or -S(O) 2 NH 2 Preferably, only one hydrogen atom is substituted. Most preferably, only one hydrogen atom on the terminal carbon atom is substituted. "Fluoro-substituted" alkyl refers to an alkyl group in which one or more hydrogen atoms are independently substituted by -F. In the case of fluorine-substituted alkyl groups, preferably more than one hydrogen atom is substituted by -F. Even more preferably, more than two hydrogen atoms are substituted by -F. A particularly preferred embodiment of fluorine-substituted alkyl groups is -CF 3 , -CHF 2 、-CH 2 CF 3 , -CF 2 CH 3 and -CF 2 CF 3 .

[0025] The term "unsubstituted alkenyl" or "alkenyl", when used without the "substituted" modifier, refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, having 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=CH 2 (vinyl), -CH=CHCH 3 、-CH=CHCH2 CH 3 、-CH 2 CH=CH 2 (allyl), -CH 2 CH=CHCH 3 and -CH=CHCH=CH 2 Preferably, the structure contains only one non-aromatic carbon-carbon double bond, preferably at the end of the structure, such as an allyl group. When "alkenyl" is used with the "substituted" modifier, unless otherwise indicated, one or more hydrogen atoms are independently replaced by -OH, -F, -Cl, -Br, -I, -NH 2 、-NO 2 , -CO 2 H, -CO 2 CH 3 、-CN、-OCH 3 、-SCH 3 、-OCH 2 CH 3 、-C(O)CH 3 、-NHCH 3 、-NHCH 2 CH 3 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)NHCH 3 、-C(O)N(CH 3 ) 2 、-OC(O)CH 3 、-NHC(O)CH 3 、-S(O) 2 CH 3 or -S(O 2 )NH 2 Preferably, only one hydrogen atom is substituted. Most preferably, only one hydrogen atom located at a terminal carbon atom is substituted. In the case of fluorine-substituted alkenyl, preferably more than one hydrogen atom is substituted by -F. Even more preferably, more than two hydrogen atoms (such as 3) are substituted by -F.

[0026] As used herein, the term "unsubstituted cycloalkyl" or "cycloalkyl", when used without the "substituted" modifier, refers to a monovalent saturated aliphatic group having a carbon atom as the point of attachment, the carbon atom forming part of a single non-aromatic ring structure, having no carbon-carbon double or triple bonds, and having no atoms other than carbon and hydrogen. Non-limiting examples include: -CH(CH 2 ) 2When "cycloalkyl" is used with the "substituted" modifier, unless otherwise indicated, one or more hydrogen atoms are independently replaced by -OH, -F, -Cl, -Br, -I, -NH 2 、-NO 2 , -CO 2 H, -CO 2 CH 3 、-CN、-OCH 3 、-SCH 3 、-OCH 2 CH 3 、-C(O)CH 3 、-NHCH 3 、-NHCH 2 CH 3 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)NHCH 3 、-C(O)N(CH 3 ) 2 、-OC(O)CH 3 、-NHC(O)CH 3 、-S(O) 2 CH 3 or -S(O 2 )NH 2 Preferably, only one hydrogen atom is substituted. "Fluoro-substituted" cycloalkyl refers to a cycloalkyl in which one or more hydrogen atoms are independently substituted by -F. In the case of fluorine-substituted cycloalkyl, preferably more than one hydrogen atom is substituted by -F. Even more preferably, more than two hydrogen atoms (such as 3) are substituted by -F.

[0027] As used herein, the term "unsubstituted bicycloalkyl" or "bicycloalkyl", when used without the "substituted" modifier, refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, the carbon atom forming part of two non-aromatic ring structures, having no carbon-carbon double or triple bonds, and having no atoms other than carbon and hydrogen. A non-limiting example is bicyclo[1.1.1]pentane. When "bicycloalkyl" is used with the "substituted" modifier, unless otherwise indicated, one or more hydrogen atoms are independently replaced by -OH, -F, -Cl, -Br, -I, -NH 2 、-NO 2 , -CO 2 H, -CO 2 CH 3 、-CN、-OCH 3 、-SCH 3 、-OCH 2 CH3 、-C(O)CH 3 、-NHCH 3 、-NHCH 2 CH 2 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)NHCH 3 、-C(O)N(CH 3 ) 2 、-OC(O)CH 3 、-NHC(O)CH 3 、-S(O) 2 CH 3 or -S(O) 2 NH 2 Preferably, only one hydrogen atom is substituted. In the case of a -F substituted cycloalkyl, preferably more than one hydrogen atom is substituted by -F. Even more preferably, more than two hydrogen atoms (such as 3) are substituted by -F.

[0028] As used herein, the term "unsubstituted alkylcycloalkyl" or "alkylcycloalkyl", when used without the "substituted" modifier, refers to an alkyl group as defined above having at least two carbon atoms with the first carbon atom as the point of attachment, wherein the other terminal carbon atom of the alkyl group forms part of a non-aromatic ring structure. Non-limiting examples include: -CH 2 -CH(CH 2 ) 2 (cyclopropylmethyl), cyclobutylmethyl, cyclopentylethyl or cyclohexylmethyl. When "alkylcycloalkyl" is used with the "substituted" modifier, unless otherwise indicated, one or more hydrogen atoms are independently replaced by -OH, -F, -Cl, -Br, -I, -NH 2 、-NO 2 , -CO 2 H, -CO 2 CH 3 、-CN、-OCH 3 、-SCH 3 、-OCH 2 CH 3 、-C(O)CH 3 、-NHCH 3 、-NHCH 2 CH 3 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)NHCH 3 、-C(O)N(CH 3 )2 、-OC(O)CH 3 、-NHC(O)CH 3 、-S(O) 2 CH 3 or -S(O) 2 NH 2 Preferably, only one hydrogen atom is substituted. Most preferably, only one hydrogen atom is substituted on a carbon atom of the non-aromatic ring structure. In the case of -F substituted alkylcycloalkyl, preferably one or more hydrogen atoms are substituted by -F. Even more preferably, two or more hydrogen atoms (such as 3) are substituted by -F.

[0029] Exemplary of compounds having Formula I are compounds having Formula Ia or Ib:

[0030]

[0031] Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is defined above in Formula I, or more specifically defined below in Formula I, Ia and / or Ib,

[0032] and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers, hydrates and / or isotopes of any of these compounds.

[0033] In a preferred embodiment of the present invention, R in the compounds of the present invention according to formula I, Ia or Ib 1 , R 2 , R 3 and R 4 Each is independently selected from H, F, Cl, Br, I and -CN. The skilled person will appreciate that whenever "R 1 , R 2 , R 3 and R 4 " in the context of Formula Ib shall be interpreted as "R 1 and R 2 ", because there is no R in Formula Ib 3 or R 4 In the above embodiment, this means that R in Formula Ib 1 and R 2 Each is independently selected from H, F, Cl, Br, I and -CN. In some embodiments of the compounds of the invention according to Formula I, Ia or Ib, R 1 , R 2 , R 3 and R4 At least one of them is an ethynyl group, preferably wherein R 2 In other embodiments of each of Formulas I, Ia and Ib, R 1 , R 2 , R 3 and R 4 In some embodiments of Formula Ia, two of R are independently selected from H, F, Cl, Br, I, -CN and ethynyl. 2 and R 3 One of the R is selected from H, F, Cl, Br, I, -CN and ethynyl, and the other is H. In a further embodiment of Formula Ia, R 1 , R 2 , R 3 and R 4 At least two of them are H, R 2 and R 3 In some embodiments, R 1 is H or F, preferably F, and R 2 is selected from F, Cl, Br, I, CN and ethynyl, preferably selected from Cl, Br, CN and ethynyl. In some embodiments of Formula Ia, R 4 is H or F, preferably F, and R 3 is selected from F, Cl, Br, I, CN and ethynyl, preferably selected from Cl, Br, CN and ethynyl. In some embodiments of Formula Ia, R 1 It's F, R 2 is Cl, and R 3 and R 4 is H, or R 1 and R 2 Yes H, R 3 is Cl, and R 4 It's F.

[0034] R of the compounds of the invention according to formula I, Ia or Ib 5 Can be selected from H, unsubstituted branched or linear C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 In a preferred embodiment of the present invention, R of the compounds of the present invention according to formula I, Ia or Ib is 5 Selected from unsubstituted branched or straight chain C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C1 -C 4 Alkyl, unsubstituted propenyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 In some embodiments of the compounds of the invention according to Formula I, Ia or Ib, R 5 is H. In some embodiments of the compounds of the invention according to Formula I, Ia or Ib, R 5 In some embodiments of the compounds of the invention according to Formula I, Ia or Ib, R 5 Selected from ethyl, isopropyl, -CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CH 3 , -CHF 2 , -CF 3 , cyclopropyl, fluorine-substituted isopropyl, propenyl, cyclopropyl, cyclobutyl, fluorine-substituted cyclobutyl and cyclopentyl. In particular, in R 5 If it is not H, R 1 , R 2 , R 3 and R 4 Preferably each is independently selected from H, F, Cl, Br and -CN and optionally ethynyl. Likewise, in particular when R 5 When it is not H, R is also assumed 1 , R 2 , R 3 and R 4 At least two of them are H, and R 2 and R 3 One or two of, preferably one of, Cl or Br. For example, R 1 Can be F, R 2 Can be Cl, and R 3 and R 4 is H. Another example is R 1 and R 2 Yes H, R 3 is Cl, and R 4 is F. In a particularly preferred embodiment, R 5 Selected from unsubstituted branched or straight chain C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl and unsubstituted propenyl.

[0035] Preferably, R of the compounds of the invention according to formula I, Ia or Ib is 6 is not an unsubstituted ethyl group, i.e., is selected from an unsubstituted straight chain C 3 -C 6 Alkyl, unsubstituted branched C 4 -C 6 Alkyl, substituted branched or straight chain 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 In the compounds of the invention according to formula I, Ia or Ib, R 6 Selected from substituted branched or straight chain C 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 In the case of alkenyl, substituted branched or straight chain C 2 -C 6 Alkyl, substituted C 3 -C 6 Cycloalkyl, substituted bicycloalkyl, substituted C 4 -C 7 Alkylcycloalkyl and substituted C 3 -C 6 The substituents of the alkenyl group are each independently selected from halogen, CN, OH, alkylthio and alkoxy. Preferably, the substituted branched or straight chain C 2 -C 6 Alkyl, substituted C 3 -C 6 Cycloalkyl, substituted bicycloalkyl, substituted C 4 -C 7 Alkylcycloalkyl and substituted C3 -C 6 The substituents of the alkenyl group are each independently selected from F, Cl, CN, -SCH 3 and OH.

[0036] A particularly preferred embodiment of the compounds according to the invention is characterized in that R 6 is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl-, allyl, -CH 2 CH 2 -S-CH 3 -、CH 2 CF 2 H, -CH 2 CF 3 and -CH 2 CH 2 CN. Most preferably, R 6 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl- and allyl. Preferably, this substituent is not present in the group forming R 6 On the carbon atom at the point of attachment to the nitrogen of formula I (or Ia or Ib, respectively).

[0037] R 5 and R 6 A particularly preferred combination is one in which R 5 Not H (such as substituted C 1 -C 4 alkyl or propenyl), and R 6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl- and allyl.

[0038] Where R 5 Illustrative of compounds of the invention that are H are compounds having one of the following formulae:

[0039]

[0040] 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.

[0041] Where R 5 Illustrative of compounds of the invention that are not H are compounds having one of the following formulae:

[0042]

[0043]

[0044]

[0045] And any pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers, hydrates and / or isotopes of these compounds. Most preferred are pharmaceutically acceptable salts of any of the above compounds.

[0046] In some embodiments, the compound according to the first aspect of the present invention is a compound according to formula Ia:

[0047]

[0048] in:

[0049] R 1 , R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, in particular, selected from H, F, Cl, Br, I and -CN, and wherein R 1 , R 2 , R 3 and R 4 At least one of them is selected from: F, Cl, Br, I, -CN and ethynyl, in particular selected from F, Cl, Br, I and -CN;

[0050] R 5 Selected from H, unsubstituted branched or linear C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted propenyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 Cycloalkyl; in particular selected from H, unsubstituted branched or linear C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 Cycloalkyl;

[0051] R 6 Selected from unsubstituted branched or straight chain C 2 -C 6 Alkyl, substituted branched or straight chain C 2 -C 6 Alkyl, unsubstituted C 3 -C 6Cycloalkyl, 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 Alkenyl,

[0052] The condition is that if R 5 is methyl, R 2 and R 3 One of them is H, the other is Cl, and R 1 and R 4 is H, then R 6 Selected from unsubstituted straight chain C 3 -C 6 Alkyl, unsubstituted branched C 4 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0053] A further condition is that if R 5 is methyl, R 1 , R 2 , R 3 and R 4 Two of them are Cl, and the other two are H, where R 1 and R 2 , R 3 and R4 , R 1 and R 3 or R 2 and R 4 is Cl, then R 6 Selected from unsubstituted branched or straight chain C 3 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0054] A further condition is that if R 5 is ethyl, R 2 and R 3 One of them is H, the other is Cl, and R 1 and R 4 is H, then R 6 Selected from unsubstituted straight chain C 3 -C 6 Alkyl, unsubstituted branched C 3 -C 6 Alkyl, substituted branched or straight chain 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 C3 -C 6 Alkenyl,

[0055] A further condition is that if R 5 is H, then the compound has one of the following formulae:

[0056]

[0057]

[0058] 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.

[0059] In a preferred embodiment of the present invention, R of the compounds of the present invention according to formula Ia 5 Selected from unsubstituted branched or straight chain C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 In particular, in this case, R 1 , R 2 , R 3 and R 4 Preferably each is independently selected from H, F, Cl, Br and -CN. Likewise, (particularly where R 5 is not H), preferably R 1 , R 2 , R 3 and R 4 At least two of them are H, and R 2 and R 3 One or two of, preferably one of, Cl or Br. For example, R 1 Can be F, R 2 Can be Cl, and R 3 and R 4 is H. Another example is where R 1 and R 2 Yes H, R 3 is Cl and R 4 is F. In a particularly preferred embodiment, R 5 Selected from unsubstituted branched or straight chain C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4Even more preferably, in the compounds according to the invention R 5 Selected from unsubstituted branched C 3 -C 4 or straight chain C 1 -C 4 Alkyl groups are preferably selected from linear C 1 -C 4 In some embodiments, R 5 It's methyl.

[0060] The compounds of the present invention according to formula Ia have R 6 Can be selected from substituted branched or straight chain C 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 Alkenyl, and substituted branched or straight chain C 2 -C 6 Alkyl, substituted C 3 -C 6 Cycloalkyl, substituted bicycloalkyl, substituted C 4 -C 7 Alkylcycloalkyl and substituted C 3 -C 6 Each substituent of the alkenyl group is independently selected from halogen, CN, OH, alkylthio and alkoxy. Preferably, the substituted branched or straight chain C 2 -C 6 Alkyl, substituted C 3 -C 6 Cycloalkyl, substituted bicycloalkyl, substituted C 4 -C 7 Alkylcycloalkyl and substituted C 3 -C 6 Each substituent of the alkenyl group is independently selected from F, Cl, CN, -SCH 3 and OH. A particularly preferred embodiment of the compounds according to the invention is characterized in that R 6 is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl-, allyl, -CH 2 CH 2 -S-CH 3 、-CH 2 CF 2 H, -CH 2 CF 3and -CH 2 CH 2 CN. Most preferably, R 6 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl- and allyl. Preferably, this substituent is not present in the group forming R 6 On the carbon atom at the point of attachment to the nitrogen of Formula I, Ia or Ib.

[0061] For compounds of the invention according to formula Ia, R 5 and R 6 The possible combinations are: 5 is a methyl group, and R 6 Those combinations selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl- and allyl.

[0062] In the 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 can be a salt of the compound according to the first aspect of the present invention with an inorganic acid, a carboxylic acid or a sulfonic acid. Particularly preferred is, for example, a salt with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic 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.

[0063] Examples of enantiomers of the present invention are selected from compounds of the following structures:

[0064]

[0065] or a pharmaceutically acceptable salt, hydrate and / or isotope of any of these compounds.

[0066] The compound according to the first aspect of the present invention is preferably capable of inhibiting the activity of extrasynaptic toxic NMDA receptors. The examples of the present application provide a suitable test for evaluating the activity of NMDA receptors. The preferred test for evaluating the inhibition of extrasynaptic toxic NMDA receptor activity is to study the activity in primary neuronal cultures, as described below. Preferably, the compound according to the present invention at a concentration of 10 μM at least reaches the same inhibitory activity level (i.e., the same index level) as 10 μM (2-aminoethyl) [(3-chlorophenyl) methyl] ethylamine (Compound P401 of WO2020 / 079244). Preferably, its inhibitory activity is even stronger than compound P401. Especially when the compound of the first aspect of the present invention reaches the same inhibitory activity at a concentration lower than compound P401 (such as 3.0 μM or lower, such as 1.0 μM, 0.3 μM, 0.1 μM, or even 0.03 μM concentration). It is preferred that the compound according to the first aspect of the present invention can interfere with the formation of NMDA receptor / TRPM4 complexes. A suitable method for assessing the ability to disrupt the complex is the co-immunoprecipitation and Western Blot assay described in the Examples section of this application.

[0067] The compound according to the invention may be part of a composition according to the invention. The composition according to the invention comprises at least one compound according to the first aspect of the invention and a suitable pharmaceutical carrier, excipient or diluent.

[0068] In a second aspect, the present invention relates to a compound for use in a method for treating or preventing a disease in the human or animal body, wherein the compound is a compound according to the following general formula I:

[0069]

[0070] in:

[0071] R 7 Selected from

[0072] And among them

[0073] R 1 , R 2 , R 3 and R 4 Each is independently selected from H, F, Cl, Br, I, -CN and ethynyl;

[0074] R 5 Selected from H, unsubstituted branched or linear C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted propenyl, unsubstituted C 3 -C6 Cycloalkyl and fluorine-substituted C 3 -C 6 Cycloalkyl;

[0075] R 6 Selected from unsubstituted branched or straight chain C 2 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0076] The condition is that if R 1 and R 4 One of them is H, the other is Cl, and R 2 , R 3 and R 5 is H, then R 6 Selected from 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 alkenyl;

[0077] The condition is that if R 2 and R 3 One of them is H, the other is Br, Cl or I, and R1 , R 4 and R 5 is H, then R 6 Selected from 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 alkenyl;

[0078] Or wherein the compound is a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer of a compound according to formula I.

[0079] The compound for use in the second aspect of the present invention may be a compound according to formula Ia or Ib:

[0080]

[0081] Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 As defined herein for Formula I, Ia or Ib, respectively.

[0082] In some embodiments, the compound of the second aspect of the invention is a compound according to formula Ia,

[0083]

[0084] The following applies:

[0085] R 1 , R 2 , R 3 and R 4 Each independently selected from H, F, Cl, Br, I and -CN;

[0086] R 5 Selected from H, unsubstituted branched or linear C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C1 -C 4 Alkyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 Cycloalkyl;

[0087] R 6 Selected from unsubstituted branched or straight chain C 2 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0088] The condition is that if R 1 and R 4 One of them is H, the other is Cl, and R 2 , R 3 and R 5 is H, then R 6 Selected from 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 alkenyl;

[0089] A further condition is that if R2 and R 3 One of them is H, the other is Cl or I, and R 1 , R 4 and R 5 is H, then R 6 Selected from 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 alkenyl; or

[0090] The compound is a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer, hydrate and / or isotope of the compound according to formula I. Most preferred is a pharmaceutically acceptable salt of the compound according to formula I.

[0091] In a third aspect, the present invention relates to a method for treating a disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound, wherein the compound is a compound according to the following general formula I:

[0092]

[0093] in:

[0094] R 7 Selected from

[0095] And among them

[0096] R 1 , R 2 , R 3 and R 4 Each is independently selected from H, F, Cl, Br, I, -CN and ethynyl;

[0097] R 5 Selected from H, unsubstituted branched or linear C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4Alkyl, unsubstituted propenyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 Cycloalkyl;

[0098] R 6 Selected from unsubstituted branched or straight chain C 2 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0099] The condition is that if R 1 and R 4 One of them is H, the other is Cl, and R 2 , R 3 and R 5 is H, then R 6 Selected from 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 alkenyl;

[0100] A further condition is that if R 2 and R3 One of them is H, the other is Br, Cl or I, and R 1 , R 4 and R 5 is H, then R 6 Selected from 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 alkenyl; or

[0101] Or wherein the compound is a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer of a compound according to formula I.

[0102] The compound used in the method of the third aspect of the invention may be a compound according to formula Ia or Ib,

[0103] Right now

[0104] Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 As defined herein for Formula I, Ia and / or Ib.

[0105] In some embodiments, the compound used in the method of the third aspect of the invention may be a compound according to formula Ia,

[0106]

[0107] in:

[0108] R 1 , R 2 , R 3 and R 4 Each independently selected from H, F, Cl, Br, I and -CN;

[0109] R 5 Selected from H, unsubstituted branched or linear C1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 Cycloalkyl;

[0110] R 6 Selected from unsubstituted branched or straight chain C 2 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0111] The condition is that if R 1 and R 4 One of them is H, the other is Cl, and R 2 , R 3 and R 5 is H, then R 6 Selected from 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 alkenyl;

[0112] A further condition is that if R 2 and R 3 One of them is H, the other is Cl or I, and R 1 , R 4 and R 5 is H, then R 6 Selected from 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 alkenyl; or

[0113] Wherein said 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 according to formula I.

[0114] The compound used in the second aspect of the present invention is the same as the compound used in the method of the third aspect of the present invention, and can be a compound according to formula I (or a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer thereof), wherein R 7 yes Optionally, R 7 yes In some embodiments, R 1 , R 2 , R 3 and R 4 Each is independently selected from H, F, Cl, Br and -CN. In some embodiments, R 1 , R 2 , R 3 and R 4 At least one of them is an ethynyl group, preferably, wherein R 2 In some embodiments, R 1 , R 2 , R 3 and R 4Two of them are independently selected from H, F, Cl, Br, I, -CN and ethynyl. 7 yes In some embodiments, R 2 and R 3 One of them is selected from H, F, Cl, Br, I, -CN and ethynyl, and the other is H. 7 yes In other embodiments, R 1 , R 2 , R 3 and R 4 At least two of them are H, R 2 and R 3 In some embodiments, R 1 is H or F, preferably F, and R 2 is selected from F, Cl, Br, I, CN and ethynyl, preferably selected from Cl, Br, CN and ethynyl. In some embodiments of Formula Ia, R 4 is H or F, preferably F, and R 3 is selected from F, Cl, Br, I, CN and ethynyl, preferably selected from Cl, Br, CN and ethynyl. 7 yes In some embodiments, R 1 It's F, R 2 is Cl, and R 3 and R 4 is H; or R 1 and R 2 Yes H, R 3 is Cl, and R 4 It's F.

[0115] The compound used in the second aspect of the invention or the compound used in the method of the third aspect of the invention may be a compound according to formula I, Ia or Ib (or a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer thereof), wherein R 5 Selected from unsubstituted branched or straight chain C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 In some embodiments, R 5 is H or methyl, as exemplified in the Examples. In other embodiments, R 5 Selected from ethyl, isopropyl, -CH 2 CF3 , -CF 2 CF 3 , -CF 2 CH 3 , -CHF 2 , -CF 3 , cyclopropyl, fluorine-substituted isopropyl, propenyl, cyclopropyl, cyclobutyl, fluorine-substituted cyclobutyl and cyclopentyl, as illustrated in the Examples.

[0116] The compound used in the second aspect of the invention or the compound used in the method of the third aspect of the invention may be a compound according to formula I, Ia or Ib (or a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer thereof), wherein R 6 Selected from substituted branched or straight chain C 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 Alkenyl, and branched or straight chain C 2 -C 6 Alkyl, substituted C 3 -C 6 Cycloalkyl, substituted bicycloalkyl, substituted C 4 -C 7 Alkylcycloalkyl and substituted C 3 -C 6 The substituents of the alkenyl group are each independently selected from F, Cl, CN, OH, alkylthio and alkoxy, preferably each independently selected from F, Cl, CN, SCH 3 In a particularly preferred embodiment, R 6 is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl-, allyl, -CH 2 CH 2 -S-CH 3 、-CH 2 CF 2 H, -CH 2 CF 3 and -CH 2 CH 2 CN. Most preferably, R 6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl- and allyl.

[0117] For the second and third aspects of the present invention, R 5 and R 6 The possible combinations are, where R 5 is a methyl group, and R 6 Those combinations selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl- and allyl.

[0118] For example: the compound according to the first aspect of the present invention is a compound eligible for use according to the second aspect of the present invention or a compound that can be used in the method according to the third aspect of the present invention. Other suitable examples are compounds selected from the following group of compounds:

[0119]

[0120] 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.

[0121] As mentioned above for the compound according to the first aspect of the present invention: in the embodiment in which the compound of the second aspect of the present invention or the compound used in the method of the third aspect of the present invention is a pharmaceutically acceptable salt, then 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 can be a salt formed with an inorganic acid, a carboxylic acid or a sulfonic acid according to the compound of the first aspect of the present invention. Particularly preferred is, for example, a salt with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic 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 salt is selected from halides, formates and trifluoroacetates.

[0122] As with the compounds according to the first aspect of the invention, the compounds according to the second aspect of the invention or any compound in the method according to the third aspect of the invention are preferably capable of inhibiting the activity of extrasynaptic toxic NMDA receptors and / or interfering with the formation of NMDA receptor / TRPM4 complexes. For suitable tests, reference is made to the corresponding paragraphs for the compounds according to the first aspect of the invention.

[0123] According to the compound of the first aspect of the present invention or the compound of the second aspect of the present invention, the compound used in the third aspect of the present invention, can be prepared, for example, according to the examples and drawings of the present application, but is not limited thereto. Tert-butyl-N-[2-(alkylamino)ethyl]carbamate F such as N-[2-(cyclopropylamino)ethyl]carbamic acid tert-butyl ester (CAS578706-31-7) is known in the literature, and can be prepared by known methods, for example, by alkylating alkylamine with 2-(tert-butyloxycarbonylamino)ethyl bromide (see WO2013062065), by reductive amination of N-Boc-2-aminoacetaldehyde (CAS89711-08-0) similar to WO2003066621, or reductive amination of ketone or aldehyde and tert-butyl-N-(2-aminoethyl)carbamate (CAS57260-73-8) similar to JP2010064982. The ketone A and the generated secondary amine F undergo reductive amination to give the tertiary amine C. Aldehyde R 6c -CHO or Ketone R 6a (R 6b )CO can be converted to N-substituted benzylamine B by reductive amination reaction with benzylamine E ( Figure 1 C). The order of the reactions can also be reversed. In this case, E first generates D and then C ( Figure 1 C) Aryl ketone A and amine R 6 -NH 2 The reductive amination reaction can also give N-substituted benzylamine B ( Figure 1 A). By reductive amination with N-Boc-2-aminoacetaldehyde (CAS 89711-08-0), for example analogously to WO2003066621, or by alkylation with a halide such as tert-butyl (2-bromoethyl)carbamate (CAS 39684-80-5) or a reagent such as tert-butyl 2,2-dioxo-1,2λ6,3-oxathiazolidine-3-carboxylate, a tertiary amine C is obtained, from which the BOC protecting group is eliminated, to obtain the compounds according to formula I of the present invention, in particular Ia of the present invention ( Figure 1 A). The order of the reactions can also be reversed. In this case, A generates D first, and then C ( Figure 1 A). For the removal of the BOC group, all common methods such as HCl / MeOH, HCl / EtOAc, TFA / DCM, hexafluoroisopropanol or all other acids are suitable. As reducing agents and catalysts for reductive amination, there are various options, such as NaBH 4 , NaBH 3 CN、NaBH(OAc) 3 / TFA, PMHS / SnCl 2 x2 2 O, Pd / C / Et 3SiH、PhSiH 3 / Bu 2 SnCl 2 , Ph 2 S H 2 / [RuCl 2 (p-cymene)] 2 / MS4A、PhSiH 3 / Cu(OAc) 2 , Et 3 SiH / InCl 3 , NaBH 4 / Ti(i-PrO) 4 、HCOOH / Pd-C、H 2 / Pd-C or B 10 H 14 . Ethers such as THF, 2-methyl-THF, dioxane or Bu 2 O, alcohols such as MeOH, EtOH, trifluoroethanol, ethylene glycol, TAME, diglyme, propanol or isopropanol, acetonitrile, butyronitrile, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetic acid, DMF, DMAC, water or a mixture thereof can be used as the solvent. The alkylation can be carried out in a solvent such as THF, 2-methyl-THF, dioxane, DMF, acetonitrile, butyronitrile, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, DMF, DMAC, diglyme, optionally in the presence of a base such as NaH, sodium carbonate, potassium carbonate, sodium formate, KOtBut, triethylamine or DIPEA, with methanesulfonate, toluenesulfonate, trifluoromethanesulfonate or a halide such as 1-chloro-2-methylthio-ethane, or tert-butyl (ethyl) carbamate, preferably tert-butyl (2-bromoethyl) carbamate, or with tert-butyl 2,2-dioxo-1,2λ6,3-oxathiazolidine-3-carboxylate. The acylation reaction can be carried out using an appropriate acid chloride and an inorganic or organic base, the corresponding acid anhydride or organic acid and a dehydrating agent such as EDCI / DMAP / DCM. In addition to BOC, all other known amino protecting groups are also conceivable, such as Cbz, Fmoc, Alloc or phthalimide, which can be cleaved by known methods. These methods include H 2 / Pd-C, HBr / AcOH, piperidine / DMF, Pd(PPh 3 ) 4 / morpholine / DCM or hydrazine hydrate. Figure 1 D lists further routes for the synthesis of compounds according to the invention. The desired ketone A ( Figure 1E) The corresponding aldehyde O can be prepared from the alcohol P by Grignard reaction with R5-magnesium halide in diethyl ether, THF, 2-methyl-THF, dioxane, MTBE and other ethers, and then oxidized with common oxidants such as Dess-Martin periodinane (DMP), pyridinium chlorochromate or activated MnO 2 Oxidation in solvents such as DCM, toluene, DMF, and DMAC gives aromatic ketone A. Ketone A can also be prepared by ortho-metallation of substituted aromatic compounds S (see Santos et al, Org. Lett. 2021, 23, 7396), where these substituted aromatic compounds S are preferentially substituted by R 1 =F and R 2 =Cl, Br or CN substitution, using a strong base such as LDA or TMP (2,2,6,6-tetramethylpiperidinyl) MgCl * LiCl, in THF, 2-methyl-THF or 1,4-dioxane solvent, the substituted aromatic compound S is ortho-metallated, and the resulting anion is reacted with R5-ester (R5-CO 2 On the other hand, these intermediate anions can also react with R5-aldehyde (R5-CHO) to give methanol P. 3 / TBAF reaction can introduce a trifluoromethyl group into benzaldehyde to obtain trimethylsilylated methanol T, which can be hydrolyzed to free methanol P (R5 = CF 3 ), the free methanol P can be oxidized to the ketone A (R = CF 3 The trifluoromethyl group can be introduced into acetophenone by the following method: first, it is converted into the corresponding triethylsilyl ether U using TESCl / DIEA / n-BuLi in an ether solvent such as THF, and then reacted with Togni reagent II in a solvent such as DMF, DMAC or NMP in the presence of CuSCN to obtain trifluoroethyl-phenyl ketone A (R5=CH 2 CF 3 The corresponding aryl halide R is reacted with tributyl(1-ethoxyvinyl)stannane in the presence of a Pd catalyst (such as Pd(PPh 3 ) 4 , palladium diacetate / 2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl / TEA, tri(dibenzylideneacetone)dipalladium / tri-tert-butylphosphine / cesium fluoride or Pd(PPh 3 ) 2 Cl 2 Under the catalytic action of catalysts such as dioxane, THF, 2-methyl-THF, toluene, benzene, NMP and other solvents, acetophenone A (R5 = CH 3 ). Amine B can be prepared from benzaldehyde O by first reacting with amine R6-NH 2The reaction is carried out in a solvent such as MeOH and catalyzed by an acid such as AcOH to give a Schiff base imine V. The R5 group can be introduced by reaction with a corresponding Grignard reagent such as R5-MgBr or other appropriate organometallic. Amine B can react with a haloacetamide (such as bromoacetamide) in a solvent such as MeCN, butyronitrile, DMF, DMAC, TAME and in the presence of a base such as potash, soda, TEA or DIPEA to give a substituted aminoacetamide G, which can be reduced with an appropriate reducing agent such as LiAlH4, BH3*Me2S, BH3*THF in a solvent such as THF or 2-methyl-THF to give the desired compound (I). Another method is to react amine B with a haloacyl chloride such as bromoacetyl bromide or chloroacetyl chloride to give a haloacetamide H. These can be aminated using potassium phthalimide to give a protected amine K, which is then deprotected by hydrazine hydrate or methylamine in methanol, ethanol and / or water to give a substituted aminoacetamide M, or by using NaBH 4 / 2-propanol, and then react with acetic acid (JO Osby, MG Martin, B. Ganem, Tetrahedron Lett, 1984, 25, 2093-2096). Haloacetamide H can also be converted to the corresponding azidoacetamide L using sodium azide in DMF or DMAC. Azidoacetamide L can then be reduced to acetamide M using triphenylphosphine in THF / water. These compounds M can be reduced with appropriate reducing agents such as LiAlH 4 , BH3*Me2S, BH3*THF in a solvent such as THF or 2-methyl-THF to reduce to the desired compound (I). It can be understood that although Figure 1 Synthetic routes for compounds according to formula Ia are illustrated, but these steps can be used analogously to generate compounds according to formula Ib used herein.

[0124] According to the second aspect or the third aspect of the invention, the disease to be treated is preferably a nervous system disease, in particular a neurodegenerative disease, or a disease that may cause or involve a neurodegenerative event, such as an infection that causes a neurodegenerative event, in particular in the brain. In some embodiments, the neurological or neurodegenerative disease may have an inflammatory component, i.e. a neuroinflammatory disease. The neurodegenerative disease may be a progressive neurodegenerative disease. Preferably, the disease or disorder is selected from the group consisting of: stroke, in particular ischemic stroke and hemorrhagic stroke, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), traumatic brain injury, sequelae of traumatic brain injury, absent-mindedness, age-related memory loss, memory decline associated with aging, progressive nuclear palsy, multiple sclerosis, thalamic degeneration, glutamate-induced excitotoxicity, dystonia, epilepsy, optic nerve disease, diabetic retinopathy, glaucoma, pain (in particular neuropathic pain), anti-NMDA receptor encephalitis, dementia (such as post-stroke dementia, HIV dementia, Creutzfeldt–Jakob dementia, Lewy body dementia (DLB), frontal lobe degeneration dementia (including Pick's disease ( disease), corticobasal degenerative 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-related brain damage), brain damage associated with HIV infection / AIDS (due to the risk of HIV), Zika virus infection (due to the possibility of Zika virus-related brain damage), or any other viral infection that may cause neurodegenerative events and corresponding neuronal or brain damage, such as viral encephalopathy, viral meningitis or SARS-COV2 virus-induced encephalitis. In a further embodiment, the disease may be a brain tumor, particularly a glioblastoma. Three papers recently published in Nature (see Nature, 2019, Vol. 573, pp. 499-501) show that glioblastoma cells express NMDA receptors, and their growth is enhanced / stimulated by the activation of NMDA receptors. Therefore, when NMDA receptor signaling is blocked, such as by the compounds described herein, the growth of glioblastoma cells may be inhibited. In contrast, in this case, conventional NMDA receptor blockers cannot be used because they interfere with the physiological role of NMDA receptors in normal synaptic transmission and cognitive functions (such as memory).Due to the universal relevance of extrasynaptic NMDA receptor signaling, the compounds disclosed herein are also suitable for treating central nervous system disorders, such as anxiety, stress and depressive states, sexual dysfunction and sleep disorders. They can also be used to control pathological disorders of food, stimulant and addictive substance intake.

[0125] Typically, the therapeutic method (in the case of the second or third aspects of the invention) will focus on stopping or slowing the development of the disease. Alternatively, this compound can also be administered in a preventive manner, for example, in the case of a subject suffering from a risk (increase) of a neurological and / or neurodegenerative disease. This includes acute (increased) risks (such as postoperative thrombotic stroke) and ongoing risks (such as due to hereditary and / or familial susceptibility to specific neurological and / or neurodegenerative diseases).

[0126] The subject to be treated is preferably a mammal, preferably selected from humans, mice, rats, dogs, cats, cows, monkeys, horses, hamsters, guinea pigs, pigs, sheep, goats, rabbits, etc. Most preferably, the subject is a human.

[0127] For the purpose of the second and third aspects of the present invention, it is easy for those skilled in the art to select appropriate routes of administration according to the specific disease to be treated or prevented and / or the body part to be treated. The route of administration can be, for example, oral, topical, intranasal, parenteral, intravenous, rectal, pulmonary, sublingual, lingual, oral, transdermal, conjunctival or any other route of administration suitable for the specific situation. The compound can also be administered by using an implant that releases the compound over time. For example, if the disease is a cerebrovascular disease, such as a stroke, then intranasal administration is a preferred route of administration. It is known to those skilled in the art that intranasal administration is particularly suitable for the administration of general neuroprotective compounds, such as in the treatment of brain damage caused by apoplexy and apoplexy. For oral administration, known forms of administration that can deliver active substances quickly and / or in modified form are all suitable, such as tablets (uncoated and coated tablets, such as tablets with enteric coating or film-coated tablets), capsules, granules, pills, powders, emulsions, suspensions, solutions and aerosols. Parenteral administration can be performed bypassing the reabsorption step (intravenous, intraarterial, intracardiac, intraspinal or intraperitoneal), or involving reabsorption (intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). For parenteral administration, suitable administration forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilized powders and sterile powders. For other administration routes, suitable forms include inhaled drugs (such as powder inhalers, atomizers), 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 itself can be transferred to the above-mentioned application forms by known means. This is accomplished using inert, non-toxic, pharmaceutically suitable excipients. These excipients include excipients (such as microcrystalline cellulose), solvents (such as polyethylene glycol), emulsifiers (such as sodium lauryl sulfate), dispersants (such as polyvinyl pyrrolidone), synthetic and natural biopolymers (such as albumin), stabilizers (such as antioxidants such as ascorbic acid), colorants (such as inorganic pigments such as iron oxide) or taste and / or odor correctors. If necessary, the active ingredient can also be present in the form of microcapsules in one or more of the above-mentioned excipients. Generally, in human and veterinary medicines, it has been found that in order to achieve the desired effect, the active ingredient of the present invention is administered in a total amount of about 0.001 mg / kg body weight, preferably to about 60 mg / kg body weight, 0.001 mg / kg body weight to 40 mg / kg body weight per 24h, optionally in the form of multiple single administrations, which is advantageous. The content of the active ingredient of the present invention in a single dose is preferably about 0.001 to about 30 mg / kg body weight, especially 0.001 to 20 mg / kg body weight.

[0128] In a fourth aspect, the present invention relates to compounds (intermediates) according to the following general formula II:

[0129]

[0130] in:

[0131] R 7 Selected from

[0132] R 1 , R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and wherein R 1 , R 2 , R 3 and R 4 At least one of them is selected from: F, Cl, Br, I, -CN and ethynyl;

[0133] R 5 Selected from H, unsubstituted branched or linear C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted propenyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 Cycloalkyl;

[0134] R 6 Selected from H, unsubstituted branched or linear C 2 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0135] The condition is that if R 5 is methyl, R 7yes R 2 and R 3 One of them is H, the other is Cl, and R 1 and R 4 is H, then R 6 Selected from unsubstituted straight chain C 3 -C 6 Alkyl, unsubstituted branched C 4 -C 6 Alkyl, substituted branched or straight chain 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 alkenyl;

[0136] A further condition is that if R 5 is methyl, R 7 yes R 1 , R 2 , R 3 and R 4 Two of them are Cl, and the other two are H, where R 1 and R 2 , R 3 and R 4 , R 1 and R 3 or R 2 and R 4 is Cl, then R 6 Selected from unsubstituted branched or straight chain C 3 -C 6 Alkyl, substituted branched or straight chain C 2 -C 6 Alkyl, unsubstituted C 3 -C 6 Cycloalkyl, substituted C 3 -C 6 Cycloalkyl, unsubstituted C 4 -C8 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 alkenyl;

[0137] A further optional condition is that if R 5 is methyl, R 7 yes R 1 and R 4 It is Cl, R 2 and R 3 If one is H and the other is F, then R 6 Selected from unsubstituted branched or straight chain C 2 -C 6 Alkyl, substituted branched or straight chain 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 alkenyl;

[0138] A further condition is that if R 5 is methyl, R 7 yes R 1 and R 4 One of them is H, another is F, and R 2 and R 3 is Cl, then R 6 Selected from unsubstituted branched or straight chain C 2 -C 6 Alkyl, substituted branched or straight chain C 2 -C6 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 alkenyl;

[0139] A further optional condition is that if R 5 is methyl, R 1 and R 4 One of them is H, the other is Cl, and R 2 and R 3 is H, then R 6 Selected from unsubstituted branched or straight chain C 2 -C 6 Alkyl, substituted branched or straight chain 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 alkenyl;

[0140] A further condition is that if R 5 is ethyl, R 2 and R 3 One of them is H, the other is Cl, and R 1 and R 4 is H, then R 6 Selected from unsubstituted straight chain C3 -C 6 Alkyl, unsubstituted branched C 3 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0141] A further condition is that if R 5 Yes H, R 7 yes Then the compound has one of the following formulas:

[0142]

[0143] and salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes of any of these compounds.

[0144] The compound according to the fourth aspect of the present invention may be a compound according to formula IIa or IIb,

[0145] Right now

[0146] Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 As defined herein for Formula II or for Formula I, Ia or Ib, respectively.

[0147] In some embodiments, the compound according to the fourth aspect of the invention may be the corresponding Boc-protected compound shown in the Examples section as a direct precursor of the compound according to the first aspect of the invention, or for use according to the second or third aspect of the invention.

[0148] In some embodiments, the compound according to the fourth aspect of the present invention is a compound according to formula IIa,

[0149]

[0150] in:

[0151] R 1 , R 2 , R 3 and R 4 Each is independently selected from H, F, Cl, Br, I and -CN, wherein R 1 , R 2 , R 3 and R 4 At least one of the following is selected from: F, Cl, Br, I and -CN;

[0152] R 5 Selected from H, unsubstituted branched or linear C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 Cycloalkyl;

[0153] R 6 Selected from H, unsubstituted branched or linear C 2 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0154] The condition is that if R 5 is methyl, R 2 and R 3One of them is H, the other is Cl, and R 1 and R 4 is H, then R 6 Selected from unsubstituted straight chain C 3 -C 6 Alkyl, unsubstituted branched C 4 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0155] A further condition is that if R 5 is methyl, R 1 , R 2 , R 3 and R 4 Two of them are Cl, and the other two are H, where R 1 and R 2 , R 3 and R 4 , R 1 and R 3 or R 2 and R 4 is Cl, then R 6 Selected from unsubstituted branched or straight chain C 3 -C 6 Alkyl, substituted branched or straight chain 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 -C7 Alkylcycloalkyl, substituted C 4 -C 7 Alkylcycloalkyl, unsubstituted C 3 -C 6 Alkenyl and substituted C 3 -C 6 Alkenyl,

[0156] A further condition is that if R 5 is methyl, R 1 and R 4 One of them is H, another is F, and R 2 and R 3 is Cl, then R 6 Selected from unsubstituted branched or straight chain C 2 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0157] A further condition is that if R 5 is ethyl, R 2 and R 3 One of them is H, the other is Cl, and R 1 and R 4 is H, then R 6 Selected from unsubstituted straight chain C 3 -C 6 Alkyl, unsubstituted branched C 3 -C 6 Alkyl, substituted branched or straight chain C 2 -C 6 Alkyl, unsubstituted C 3 -C 6 Cycloalkyl, substituted C 3 -C 6 Cycloalkyl, unsubstituted C4 -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 Alkenyl,

[0158] A further condition is that if R 5 is H, then the compound has one of the following formulae:

[0159]

[0160] and salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes of any of these compounds.

[0161] The above compounds of formula II, IIa and IIb (intermediates for preparing compounds according to formula I, Ia and Ib) are particularly suitable for preparing compounds according to the first aspect of the invention or for preparing compounds according to the second aspect of the use according to the invention (or compounds according to the method according to the third aspect of the invention). As mentioned above, for removing the BOC group, all common methods are suitable, such as HCl / MeOH, HCl / EtOAc, TFA / DCM, hexafluoroisopropanol or all other acids. The above preferred embodiments of the compounds of the invention according to the first aspect of the invention are also applicable to the compounds of the fourth aspect of the invention. A particularly preferred embodiment is R 5 Selected from unsubstituted branched or straight chain C 1 -C 4 Alkyl groups are preferably selected from linear C 1 -C 4 Most preferably, the intermediate R 5 A particularly preferred embodiment of the intermediate according to the invention is characterized in that R 6 is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl-, allyl, -CH 2 CH 2 -S-CH 3 , CH 2 CF 2 H, -CH 2 CF 3 and -CH 2 CH 2 CN. Most preferably, the intermediate R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl- and allyl. 1 , R 2 , R 3 and R 4 Preferably, each is independently selected from H, F, Cl and -CN. Also preferably, R 1 , R 2 , R 3 and R 4 At least two of them are H, and R 2 and R 3 One or two of, preferably one of, Cl. Particularly preferred R 5 and R 6 A combination of R 5 is a methyl group, and R 6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl- and allyl.

[0162] In a preferred embodiment, the intermediate compound according to the fourth aspect of the present invention is selected from one of the following formulae:

[0163]

[0164] and salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes of any of these compounds.

[0165] 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 are compounds according to the following general formula III:

[0166]

[0167] in:

[0168] R 7 Selected from

[0169] R 1 , R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and wherein R 1 , R 2 , R 3 and R 4 At least one of them is selected from: F, Cl, Br, I, -CN and ethynyl;

[0170] R 5 Selected from H, unsubstituted branched or linear C1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted propenyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 Cycloalkyl;

[0171] R 6 Selected from H, unsubstituted branched or linear C 2 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0172] and its salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes.

[0173] The compound according to the fifth aspect of the present invention may be a compound according to formula IIIa or IIIb,

[0174] Right now

[0175] Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 As defined herein for Formula III or Formula I, Ia or Ib, respectively.

[0176] In a sixth aspect, the present invention relates to further intermediates, which are not within the scope of Formula II or Formula III, but are compounds according to the following general formula IV:

[0177]

[0178] in:

[0179] R 7 Selected from

[0180] R 1 , R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and wherein R 1 , R 2 , R 3 and R 4 At least one of them is selected from: F, Cl, Br, I, -CN and ethynyl;

[0181] R 5 Selected from H, unsubstituted branched or linear C 1 -C 4 Alkyl, fluorine-substituted branched or straight chain C 1 -C 4 Alkyl, unsubstituted propenyl, unsubstituted C 3 -C 6 Cycloalkyl and fluorine-substituted C 3 -C 6 Cycloalkyl;

[0182] R 6 Selected from H, unsubstituted branched or linear C 2 -C 6 Alkyl, substituted branched or straight chain 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 Alkenyl,

[0183] and its salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes.

[0184] The compound according to the sixth aspect of the present invention may be a compound according to formula IVa or IVb,

[0185] Right now

[0186] Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 As defined herein for Formula IV or Formula I, Ia or Ib, respectively.

[0187] In the examples of the present invention, various direct precursors of the compounds synthesized according to the first aspect of the present invention or according to the second or third aspect of the present invention are described in more detail, which are 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 present invention, respectively.

[0188] As used herein, the term "comprising" should not be understood to be limited to the meaning of "consisting of" (i.e., excluding the presence of other substances). Instead, "comprising" means that additional substances may optionally be present. The term "comprising" encompasses the embodiments of "consisting of" (i.e., excluding the presence of additional substances) and "including but not consisting of" (i.e., requiring the presence of other substances) as specifically contemplated to fall within its scope, with the former being more preferred. BRIEF DESCRIPTION OF THE DRAWINGS

[0189] A brief description of the accompanying drawings will be given below. The accompanying drawings are intended to illustrate various aspects of the present invention in more detail. However, they are not intended to limit the scope of the present invention.

[0190] Figure 1 Various general reaction schemes are provided to illustrate the synthesis of compounds used in this application. Different precipitates lead to tert-butyloxycarbonyl protected compounds (Intermediate C), which are then converted to the final products (Formula I); R 6a and R 6b are those that, after reductive amination, form R 6 Part of a chain or ring member; similarly, R 6c -CHO forms R 6 Part; 1A) Obtaining compounds according to the invention starting from aromatic ketones or benzaldehydes; 1B) Synthesis routes for compounds of formula I, in particular compounds Ia; 1C) Obtaining compounds according to the invention starting from benzylamine; 1D) Further possible synthesis routes for compounds according to the invention; 1E) Synthesis of ketone A and alcohol P; 1F) Introduction of a trifluoromethyl group into benzaldehyde and acetophenone.

[0191] Figure 2 Quantification of cell survival after glutamate / NMDA treatment in primary cultured neurons is shown. The area above the curve (AAC, shaded area in the vehicle and compound P401 groups) was quantified to determine the protection index of other compounds. Compound P401 (10 μM) in WO2020 / 079244 provided approximately 60% protection, and the protection index was defined as 6.0.

[0192] Figure 3 The results show that H 2 O 2 Quantification of cell survival after treatment. A) Compound P401 (see WO2020 / 079244) has a positive effect on H compared to the FDA-approved ALS drugs riluzole and edaravone. 2 O 2 B) Compared with 10 μM P401, compound 220 has a better protection against H 2 O 2 The damage of 1 μM provided better protection, which was similar to that of compound 220 at 0.1 μM.

[0193] Figure 4 Quantification of cell survival (%) after glutamate / NMDA treatment in human iPSC-derived prefrontal cortex organotypic tissue is shown. Compound 120 provides superior protection to compound P401 (see WO2020 / 079244).

[0194] Figure 5 The co-immunoprecipitation results of TRPM4 and NMDA receptor subunits are provided. Lysates of human iPSC-derived brain organoids were precipitated with anti-TRPM4. In SDS-PAGE, the input group (5%) and the immunoprecipitate were separated, transferred, and blotted with antibodies against GluN2A, GluN2B, GluA2, TRPM4, and tubulin. In the presence of compound 120, the NMDAR / TRPM4 complex was destroyed. DETAILED DESCRIPTION

[0195] Example

[0196] The following will show the embodiments of the present invention and specific examples of various aspects. However, the scope of the present invention should not be limited to the specific embodiments described herein. In fact, in addition to what is described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description and the following embodiments. All of these modifications fall within the scope of the appended claims.

[0197] Example 1: General Procedure

[0198] The compounds used in the present invention for attenuating the activity of extrasynaptic toxic NMDA receptors are generally prepared as follows.

[0199] Reductive amination - Preparation of BOC-protected intermediate C

[0200] To a solution of tert-butyl N-(2-aminoethyl)carbamate (100 mg, 624.2 μmol, 98 μL, 1 eq) in MeOH (3 mL) was added an appropriate benzaldehyde or acetophenone (e.g., compound 109) derivative (1 eq). The mixture was stirred at 65 °C for 12 h. NaBH was then added 3 CN (196 mg, 3.1 mmol, 5 eq), and the mixture was stirred at 65 ° C for 2 h. Then acetaldehyde (344 mg, 3.1 mmol, 438 μL, 40% purity, 5 eq) (for example, see compounds 91, 92, 94, 95, 109) or an appropriate cyclopropanealdehyde derivative (for example, see compounds 153 and 157) was added, and the mixture was stirred at 65 ° C for 4 h. The reaction mixture was concentrated, then diluted with 5 mL of EtOAc, and washed with H 2 O (5 mL × 3). The combined organic layers were washed with Na 2 SO 4 Drying and concentration under reduced pressure gave a residue (Intermediate C).

[0201] Removal of Boc group

[0202] Intermediate C (637 μmol, 1 eq) was stirred in HCl / EtOAc (2 mL, 4 M) solution at 20 ° C for 0.5 h, and LC-MS showed that the starting material was consumed. The reaction mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC (HCl conditions, chromatographic column: Phenomenex Luna 80×30 mm×3 μm; mobile phase: [water (HCl)-ACN]; B%: 1%-1%, 8 min), and after vacuum evaporation, the final product (compound according to formula I) was obtained as shown in the table.

[0203] According to the general procedure, the following compounds were prepared:

[0204]

[0205]

[0206] Example 2: Synthesis of N1-(3-chlorobenzyl)-N1-cyclobutylethane-1,2-diamine hydrochloride (Compound 123)

[0207] 1) tert-Butyl N-[2-[(3-chlorophenyl)methylamino]ethyl]carbamate

[0208]

[0209] To a solution of tert-butyl N-(2-aminoethyl)carbamate (2.28 g, 14.23 mmol, 2.23 mL, 1 eq) in MeOH (30 mL) was added 3-chlorobenzaldehyde (2 g, 14.23 mmol, 1.61 mL, 1 eq). The mixture was stirred at 25 °C for 12 h. NaBH 3 CN (4.47 g, 71.14 mmol, 5 eq). 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. 100 mL of NH 4 The reaction was quenched with aqueous Cl solution. The residue was stirred for 2 h. 2 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) and washed with Na 2 SO 4 The residue was purified by flash silica gel chromatography ( 20g Sepa Silica gel flash column, 0-100% ethyl acetate / petroleum ether gradient elution, 150 mL / min) to give the compound N-[2-[(3-chlorophenyl)methylamino]ethyl]carbamic acid tert-butyl ester (2.3 g) as a yellow oil. 1 HNMR (400 MHz, chloroform-d 6 )δ=7.60 (dd, J=1.1, 2.1Hz, 5H), 4.11 (q, J=7.2Hz, 6H), 2.03 (s, 9H), 1.24 (t, J=7.2Hz, 13H).

[0210] 2) tert-Butyl N-[2-[(3-chlorophenyl)methyl-cyclobutyl-amino]ethyl]carbamate

[0211]

[0212] To a solution of tert-butyl N-[2-[(3-chlorophenyl)methylamino]ethyl]carbamate (100 mg, 351 μmol, 1 eq) in EtOH (2 mL) was added cyclobutanone (246 mg, 3.51 mmol, 262 μL, 10 eq) dropwise at 20°C. Then, CH 3 COOH was used to adjust the pH to 4-5, and the mixture was stirred at this temperature for 1 h, and then NaBH was added dropwise 3 CN (66.20 mg, 1.05 mmol, 3 eq). The resulting mixture was stirred at 40 °C for 12 h. LCMS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by HPLC.2 O (3 mL), and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give tert-butyl N-[2-[(3-chlorophenyl)methyl-cyclobutyl-amino]ethyl]carbamate (100 mg, crude) as a colorless oil.

[0213] 3) N1-(3-chlorobenzyl)-N1-cyclobutylethane-1,2-diamine hydrochloride (Compound 123)

[0214]

[0215] A solution of tert-butyl N-[2-[(3-chlorophenyl)methyl-cyclobutyl-amino]ethyl]carbamate (100 mg, 295 μmol, 1 eq) in HCl / EtOAc (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 obtain a residue, which was purified by preparative-HPLC (HCl conditions, chromatographic column: Phenomenex Luna 80×30mm×3μm; mobile phase: [water (HCl)-ACN]; B%: 1%-1%, 8 min) to obtain a white solid compound N 1 -(3-Chlorobenzyl)-N 1 -Cyclobutylethane-1,2-diamine hydrochloride (Compound 123; 29 mg, 103 μmol, yield 35%, purity 98.7%, HCl). MS (ESI): m / z = 239.1 [M+H] + ; Retention time: 1.542min, method: A; 1 H NMR (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).

[0216] Example 3: Synthesis of Compounds 124, 134 and 135

[0217] The following further compounds were prepared in a similar manner to compound 123 (Example 2) above:

[0218]

[0219]

[0220] Example 4: N-(2-aminoethyl)-N-[(3-chlorophenyl)methyl]but-3-enamide hydrochloride (Compound 137) Synthesis

[0221] 1) tert-Butyl N-[2-[but-3-enoyl-[(3-chlorophenyl)methyl]amino]ethyl]carbamate

[0222]

[0223] To a solution of tert-butyl N-[2-[(3-chlorophenyl)methylamino]ethyl]carbamate (100 mg, 351.2 μmol, 1 eq) in DCM (2 mL) was added EDCI (87.5 mg, 456.5 μmol, 1.3 eq) and DMAP (5.6 mg, 45.7 μmol, 0.13 eq). The mixture was stirred at 20 ° C for 20 min. Then, but-3-enoic acid (39.3 mg, 456.5 μmol, 1.3 eq) 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 stirred in DCM (2 mL) and H 2 O (3 mL × 2). Separate the organic phase and use Na 2 SO 4 Dry, filter and concentrate 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.

[0224] 2) N-(2-aminoethyl)-N-[(3-chlorophenyl)methyl]but-3-enamide hydrochloride (Compound 137)

[0225]

[0226] A solution of tert-butyl N-[2-[but-3-enoyl-[(3-chlorophenyl)methyl]amino]ethyl]carbamate (60 mg, 170 μmol, 1 eq) in HCl / EtOAc (2 mL, 4 M) was stirred at 20°C for 1 h. LCMS showed that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-HPLC (HCl conditions, chromatographic column: Phenomenex Luna 80 mm×4.5 mm; mobile phase: [water (HCl)-ACN]; B%: 10%-45%, 8 min) to obtain a white solid compound N-(2-aminoethyl)-N-[(3-chlorophenyl)methyl]but-3-enoamide hydrochloride (19 mg, 62.4 μmol, yield 37%, purity 97.5%, HCl). MS (ESI): m / z=253.1[M+H] + ; Retention time: 1.778min, method: B; 1H 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).

[0227] Example 5: N1-(3-chloro-2-fluorobenzyl)-N1-(2,2-difluoroethyl)ethane-1,2-diamine (Compound 118) Synthesis

[0228] 1) N-[(3-chloro-2-fluorophenyl)methyl]-2,2-difluoroethylamine

[0229]

[0230] AcOH was added to a solution of 3-chloro-2-fluorobenzaldehyde (500 mg, 3.15 mmol, 1 eq) and 2,2-difluoroethylamine (384 mg, 4.7 mmol, 1.5 eq) in MeOH (15 mL) to adjust the pH to 4-5. After the addition, the mixture was stirred at 25 °C for 2 h, and then NaBH was added at 25 °C. 3 CN (793 mg, 12.6 mmol, 4 eq). LC-MS showed that the desired compound was detected. Saturated NaHCO was added to the reaction mixture at 25 °C. 3 The solution was quenched with ethyl acetate (10 mL) and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saline solution (15 mL × 2) and washed with Na 2 SO 4 The solution was dried, filtered and concentrated under reduced pressure to obtain a yellow liquid compound N-[(3-chloro-2-fluorophenyl)methyl]-2,2-difluoroethylamine (712 mg, crude product).

[0231] 2) N-[2-[(3-chloro-2-fluorophenyl)methyl-(2,2-difluoroethyl)amino]ethyl]carbamate

[0232]

[0233] To the CH 2 Cl 2 AcOH (10 mL) was added to the solution to adjust the pH to 4-5. The mixture was stirred at 25 °C for 2 h. NaBH(OAc) was then added 3(190 mg, 894.4 μmol, 1 eq). The final mixture was stirred for 12 h. LC-MS showed that the desired compound was detected. Saturated NaHCO was added to the reaction mixture at 25 °C. 3 The solution (15 mL) was quenched with CH 2 Cl 2 The combined organic layers were washed with saline solution (15 mL × 2) and washed with Na 2 SO 4 The solution was dried, filtered and concentrated under reduced pressure to obtain a colorless oily compound N-[2-[(3-chloro-2-fluorophenyl)methyl-(2,2-difluoroethyl)amino]ethyl]carbamate (283 mg, crude product).

[0234] 3) N1-(3-chloro-2-fluorobenzyl)-N1-(2,2-difluoroethyl)ethane-1,2-diamine (Compound 118)

[0235]

[0236] A mixture of tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methyl-(2,2-difluoroethyl)amino]ethyl]carbamate (160 mg, 436.5 μmol, 1 eq) and HCl / EtOAc (3 mL 4M) was stirred at 25 °C for 1 h. LC-MS showed that the desired compound was detected. The residue was purified by preparative-HPLC (HCL conditions: column: Phenomenex LunaC18 100×30 mm×5 μm; mobile phase: [water (HCL)-ACN]; B%: 45%-75%, 10 min) to give a yellow liquid compound N1-(3-chloro-2-fluorobenzyl)-N1-(2,2-difluoroethyl)ethane-1,2-diamine hydrochloride (15 mg, 49.5 μmol, yield 11%, HCl). MS (ESI): m / z=267.1[M+H] + ; Retention time: 1.899min, 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).

[0237] Example 6: N1-(3-chloro-2-fluorobenzyl)-N1-(2,2,2-trifluoroethyl)ethane-1,2-diamine (Compound 119) Synthesis

[0238] According to the similar method of compound 118 (Example 5) above, the following compound was prepared:

[0239]

[0240]

[0241] Example 7: N1-(3-chloro-2-fluorobenzyl)-N1-(2-(methylthio)ethyl)ethane-1,2-diamine hydrochloride (Chemical Synthesis of Compound 168)

[0242] 1) tert-Butyl N-[2-[(3-chloro-2-fluorophenyl)methylamino]ethyl]carbamate

[0243]

[0244] To a solution of 3-chloro-2-fluoro-benzaldehyde (10 g, 63 mmol, 1 eq) in MeOH (150 mL) was added tert-butyl N-(2-aminoethyl)carbamate (10.1 g, 63 mmol, 9.91 mL, 1 eq). The mixture was stirred at 65 °C for 12 h. NaBH was then added at 20 °C. 3 CN (19.82 g, 315.3 mmol, 5 eq). The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 150 mL of H 2 O and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with H 2 O (100 mL × 2) and washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography ( 40g Silica gel flash column, 0-36% ethyl acetate / petroleum ether gradient elution, 120 mL / min) to obtain a yellow oily compound N-[2-[(3-chloro-2-fluorophenyl)methylamino]ethyl]carbamic acid tert-butyl ester (10 g, 33 mmol, yield 52.4%).

[0245] 2) N-[2-[(3-chloro-2-fluorophenyl)methyl-(2-methylthioethyl)amino]ethyl]carbamate

[0246]

[0247] Tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methylamino]ethyl]carbamate (500 mg, 1.65 mmol, 1 eq), 1-chloro-2-methylthioethane (182 mg, 1.65 mmol, 163 μL, 1 eq), K 2 CO 3 (685 mg, 4.95 mmol, 3 eq) in CH 3The mixture in CN (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 K 2 CO 3 , and then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 12g Silica gel flash column, 0-100% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to give a colorless oily compound N-[2-[(3-chloro-2-fluorophenyl)methyl-(2-methylthioethyl)amino]ethyl]carbamate (200 mg, 500.7 μmol, yield 30%, purity 94.4%).

[0248] 3) N1-(3-chloro-2-fluorobenzyl)-N1-(2-(methylthio)ethyl)ethane-1,2-diamine hydrochloride (Compound 168)

[0249]

[0250] A solution of tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methyl-(2-methylthioethyl)amino]ethyl]carbamate (50 mg, 133 μmol, 1 eq) in HCl / EtOAc (1 mL, 4 M) was stirred at 25 °C for 1 h. LC-MS showed that the desired compound was detected. The mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (HCl conditions: column: Phenomenex Luna 80×30 mm×3 μm; mobile phase: [water (HCl)-ACN]; B%: 1%-20%, 8 min) to obtain a white solid compound N1-(3-chloro-2-fluorobenzyl)-N1-(2-(methylthio)ethyl)ethane-1,2-diamine hydrochloride (7.5 mg, 26.7 μmol, yield 20%, purity 98.5%). MS (ESI): m / z=277.1[M+H] + ; Retention time: 1.777min, 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).

[0251] Example 8: Synthesis of Compounds 126, 136 and 160

[0252] According to the similar method of compound 168 (Example 7) above, the following compound was prepared:

[0253]

[0254] Example 9: Preparation of 3-(((2-aminoethyl)(ethyl)amino)methyl)-2-fluorobenzonitrile TFA salt (Compound 175) synthesis

[0255] 1) tert-Butyl N-[2-[(3-bromo-2-fluorophenyl)methylamino]ethyl]carbamate

[0256]

[0257] To a solution of 3-bromo-2-fluoro-benzaldehyde (400 mg, 1.97 mmol, 1 eq) and tert-butyl N-(2-aminoethyl)carbamate (316 mg, 2 mmol, 310 μL, 1 eq) in MeOH (5 mL) was added AcOH to adjust the pH to 4-5, and the mixture was stirred at 40 °C for 12 h, and then NaBH 3 CN (372 mg, 5.9 mmol, 3 eq), the mixture was stirred at 25 ° C for 2 h. The mixture was concentrated to obtain a residue, which was poured into water and extracted with ethyl acetate (5 mL × 3). The combined organic layer was then washed with brine (5 mL × 2) and then with Na 2 SO 4 The solution was dried, filtered and the filtrate was concentrated in vacuo to give tert-butyl N-[2-[(3-bromo-2-fluoro-phenyl)methylamino]ethyl]carbamate as a colorless oil (600 mg, crude product).

[0258] 2) N-[2-[(3-bromo-2-fluoro-phenyl)methyl-ethyl-amino]ethyl]carbamic acid tert-butyl ester

[0259]

[0260] To a solution of tert-butyl N-[2-[(3-bromo-2-fluoro-phenyl)methylamino]ethyl]carbamate (600 mg, 1.73 mmol, 1 eq) and acetaldehyde (761 mg, 6.9 mmol, 970 μL, 40% purity, 4 eq) in MeOH (5 mL) was added AcOH to adjust the pH to 4-5, and the mixture was stirred at 25 °C for 12 h, and then NaBH 3 CN (326 mg, 5.18 mmol, 3 eq), the mixture was stirred at 25 ° C for 12 h. The mixture was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give a colorless oily N-[2-[(3-bromo-2-fluoro-phenyl)methyl-ethyl-amino]ethyl]carbamic acid tert-butyl ester compound (300 mg, 799.4 μmol, yield 46%).

[0261] 3) tert-Butyl N-[2-[(3-cyano-2-fluoro-phenyl)methyl-ethyl-amino]ethyl]carbamate

[0262]

[0263] N-[2-[(3-bromo-2-fluoro-phenyl)methyl-ethyl-amino]ethyl]carbamic acid tert-butyl ester (200 mg, 533 μmol, 1 eq), Zn(CN) 2 (188mg, 1.6mmol, 101.5μL, 3eq), Pd 2 (dba) 3 A mixture of dppf (49 mg, 53.3 μmol, 0.1 eq) and dppf (59 mg, 106.6 μmol, 0.2 eq) in DMF (3 mL) was degassed and heated with N 2 Purge 3 times, then 2 The mixture was stirred at 100°C for 12 h under a 3-H atmosphere. 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) and then with Na 2 SO 4 Dry, filter and concentrate the filtrate in vacuo to give tert-butyl N-[2-[(3-cyano-2-fluoro-phenyl)methyl-ethyl-amino]ethyl]carbamate compound (150 mg, crude) as a colorless oil.

[0264] 4) 3-(((2-aminoethyl)(ethyl)amino)methyl)-2-fluorobenzonitrile TFA salt (Compound 175)

[0265]

[0266] To a solution of tert-butyl N-[2-[(3-cyano-2-fluorophenyl)methyl-ethyl-amino]ethyl]carbamate (150 mg, 467 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 29 eq). The mixture was stirred at 25 °C for 12 h and then concentrated in vacuo to give a residue. The residue was purified by preparative-HPLC (TFA conditions; chromatographic column: C18-1 150×30mm×10mm×4mm; mobile phase: [water (TFA)-ACN]; B%: 1%-25%, 8min), and then purified by preparative-HPLC TFA conditions chromatographic column: C18-1 150×30mm×5μm; mobile phase: [water (TFA)-ACN]; B%: 1%-25%, 8min) to obtain a colorless gummy compound 3-[[2-aminoethyl (ethyl) amino] methyl]-2-fluorobenzonitrile TFA salt (145 mg, 413.4 μmol, yield 88.6%, purity 95.5%, TFA). MS (ESI): m / z=222.1[M+H] + ; Retention time: 0.497min, 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).

[0267] Example 10: Synthesis of Compound 175A

[0268] Following a similar procedure as described above for compound 175 (Example 9), omitting step 3 and using HCl instead of TFA in the deprotection step, compound 175A was prepared:

[0269]

[0270] Example 11: N1-(3-chloro-2-fluorobenzyl)-N1-cyclobutylethane-1,2-diamine hydrochloride (Compound 159) synthesis

[0271] 1) tert-Butyl (2-((3-chloro-2-fluorobenzyl)(cyclobutyl)amino)ethyl)carbamate

[0272]

[0273] To a solution of tert-butyl N-[2-[(3-chloro-2-fluorophenyl)methylamino]ethyl]carbamate (150 mg, 495.4 μmol, 1 eq) and cyclobutanone (69.5 mg, 991 μmol, 74 μL, 2 eq) 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 NaBH 3 CN (93.4 mg, 1.49 mmol, 3 eq). The mixture was poured into 5 mL of water and then extracted with ethyl acetate (3 mL × 3). The organic layer was washed with brine (2 mL × 2) and then filtered, and the filtrate was concentrated in vacuo to obtain a white solid compound N-[2-[(3-chloro-2-fluoro-phenyl)methyl-cyclobutyl-amino]ethyl]carbamic acid tert-butyl ester (170 mg, crude product).

[0274] 2) N1-(3-chloro-2-fluorobenzyl)-N1-cyclobutylethane-1,2-diamine dihydrochloride (Compound 159)

[0275]

[0276] EtOAc (2 mL) was added to a solution of tert-butyl N-[2-[(3-chloro-2-fluoro-phenyl)methyl-cyclobutyl-amino]ethyl]carbamate (170 mg, 476 μmol, 1 eq) in HCl / EtOAc (1 mL, 4M), and the mixture was stirred at 25°C for 12 h. The mixture was concentrated in vacuo to give a residue, which was purified by preparative-HPLC (HCl conditions; column: Phenomenex lunaC18 80*40mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 1%-30%, 7 min) to give a white gummy compound N1-(3-chloro-2-fluorobenzyl)-N1-cyclobutylethane-1,2-diamine dihydrochloride (99 mg, 337.3 μmol, yield 71%, purity 100%, 2HCl). MS (ESI): m / z=257.0[M+H] + ; Retention time: 1.337min, method: A; 1 H NMR (400 MHz, DMSO-d 6 )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).

[0277] Example 12: (R)-N1-(1-(3-chlorophenyl)ethyl)-N1-ethylethane-1,2-diamine dihydrochloride (compound Synthesis of Compound 176

[0278] 1) Tert-butyl (R)-(2-((1-(3-chlorophenyl)ethyl)amino)ethyl)carbamate

[0279]

[0280] To a solution of tert-butyl N-(2-oxoethyl)carbamate (198.89 mg, 1.25 mmol, 1.2 eq) and (1R)-1-(3-chlorophenyl)ethanamine hydrochloride (200 mg, 1.04 mmol, 1 eq) in MeOH (3 mL) were added AcOH (420 mg, 7 mmol, 400 μL, 6.72 eq) and NaOAc (85.4 mg, 1.04 mmol, 1 eq), followed by NaBH 3 CN (78.5 mg, 1.25 mmol, 1.2 eq). 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 washed with saturated NaHCO 3 (3 mL) and extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (5 mL×2) and washed with Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give tert-butyl (R)-(2-((1-(3-chlorophenyl)ethyl)amino)ethyl)carbamate (300 mg, 1 mmol, yield 96.4%) as a colorless oil.

[0281] 2)(R)-tert-Butyl(2-((1-(3-chlorophenyl)ethyl)(ethyl)amino)ethyl)carbamate

[0282]

[0283] To a solution of tert-butyl N-[2-[[(1R)-1-(3-chlorophenyl)ethyl]amino]ethyl]carbamate (260 mg, 870 μmol, 1 eq) and acetaldehyde (192 mg, 4.35 mmol, 244 μL, 5 eq) in DCM (4 mL) was added AcOH to adjust the pH to 4-5, the mixture was stirred at 20° C. for 2 h, and then NaBH(OAc) was added. 3 (369 mg, 1.74 mmol, 2 eq), the mixture was stirred at 20 ° C for 2 h. LC-MS showed that reactant 2 was completely consumed and ~49% of the desired compound was detected. The mixture was concentrated to give a residue. Saturated NaHCO was added to the reaction mixture. 3The reaction mixture was quenched with ethyl acetate (10 ml x 3) to pH 8. The combined organic phases were washed with anhydrous Na 2 SO 4 The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative-TLC (SiO 2 , petroleum ether / ethyl acetate=1 / 1, Rf=0.44) to give colorless oily (R)-tert-butyl (2-((1-(3-chlorophenyl)ethyl)(ethyl)amino)ethyl)carbamate (100 mg, 306 μmol, yield 35%).

[0284] 3) (R)-N1-(1-(3-chlorophenyl)ethyl)-N1-ethylethane-1,2-diamine dihydrochloride (Compound 176)

[0285]

[0286] A solution of tert-butyl N-[2-[[(1R)-1-(3-chlorophenyl)ethyl]-ethylamino]ethyl]carbamate (70 mg, 214 μmol, 1 eq) in hexafluoroisopropanol (0.5 mL) was stirred at 80°C for 3 h. LC-MS showed that reactant 3 was completely consumed and ~94% of the desired compound was detected. The mixture was concentrated to obtain a residue. The residue was purified by preparative-HPLC (HCl conditions, column: Phenomenex luna C18 80×40mm×3μm; mobile phase: [water (HCl)-ACN]; B%: 1%-30%, 7 min) to obtain a white solid (R)-N1-(1-(3-chlorophenyl)ethyl)-N1-ethylethane-1,2-diamine dihydrochloride (13 mg, 48 μmol, yield 22%, purity 97.3%, 2HCl). MS (ESI): m / z=227.1[M+H] + ; Retention time: 1.799min, method: K; 1 HNMR (400 MHz, DMSO-d 6 )δ10.99-12.28(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 (brs, 3H), 3.48 (brs, 1H), 2.82-3.22 (m, 2H), 1.74 (d, J=6.85Hz, 3H), 1.17-1.41 (m, 3H).

[0287] Example 13: (S)-N1-(1-(3-chlorophenyl)ethyl)-N1-ethylethane-1,2-diamine dihydrochloride (compound Synthesis of Compound 177

[0288] According to the similar method of compound 176 (Example 12) above, compound 177 was prepared:

[0289]

[0290] Example 14: N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopentylethane-1,2-diamine dihydrochloride (Chemical Synthesis of Compound 184

[0291] 1) N-(1-(3-chloro-2-fluorophenyl)ethyl)cyclopentylamine

[0292]

[0293] A solution of 1-(3-chloro-2-fluorophenyl)ethanone (500 mg, 2.90 mmol, 1 eq) and cyclopentylamine (493 mg, 5.79 mmol, 571.7 μL, 2 eq) in tetraisopropoxytitanium (1.07 g, 3.8 mmol, 1.1 mL, 1.3 eq) was stirred at 20 °C for 1 h. MeOH (10 mL) and NaBH were then added at 0 °C. 4 (186 mg, 4.93 mmol, 1.7 eq), the mixture was stirred at 20 °C for 2 h. LC-MS showed that reactant 1 was completely consumed, and 70% of the desired compound was detected. The reaction mixture was washed with 10 mL of H 2 O and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with anhydrous Na 2 SO 4 After drying, the mixture was filtered and the filtrate was concentrated in vacuo to give N-(1-(3-chloro-2-fluorophenyl)ethyl)cyclopentylamine (400 mg, crude) as a yellow oil.

[0294] 2. tert-Butyl (2-((1-(3-chloro-2-fluorophenyl)ethyl)(cyclopentyl)amino)ethyl)carbamate

[0295]

[0296] To a solution of N-(1-(3-chloro-2-fluorophenyl)ethyl)cyclopentylamine (280 mg, 1.16 mmol, 1 eq) and tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate (259 mg, 1.16 mmol, 1 eq) in THF (6 mL) was added NaH (56 mg, 1.39 mmol, 60% purity, 1.2 eq) at 0°C, and the mixture was heated at 80°C under N 2 The mixture was stirred for 2 h under atmosphere. LC-MS showed that the reactant 2 remained at 42% and 21% of the desired compound was detected. The reaction mixture was washed with 10 mL of H 2O and extracted with EtOAc (8 mL x 3). The combined organic phases were washed with anhydrous Na 2 SO 4 After drying, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (HCl conditions; chromatographic column: Phenomenex Luna 80×30mm×3μm; mobile phase: [water (HCl)-ACN]; B%: 20%-45%, 8min) to give a white solid (tert-butyl 2-((1-(3-chloro-2-fluorophenyl)ethyl)(cyclopentyl)amino)ethyl)carbamate (240 mg, 624μmol, yield 54%).

[0297] 3. N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopentylethane-1,2-diamine dihydrochloride (Compound 184)

[0298]

[0299] A solution of tert-butyl (2-((1-(3-chloro-2-fluorophenyl)ethyl)(cyclopentyl)amino)ethyl)carbamate (40 mg, 103.9 μmol, 1 eq) and HCl / EtOAc (4M, 1.5 mL, 57.74 eq) in EtOAc (1 mL) was stirred at 20° C. for 2 h. LC-MS showed that reactant 3 was completely consumed, and ˜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; chromatographic column: Phenomenex Luna 80×30mm×3μm; mobile phase: [water (HCl)-ACN]; B%: 5%-25%, 8min) to obtain colorless gum N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopentylethane-1,2-diamine dihydrochloride (10.24 mg, 33.19μmol, yield 31.9%, purity 92.3%, 2HCl). MS (ESI): m / z=285.1[M+H] + ; Retention time: 1.641min, method: A; 1 H NMR (400 MHz, DMSO-d 6 )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).

[0300] Example 15: N'-[1-(3-chloro-2-fluorophenyl)ethyl]-N'-cyclopropyl-ethane-1,2-diamine hydrochloride (Chemical Synthesis of compound 220) and its enantiomers

[0301] 1) N-(1-(3-chloro-2-fluorophenyl)ethyl)cyclopropylamine

[0302]

[0303] To a solution of 1-(3-chloro-2-fluorophenyl)ethanone (200 mg, 1.16 mmol, 1 eq) and cyclopropylamine (99.3 mg, 1.74 mmol, 120.4 μL, 1.5 eq) in MeOH (2 mL) was added AcOH to adjust the pH to 4-5, and stirred at 40° C. for 2 h. Then NaBH 3 CN (218.47 mg, 3.48 mmol, 3 eq), the mixture was stirred at 40 ° C for 2 h. The mixture was concentrated to obtain a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=10 / 1 to 3 / 1) to give a colorless oily compound N-[1-(3-chloro-2-fluorophenyl)ethyl]cyclopropylamine (200 mg, 936 μmol, yield 81%).

[0304] 2)(tert-Butyl)(2-((1-(3-chloro-2-fluorophenyl)ethyl)(cyclopropyl)amino)ethyl)carbamate

[0305]

[0306] A solution of N-[1-(3-chloro-2-fluorophenyl)ethyl]cyclopropylamine (200 mg, 936 μmol, 1 eq) and tert-butyl N-(2-oxoethyl)carbamate (149 mg, 936 μmol, 1 eq) in MeOH (3 mL) was adjusted to pH 4-5 with AcOH, and the mixture was stirred at 40 °C for 2 h, and then NaBH 3 CN (177 mg, 2.8 mmol, 3 eq), the mixture was stirred at 40° C. for 12 h. The mixture was concentrated in vacuo to give a white solid compound N-[2-[1-(3-chloro-2-fluoro-phenyl)ethyl-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester (250 mg, crude product).

[0307] 3) N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 220)

[0308]

[0309] HCl / EtOAc (1 mL, 4 M) was added to a solution of tert-butyl N-[2-[1-(3-chloro-2-fluoro-phenyl)ethyl-cyclopropyl-amino]ethyl]carbamate (200 mg, 560.4 μmol, 1 eq) in EtOAc (2 mL). The mixture was stirred at 25°C for 1 h. The mixture was concentrated to give a residue, which was purified by preparative-HPLC (HCl conditions; column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 5%-30%, 8 min) to give a white solid compound N'-[1-(3-chloro-2-fluorophenyl)ethyl]-N'-cyclopropyl-ethane-1,2-diamine hydrochloride (117 mg, 399 μmol, yield 71%, purity 100%, HCl). MS (ESI): m / z=257.0[M+H] + ; Retention time: 1.744min, 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).

[0310] 4) Enantiomers of N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopropylethane-1,2-diamine

[0311] 200 mg of compound 220 was further separated by SFC (instrument: Waters SFC80 preparative SFC; column: Daicel Chiral Pak 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: CO 2 ; B: [0.1% NH 3 *H 2 O in MeOH solution]; B%: 30%-30%, 3 min)(P 1 Relative retention time = 1.245, P 2Relative retention time = 1.506), and then the product with relative retention time = 1.245 was further purified by preparative HPLC (neutral condition column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: A: water (NH 3 *H 2 O+NH 4 HCO 3 ); B: MeCN; B%: 5%-70%, 8min), to obtain brown oily compound 220A (+)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopropylethane-1,2-diamine (relative retention time = 1.245; 20.2 mg, 76.88 μmol, yield 20%, purity 97.72%). ((+) spin in DMSO @ 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).

[0312] As the second fraction, brown oily compound 220B (-)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)-N1-cyclopropylethane-1,2-diamine ((relative retention time = 1.506; 26.8 mg, 101.79 μmol, yield 27%, purity 97.52%) was obtained ((-) spin in DMSO @ 589 nm / 19.9 ° C, ee% = 97.86%). MS (ESI): m / z = 257.0 [M + H] + , 1 HNMR (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).

[0313] Example 16: N'-[1-(2-chloro-3,5-difluoro-phenyl)ethyl]-N'-cyclopropyl-ethane-1,2-diamine hydrochloric acid Synthesis of salt (Compound 188)

[0314] Compound 188 was prepared in a similar manner to compound 220 (Example 15) above:

[0315]

[0316]

[0317] Example 17: N1-(bicyclo[1.1.1]pentan-1-yl)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1, Synthesis of 2-diamine hydrochloride (Compound 182)

[0318] 1) N-(1-(3-chloro-2-fluorophenyl)ethyl)bicyclo[1.1.1]pentane-1-amine

[0319]

[0320] AcOH was added to a solution of 1-(3-chloro-2-fluorophenyl)ethanone (400 mg, 2.3 mmol, 1 eq) and bicyclo[1.1.1]pentane-1-amine (289 mg, 3.48 mmol, 1.5 eq) in MeOH (5 mL) to adjust the pH to 4-5 and stirred at 40 °C for 12 h. NaBH was then added at 20 °C. 3 CN (437 mg, 7 mmol, 3 eq). The mixture was stirred at 40 °C for 2 h. LC-MS showed that reactant 1 was completely consumed and ~30% of the desired compound was detected. Saturated NaHCO was added to the reaction mixture at 0 °C. 3 The solution (10 mL) was quenched to pH 7 and then heated to 40 °C with H 2 O (5 mL), and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with anhydrous Na 2 SO 4 The mixture was dried, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography ( 12g Silica gel flash column, 0-7% ethyl acetate / petroleum ether gradient elution, 90 mL / min). (Petroleum ether / ethyl acetate = 1 / 1, Rf = 0.62) to obtain colorless oily N-(1-(3-chloro-2-fluorophenyl)ethyl)bicyclo[1.1.1]pentane-1-amine (300 mg, 1.25 mmol, yield 54%).

[0321] 2) tert-Butyl N-[2-[1-bicyclo[1.1.1]pentyl-[1-(3-chloro-2-fluorophenyl)ethyl]amino]ethyl]carbamate

[0322]

[0323] To a solution of N-[1-(3-chloro-2-fluorophenyl)ethyl]bicyclo[1.1.1]pentan-1-amine (270 mg, 1.13 mmol, 1 eq) and tert-butyl N-(2-oxoethyl)carbamate (179 mg, 1.13 mmol, 1 eq) in MeOH (4 mL), AcOH was added to adjust the pH to 4-5 and stirred at 40° C. for 2 h. NaBH was then added. 3 CN (212 mg, 3.38 mmol, 3 eq), the mixture was stirred at 40 °C for 12 h. LC-MS showed that reactant 2 remained at 15%, and 37% of the desired compound was detected. Saturated NaHCO was added to the reaction mixture at 0 °C. 3 The solution (5 mL) was quenched and then 2 O (10 mL), and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with anhydrous Na 2 SO 4 The mixture was dried, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative-TLC (SiO 2 , petroleum ether / ethyl acetate=1 / 1, Rf=0.54) to obtain tert-butyl N-[2-[1-bicyclo[1.1.1]pentyl-[1-(3-chloro-2-fluoro-phenyl)ethyl]amino]ethyl]carbamate (100 mg, 261 μmol, yield 23%) as a colorless oil.

[0324] 3) N1-(bicyclo[1.1.1]pentan-1-yl)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (Compound 182)

[0325]

[0326] A solution of tert-butyl N-[2-[1-bicyclo[1.1.1]pentyl-[1-(3-chloro-2-fluorophenyl)ethyl]amino]ethyl]carbamate (50 mg, 130.6 μmol, 1 eq) in EtOAc (1 mL) and HCl / EtOAc (0.5 mL, 4 M) was stirred at 20° C. for 1 h. LC-MS showed that reactant 1 was completely consumed, and ˜64% of the desired compound was detected. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (HCl conditions, column: Phenomenex Luna 80×30mm×3μm; mobile phase: [water (HCl)-ACN]; B%: 1%-40%, 8min) to give a white solid N1-(bicyclo[1.1.1]pentane-1-yl)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (33.5 mg, 118.5 μmol, yield 91%, purity 100%, HCl). MS (ESI): m / z=283.0[M+H] + ; Retention time: 2.127min, method: A; 1 HNMR(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).

[0327] Example 18: N1-(cyclobutyl)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (Chemical Compound 180) and N1-(cyclopropyl)-N1-(1-(2,5-dichlorophenyl)ethyl)ethane-1,2-diamine hydrochloride (Compound 185) Synthesis

[0328] According to the similar method of compound 182 (Example 17) above, the following compound was prepared:

[0329]

[0330] Example 19: N1-allyl-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (compound Synthesis of Compound 172

[0331] 1) tert-Butyl 2-((1-(3-chloro-2-fluorophenyl)ethyl)amino)ethyl)carbamate

[0332]

[0333] To a solution of 1-(3-chloro-2-fluorophenyl)ethanone (2 g, 11.59 mmol, 1 eq) and tert-butyl N-(2-aminoethyl)carbamate (1.86 g, 11.59 mmol, 1.82 mL, 1 eq) in MeOH (20 mL) was added AcOH and the pH was adjusted to 4-5. The mixture was stirred at 70 °C for 12 h, and then NaBH 3 CN (2.18 g, 34.77 mmol, 3 eq), the mixture was stirred at 70 °C for 2 h, and then NaBH 3 CN (2.18 g, 34.77 mmol, 3 eq), and the mixture was stirred at 70 ° C for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent to obtain a residue, which was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine (10 mL × 2) and washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give a red oily compound N-[2-[1-(3-chloro-2-fluorophenyl)ethylamino]ethyl]carbamic acid tert-butyl ester (1.8 g, 5.68 mmol, yield 49%).

[0334] 2)(tert-Butyl (2-(allyl (1-(3-chloro-2-fluorophenyl)ethyl)amino)ethyl)carbamate

[0335]

[0336] To a solution of tert-butyl N-[2-[1-(3-chloro-2-fluorophenyl)ethylamino]ethyl]carbamate (200 mg, 631.3 μmol, 1 eq) in MeCN (2 mL) was added K 2 CO 3 (262 mg, 1.89 mmol, 3 eq) and 3-bromoprop-1-ene (115 mg, 947 μmol, 1.5 eq). The mixture was stirred at 70 ° C for 12 h. The mixture was then filtered and the filtrate was concentrated to obtain a yellow oily compound N-[2-[allyl-[1-(3-chloro-2-fluorophenyl)ethyl]amino]ethyl]carbamic acid tert-butyl ester (200 mg, crude product).

[0337] 3) N1-allyl-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine hydrochloride (Compound 172)

[0338]

[0339] HCl / EtOAc (1 mL, 4 M) was added to a solution of tert-butyl N-[2-[allyl-[1-(3-chloro-2-fluorophenyl)ethyl]amino]ethyl]carbamate (100 mg, 280.2 μmol, 1 eq) in EtOAc (2 mL). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated to obtain a residue. The residue was purified by preparative-HPLC (HCl conditions; chromatographic column: Phenomenex Luna 80×30 mm×3 μm; mobile phase: [water (HCl)-ACN]; B%: 15%-45%, 8 min) to obtain a colorless oily 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). MS (ESI): m / z = 257.0 [M+H] + ; Retention time: 1.607min, method: K; 1 H 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).

[0340] Example 20: N1-(2-(methylthio)ethyl)-N1-(1-(3-chloro-2-fluorophenyl)ethyl)ethane-1,2-diamine Synthesis of (Compound 169)

[0341] According to the similar method of compound 172 (Example 19) above, the following compound was prepared:

[0342]

[0343] Example 21: N1-(3-chloro-2-fluorobenzyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 120) synthesis

[0344] 1) N-(3-chloro-2-fluorobenzyl)cyclopropylamine

[0345]

[0346] To a solution of 3-chloro-2-fluoro-benzaldehyde (500 mg, 3.15 mmol, 1 eq) and cyclopropylamine (360 mg, 6.31 mmol, 437 μL, 2 eq) in MeOH (20 mL) was added AcOH to adjust the pH to 4-5, and the mixture was stirred at 25 °C for 12 h. NaBH 3CN (595 mg, 9.46 mmol, 3 eq), and the mixture was stirred at 25 °C for 2 h. Saturated NaHCO 3 The solution was quenched with 5 mL of ethyl acetate (15 mL × 3). The combined organic layer was washed with brine (5 mL × 2) and washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a colorless oily compound N-[(3-chloro-2-fluorophenyl)methyl]cyclopropylamine (600 mg, crude product).

[0347] 2)(tert-Butyl 2-((3-chloro-2-fluorobenzyl)(cyclopropyl)amino)ethyl)carbamate

[0348]

[0349] To a solution of N-[(3-chloro-2-fluorophenyl)methyl]cyclopropylamine (200 mg, 1 mmol, 1 eq) in DCM (3 mL) was added tert-butyl N-(2-oxoethyl)carbamate (160 mg, 1 mmol, 1 eq), AcOH was added to the mixture to adjust the pH to 4-5, and stirred at 25°C for 1 h. Then NaBH(OAc) was added 3 (637 mg, 3 mmol, 3 eq), the mixture was stirred at 25° C. for 12 h. The mixture was concentrated in vacuo to give crude N-[2-[(3-chloro-2-fluoro-phenyl)methyl-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester (160 mg, crude) as a pale yellow oil.

[0350] 3) N1-(3-chloro-2-fluorobenzyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 120)

[0351]

[0352] A mixture of tert-butyl N-[2-[(3-chloro-2-fluoro-phenyl)methyl-cyclopropyl-amino]ethyl]carbamate (160 mg, 467 μmol, 1 eq) in HCl / EtOAc (2 mL, 4 M) was stirred at 25°C for 30 min. The mixture was concentrated in vacuo to obtain a residue, which was purified by preparative-HPLC (HCl condition column: Phenomenex luna C18 80*40mm*3μm; mobile phase: [water (HCl)-ACN]; B%: 1%-20%, 7 min;) to obtain a white solid compound N1-(3-chloro-2-fluorobenzyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (59 mg, 210 μmol, yield 45%, purity 99.7%, HCl). MS (ESI): m / z=243.0[M+H]+ ; Retention time: 1.654min, Method: A 1 H NMR(400MHz,DMSO-d6)δ8.16(brs,3H),7.44-7.65(m,2H),7.21(t,J=7.76Hz,1H),4.51(q,J=6.93Hz,1H),3.0 1-3.25(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).

[0353] Example 22: Synthesis of Compound 130

[0354] According to the similar method of compound 120 (Example 21) above, compound 130 was prepared:

[0355]

[0356]

[0357] Example 23: N 1 -(1-(3-bromo-2-fluorophenyl)ethyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride (compound Synthesis of Compound 191

[0358] 1) N-(1-(3-bromo-2-fluorophenyl)ethyl)cyclopropylamine

[0359]

[0360] To a solution of 1-(3-bromo-2-fluoro-phenyl)ethanone (CAS 161957-61-5) (500 mg, 2.3 mmol, 1 eq) in MeOH (5 mL) was added cyclopropylamine (197.3 mg, 3.5 mmol, 239.4 μL, 1.5 eq). The reaction was then stirred at 60 °C for 12 h. NaBH was added at 20 °C. 3 CN (579.1 mg, 9.2 mmol, 4 eq), and then the mixture was stirred at 60 ° C for 2 h. LC-MS showed that reactant 1 had been consumed and the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 6 mL of H 2 O and extracted with ethyl acetate (4 mL x 3). The combined organic layers were washed with H 2 O (8 mL × 2) and washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2, petroleum ether / ethyl acetate = 5 / 1) to obtain a white solid compound N-[1-(3-bromo-2-fluorophenyl)ethyl]cyclopropylamine (320 mg, 1.2 mmol, yield 53.8%).

[0361] 2) 2-((1-(3-bromo-2-fluorophenyl)ethyl)(cyclopropyl)amino)acetamide

[0362]

[0363] To a solution of N-[1-(3-bromo-2-fluorophenyl)ethyl]cyclopropylamine (290 mg, 1.1 mmol, 1 eq) in ACN (4 mL) were added 2-bromoacetamide (372.0 mg, 2.7 mmol, 2.4 eq) and K 2 CO 3 (465.81 mg, 3.37 mmol, 3 eq). The mixture was stirred at 80 °C for 12 h. LC-MS showed that the residual amount of 2 was 50%, and the desired compound was detected at 24%. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 6 mL of H 2 O and extracted with ethyl acetate (4 mL x 3). The combined organic layers were washed with H 2 O (8 mL × 2) and washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2 , petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow oily compound 2-[1-(3-bromo-2-fluoro-phenyl)ethyl-cyclopropyl-amino]acetamide (58 mg, 184.0 μmol, yield 16.4%).

[0364] 3)N 1 -(1-(3-bromo-2-fluorophenyl)ethyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride (Compound 191)

[0365]

[0366] To a solution of 2-[1-(3-bromo-2-fluoro-phenyl)ethyl-cyclopropyl-amino]acetamide (58 mg, 184.0 μmol, 1 eq) in THF (1 mL) was added BH 3.THF (1M, 736.1μL, 4eq). The mixture was stirred at 70°C for 12h. LC-MS showed that the desired compound was detected. The residue was diluted with 5mL MeOH and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative-HPLC (HCl conditions, chromatographic column: Phenomenex luna C18 80×40mm×3μm; mobile phase: [water (HCl)-ACN]; B%: 5%-35%, 7min). A colorless oily compound N was obtained. 1 -(1-(3-bromo-2-fluorophenyl)ethyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride (4.3 mg, 14.3 μmol, yield 7.8%, HCl, purity 100%). MS (ESI): m / z=301.3 [M+H] + ; Retention time: 1.838min, 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).

[0367] Example 24: Synthesis of Compounds 242, 243, 244 and 245

[0368] According to the similar method of compound 191 (Example 23) above, the following compound was prepared:

[0369]

[0370] Example 25: N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (compound Synthesis of Compound 224

[0371] 1) 1-(3-chloro-2-fluorophenyl)propan-1-ol

[0372]

[0373] In N 2 To a solution of 3-chloro-2-fluorobenzaldehyde (1 g, 6.3 mmol, 1 eq) in THF (5 mL) was added bromo(ethyl)magnesium (3 M, 2.5 mL, 1.2 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. TLC showed that reactant 1 was completely consumed and a new spot was formed. Saturated NH 4 Cl solution (20 mL) was used for quenching, and then extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with NaCl (20 mL×2) and washed with Na2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a yellow oily crude product of 1-(3-chloro-2-fluorophenyl)propan-1-ol (1 g, 5.3 mmol, yield 84.1%).

[0374] 2) 1-(3-Chloro-2-fluorophenyl)propan-1-one

[0375]

[0376] To a solution of 1-(3-chloro-2-fluorophenyl)propan-1-ol (1 g, 5.3 mmol, 1 eq) in DCM (20 mL) was added DMP (3.4 g, 8.0 mmol, 1.5 eq). The mixture was stirred at 20 °C for 12 h. TLC showed that 2 was consumed and a major new spot with a higher polarity was detected. The residue was washed with 20 mL of saturated Na 2 SO 3 The mixture was quenched and extracted with 30 mL DCM (10 mL×3). The combined organic layers were washed with Na 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-20% ethyl acetate / petroleum ether gradient elution, 120 mL / min) to obtain a colorless oily compound 1-(3-chloro-2-fluorophenyl)propan-1-one (790 mg, 4.23 mmol, yield 79.85%).

[0377] 3) N-(1-(3-chloro-2-fluorophenyl)propyl)cyclopropylamine

[0378]

[0379] Cyclopropylamine (179.0 mg, 3.1 mmol, 217.2 u L, 1.5 eq) was added to a solution of 1-(3-chloro-2-fluorophenyl)propan-1-one (390 mg, 2.1 mmol, 1 eq) in MeOH (2 mL). The reaction was then stirred at 60 °C for 12 h. NaBH 3 CN (525.3 mg, 8.4 mmol, 4 eq), 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 washed with 6 mL of H 2 O and extracted with ethyl acetate (4 mL x 3). The combined organic layers were washed with H 2 O (8 mL × 2) and washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2, petroleum ether / ethyl acetate = 3:1) to obtain a yellow oily compound N-(1-(3-chloro-2-fluorophenyl)propyl)cyclopropylamine (250 mg, 805.2 μmol, yield 38.5%, purity 73.3%).

[0380] 4) 2-((1-(3-chloro-2-fluorophenyl)propyl)(cyclopropyl)amino)acetamide

[0381]

[0382] To a solution of 2-bromoacetamide (455.3 mg, 3.3 mmol, 3 eq) in ACN (5 mL) was added K 2 CO 3 (456.09 mg, 3.30 mmol, 3 eq) and N-(1-(3-chloro-2-fluorophenyl)propyl)cyclopropylamine (250 mg, 1.1 mmol, 1 eq). 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 washed with 50 mL of H 2 O, extracted with 150 mL of EtOAc (50 mL × 3), and washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2 , petroleum ether / ethyl acetate = 0:1). The residue was purified by preparative HPLC (HCl conditions). (Chromatographic column: Phenomenex Luna 80×30mm×3μm; mobile phase: [water (HCl)-ACN]; B%: 10%-45%, 8min) to obtain a white solid compound 2-((1-(3-chloro-2-fluorophenyl)propyl)(cyclopropyl)amino)acetamide (110 mg, 353.6 μmol, yield 32.2%, purity 91.6%).

[0383] 5) N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 224)

[0384]

[0385] 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 BH 3.THF (1M, 2.4mL, 6eq). The mixture was stirred at 70°C for 12h. LC-MS showed that the desired compound was detected. 2mL MeOH was added to the reactant. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl conditions): chromatographic column: Phenomenex Luna 80×30mm×3μm; mobile phase: [water (HCl)-ACN]; B%: 5%-35%, 8min, to obtain a colorless oily compound N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (37mg, 136.7μmol, yield 35.4%, purity 100%, HCl). MS (ESI): m / z=271.1[M+H] + ; Retention time: 1.558min, 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).

[0386] Example 26: N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-propylethane-1,2-diamine hydrochloride (compound 262) Synthesis

[0387] 1) 1-(3-chloro-2-fluorophenyl)propan-1-ol

[0388]

[0389] In N 2 To a solution of 3-chloro-2-fluorobenzaldehyde (1 g, 6.3 mmol, 1 eq) in THF (5 mL) was added bromo(ethyl)magnesium (3 M, 2.5 mL, 1.2 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. TLC showed that reactant 1 was completely consumed and a new spot was formed. Saturated NH 4 Cl solution (20 mL) was used for quenching, and then extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with NaCl (20 mL × 2) and washed with Na 2 SO 4The residue was dried and concentrated under reduced pressure to obtain a yellow oily crude product of 1-(3-chloro-2-fluorophenyl)propan-1-ol (1 g, 5.3 mmol, yield 84.1%).

[0390] 2) 1-(3-Chloro-2-fluorophenyl)propan-1-one

[0391]

[0392] To a solution of 1-(3-chloro-2-fluorophenyl)propan-1-ol (1 g, 5.3 mmol, 1 eq) in DCM (20 mL) was added DMP (3.4 g, 8.0 mmol, 1.5 eq). The mixture was stirred at 20 °C for 12 h. TLC showed that a new spot with a higher polarity was detected. The residue was washed with 200 mL of saturated Na 2 SO 3 The combined organic layers were diluted and extracted with 300 mL DCM (100 mL×3). 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-20% ethyl acetate / petroleum ether gradient elution, 120 mL / min) to obtain a colorless oily compound 1-(3-chloro-2-fluorophenyl)propan-1-one (790 mg, 4.23 mmol, yield 79.85%).

[0393] 3) 1-(3-chloro-2-fluorophenyl)-N-propyl-1-propylamine

[0394]

[0395] To a solution of 1-(3-chloro-2-fluorophenyl)propan-1-one (200 mg, 1.1 mmol, 1 eq) in MeOH (3 mL) was added propan-1-amine (95.0 mg, 1.6 mmol, 132.2 μL, 1.5 eq) and Ti(i-PrO) 4 (913.8 mg, 3.2 mmol, 948.9 μL, 3 eq). The mixture was stirred at 60 °C for 12 h. NaBH was added to the reaction at 20 °C. 3 CN (269.4 mg, 4.3 mmol, 4 eq) and stirred at 60 °C for 2 h. LC-MS showed that 3 was completely consumed and a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 15 mL of H 2 O, and extracted with 30 mL of EtOAc (10 mL×3), and then with Na 2 SO 4The residue was dried, filtered, and concentrated under reduced pressure to give a yellow oily crude product of 1-(3-chloro-2-fluorophenyl)-N-propyl-1-amine (210 mg, crude product).

[0396] 4) tert-Butyl (2-((1-(3-chloro-2-fluorophenyl)propyl)(propyl)amino)ethyl)carbamate

[0397]

[0398] To a solution of 1-(3-chloro-2-fluorophenyl)-N-propyl-1-propylamine (150 mg, 653.0 μmol, 1 eq) in MeOH (2 mL) were added tert-butyl N-(2-oxoethyl)carbamate (727.6 mg, 4.6 mmol, 7 eq) and AcOH to adjust the pH to 5, and the mixture was stirred at 60° C. for 12 h. NaBH was then added at 20° C. 3 CN (164.1 mg, 2.6 mmol, 4 eq). The mixture was stirred at 60 °C for 2 h. LC-MS showed that 4 was completely consumed and a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 10 mL of H 2 O, extracted with 30 mL EtOAc (10 mL × 3), and washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2 , petroleum ether / ethyl acetate=3 / 1) to give a white solid compound tert-butyl (2-((1-(3-chloro-2-fluorophenyl)propyl)(propyl)amino)ethyl)carbamate (73 mg, 195.8 μmol, yield 30.0%).

[0399] 5) N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-propylethane-1,2-diamine hydrochloride (Compound 262)

[0400]

[0401] A solution of tert-butyl N-[2-[1-(3-chloro-2-fluoro-phenyl)propyl-propyl-amino]ethyl]carbamate (73 mg, 195.8 μmol, 1 eq) in HCl / EtOAc (5 mL) was stirred at 20 °C for 1 h. LC-MS showed that 5 was completely consumed and a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. 2 mL of MeOH was added to the reaction. The residue was purified by preparative-HPLC (HCl conditions). (Chromatographic column: Phenomenex Luna 80×30mm×3μm; mobile phase: [water (HCl)-ACN]; gradient: 10%-35% B, 8min) to obtain a yellow oily compound N1-(1-(3-chloro-2-fluorophenyl)propyl)-N1-propylethane-1,2-diamine hydrochloride (28.03 mg, 90.64μmol, yield 46.30%, purity 100%, HCl). MS (ESI): m / z=273.3[M+H] + ; Retention time: 1.368min, Method: M. Specific 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).

[0402] Example 27: Synthesis of Compounds 190, 258 and 248

[0403] According to the similar method of compound 262 (Example 26) above, the following compound was prepared:

[0404]

[0405]

[0406] Example 28: Synthesis of Compounds 218 and 227

[0407] Starting with 3-acetyl-2-fluorobenzonitrile (CAS 112279-89-7) instead of intermediate 3 in step 3, and using cyclopropylamine or cyclobutylamine, respectively, the following compounds were prepared according to the method described for the synthesis of compound 262 (Example 26):

[0408]

[0409] Example 29: N 1 -(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N 1 -Cyclopropylethane-1,2-diamine salt Synthesis of Acid Salt (Compound 275)

[0410] 1) 1-(3-chloro-2-fluorophenyl)-2,2-difluoroethan-1-one

[0411]

[0412] A solution of 1-chloro-2-fluorobenzene (3 g, 23.0 mmol, 1 eq) in THF (30 mL) was degassed and heated with N 2 After purging 3 times, LDA (2M, 23.0 mL, 2 eq) was added to the reaction at -78 °C, and the mixture was stirred under N 2 Stir at -78°C for 15 min under N atmosphere. Then, ethyl 2,2-difluoroacetate (3.1 g, 25.3 mmol, 1.1 eq) was added to the reaction at -78°C, and the mixture was stirred at N 2 Stir at 25°C for 12 h under atmosphere. TLC showed that reactant 1 was completely consumed and many new spots were formed. 10 mL of saturated NH 4 Cl was quenched, and then extracted with 30 mL of ethyl acetate (10 mL×3). The combined organic layers were washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, eluted with 0-10% ethyl acetate / petroleum ether gradient, 80 mL / min) to obtain a yellow oily compound 1-(3-chloro-2-fluorophenyl)-2,2-difluoro-ethanone (pure product 0.4 g, crude product 2.5 g).

[0413] 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).

[0414] 2) N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)cyclopropylamine

[0415]

[0416] To a solution of 1-(3-chloro-2-fluorophenyl)-2,2-difluoro-ethanone (2.5 g, 11.8 mmol, 1 eq) in MeOH (2 mL) was added cyclopropylamine (1.0 g, 17.6 mmol, 1.2 mL, 1.5 eq) and Ti(i-PrO) 4 (10.0 g, 35.2 mmol, 10.4 mL, 3 eq). The mixture was stirred at 60 °C for 12 h. Then NaBH3 CN (3.0 g, 47.0 mmol, 4 eq), the resulting mixture was stirred at 60 ° C for 3 h. LC-MS showed that ~29% of the desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (20 g silica gel flash column, 0-5% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a white solid compound N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)cyclopropylamine (2.0 g, 2.8 mmol, yield 23.9%, purity 35%).

[0417] 3) 2-Bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide

[0418]

[0419] To a solution of N-[1-(3-chloro-2-fluorophenyl)ethyl]-3,3-difluoro-prop-2-en-1-amine (1.8 g, 7.4 mmol, 1 eq) in DCM (20 mL) was added K 2 CO 3 (2.0 g, 14.7 mmol, 2 eq) in water (20 mL) and 2-bromoacetyl bromide (1.8 g, 8.8 mmol, 768.1 μL, 1.2 eq). The mixture was stirred at 25 °C for 12 h. LC-MS showed complete consumption of reactant 3, and ~65% of the desired mass was detected. The reaction mixture was extracted with 60 mL DCM (20 mL×3). The combined organic layers were washed with saturated 20 mL NaCl and washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, gradient elution with 0-10% ethyl acetate / petroleum ether, 80 mL / min) to obtain a yellow oily compound 2-bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide (1.5 g, 4.0 mmol, yield 54.0%).

[0420] 4) N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide

[0421]

[0422] To a solution of 2-bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide (1.5 g, 4.0 mmol, 1 eq) in DMF (15 mL) was added (1,3-dioxoisoindolin-2-yl) potassium (952.8 mg, 5.1 mmol, 1.3 eq). The mixture was stirred at 25 °C for 12 h. LC-MS showed complete consumption of reactant 4, and ~20% of the desired mass was detected. The reaction mixture was quenched by adding 20 mL of water at 25 °C, and then extracted with 60 mL (20 mL×3) of ethyl acetate. The combined organic layers were washed with 20 mL of saturated NaCl and washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, 0-80% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain an off-white solid 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, yield 33.8%).

[0423] 5) 2-amino-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide

[0424]

[0425] 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 eq) in EtOH (10 mL) was added N 2 H 4 -H 2 O (83.6 mg, 1.3 mmol, 81.0 μL, purity 80%, 1 eq). The mixture was stirred at 80 ° C for 12 h. LC-MS showed that the reactant 5 was completely consumed and ~27% of the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (4 g silica gel flash column, 0-8% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to give a yellow oily compound 2-amino-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide (0.4 g, 1.3 mmol, yield 97.7%).

[0426] 6) N1-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N1-cyclopropylethane-1,2-diamine hydrochloride (Compound 275)

[0427]

[0428] A mixture of 2-amino-N-(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N-cyclopropylacetamide (0.4 g, 1.1 mmol, 1 eq) in THF (10 mL) was degassed and heated with N 2 Purge 3 times, then add BH to the reaction at 0 °C 3. THF (1 M, 11.4 mL, 10 eq) was added and stirred at 0 °C for 30 min, then heated under N 2 The mixture was stirred at 60°C for 12 min under a 4% CO atmosphere. LC-MS showed complete consumption of reactant 6, with ~66% of the desired mass detected. The reaction mixture was quenched at 0°C by adding 2 mL of MeOH, then diluted with 5 mL of water and extracted with 15 mL (5 mL x 3) of ethyl acetate. The combined organic layers were washed with saturated 10 mL of NaCl and washed with Na 2 SO 4 The crude product was purified by reverse phase HPLC (0.04% HCl, column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [H 2 O (0.04% HCl)-ACN]; gradient: 15%-45% B, 8.0 min) to obtain a white solid compound N 1 -(1-(3-chloro-2-fluorophenyl)-2,2-difluoroethyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride (0.2 g, 616.4 μmol, yield 54.0%, purity 99.2%, HCl). MS (ESI): m / z = 293.2 [M+H] + ; Retention time: 1.600min, 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).

[0429] Example 30: Synthesis of Compounds 225 and 274

[0430] According to the similar method of compound 275 (Example 30) above, the following compound was prepared:

[0431]

[0432] Example 31: N'-[1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl]-N'-cyclopropyl-ethane-1,2-difluorophenyl Synthesis of amine hydrochloride (Compound 247)

[0433] 1)((1-(3-chloro-2-fluorophenyl)vinyl)oxy)triethylsilane

[0434]

[0435] To a stirred solution of DIEA (1.9 g, 19.1 mmol, 2.7 mL, 1.1 eq) in THF (10 mL) at -78 °C was added n-BuLi (2.5 M, 7.7 mL, 1.1 eq) 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 eq) followed by chloro(triethyl)silane (2.9 g, 19.1 mmol, 3.3 mL, 1.1 eq) and the reaction mixture was stirred at 20 °C for 12 h. 2 mL of H was added at 0 °C. 2 O, and then 20 mL of HO was used to quench the reaction mixture. 2 O and extracted with 45 mL (15 mL × 3) EtOAc. 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (12 g silica gel flash column, 0-0% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a colorless oily compound ((1-(3-chloro-2-fluorophenyl)vinyl)oxy)triethylsilane (2.0 g, 7.0 mmol, yield 40.1%).

[0436] 2) 1-(3-Chloro-2-fluorophenyl)-3,3,3-trifluoropropan-1-one

[0437]

[0438] In N 2 Under atmosphere, 1-(trifluoromethyl)-1λ3,2-benzoxazol-3-one (2.5 g, 7.8 mmol, 1.5 eq) and CuSCN (65.7 mg, 522.9 μmol, 0.1 eq) were added. ((1-(3-chloro-2-fluorophenyl)vinyl)oxy)triethylsilane (1.5 g, 5.23 mmol, 1 eq) and DMF (15 mL) were added to the mixture. The mixture was stirred at 20 °C for 12 h. TLC showed that 2 was completely consumed and a major new spot was formed. The reaction mixture was washed with 25 mL of H 2O and extracted with 75 mL of EtOAc (25 mL×3). The combined organic layers were washed with 20 mL (10 mL×2) of brine and washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (12 g silica gel flash column, 0-0% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a yellow oily compound 1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropan-1-one (0.8 g, 3.4 mmol, yield 64.4%). 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).

[0439] 3) N-(1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)cyclopropylamine

[0440]

[0441] In N 2 1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropan-1-one (300 mg, 1.3 mmol, 1 eq) and cyclopropylamine (106.8 mg, 1.9 mmol, 129.6 μL, 1.5 eq) were dissolved in dry DCM (6 mL). AlMe was added dropwise to the reaction mixture via a syringe. 3 (2M, 935.2 μL, 1.5 eq). The solution was stirred at 20 °C for 15 h. BH 3 -Me 2 S (10M, 249.4 μL, 2 eq). The mixture was stirred at 20°C for 2 h. LC-MS showed that a major peak with the desired m / z was detected. The reaction mixture was quenched by adding 20% ​​aqueous NaOH solution dropwise. 2 Cl 2 (3 × 30 mL) to extract the aqueous layer. The organic layer was treated with Na 2 SO 4 The residue was purified by preparative-TLC (SiO 2 , petroleum ether / ethyl acetate = 5 / 1) to give a yellow oily compound N-(1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)cyclopropylamine (170 mg, 603.5 μmol, yield 48.4%).

[0442] 4) 2-((1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)(cyclopropyl)amino)acetamide

[0443]

[0444] To a solution of N-(1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)cyclopropylamine (170 mg, 603.5 μmol, 1 eq) in ACN (3 mL) was added K 2 CO 3 (417.06 mg, 3.02 mmol, 5 eq) and 2-bromoacetamide (499.59 mg, 3.62 mmol, 6 eq). The mixture was stirred at 80 °C for 12 h. LC-MS showed that 4 was completely consumed and a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 15 mL of H 2 O, extracted with 30 mL (10 mL × 3) EtOAc, and 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2 , petroleum ether / ethyl acetate = 5 / 1) to give a yellow oily compound 2-((1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)(cyclopropyl)amino)acetamide (101 mg, 298.2 μmol, yield 49.4%).

[0445] 5)N 1 -(1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride (Compound 247)

[0446]

[0447] To a solution of 2-[[1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl]-cyclopropyl-amino]acetamide (101 mg, 298.2 μmol, 1 eq) in THF (10 mL) was added BH 3 .THF (1M, 3.0 mL, 10 eq). The mixture was stirred at 70°C for 12 h. LC-MS showed that 5 was completely consumed and a peak with the desired m / z was detected. The residue was washed with 5 mL NH 4 Cl was diluted, extracted with 15 mL (5 mL × 3) EtOAc, and then 2 SO 4Dry, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (HCl conditions, column: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [water (HCl)-ACN]; B%: 25%-55%, 8min) to obtain a colorless oily compound N'-[1-(3-chloro-2-fluorophenyl)-3,3,3-trifluoropropyl]-N'-cyclopropylethane-1,2-diamine hydrochloride (11 mg, 30.2μmol, yield 10.1%, purity 99%, HCl). MS (ESI): m / z=325.3[M+H] + ; Retention time: 1.790min, 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).

[0448] Example 32: N 1 -((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride Synthesis of (Compound 267)

[0449] 1)(3-Chloro-2-fluorophenyl)(cyclobutyl)methanol

[0450]

[0451] A solution of 1-chloro-2-fluorobenzene (1 g, 7.7 mmol, 1 eq) in THF (10 mL) was degassed and heated with N 2 After purging three times, LDA (2M, 7.7 mL, 2 eq) was added to the reaction at -78 °C. The mixture was stirred at -78 °C for 15 min. Cyclobutanecarboxaldehyde (708.8 mg, 8.4 mmol, 1.1 eq) was then added to the reaction and stirred at 25 °C for 12 h. TLC showed that reactant 1 was completely consumed and a new spot was detected. 10 mL of saturated NH 4 The reaction mixture was quenched with Cl and then extracted with 30 mL (10 mL × 3) of ethyl acetate. The combined organic layers were washed with Na 2 SO 4Dry, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, 0-5% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a yellow oily compound (3-chloro-2-fluorophenyl)(cyclobutyl)methanol (1.0 g, 4.8 mmol, yield 63.3%). 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).

[0452] 2)(3-Chloro-2-fluorophenyl)(cyclobutyl)methanone

[0453]

[0454] DMP (2.5 g, 5.8 mmol, 1.8 mL, 1.2 eq) was added to a solution of (3-chloro-2-fluorophenyl)(cyclobutyl)methanol (1.0 g, 4.8 mmol, 1 eq) in DCM (10 mL). The mixture was stirred at 25 °C for 12 h. TLC showed that 2 was completely consumed and a new spot was formed. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, 0-8% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a yellow oily compound (3-chloro-2-fluorophenyl)(cyclobutyl)methanone (0.5 g, 2.3 mmol, yield 46.7%). 1 H NMR (400MHz, chloroform-d) δ = 7.74 (ddd, J = 1.8, 6.3, 7.9Hz, 1H), 7.59-7.53 (m, 1H), 7.18 (t, J = 7.9Hz, 1H), 3.90 (dquin, J = 2.8, 8.3Hz, 1H), 2.40-2.27 (m, 4H), 2.12-1.99 (m, 1H), 1.95-1.84 (m, 1H).

[0455] 3) N-((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)cyclopropylamine

[0456]

[0457] To a solution of (3-chloro-2-fluorophenyl)(cyclobutyl)methanone (0.5 g, 2.3 mmol, 1 eq) in MeOH (5 mL) was added cyclopropylamine (193.9 mg, 3.4 mmol, 235.3 μL, 1.5 eq) and Ti(i-PrO) 4(1.9 g, 6.8 mmol, 2.0 mL, 3 eq). The mixture was stirred at 60 °C for 12 h. Then NaBH 3 CN (569.0 mg, 9.0 mmol, 4 eq). The resulting mixture was stirred at 60 ° C for 3 h. LC-MS showed that 3 was completely consumed and the required mass was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (4 g silica gel flash column, 0-5% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to obtain a yellow oily compound N-((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)cyclopropylamine (0.3 g, 1.2 mmol, yield 52.2%).

[0458] 4) N-((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)cyclopropylamine

[0459]

[0460] To a solution of N-((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)cyclopropylamine (0.1 g, 512.3 μmol, 1 eq) in MeOH (1 mL) was added tert-butyl N-(2-oxoethyl)carbamate (489.3 mg, 3.1 mmol, 6 eq). The mixture was stirred at 60 °C for 12 h, and then NaBH was added to the reaction. 3 CN (128.8 mg, 2.1 mmol, 4 eq). The mixture was stirred at 60 ° C for 3 h. LC-MS showed that 4 was completely consumed and the required 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, yield 73.8%, purity 37.5%) was obtained as a yellow oil.

[0461] 5)N 1 -((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride (Compound 267)

[0462]

[0463] A solution of tert-butyl (2-(((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)(cyclopropyl)amino)ethyl)carbamate (0.2 g, 377.9 μmol, 1 eq) in HCl / EtOAc (3 mL) was stirred at 25°C for 1 h. LC-MS showed that the reactant 5 remained at 3%. Several new peaks appeared on LC-MS, and 40% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to obtain 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: [H 2 O (0.04% HCl)-ACN]; gradient: 15%-45% B, 8.0 min) to obtain yellow oily compound N 1 -((3-chloro-2-fluorophenyl)(cyclobutyl)methyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride (0.08 g, 271.7 μmol, yield 71.9%, purity 99.6%, HCl). MS (ESI): m / z = 297.1 [M+H] + ; Retention time: 2.021min, method: M. 1 HNMR(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).

[0464] Example 33: Synthesis of Compounds 268 and 273

[0465] According to the similar method of compound 267 (Example 33) above, the following compound was prepared:

[0466]

[0467] Example 34: 3-(1-((2-aminoethyl)(cyclopropyl)amino)propyl)-2-fluorobenzonitrile hydrochloride (Compound 257) Synthesis

[0468] 1) 2-Fluoro-3-(1-hydroxypropyl)benzonitrile

[0469]

[0470] In use N 2The desired 2-fluorobenzonitrile (1.5 g, 12.4 mmol, 1.3 mL, 1 eq) and THF (20 mL) were charged into a rinsed, dry round-bottom flask. Base, lithium chloride-(2,2,6,6-tetramethyl-1-piperidinyl)magnesium chloride (1 M, 16.1 mL, 1.3 eq) was added dropwise, and the reaction was maintained at 20 ° C for 1 h. The generated organomagnesium species were trapped with propionaldehyde (791.3 mg, 13.6 mmol, 991.6 μL, 1.1 eq), and the mixture was reacted at 20 ° C for 12 h. TLC showed that reactant 1 was completely consumed and a new major spot was formed. With saturated NH 4 The reaction was quenched with aqueous Cl solution and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with Na 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g silica gel flash column, 0-5% ethyl acetate / petroleum ether gradient elution, 60 mL / min) to obtain a yellow oily 2-fluoro-3-(1-hydroxypropyl)benzonitrile compound (876.9 mg, 4.9 mmol, yield 39.5%).

[0471] 2) 2-Fluoro-3-propionylbenzonitrile

[0472]

[0473] To a solution of 2-fluoro-3-(1-hydroxypropyl)benzonitrile (800 mg, 4.5 mmol, 1 eq) in DCM (35 mL) was added DMP (2.3 g, 5.36 mmol, 1.2 eq). The mixture was stirred at 20 °C for 12 h. TLC showed complete consumption of 2 and the formation of a new major spot. The reaction mixture was washed with 6 mL of H 2 O, extracted with 15 mL (5 mL × 3) DCM, and washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (12 g silica gel flash column, 0-3% ethyl acetate / petroleum ether gradient elution, 60 mL / min) to obtain a white solid compound 2-fluoro-3-propionylbenzonitrile (468 mg, 2.6 mmol, yield 59.2%).

[0474] 3) 3-(1-(Cyclopropylamino)propyl)-2-fluorobenzonitrile

[0475]

[0476] To a solution of 2-fluoro-3-propionylbenzonitrile (200 mg, 1.1 mmol, 1 eq) in MeOH (3 mL) was added cyclopropylamine (96.7 mg, 1.7 mmol, 117.3 μL, 1.5 eq) and Ti(i-PrO) 4 (962.5 mg, 3.4 mmol, 999.5 μL, 3 eq). The mixture was stirred at 60°C for 12 h. NaBH 3 CN (283.6 mg, 4.5 mmol, 4 eq) was added to the reaction and stirred at 60 °C for 2 h. LC-MS showed that a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 15 mL of H 2 O, extracted with 30 mL (10 mL × 3) EtOAc, and 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure to obtain a yellow oily compound, 3-(1-(cyclopropylamino)propyl)-2-fluorobenzonitrile (263 mg, crude product).

[0477] 4) tert-Butyl (2-((1-(3-cyano-2-fluorophenyl)propyl)(cyclopropyl)amino)ethyl)carbamate

[0478]

[0479] To a solution of 3-[1-(cyclopropylamino)propyl]-2-fluorobenzonitrile (150 mg, 687.2 μmol, 1 eq) in MeOH (3 mL) was added tert-butyl N-(2-oxoethyl)carbamate (656.4 mg, 4.1 mmol, 6 eq) and AcOH to adjust the pH value to pH = 5, and the mixture was stirred at 60 ° C for 12 h. Then, NaBH was added at 20 ° C. 3 CN (172.8 mg, 2.8 mmol, 4 eq). The mixture was stirred at 60 °C for 2 h. LC-MS showed that 4 was completely consumed and a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 10 mL of H 2 O, extracted with 30 mL (10 mL × 3) EtOAc, and 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2 , petroleum ether / ethyl acetate=5 / 1) to give a yellow oily compound (tert-butyl 2-((1-(3-cyano-2-fluorophenyl)propyl)(cyclopropyl)amino)ethyl)carbamate (220 mg, 608.7 μmol, yield 88.6%).

[0480] 5) 3-(1-((2-aminoethyl)(cyclopropyl)amino)propyl)-2-fluorobenzonitrile hydrochloride (Compound 257)

[0481]

[0482] A solution of tert-butyl N-[2-[1-(3-cyano-2-fluorophenyl)propyl-cyclopropyl-amino]ethyl]carbamate (220 mg, 608.7 μmol, 1 eq) in HCl / EtOAc (5 mL) was stirred at 20 °C for 3 h. LC-MS showed complete consumption of 5 and a major peak with the desired m / z was detected. 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: [H 2 O(0.04% HCl)-ACN]; gradient: 10%-40% B, 8 min, to give a yellow oily compound 3-(1-((2-aminoethyl)(cyclopropyl)amino)propyl)-2-fluorobenzonitrile hydrochloride (91.2 mg, 306.3 μmol, yield 50.3%, purity 100%, HCl). MS (ESI): m / z=262.4[M+H] + ; Retention time: 1.496min, Method: M. Specific 1 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,J=4.3,10.4Hz,1H),3.54–3.38(m,1H),3.30–3.05(m,3H),2.42–2.27(m,2H),2.17–2.06(m,1H),0.97(br s,2H),0.73(t,J=7.3Hz,5H).

[0483] Example 35: Synthesis of Compound 259

[0484] According to the similar method of compound 257 (Example 35) above, the following compound was prepared:

[0485]

[0486] Example 36: 3-(((2-Aminoethyl)(cyclopropyl)amino)methyl)-2-fluorobenzonitrile hydrochloride (Compound 219) Synthesis

[0487] 1) 3-((Cyclopropylamino)methyl)-2-fluorobenzonitrile

[0488]

[0489] Cyclopropylamine (287.2 mg, 5.0 mmol, 348.5 uL, 1.5 eq) was added to a solution of 2-fluoro-3-formylbenzonitrile (500 mg, 3.4 mmol, 1 eq) in MeOH (3 mL). The mixture was stirred at 60 °C for 12 h. NaBH was added to the reaction at 20 °C. 3 CN (842.8 mg, 13.4 mmol, 4 eq) was added and stirred at 60 °C for 2 h. LC-MS showed that reactant 2 was completely consumed and a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure. The residue was washed with 15 mL of H 2 O, extracted with 45 mL (15 mL × 3) EtOAc, and washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified or purified by preparative-TLC (SiO 2 , petroleum ether / ethyl acetate=10 / 1) to give a yellow oily compound 3-((cyclopropylamino)methyl)-2-fluorobenzonitrile (363.0 mg, 1.9 mmol, yield 56.9%).

[0490] 2)(tert-Butyl 2-((3-cyano-2-fluorobenzyl)(cyclopropyl)amino)ethyl)carbamate

[0491]

[0492] To a solution of 3-((cyclopropylamino)methyl)-2-fluorobenzonitrile (200.0 mg, 1.1 mmol, 1 eq) in MeOH (3 mL) was added tert-butyl N-(2-oxoethyl)carbamate (1.0 g, 6.3 mmol, 6 eq). The mixture was stirred at 60 °C for 12 h. NaBH was added to the reaction at 20 °C. 3 CN (264.3 mg, 4.2 mmol, 4 eq) was added and stirred at 60 °C for 2 h. LC-MS showed that reactant 3 was completely consumed and a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 15 mL of H 2 O, extracted with 45 mL (15 mL × 3) EtOAc, and the combined organic layers were washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2, petroleum ether / ethyl acetate=3 / 1) to give a yellow oily compound (tert-butyl 2-((3-cyano-2-fluorobenzyl)(cyclopropyl)amino)ethyl)carbamate (262.6 mg, 787.6 μmol, yield 74.9%).

[0493] 3) 3-(((2-aminoethyl)(cyclopropyl)amino)methyl)-2-fluorobenzonitrile hydrochloride (Compound 219)

[0494]

[0495] A solution of tert-butyl (2-((3-cyano-2-fluorobenzyl)(cyclopropyl)amino)ethyl)carbamate (262.6 mg, 787.6 μmol, 1 eq) in HCl / EtOAc (3 mL) was stirred at 20°C for 1 h. LC-MS showed that reactant 4 was completely consumed. Several new peaks appeared on LC-MS, and 18% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (HCl conditions, chromatographic column: Phenomenex Luna 80×30mm×3μm; mobile phase: [water (HCl)-ACN]; B%: 1%-25%, 8 min) to obtain a dark brown oily compound 3-(((2-aminoethyl)(cyclopropyl)amino)methyl)-2-fluorobenzonitrile hydrochloride (25.1 mg, 107.6 μmol, yield 13.7%, purity 100%, HCl). MS (ESI): m / z = 234.3 [M+H] + , retention time: 1.253min, 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).

[0496] Example 37: Synthesis of Compounds 186, 187, 219B, 227B and 246

[0497] According to the similar method of compound 219 (Example 39) above, the following compound was prepared:

[0498]

[0499]

[0500] Example 38: 3-(1-((2-aminoethyl)(cyclopropyl)amino)-2-methylpropyl)-2-fluorobenzonitrile TFA salt Synthesis of (Compound 264)

[0501] 1) 2-Fluoro-3-(1-hydroxy-2-methylpropyl)benzonitrile

[0502]

[0503] In use N 2 The desired 2-fluorobenzonitrile (2 g, 16.51 mmol, 1.76 mL, 1 eq) and THF (25 mL) were injected into the rinsed and dried round-bottom flask. Base, lithium chloride-(2,2,6,6-tetramethyl-1-piperidinyl)magnesium chloride (1 M, 21.47 mL, 1.3 eq) was added dropwise, and the reaction was maintained at 20 ° C for 1 h. The generated organomagnesium was trapped with 2-methylpropanal (1.31 g, 18.17 mmol, 1.66 mL, 1.1 eq), and the mixture was reacted at 20 ° C for 12 h. TLC showed that reactant 1 was completely consumed and a new major spot was formed. With saturated NH 4 The reaction was quenched with aqueous Cl solution and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with Na 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-6% ethyl acetate / petroleum ether gradient elution, 60 mL / min) to obtain a yellow oily compound 2-fluoro-3-(1-hydroxy-2-methylpropyl)benzonitrile (1.2 g, 6.21 mmol, yield 37.61%). 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).

[0504] 2) 2-Fluoro-3-isobutyrylbenzonitrile

[0505]

[0506] To a solution of 2-fluoro-3-(1-hydroxy-2-methyl-propyl)benzonitrile (1.2 g, 6.21 mmol, 1 eq) in DCM (30 mL) was added DMP (3.16 g, 7.45 mmol, 2.31 mL, 1.2 eq). The mixture was stirred at 20 °C for 12 h. TLC showed complete consumption of reactant 2 and the formation of a new major spot. The reaction mixture was washed with 10 mL of H 2 O, extracted with 30 mL (10 mL × 3) DCM, and 2 SO 4The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-5% ethyl acetate / petroleum ether gradient elution, 60 mL / min) to obtain a yellow oily compound 2-fluoro-3-isobutyrylbenzonitrile (840 mg, 4.39 mmol, yield 70.74%). 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).

[0507] 3) 3-(1-(Cyclopropylamino)-2-methylpropyl)-2-fluorobenzonitrile

[0508]

[0509] To a solution of 2-fluoro-3-(2-methylpropanoyl)benzonitrile (840 mg, 4.39 mmol, 1 eq) in MeOH (8 mL) was added cyclopropylamine (376.25 mg, 6.59 mmol, 456.61 μL, 1.5 eq) and Ti(i-PrO) 4 (3.75 g, 13.18 mmol, 3.89 mL, 3 eq). The mixture was stirred at 60 °C for 12 h. NaBH was added to the reaction at 20 °C. 3 CN (1.10 g, 17.57 mmol, 4 eq) was added and stirred at 60 °C for 2 h. LC-MS showed that a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 10 mL of H 2 O, extracted with 30 mL (10 mL × 3) EtOAc, and 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-7% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a colorless oily compound 3-(1-(cyclopropylamino)-2-methylpropyl)-2-fluorobenzonitrile (577 mg, 2.48 mmol, yield 56.54%).

[0510] 4) 2-Bromo-N-(1-(3-cyano-2-fluorophenyl)-2-methylpropyl)-N-cyclopropylacetamide

[0511]

[0512] To the stirred cold K 2 CO 3(686.60 mg, 4.97 mmol, 2 eq) 2 To the DCM (5 mL) solution was added 3-[1-(cyclopropylamino)-2-methyl-propyl]-2-fluoro-benzonitrile (577 mg, 2.48 mmol, 1 eq) and then 2-bromoacetyl bromide (601.63 mg, 2.98 mmol, 259.66 μL, 1.2 eq). The reaction mixture was stirred at 20 °C for 1 h. LC-MS showed that reactant 4 was completely consumed and a major peak with the desired m / z was detected. The reaction mixture was washed with 10 mL of H 2 O and extracted with 30 mL (10 mL × 3) DCM. 2 SO 4 Drying, filtration and concentration under reduced pressure gave the crude product 2-bromo-N-[1-(3-cyano-2-fluorophenyl)-2-methyl-propyl]-N-cyclopropylacetamide (820 mg, crude yellow oil).

[0513] 5) N-(1-(3-cyano-2-fluorophenyl)-2-methylpropyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide

[0514]

[0515] To a solution of 2-bromo-N-[1-(3-cyano-2-fluorophenyl)-2-methyl-propyl]-N-cyclopropylacetamide (820 mg, 2.32 mmol, 1 eq) in DMF (20 mL) was added potassium (1,3-dioxoisoindolin-2-yl) (515.98 mg, 2.79 mmol, 1.2 eq). The mixture was stirred at 20 °C for 12 h. LC-MS showed complete consumption of reactant 5 and a major peak with the desired m / z was detected. The reaction mixture was washed with 15 mL of H 2 O and extracted with 45 mL (15 mL × 3) of EtOAc. The combined organic layer was washed with 20 mL (10 mL × 2) of NaCl aqueous solution and washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-20% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a yellow oily crude product N-(1-(3-cyano-2-fluorophenyl)-2-methylpropyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (1.08 g, crude product).

[0516] 6) 2-amino-N-(1-(3-cyano-2-fluorophenyl)-2-methylpropyl)-N-cyclopropylacetamide

[0517]

[0518] To a solution of N-[1-(3-cyano-2-fluorophenyl)-2-methylpropyl]-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (200 mg, 476.82 μmol, 1 eq) in EtOH (20 mL) was added N 2 H 4 .H 2 O (59.67 mg, 953.64 μmol, 57.82 μL, 80% purity, 2 eq). The mixture was stirred at 80 ° C for 3 h. LC-MS showed that the reactant 6 was completely consumed and a major peak with the desired m / z was detected. The mixture was cooled to 4 ° C and filtered to remove phthalic acid hydrazide. Ethanol was removed in vacuo. The solution was extracted with 30 mL (10 mL × 3) EtOAc and the organic extract was washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a yellow oily crude product of 2-amino-N-[1-(3-cyano-2-fluorophenyl)-2-methylpropyl]-N-cyclopropylacetamide (146 mg, crude product).

[0519] 7) 3-(1-((2-aminoethyl)(cyclopropyl)amino)-2-methylpropyl)-2-fluorobenzonitrile TFA salt

[0520]

[0521] In use N 2 The desired 2-amino-N-[1-(3-cyano-2-fluorophenyl)-2-methylpropyl]-N-cyclopropyl-acetamide (96 mg, 331.78 μmol, 1 eq) and THF (5 mL) were added to the rinsed dry round-bottom flask, and BH 3 -Me 2 S (10M, 66.36 μL, 2 eq) and stirred at 20 °C for 4 h. LC-MS showed that reactant 7 was completely consumed and a major peak with the desired m / z was detected. 2 mL of MeOH was added to the reaction mixture at 0 °C for quenching and stirred at 60 °C for 2 h, then washed with 10 mL of H 2 O, extracted with 30 mL (10 mL × 3) EtOAc, and 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (TFA conditions). Chromatographic column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H 2O (0.1% TFA)-ACN]; gradient: 15%-45% B, 8.0 min, to obtain yellow oily 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). MS (ESI): m / z=276.3 [M+H] + , retention time: 1.702min, 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).

[0522] Example 39: N 1 -(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N 1 -Cyclopropylethane-1,2-diamine Synthesis of hydrochloride salt (Compound 263)

[0523] 1) 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-ol

[0524]

[0525] To a solution of 3-chloro-2-fluorobenzaldehyde (4 g, 25.2 mmol, 1 eq) in DMF (20 mL) was added TMSCF 3 (4.7 g, 32.8 mmol, 1.3 eq) and stirred at 0 ° C for 15 min, then TBAF (1 M, 252.3 μL, 0.01 eq) was added to the reaction mixture. The mixture was stirred at 25 ° C for 12 h. HCl (2 M, 25.2 mL, 2 eq) was then 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 were formed. The reaction mixture was distributed between 20 mL of ethyl acetate and the reaction mixture. The organic phase was separated, washed with 20 mL of saturated NaCl, and washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (20 g silica gel flash column, 0-5% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a white solid compound 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-ol (5.1 g, 22.2 mmol, yield 88.1%). 1H 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).

[0526] 2) 1-(3-Chloro-2-fluorophenyl)-2,2,2-trifluoroethan-1-one

[0527]

[0528] DMP (5.6 g, 13.1 mmol, 4.1 mL, 1.2 eq) was added to a solution of 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-ol (2.5 g, 10.9 mmol, 1 eq) in DCM (10 mL). The mixture was stirred at 25 ° C for 12 h. TLC showed that reactant 3 was completely consumed and two new spots were formed. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, 0-10% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a white solid compound 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one (1.3 g, 5.9 mmol, yield 54.1%). 1H NMR (400 MHz, chloroform-d) δ=7.76-7.62 (m, 2H), 7.27-7.16 (m, 1H).

[0529] 3) (E)-1-(3-chloro-2-fluorophenyl)-N-cyclopropyl-2,2,2-trifluoroethane-1-imine

[0530]

[0531] In N 2 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethan-1-one (1.3 g, 5.9 mmol, 1 eq) and cyclopropylamine (506.5 mg, 8.9 mmol, 614.7 μL, 1.5 eq) were dissolved in DCM (5 mL). AlMe 3 (2M, 4.4 mL, 1.5 eq). The solution was stirred at 20 °C for 5 h. LC-MS showed ~23% of the desired compound was detected. The reaction mixture was quenched by adding 20% ​​aqueous NaOH dropwise. 2 Cl 2 (3 × 30 mL) to extract the aqueous layer. The organic layer was treated with Na 2 SO 4Dry. Remove the solvent under reduced pressure. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, 0-10% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a yellow oily compound (E)-1-(3-chloro-2-fluorophenyl)-N-cyclopropyl-2,2,2-trifluoroethane-1-imine (0.58 g, 1.3 mmol, yield 22.5%, purity 61.4%).

[0532] 4) N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)cyclopropylamine

[0533]

[0534] A mixture of (E)-1-(3-chloro-2-fluorophenyl)-N-cyclopropyl-2,2,2-trifluoroethane-1-imine (0.58 g, 2.2 mmol, 1 eq) in THF (6 mL) was degassed and heated to 40 °C. 2 After purging 3 times, LAH (2.5 M, 1.7 mL, 2.0 eq) was added to the reaction at 0 °C, and the mixture was stirred under N 2 The mixture was stirred at 0 °C for 2 h under atmosphere. LC-MS showed complete consumption of reactant 5 and the desired mass was detected. Saturated MgSO 4 10mL was used for quenching, and then extracted with 30mL (10mL×3) of ethyl acetate. The combined organic layer was washed with 30mL of water and washed with Na 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, 0-10% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a yellow oily compound N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)cyclopropylamine (0.5 g, 805.5 μmol, yield 37.1%, purity 41.5%).

[0535] 5) 2-Bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide

[0536]

[0537] To a solution of N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)cyclopropylamine (0.5 g, 1.9 mmol, 1 eq) in DCM (6 mL) was added K 2 CO 3 (537.0 mg, 3.9 mmol, 2 eq) 2O (6mL) solution, and added 2-bromoacetyl bromide (470.6mg, 2.3mmol, 203.1μL, 1.2eq) to the reaction at 0°C. The mixture was stirred at 25°C for 12h. LC-MS showed that reactant 6 was completely consumed, and ~48% of the desired mass was detected. The reaction mixture was extracted with 15mL of dichloromethane (5mL×3). The combined organic layers were washed with 10mL of saturated NaCl and washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to give a yellow oily crude product, 2-bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide (0.56 g, 682.6 μmol, yield 35.1%, purity 47.5%).

[0538] 6) 2-Azido-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide

[0539]

[0540] 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 eq) in DMSO (1 mL) was added NaN 3 (82.8 mg, 1.3 mmol, 1.1 eq). The mixture was stirred at 20 °C for 12 h. LC-MS showed complete consumption of reactant 7, and ~16% of the desired mass was detected. The reaction mixture was quenched by adding 10 mL of water at 0 °C, and then extracted with 15 mL (5 mL x 3) of ethyl acetate. The combined organic layers were washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue. The crude product was purified by reverse phase HPLC (0.1% NH 3 -H 2 O conditions, chromatographic column: Waters XbridgeBEH C18 100*30mm*10μm; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 50%-80% B, 8.0 min, to give a white solid 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%). 1H 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).

[0541] 7) 2-amino-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide

[0542]

[0543] 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 eq) in THF (1.5 mL) and water (0.5 mL) was added PPh 3 (89.8 mg, 342.2 μmol, 1.5 eq). The mixture was stirred at 25 °C for 12 h. LC-MS showed complete consumption of reactant 8, and ~49% of the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , DCM / MeOH=10 / 1) to give a colorless oily compound 2-amino-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide (0.02 g, 61.6 μmol, yield 27.0%).

[0544] 8)N 1 -(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N 1 -Cyclopropylethane-1,2-diamine hydrochloride

[0545]

[0546] A mixture of 2-amino-N-(1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide (0.02 g, 61.6 μmol, 1 eq) in THF (5 mL) was degassed and heated with N 2 Purge 3 times, then add BH to the reaction at 0 °C 3 .THF (1M, 616.0 μL, 10 eq) and stirred at 0°C for 30 min, then heated under N 2The mixture was stirred at 60°C for 12 h under a 4% atmosphere. LC-MS showed complete consumption of reactant 9, and ~41% of the desired mass was detected. The reaction mixture was quenched by adding 2 mL of MeOH at 0°C, then diluted with 5 mL of water and extracted with 15 mL (5 mL x 3) of ethyl acetate. The combined organic layers were washed with 10 mL of saturated NaCl and washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue. The crude product was purified by reverse phase HPLC (0.04% HCl condition). Chromatographic column: Phenomenex luna C18 8*30mm*3μm; mobile phase: [H 2 O (0.04% HCl)-ACN]; gradient: 20%-50% B, 8.0 min. White solid 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, yield 76.7%, purity 97.93%, HCl). MS (ESI): m / z = 311.2 [M+H] + ; Retention time: 1.706min, 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,1 H),5.18-5.07(m,1H),3.06-2.67(m,4H),2.00-1.92(m,1H),0.68-0.44(m,4H).

[0547] Example 40: N'-[1-(3-chloro-2-fluorophenyl)but-3-enyl]-N'-cyclopropylethane-1,2-diamine TFA salt Synthesis of (Compound 271A)

[0548] 1)(Z)-1-(3-chloro-2-fluorophenyl)-N-cyclopropylmethanimine

[0549]

[0550] Cyclopropylamine (2.70 g, 47.30 mmol, 3.28 mL, 1.5 eq) and AcOH (5.68 g, 94.60 mmol, 5.42 mL, 3 eq) were added to a solution of 3-chloro-2-fluoro-benzaldehyde (5 g, 31.5 mmol, 1 eq) in MeOH (70 mL). 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 obtain a yellow oily compound (Z)-1-(3-chloro-2-fluorophenyl)-N-cyclopropylmethylamine (6 g, crude product).

[0551] 2) N-(1-(3-chloro-2-fluorophenyl)but-3-en-1-yl)cyclopropylamine

[0552]

[0553] To a mixture of (Z)-1-(3-chloro-2-fluorophenyl)-N-cyclopropyl-formanimine (6 g, 30.36 mmol, 1 eq) in THF (150 mL) was added allyl(bromo)magnesium (1 M, 45.54 mL, 1.5 eq). The mixture was degassed and heated with N 2 Purge 3 times, then 2 The mixture was stirred at -78 °C for 3 h under atmosphere. LCMS showed the formation of the desired compound. NH 4 The reaction mixture was quenched with Cl (100 mL) and then treated with H 2 O (100 mL) and extracted with EtOAc 150 mL (50 mL * 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (40 g silica gel flash column, 0-3% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a yellow oily compound N-[1-(3-chloro-2-fluorophenyl)but-3-enyl]cyclopropylamine (2.5 g, 10.43 mmol, yield 34.35%).

[0554] 3) tert-Butyl (2-((1-(3-chloro-2-fluorophenyl)but-3-en-1-yl)(cyclopropyl)amino)ethyl)carbamate

[0555]

[0556] To a solution of N-[1-(3-chloro-2-fluorophenyl)but-3-enyl]cyclopropylamine (1 g, 4.17 mmol, 1 eq) in MeOH (20 mL) was added tert-butyl N-(2-oxoethyl)carbamate (3.98 g, 25.03 mmol, 6 eq). The mixture was stirred at 60 °C for 12 h. NaBH was then added at 25 °C. 3 CN (1.05 g, 16.6 mmol, 4 eq). The mixture was stirred at 60 °C for 2 h. LCMS showed the formation of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 10 mL of H 2 O and extracted with 15 mL (5 mL * 3) EtOAC. The combined organic layers were washed with [Na 2 SO 4] dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (20 g, silica gel flash column, 0-15% ethyl acetate / petroleum ether gradient elution, 120 mL / min) to obtain a yellow solid compound N-[2-[1-(3-chloro-2-fluorophenyl)but-3-enyl-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester (314 mg, 820.06 μmol, yield 19.66%).

[0557] 4) N1-(1-(3-chloro-2-fluorophenyl)but-3-en-1-yl)-N1-cyclopropylethane-1,2-diamine TFA salt

[0558]

[0559] A solution of tert-butyl N-[2-[1-(3-chloro-2-fluorophenyl)but-3-enyl-cyclopropyl-amino]ethyl]carbamate (20 mg, 52.23 μmol, 1 eq) in TFA (1 mL) and DCM (1 mL) was stirred at 25 °C for 0.5 h. LCMS showed that the desired compound was formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative-HPLC (TFA conditions, column: Phenomenex lunaC18100*40mm*3μm; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 15%-45% B, 8.0 min), to obtain a yellow oily compound N'-[1-(3-chloro-2-fluorophenyl)but-3-enyl]-N'-cyclopropyl-ethane-1,2-diamine TFA salt (21.4 mg, 53.43 μmol, yield 51.15%, purity 99.08%, TFA). MS (ESI): m / z=282.13 [M+H] + ; Retention time: 1.773min, 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).

[0560] Example 41: N'-[1-(4-chloro-2-thienyl)ethyl]-N'-cyclopropyl-ethane-1,2-diamine hydrochloride (Chemical Synthesis of Compound 279

[0561] 1) N-(1-(4-chlorothiophen-2-yl)ethyl)cyclopropylamine

[0562]

[0563] To a solution of cyclopropylamine (266.6 mg, 4.7 mmol, 323.5 μL, 1.5 eq) and 1-(4-chloro-2-thienyl)ethanone (500 mg, 3.1 mmol, 1 eq) in MeOH (20 mL) was added Ti(i-PrO) 4 (2.6 g, 9.3 mmol, 2.8 mL, 3 eq) and AcOH (373.9 mg, 6.2 mmol, 356.4 μL, 2 eq). The mixture was stirred at 60 °C for 12 h. NaBH 3 CN (782.5 mg, 12.5 mmol, 4 eq). 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 washed with 15 mL of H 2 O and extracted with EtOAc (15 mL*3). The combined organic layers were washed with brine (15 mL*2) and washed with Na 2 SO 4 The solution was dried, filtered and concentrated under reduced pressure to obtain a yellow oily compound N-(1-(4-chlorothien-2-yl)ethyl)cyclopropylamine (300 mg, crude product). 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).

[0564] 2)(tert-Butyl 2-((1-(4-chlorothiophen-2-yl)ethyl)(cyclopropyl)amino)ethyl)carbamate

[0565]

[0566] To a solution of tert-butyl N-(2-oxoethyl)carbamate (1.2 g, 7.4 mmol, 6 eq) and N-[1-(4-chloro-2-thienyl)ethyl]cyclopropylamine (250 mg, 1.2 mmol, 1 eq) in MeOH (10 mL), AcOH (89.31 mg, 1.5 mmol, 85.1 μL, 1.2 eq) was added to adjust the pH value to pH = 5. The mixture was stirred at 60 ° C for 12 h. Then NaBH 3CN (311.5 mg, 5.0 mmol, 4 eq). 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 washed with 10 mL of H 2 O and extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (10 mL*2) and washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2 , petroleum ether:ethyl acetate=5:1) to give a white solid compound (tert-butyl 2-((1-(4-chlorothiophen-2-yl)ethyl)(cyclopropyl)amino)ethyl)carbamate (purity 66.23%, 500 mg).

[0567] 3) N1-(1-(4-chlorothiophen-2-yl)ethyl)-N1-cyclopropylethane-1,2-diamine hydrochloride

[0568]

[0569] A solution of tert-butyl N-[2-[1-(4-chloro-2-thienyl)ethyl-cyclopropyl-amino]ethyl]carbamate (200 mg, 579.9 μmol, 1 eq) in HCl / EtOAc (4 mL, 4 M) was stirred at 20 °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 purified by preparative-HPLC (HCl conditions; chromatographic column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H 2 O (0.04% HCl)-ACN]; gradient: 5%-35% B, 8.0min), to obtain a white solid compound N'-[1-(4-chloro-2-thienyl)ethyl]-N'-cyclopropyl-ethane-1,2-diamine hydrochloride (20.0 mg, 71.2 μmol, yield 12.3%, purity 100%, HCl). MS (ESI): m / z=245.1[M+H]+, retention time: 1.441min, 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).

[0570] Example 42: 3-[1-[2-Aminoethyl(cyclopropyl)amino]-2-fluoro-2-methylpropyl]-2-fluorobenzonitrile TFA salt Synthesis of (Compound 287)

[0571] 1) 2-Fluoro-3-(2-fluoro-2-methylpropionyl)benzonitrile

[0572]

[0573] To a solution of 2-fluorobenzonitrile (5.50 g, 45.41 mmol, 4.83 mL, 1 eq) in THF (50 mL) was added chloro-(2,2,6,6-tetramethyl-1-piperidinyl) lithium magnesium chloride (1 M, 59.03 mL, 1.3 eq). The mixture was stirred at -78 ° C for 1 h, and then methyl 2-fluoro-2-methylpropanoate (12 g, 99.90 mmol, 2.2 eq) was added. The mixture was stirred at 20 ° C for 11 h. TLC showed that 1 was completely consumed and many new spots were formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 100 mL of H 2 O and extracted with EtOAc (80 mL*3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-3% ethyl acetate / petroleum ether gradient elution, 120 mL / min) to obtain 2-fluoro-3-(2-fluoro-2-methylpropanoyl)benzonitrile (1.7 g, 8.13 mmol, yield 17.90%) 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).

[0574] 2) 3-[(E)-N-cyclopropyl-C-(1-fluoro-1-methyl-ethyl)carboimidoyl]-2-fluorobenzonitrile

[0575]

[0576] To a solution of 2-fluoro-3-(2-fluoro-2-methyl-acyl)benzonitrile (500 g, 2.39 mol, 1 eq) in MeOH (4 L) was added cyclopropylamine (204.70 g, 3.59 mol, 248.42 L, 1.5 eq) and Ti(i-PrO) 4 (2.04, 7.17 mol, 2.12 L, 3 q). The mixture was stirred at 60 °C for 12 h. LC-MS showed that 2 had been consumed and ~66% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 5 mL of H 2 O and extracted with EtOAc (4 mL*3). The combined organic layers were washed with Na2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-3% ethyl acetate / petroleum ether gradient elution, 60 mL / min) to obtain 3-[(E)-N-cyclopropyl-C-(1-fluoro-1-methyl-ethyl)carbonyl]-2-fluorobenzonitrile (380 mg, 1.30 mmol, yield 54.44%, purity 85.01%) as a yellow oil.

[0577] 3) 3-[1-(Cyclopropylamino)-2-fluoro-2-methyl-propyl]-2-fluorobenzonitrile

[0578]

[0579] To a solution of 3-[(E)-N-cyclopropyl-C-(1-fluoro-1-methyl-ethyl)carboimidoyl]-2-fluorobenzonitrile (360 mg, 1.45 mmol, 1 eq) in MeOH (3 mL) was added TFA (181.87 mg, 1.60 mmol, 118.48 μL, 1.1 eq) and NaBH 3 CN (364.49 mg, 5.80 mmol, 4 eq). The mixture was stirred at 20 °C for 12 h. LC-MS showed that the residual amount of 3 was 36%, and 46% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 5 mL of H 2 O and extracted with EtOAc (4 mL*3). The combined organic layers were washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-3% ethyl acetate / petroleum ether gradient elution, 40 mL / min). The residue was purified by preparative HPLC (TFA conditions; chromatographic column: Phenomenex lunaC C18100*40mm*5μm; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 1%-35% B, 7.0 min) to give 3-[1-(cyclopropylamino)-2-fluoro-2-methyl-propyl]-2-fluorobenzonitrile (230 mg, 748.48 μmol, yield 51.62%, purity 81.45%) as a white solid. 1H 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).

[0580] 4) tert-Butyl N-[2-[[1-(3-cyano-2-fluorophenyl)-2-fluoro-2-methyl-propyl]-cyclopropylamino]ethyl]carbamate

[0581]

[0582] To a solution of 3-[1-(cyclopropylamino)-2-fluoro-2-methyl-propyl]-2-fluorobenzonitrile (200 mg, 799.08 μmol, 1 eq) and tert-butyl N-(2-oxoethyl)carbamate (763.20 mg, 4.79 mmol, 6 eq) in MeOH (3 mL) was added AcOH until pH = 6, the mixture was stirred at 20 ° C for 1 h, and then NaBH was added 3 CN (200.86 mg, 3.20 mmol, 4 eq), the mixture was stirred at 20 °C for 1 h. LC-MS showed that the residual amount of 4 was 74%, and 18% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 5 mL of H 2 O and extracted with EtOAc (4 mL*3). The combined organic layers were washed with Na 2 SO 4 The residue was purified by flash silica gel chromatography ( Silica gel flash column, 0-10% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to give a white solid N-[2-[[1-(3-cyano-2-fluoro-phenyl)-2-fluoro-2-methyl-propyl]-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester (30 mg, 72.26 μmol, yield 9.04%, purity 94.77%).

[0583] 5) 3-[1-[2-aminoethyl(cyclopropyl)amino]-2-fluoro-2-methyl-propyl]-2-fluorobenzonitrile TFA salt

[0584]

[0585] 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 eq) in DCM (1 mL) was added TFA (335.01 mg, 2.94 mmol, 218.25 μL, 38.54 eq). The mixture was stirred at 20°C for 0.5 h. LC-MS showed that the residual amount of 5 was 4%, and ~82% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-HPLC (TFA conditions; chromatographic column: Phenomenex luna C18 100*40mm*5μm; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 25%-55% B, 8.0 min) to give a white solid 3-[1-[2-aminoethyl(cyclopropyl)amino]-2-fluoro-2-methyl-propyl]-2-fluorobenzonitrile TFA salt (10.13 mg, 24.87 μmol, yield 32.61%, purity 100%, TFA). MS (ESI): m / z=293.17 [M+H]+, retention time: 1.603 min, method: Bhalo. 1 NMR (400MHz, 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).

[0586] Example 43: N'-[1-(3-chloro-2-fluorophenyl)-2-methyl-propyl]-N'-(2,2-difluoroethyl)ethane-1, Synthesis of 2-diamine TFA salt (Compound 282)

[0587] 1) 1-(3-chloro-2-fluorophenyl)-2-methyl-propan-1-ol

[0588]

[0589] At -78°C and N 2 To a solution of 3-chloro-2-fluorobenzaldehyde (10 g, 63.07 mmol, 1 eq) in THF (100 mL) was added isopropylmagnesium chloride (2 M, 47.30 mL, 1.5 eq). The mixture was then stirred at 25 °C for 1 h (under N 2 LC-MS showed no 1 remaining and ~33% of the desired compound was detected. 2 Then, 30 mL NH4 Cl 10min, quench the reaction. The aqueous phase was extracted with ethyl acetate (200mL*3). The combined organic layer was washed with brine (100mL) and washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a crude product. The residue was purified by flash silica gel chromatography (20 g silica gel flash column, 0-2% ethyl acetate / petroleum ether gradient elution, 100 mL / min) to obtain 1-(3-chloro-2-fluorophenyl)-2-methyl-propan-1-ol (3.5 g, 17.27 mmol, yield 27.38%) as a yellow oil.

[0590] 2) 1-(3-Chloro-2-fluorophenyl)-2-methyl-propan-1-one

[0591]

[0592] At 0°C (in N 2 (20 mL) DMP (12.56 g, 29.61 mmol, 9.17 mL, 3 eq) was added to a solution of 1-(3-chloro-2-fluorophenyl)-2-methyl-propan-1-ol (2 g, 9.87 mmol, 1 eq) in DCM. The mixture was stirred at 25 °C for 1 h. LC-MS showed no 2 remained and ~30% of the desired compound was detected. 100 mL of H 2 O diluted the reaction mixture and extracted with EtOAc (100 mL * 3). The combined organic layer was washed with brine (100 mL * 1) and washed with anhydrous Na 2 SO 4 The crude product was washed with petroleum ether (20 mL), and the liquid was concentrated under reduced pressure to obtain yellow oily 1-(3-chloro-2-fluorophenyl)-2-methyl-propan-1-one (1.5 g, 7.48 mmol, yield 75.75%).

[0593] 3) 1-(3-chloro-2-fluorophenyl)-N-(2,2-difluoroethyl)-2-methyl-propan-1-amine

[0594]

[0595] To a solution of 2,2-difluoroethylamine (4.85 g, 59.81 mmol, 8 eq) and 1-(3-chloro-2-fluorophenyl)-2-methyl-propan-1-one (1.50 g, 7.48 mmol, 1 eq) in MeOH (10 mL) was added tetraisopropoxytitanium (17.00 g, 59.81 mmol, 17.65 mL, 8 eq). The mixture was stirred at 60 °C for 12 h. Sodium cyanoborate (2.82 g, 44.86 mmol, 6 eq) was added to the reaction and stirred at 60 °C for 2 h. LC-MS showed that the residual amount of 3 was ~10%, and ~55% of the desired compound was detected. 50 mL of H 2 O diluted the reaction mixture and extracted with EtOAc (50 mL * 3). The combined organic layer was washed with brine (50 mL) and washed with anhydrous Na 2 SO 4 The crude product was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 250*150mm*15μm; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 30%-60% B, 20.0 min) to give 1-(3-chloro-2-fluorophenyl)-N-(2,2-difluoroethyl)-2-methyl-propan-1-amine (1.4 g, 5.27 mmol, yield 70.48%) as a yellow oil.

[0596] 4) tert-Butyl N-[2-[[1-(3-chloro-2-fluorophenyl)-2-methylpropyl]-(2,2-difluoroethyl)amino]ethyl]carbamate

[0597]

[0598] To a solution of 1-(3-chloro-2-fluorophenyl)-N-(2,2-difluoroethyl)-2-methyl-propan-1-amine (500 mg, 1.65 mmol, 1 eq, HCl), triethanolamine (167.44 mg, 1.65 mmol, 230.32 μL, 1 eq) and tert-butyl N-(2-oxoethyl)carbamate (1.05 g, 6.62 mmol, 4 eq) in MeOH (4 mL) was added AcOH until pH = 6. The mixture was stirred at 20 °C for 1 h, and then NaBH 3CN (415.93 mg, 6.62 mmol, 4 eq), the mixture was stirred at 20 ° C for 11 h. LC-MS showed that the residual amount of 4 was 86%, and 10% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-HPLC (TFA conditions; chromatographic column: Phenomenex luna C18 100*40mm*5μm; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 45%-100% B, 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.

[0599] 5) N'-[1-(3-chloro-2-fluorophenyl)-2-methyl-propyl]-N'-(2,2-difluoroethyl)ethane-1,2-diamine

[0600]

[0601] To a solution of tert-butyl N-[2-[[1-(3-chloro-2-fluorophenyl)-2-methyl-propyl]-(2,2-difluoroethyl)amino]ethyl]carbamate (40 mg, 97.83 μmol, 1 eq) in DCM (2 mL) was added TFA (429.84 mg, 3.77 mmol, 280.02 μL, 38.54 eq). The mixture was stirred at 20 °C for 1 h. LC-MS showed that no 4A remained and ~82% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-HPLC (TFA conditions; column: Phenomenex luna C18 100*40mm*5μm; mobile phase: [H 2 O (0.1% TFA)-ACN]; Gradient: 15%-65% B, 7.0 min) to give a colorless oil N'-[1-(3-chloro-2-fluorophenyl)-2-methyl-propyl]-N'-(2,2-difluoroethyl)ethane-1,2-diamine TFA salt (41 mg, 96.97 μmol, yield 99.13%, purity 100%, TFA). MS (ESI): m / z=308.13 [M+H]+, retention time: 1.726 min, method: Bhalo. 1H 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).

[0602] Example 44: N'-cyclopropyl-N'-[1-(3-ethynyl-2-fluorophenyl)ethyl]ethane-1,2-diamine TFA salt Synthesis of (Compound 295)

[0603] 1) N-[1-(3-bromo-2-fluorophenyl)ethyl]cyclopropylamine

[0604]

[0605] To a solution of 1-(3-bromo-2-fluorophenyl)ethanone (5 g, 23.04 mmol, 1 eq) in MeOH (50 mL) was added cyclopropylamine (1.97 g, 34.56 mmol, 2.39 mL, 1.5 eq) and Ti(i-PrO) 4 (19.64 g, 69.11 mmol, 20.40 mL, 3 eq). The mixture was stirred at 60 °C for 12 h, and then NaBH 3 CN (5.79 g, 92.15 mmol, 4 eq), the mixture was stirred at 60 °C for 2 h. LC-MS showed no 1 remained, and ~86% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 50 mL of H 2 O and extracted with ethyl acetate (40 mL*3). The combined organic layers were washed with Na 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (20 g silica gel flash column, 0-2% ethyl acetate / petroleum ether gradient elution, 100 mL / min) to obtain a light yellow oily compound N-[1-(3-bromo-2-fluorophenyl)ethyl]cyclopropylamine (3.8 g, 14.54 mmol, yield 63.10%, purity 98.75%).

[0606] 2) tert-Butyl N-[2-[1-(3-bromo-2-fluorophenyl)ethylcyclopropylamino]ethyl]carbamate

[0607]

[0608] To a solution of N-[1-(3-bromo-2-fluorophenyl)ethyl]cyclopropylamine (1 g, 3.87 mmol, 1 eq) and tert-butyl N-(2-oxoethyl)carbamate (1.54 g, 9.69 mmol, 2.5 eq) in MeOH (10 mL) was added NaBH 3 CN (486.89 mg, 7.75 mmol, 2 eq) and ZnCl 2 (1.06 g, 7.75 mmol, 363.27 μL, 2 eq). The mixture was stirred at 20 °C for 12 h. LC-MS showed no 2 remained and ~95% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 10 mL of H 2 O and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with Na 2 SO 4 Drying, filtering, and concentrating under reduced pressure gave tert-butyl N-[2-[1-(3-bromo-2-fluorophenyl)ethyl-cyclopropyl-amino]ethyl]carbamate (2 g, crude) as a white solid.

[0609] 3) tert-Butyl N-[2-[cyclopropyl-[1-[2-fluoro-3-(2-trimethylsilylethynyl)phenyl]ethyl]amino]ethyl]carbamate

[0610]

[0611] To a solution of tert-butyl N-[2-[1-(3-bromo-2-fluoro-phenyl)ethyl-cyclopropyl-amino]ethyl]carbamate (1 g, 2.49 mmol, 1 eq) and ethynyl(trimethyl)silane (1.22 g, 12.46 mmol, 1.73 mL, 5 eq) in dioxane (10 mL) were added CuI (47.46 mg, 249.18 μmol, 0.1 eq), Pd(PPh 3 ) 2 Cl 2 (174.90 mg, 249.18 μmol, 0.1 eq) and TEA (1.26 g, 12.46 mmol, 1.73 mL, 5 eq). The mixture was heated to 40 ℃ and then heated to 30 ℃. 2 The mixture was stirred at 80 °C for 6 h under a 3-(4-)- atmosphere. LC-MS showed that the residual amount of 3 was 13%, and 11% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 15 mL of H 2 O and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with Na 2 SO 4The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (TFA conditions; chromatographic column: Phenomenex luna C18 100*40mm*3μm; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 40%-70% B, 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 light yellow oil.

[0612] 4) tert-Butyl N-[2-[cyclopropyl-[1-(3-ethynyl-2-fluorophenyl)ethyl]amino]ethyl]carbamate

[0613]

[0614] 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 eq) in THF (2 mL) was added TBAF (1 M, 662.89 μL, 1.5 eq). The mixture was stirred at 20 °C for 1 h. LC-MS showed no residual 4 and ~93% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 4 mL of H 2 O and extracted with ethyl acetate (3 mL*3). The combined organic layers were washed with Na 2 SO 4 The solution was dried, 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.

[0615] 5) N'-cyclopropyl-N'-[1-(3-ethynyl-2-fluorophenyl)ethyl]ethane-1,2-diamine TFA salt

[0616]

[0617] To a solution of tert-butyl N-[2-[cyclopropyl-[1-(3-ethynyl-2-fluorophenyl)ethyl]amino]ethyl]carbamate (180 mg, 519.57 μmol, 1 eq) in DCM (2 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 12.96 eq). The mixture was stirred at 20°C for 1 h. LC-MS showed no residual 5 and ~86% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-HPLC (TFA conditions; column: Phenomenexluna C18 100*40mm*5μm; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 1%-40% B, 8.0 min), to obtain a pale yellow oily 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%, 1TFA). MS (ESI): m / z=246.15 [M+H] + , retention time: 1.360min, 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).

[0618] Example 45: 5-[1-[2-aminoethyl(cyclopropyl)amino]ethyl]-4-fluoro-3-thiophenecarbonitrile TFA salt and N'- Synthesis of [1-(4-bromo-3-fluoro-2-thienyl)ethyl]-N'-cyclopropylethane-1,2-diamine TFA salt (Compounds 297 and 297A) become

[0619] 1) 4-Bromo-3-fluoro-thiophene-2-carboxylic acid

[0620]

[0621] To 4-bromo-3-fluoro-thiophene-2-carboxylic acid methyl ester (0.7 g, 2.93 mmol, 1 eq) in THF (10 mL) and H 2 O (10 mL) was added to the solution of LiOH. 2O (245.75 mg, 5.86 mmol, 2 eq), the mixture was stirred at 20 ° C for 1 h. LC-MS showed that 1 was completely consumed and a main peak was detected. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was acidified with HCl (1 M), the pH value was adjusted to about 3, and then extracted with EtOAc (5 mL * 2). The combined organic layer was washed with brine (5 mL) and washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give 4-bromo-3-fluoro-thiophene-2-carboxylic acid (0.69 g, crude) as a white solid.

[0622] 2) 4-Bromo-3-fluoro-N-methoxy-N-methyl-thiophene-2-carboxamide

[0623]

[0624] To a solution of 4-bromo-3-fluoro-thiophene-2-carboxylic acid (0.69 g, 3.07 mmol, 1 eq) and N-methoxymethylamine (448.63 mg, 4.60 mmol, 1.5 eq, HCl) in DCM (20 mL) was added HOBt (497.18 mg, 3.68 mmol, 1.2 eq), EDCI (705.35 mg, 3.68 mmol, 1.2 eq) and TEA (775.66 mg, 7.67 mmol, 1.07 mL, 2.5 eq). The mixture was stirred at 20 °C for 2 h. LC-MS showed that 1A was completely consumed and a major peak with the desired mass was detected. 10 mL of HCl was added at 20 °C. 2 O quenched the reaction mixture and then extracted with EtOAc (10 mL*2). The combined organic layers were washed with brine (10 mL) and washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (12 g silica gel flash column, 0-20% ethyl acetate / petroleum ether gradient elution, 60 mL / min) to obtain a colorless oily compound 4-bromo-3-fluoro-N-methoxy-N-methylthiophene-2-carboxamide (0.7 g, 2.61 mmol, yield 85.15%). 1 H NMR (400 MHz, chloroform-d) δ = 7.39 (d, J = 4.0 Hz, 1H), 3.75 (s, 3H), 3.35 (s, 3H).

[0625] 3) 1-(4-bromo-3-fluoro-2-thienyl)ethanone

[0626]

[0627] To a solution of 4-bromo-3-fluoro-N-methoxy-N-methylthiophene-2-carboxamide (0.6 g, 2.24 mmol, 1 eq) in THF (10 mL) was added MeMgBr (3 M, 895.18 μL, 1.2 eq) at -78 °C, and the mixture was stirred at 20 °C for 1 h. TLC showed that 2 was completely consumed and a new spot was formed. 10 mL of NH 4 The reaction mixture was quenched with Cl and then extracted with EtOAc (10 mL*2). The combined organic layers were washed with brine (10 mL) and washed with Na 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure to obtain 1-(4-bromo-3-fluoro-2-thienyl)ethanone (0.55 g, crude product) as a colorless oily compound. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.55-7.48 (m, 1H) 2.61 (d, J=2.88 Hz, 3H).

[0628] 4) 1-(3-bromo-2-fluorophenyl)-2-methyl-propan-1-one

[0629]

[0630] To a solution of 1-(4-bromo-3-fluoro-2-thienyl)ethanone (500 mg, 2.24 mmol, 1 eq) in MeOH (5 mL) was added cyclopropylamine (191.97 mg, 3.36 mmol, 232.97 μL, 1.5 eq) and Ti(i-PrO) 4 (1.91 g, 6.72 mmol, 1.98 mL, 3 eq). The mixture was stirred at 60 °C for 12 h, and then NaBH 3 CN (563.43 mg, 8.97 mmol, 4 eq). The mixture was stirred at 60 °C for 2 h. LC-MS showed no 3 remained and ~66% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 5 mL of H 2 O and extracted with EtOAc (4 mL*3). The combined organic layers were washed with Na 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (4 g silica gel flash column, 0-2% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to obtain a yellow oily compound N-[1-(4-bromo-3-fluoro-2-thienyl)ethyl]cyclopropylamine (350 mg, 1.29 mmol, yield 57.50%, purity 97.27%).

[0631] 5) tert-Butyl N-[2-[1-(4-bromo-3-fluoro-2-thienyl)ethylcyclopropylamino]ethyl]carbamate

[0632]

[0633] To a solution of N-[1-(4-bromo-3-fluoro-2-thienyl)ethyl]cyclopropylamine (300 mg, 1.14 mmol, 1 eq) and tert-butyl N-(2-oxoethyl)carbamate (542.34 mg, 3.41 mmol, 3 eq) in MeOH (3 mL) was added NaBH 3 CN (142.73 mg, 2.27 mmol, 2 eq) and ZnCl 2 (309.59 mg, 2.27 mmol, 106.50 μL, 2 eq). The mixture was stirred at 20 °C for 3 h. LC-MS showed no 4 remained and ~94% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 5 mL of H 2 O and extracted with EtOAc (3 mL*3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (4 g silica gel flash column, 0-2% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to obtain a yellow oily compound N-[2-[1-(4-bromo-3-fluoro-2-thienyl)ethyl-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester (350 mg, 776.40 μmol, yield 68.36%, purity 90.36%).

[0634] 6) N-[2-[1-(4-cyano-3-fluoro-2-thienyl)ethyl-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester

[0635]

[0636] 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 eq) and dppf (108.88 mg, 196.40 μmol, 0.4 eq) in DMF (2 mL) were added Zn (16.05 mg, 245.49 μmol, 0.5 eq), Zn(CN) 2 (130 mg, 1.11 mmol, 70.27 μL, 2.25 eq) and Pd 2 (dba) 3 (89.92 mg, 98.20 μmol, 0.2 eq). The mixture was heated at 80 °C and N2 The mixture was stirred for 12 h under a 3% atmosphere. LC-MS showed no 5 residue and ~17% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 5 mL of H 2 O and extracted with EtOAc (4 mL*3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (4 g silica gel flash column, 0-3% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to obtain a yellow solid compound N-[2-[1-(4-cyano-3-fluoro-2-thienyl)ethyl-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester (160 mg, 307.14 μmol, yield 62.56%, purity 67.85%).

[0637] 7) 5-[1-[2-aminoethyl(cyclopropyl)amino]ethyl]-4-fluoro-3-thiophenecarbonitrile TFA salt

[0638]

[0639] 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 eq) 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 residue and ~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: Phenomenexluna C18 100*40mm*5μm; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 1%-40% B, 8.0 min) to obtain a colorless oily compound 5-[1-[2-aminoethyl(cyclopropyl)amino]ethyl]-4-fluoro-thiophene-3-carbonitrile TFA salt (49.6 mg, 134.44 μmol, yield 29.70%, purity 99.57%, TFA). MS (ESI): m / z=253.10 [M+H] + , retention time: 1.362min, method: M. 1H 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).

[0640] 8) N'-[1-(4-bromo-3-fluoro-2-thienyl)ethyl]-N'-cyclopropyl-ethane-1,2-diamine TFA salt

[0641]

[0642] 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 eq) in DCM (1 mL) was added TFA (1.19 g, 10.41 mmol, 772.99 μL, 38.54 eq). The mixture was stirred at 20 °C for 1 h. LC-MS showed ~5% of 5 remaining, and ~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: [H 2 O (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: 1.535min, method: B. 1 H NMR (400MHz, chloroform-d) δppm 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).

[0643] Example 46: 3-[1-[2-aminoethyl(cyclopropyl)amino]-2,2,2-trifluoroethyl]-2-fluorobenzonitrile hydrochloride Synthesis of salt (Compound 261)

[0644] 1)(tert-Butyl 2-((1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)(cyclopropyl)amino)ethyl)carbamate

[0645]

[0646] 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 eq) in THF (40 mL) was added Boc 2 O (6.14 g, 28.16 mmol, 6.47 mL, 5 eq). 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 washed with 50 mL of H 2 O and extracted with 150 mL (50 mL * 3) DCM. The combined organic layers were washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (20 g silica gel flash chromatography column, 0-5% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a white solid compound N-[2-[[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoro-ethyl]-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester (750 mg, 1.65 mmol, yield 29.25%).

[0647] 2)(tert-Butyl 2-((1-(3-cyano-2-fluorophenyl)-2,2,2-trifluoroethyl)(cyclopropyl)amino)ethyl)carbamate

[0648]

[0649] N-[2-[[1-(3-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethyl]-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester (200 mg, 439.29 μmol, 1 eq), Pd 2 (dba) 3 (40.23mg, 43.93μmol, 0.1eq), Zn(CN) 2 A mixture of s-Phos (154.75 mg, 1.32 mmol, 83.65 μL, 3 eq) and s-Phos (18.03 mg, 43.93 μmol, 0.1 eq) in DMF (4 mL) was degassed and heated with N 2 Purge 3 times, then the mixture is heated under N 2The mixture was stirred at 120 °C for 12 h under an atmosphere of 4% CO. LCMS showed the formation of the desired compound. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was washed with 10 mL of H 2 O and extracted with 30 mL (10 mL * 3) EtOAC. The combined organic layer was washed with 30 mL (10 mL * 3) brine and washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2 , petroleum ether / ethyl acetate = 3:1) to obtain a yellow oily compound N-[2-[[1-(3-cyano-2-fluoro-phenyl)-2,2,2-trifluoro-ethyl]-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester (110 mg, 274.04 μmol, yield 62.38%).

[0650] 3) 3-(1-((2-aminoethyl)(cyclopropyl)amino)-2,2,2-trifluoroethyl)-2-fluorobenzonitrile hydrochloride

[0651]

[0652] A solution of tert-butyl N-[2-[[1-(3-cyano-2-fluorophenyl)-2,2,2-trifluoro-ethyl]-cyclopropyl-amino]ethyl]carbamate (110 mg, 274.04 μmol, 1 eq) in HCl / EtOAc (2 mL) was stirred at 25 °C for 0.5 h. LCMS showed that the desired compound was formed. 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*30mm*3μm; mobile phase: [H 2 O (0.04% HCl)-ACN]; gradient: 10%-40% B, 8.0 min) to obtain a white solid 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). MS (ESI): m / z=301.12 [M+H] + ; Retention time: 1.584min, method: M. 1 H NMR (400 MHz, DMSO-d 6)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).

[0653] Example 47: N'-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N'-cyclopropylethane-1,2-diamine Synthesis of Hydrochloride Salt (Compound 261A)

[0654] 1) 1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethane-1-ol

[0655]

[0656] A mixture of 3-bromo-2-fluorobenzaldehyde (10 g, 49.26 mmol, 1 eq) in DMF (100 mL) was then added with TMSCF 3 (9.11 g, 64.04 mmol, 1.3 eq), the mixture was stirred at 0°C. After 15 min, TBAF (1 M, 492.59 μL, 0.01 eq) was added dropwise via syringe. The mixture was degassed and heated with N 2 Purge 3 times, then 2 The mixture was stirred at 20°C for 12 h under a 4% CO atmosphere. After the reaction was complete, HCl (2M, 49.26 mL, 2 eq) was added to the solution and stirred at 20°C for 4 h. TLC showed that reactant 1 was completely consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 20 mL of H 2 O and extracted with 90 mL (30 mL * 3) EtOAC. The combined organic layer was washed with 90 mL (30 mL * 3) of brine and washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (40 g silica gel flash column, 0-3% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a yellow oily compound 1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethanol (9.6 g, 35.16 mmol, yield 71.38%).

[0657] 2) 1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethan-1-one

[0658]

[0659] DMP (16.41 g, 38.6 mmol, 11.98 mL, 1.1 eq) was added to a solution of 1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethanol (9.6 g, 35.16 mmol, 1 eq) in DCM (200 mL). The mixture was stirred at 25 °C for 12 h. TLC showed that 3 was completely consumed and a new spot was 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 gel flash column, 0-2% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to give a yellow oily compound 1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoro-ethanone (6.62 g, 24.43 mmol, yield 69.47%).

[0660] 3) (E)-1-(3-bromo-2-fluorophenyl)-N-cyclopropyl-2,2,2-trifluoroethane-1-imine

[0661]

[0662] A mixture of 1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoro-ethanone (6.6 g, 24.35 mmol, 1 eq) and cyclopropylamine (2.09 g, 36.53 mmol, 2.53 mL, 1.5 eq) in DCM (70 mL) was then stirred at N 2 Add AlMe 3 (2M, 12.18 mL, 1 eq), the mixture was stirred at N 2 and stirred at 25°C for 12 h. LCMS showed the formation of the desired compound. The residue was diluted with 50 mL of NaOH (20%) and extracted with 90 mL (30 mL*3) of DCM. The combined organic layers were washed with Na 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure to give a yellow oily compound (E)-1-(3-bromo-2-fluorophenyl)-N-cyclopropyl-2,2,2-trifluoroethyleneimine (8 g, crude product).

[0663] 4) N-(1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)cyclopropylamine

[0664]

[0665] To a solution of (E)-1-(3-bromo-2-fluorophenyl)-N-cyclopropyl-2,2,2-trifluoroethaneimine (8 g, 25.80 mmol, 1 eq) in MeOH (90 mL) were added TFA (2.94 g, 25.80 mmol, 1.92 mL, 1 eq) and NaBH 3CN (6.49 g, 103.20 mmol, 4 eq). The mixture was stirred at 60 °C for 1 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 flash silica gel chromatography (40 g Silica gel flash chromatography column, 0-4% ethyl acetate / petroleum ether gradient elution, 120 mL / min) to obtain a yellow oily compound N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]cyclopropylamine (3.14 g, 9.68 mmol, yield 37.51%, purity 96.2%).

[0666] 5) 2-Bromo-N-(1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide

[0667]

[0668] To a solution of N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]cyclopropylamine (2.4 g, 7.69 mmol, 1 eq) in DCM (30 mL) and H 2 O (30 mL) was added to the solution 2 CO 3 (2.13 g, 15.38 mmol, 2 eq) and 2-bromoacetyl bromide (2.79 g, 13.84 mmol, 1.21 mL, 1.8 eq). The mixture was stirred at 25 °C for 0.5 h. LCMS showed the formation of the desired compound. The residue was washed with 20 mL of H 2 O and extracted with 90 mL (30 mL * 3) DCM. The combined organic layers were washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (20 g silica gel flash column, 0-7% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain a white solid compound 2-bromo-N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N-cyclopropylacetamide (3 g, 6.93 mmol, yield 90.09%).

[0669] 6) N-(1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide

[0670]

[0671] 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 eq) in DMF (40 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (1.50 g, 8.08 mmol, 1.1 eq). The mixture was stirred at 20 °C for 4 h. LCMS showed the formation of the desired compound. The residue was purified by HPLC. 2 O 20mL dilution, and extracted with EtOAc 60mL (20mL*3). The combined organic layer was washed with brine 60mL (20mL*3), 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (20 g silica gel flash column, 0-20% ethyl acetate / petroleum ether gradient elution, 100 mL / min) to obtain a white solid 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, yield 77.01%, purity 68.7%).

[0672] 7) 2-amino-N-(1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)-N-cyclopropylacetamide

[0673]

[0674] 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 eq) in EtOH (40 mL) was added NH 2 NH 2 .H 2 O (841.04 mg, 16.46 mmol, 814.96 μL, purity 98%, 2 eq). The mixture was stirred at 80 ° C for 3 h. LCMS showed that the desired compound was formed. 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 a white solid compound 2-amino-N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N-cyclopropyl-acetamide (2.4 g, crude product).

[0675] 8) N1-(1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl)-N1-cyclopropylethane-1,2-diamine hydrochloride

[0676]

[0677] To a solution of 2-amino-N-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N-cyclopropyl-acetamide (47 mg, 127.32 μmol, 1 eq) in THF (2 mL) was added BH 3 .THF (1M, 1.27mL, 10eq). The mixture was stirred at 70°C for 12h. LCMS showed that the desired compound was formed. The reaction mixture was quenched with MeOH (5ml) at 70°C for 2h and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative-HPLC (HCL conditions), chromatographic column: Phenomenex luna C 1880*30mm*3μm; mobile phase: [H 2 O (0.04% HCl)-ACN]; gradient: 22%-52% B, 8.0 min, to obtain a white solid compound N'-[1-(3-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl]-N'-cyclopropyl-ethane-1,2-diamine hydrochloride (16 mg, 40.32 μmol, yield 31.67%, purity 98.68%, HCl). MS (ESI): m / z=354.04 [M+H] + ; Retention time: 1.765min, method: M. 1 H NMR (400 MHz, DMSO-d 6 )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).

[0678] Example 48: N1-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N1-cyclopropylethane-1,2- Synthesis of diamine TFA salt (Compound 270)

[0679] 1) 1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropan-1-ol

[0680]

[0681] In use N 2The rinsed dry round-bottom flask was charged with the desired 1-chloro-2-fluoro-benzene (2 g, 15.3 mmol, 1 eq) and THF (45 mL), and the base, LDA (2 M, 8.4 mL, 1.1 eq) was added dropwise, and the reaction was maintained at -70 ° C for 0.25 h. Then ethyl 2,2,3,3,3-pentafluoropropionate (3.5 g, 18.4 mmol, 1.2 eq) was added, and the mixture was reacted at 20 ° C for 12 h. TLC showed that reactant 1 was completely consumed and a major new spot was formed. With saturated NH 4 The reaction was quenched with aqueous Cl solution and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (12 g Silica gel flash column, 0-0% ethyl acetate / petroleum ether gradient elution, 60 mL / min) to give 1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropan-1-ol (1.6 g, 5.7 mmol, yield 37.5%) as a yellow oil.

[0682] 2) 1-(3-Chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropan-1-one

[0683]

[0684] To a solution of 1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoro-propan-1-ol (1.7 g, 6.1 mmol, 1 eq) in DCM (30 mL) was added DMP (3.1 g, 7.3 mmol, 1.2 eq). The mixture was stirred at 20 °C for 12 h. TLC showed complete consumption of 2 and the formation of a major new spot. The reaction mixture was washed with 5 mL of H 2 O, extracted with 15 mL (5 mL * 3) DCM, and 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (12 g Silica gel flash column, 0-0% ethyl acetate / petroleum ether gradient elution, 60 mL / min) to give 1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropan-1-one (952 mg, 3.4 mmol, yield 56.4%) as a yellow oil.

[0685] 3) (E)-1-(3-chloro-2-fluorophenyl)-N-cyclopropyl-2,2,3,3,3-pentafluoropropane-1-imine

[0686]

[0687] To a solution of 1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoro-propan-1-one (1 g, 3.6 mmol, 1 eq) in MeOH (15 mL) was added cyclopropylamine (309.7 mg, 5.4 mmol, 375.8 μL, 1.5 eq) and Ti(i-PrO) 4 (3.1 g, 10.9 mmol, 3.2 mL, 3 eq). The mixture was stirred at 60 °C for 12 h. LC-MS showed that a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 100 mL of H 2 O, extracted with 300 mL (100 mL*3) EtOAc, and washed with Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a residue, (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.

[0688] 4) N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)cyclopropylamine

[0689]

[0690] To a solution of (E)-1-(3-chloro-2-fluorophenyl)-N-cyclopropyl-2,2,3,3,3-pentafluoro-propan-1-imine (500 mg, 1.6 mmol, 1 eq) in MeOH (15 mL) was added NaBH 3 CN (398.2 mg, 6.3 mmol, 4 eq) and TFA (198.7 mg, 1.7 mmol, 129.4 μL, 1.1 eq). The mixture was stirred at 20 °C for 12 h. LC-MS showed that 4 was completely consumed and a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 8 mL of H 2 O, extracted with 30 mL (10 mL * 3) EtOAc, and 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2 , petroleum ether / ethyl acetate=10 / 1) to give a white solid N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)cyclopropylamine (360 mg, 1.1 mmol, yield 71.5%).

[0691] 5) 2-Bromo-N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N-cyclopropylacetamide

[0692]

[0693] To K 2 CO 3 (261.1 mg, 1.9 mmol, 2 eq) H 2 O (10 mL) was stirred and cooled, and N-[1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl]cyclopropylamine (300.0 mg, 944.4 μmol, 1 eq) was added, followed by 2-bromoacetyl bromide (228.8 mg, 1.1 mmol, 98.7 μL, 1.2 eq). The reaction mixture was stirred at 20 ° C for 1 h, and LC-MS showed that 5 still partially remained. K was added to the reaction mixture 2 CO 3 (261.1 mg, 1.9 mmol, 2 eq) and 2-bromoacetyl bromide (228.8 mg, 1.1 mmol, 98.7 μL, 1.2 eq) were added and then stirred at 20 °C for 1 h. LC-MS showed that reactant 5 was completely consumed and a major peak with the desired m / z was detected. The reaction mixture was washed with 10 mL of H 2 O and extracted with 30 mL (10 mL * 3) DCM. 2 SO 4 Drying, filtration and concentration under reduced pressure gave 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.

[0694] 6) N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide

[0695]

[0696] To a solution of 2-bromo-N-[1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoro-propyl]-N-cyclopropyl-acetamide (400 mg, 912.0 μmol, 1 eq) in DMF (20 mL) was added (1,3-dioxoisoindolin-2-yl) potassium (202.7 mg, 1.1 mmol, 1.2 eq). The mixture was stirred at 20 °C for 12 h. LC-MS showed complete consumption of 6 and a major peak with the desired m / z was detected. The reaction mixture was washed with 25 mL of H 2 O and extracted with 75 mL (25 mL * 3) EtOAc. The combined organic layer was washed with 20 mL (10 mL * 2) of NaCl aqueous solution and washed with Na 2SO 4 The reaction mixture was dried, 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 product) as a yellow oil.

[0697] 7) 2-Amino-N-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N-cyclopropylacetamide

[0698]

[0699] To a solution of N-[1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoro-propyl]-N-cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (300 mg, 594.3 μmol, 1 eq) in EtOH (15 mL) was added N 2 H 4 .H 2 O (74.4 mg, 1.2 mmol, 72.1 μL, 80% purity, 2 eq). The mixture was stirred at 80 °C for 2.5 h. LC-MS showed complete consumption of 7 and a major peak with the desired m / z was detected. The mixture was cooled to 4 °C and filtered to remove phthalic acid hydrazide. The ethanol was removed in vacuo. The solution was washed with 20 mL of H 2 O, then extracted with 30 mL EtOAc (10 mL*3), and the organic layer was washed with Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave 2-amino-N-[1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoro-propyl]-N-cyclopropylacetamide (176 mg, crude) as a yellow oil which was used in the next step without further purification.

[0700] 8) N1-(1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoropropyl)-N1-cyclopropylethane-1,2-diamine

[0701]

[0702] To a solution of 2-amino-N-[1-(3-chloro-2-fluorophenyl)-2,2,3,3,3-pentafluoro-propyl]-N-cyclopropyl-acetamide (176 mg, 469.7 μmol, 1 eq) in THF (15 mL) was added BH 3 .THF (1M, 2.8 mL, 6 eq). The mixture was stirred under N 2The mixture was stirred at 60 °C for 12 h under atmosphere. LC-MS showed complete consumption of 8 and a major peak with the desired m / z was detected. The reaction mixture was quenched by adding 2 mL of MeOH at 0 °C and stirred at 60 °C for 2 h, then washed with 10 mL of H 2 O, extracted with 30 mL (10 mL * 3) EtOAc, and 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (TFA conditions). Chromatographic column: Phenomenex Luna C1875*30mm*3μm; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 15%-45% B, 8.0 min, to give yellow oily 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, yield 10.2%, purity 99.3%). MS (ESI): m / z=361.1 [M+H]+, retention time: 1.914 min, 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).

[0703] Example 49: 3-(1-((2-aminoethyl)(cyclopropyl)amino)-3,3,3-trifluoropropyl)-2-fluorobenzonitrile salt Synthesis of Acid Salt (Compound 280)

[0704] 1)((1-(3-bromo-2-fluorophenyl)vinyl)oxy)triethylsilane

[0705]

[0706] In use N 2 The desired 1-(3-bromo-2-fluorophenyl)ethanone (2.5 g, 11.5 mmol, 1 eq) and THF (15 mL) were added to the rinsed dry round bottom flask. Base, LDA (2M, 6.9 mL, 1.2 eq) was added dropwise and the reaction was kept at -70 °C for 1 h. Chloro(triethyl)silane (2.1 g, 13.8 mmol, 2.4 mL, 1.2 eq) was added to the reactants at -70 °C and stirred at 20 °C for 12 h. TLC showed that reactant 1 was completely consumed and a new spot was formed. 50 mL of saturated NH4 The reaction was quenched with aqueous Cl solution and then extracted with ethyl acetate (3×80 mL). The combined organic phases were washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g silica gel flash column, 0-0% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain ((1-(3-bromo-2-fluorophenyl)vinyl)oxy)triethylsilane (1.0 g, 3.1 mmol, yield 27.0%) as a colorless oil.

[0707] 2) 1-(3-Bromo-2-fluorophenyl)-3,3,3-trifluoropropan-1-one

[0708]

[0709] In N 2 Under atmosphere, 1-(trifluoromethyl)-1,2-benzoxazol-3-one (1.4 g, 4.5 mmol, 1.5 eq) and CuSCN (37.9 mg, 301.9 μmol, 0.1 eq) were added. 1-(3-bromo-2-fluorophenyl)vinyloxytriethylsilane (1.0 g, 3.0 mmol, 1 eq) and DMF (20 mL) were added to the mixture. The mixture was stirred at 20 ° C for 12 h. TLC showed that 2 was completely consumed and many new spots were formed. The reaction mixture was washed with 25 mL of H 2 O and extracted with 75 mL (25 mL * 3) EtOAc. The combined organic layer was washed with brine 20 mL (10 mL * 2) and washed with Na 2 SO 4 The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (12 g silica gel flash column, 0-3% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain 1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropan-1-one (530 mg, 1.9 mmol, yield 61.6%) as a yellow oil.

[0710] 3) N-(1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropyl)cyclopropylamine

[0711]

[0712] In N 2 1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoro-propan-1-one (300 mg, 1.1 mmol, 1 eq) and cyclopropylamine (90.1 mg, 1.6 mmol, 109.4 μL, 1.5 eq) were dissolved in dry DCM (15 mL). AlMe was added dropwise to the reaction mixture via a syringe. 3(2M, 789.4 μL, 1.5 eq). The solution was stirred at 20 °C for 15 h. BH 3 -Me 2 S (10M, 210.5 μL, 2 eq). The mixture was stirred at 20°C for 2 h. LC-MS showed that a major peak with the desired m / z was detected. The reaction mixture was quenched by adding 20% ​​aqueous NaOH solution dropwise. 2 Cl 2 (3 × 30 mL) to extract the aqueous layer. The organic layer was treated with Na 2 SO 4 Dry. Remove the solvent under reduced pressure. The residue was purified by flash silica gel chromatography (12 g silica gel flash column, 0-3% ethyl acetate / petroleum ether gradient elution, 60 mL / min) to obtain yellow oily N-(1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropyl)cyclopropylamine (120 mg, 368.0 μmol, yield 35.0%).

[0713] 4) tert-Butyl (2-((1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropyl)(cyclopropyl)amino)ethyl)carbamate

[0714]

[0715] To a solution of N-[1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoro-propyl]cyclopropylamine (120 mg, 368.0 μmol, 1 eq) and tert-butyl N-(2-oxoethyl)carbamate (175.7 mg, 1.1 mmol, 3 eq) in MeOH (2 mL) was added ZnCl 2 (100.3 mg, 735.9 μmol, 34.5 μL, 2 eq) and NaBH 3 CN (92.5 mg, 1.5 mmol, 4 eq). The mixture was stirred at 20 °C for 12 h. LC-MS showed 4 residues and a major peak with the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 5 mL of H 2 O, extracted with 15 mL (5 mL * 3) EtOAc, and 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2 , 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, yield 59.7%) as a yellow oil.

[0716] 5) tert-Butyl (2-((1-(3-cyano-2-fluorophenyl)-3,3,3-trifluoropropyl)(cyclopropyl)amino)ethyl)carbamate

[0717]

[0718] N-[2-[[1-(3-bromo-2-fluorophenyl)-3,3,3-trifluoro-propyl]-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester (100 mg, 213.1 μmol, 1 eq), Zn(CN) 2 (75.1mg, 639.2μmol, 40.6μL, 3eq), Pd 2 (dba) 3 A mixture of s-Phos (19.5 mg, 21.3 μmol, 0.1 eq) and s-Phos (8.8 mg, 21.1 μmol, 0.1 eq) in DMF (3 mL) was stirred under N 2 The mixture was stirred at 120°C for 12 h under an atmosphere of 4% CO. LC-MS showed that 5 was partially consumed and a major peak with the desired m / z was detected. The reaction mixture was quenched by adding 10 mL of water at 0°C and then extracted with 15 mL (5 mL*3) of ethyl acetate. The combined organic layers were washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO 2 , 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, yield 39.5%) as a yellow oil.

[0719] 6) 3-(1-((2-aminoethyl)(cyclopropyl)amino)-3,3,3-trifluoropropyl)-2-fluorobenzonitrile hydrochloride

[0720]

[0721] A solution of tert-butyl N-[2-[[1-(3-cyano-2-fluorophenyl)-3,3,3-trifluoro-propyl]-cyclopropyl-amino]ethyl]carbamate (35 mg, 84.6 μmol, 1 eq) in HCl / EtOAc (5 mL) was stirred at 20 °C for 1 h. LC-MS showed that 6 was completely consumed and a major peak with the desired mass was detected. 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*30mm*3μm; mobile phase: [H 2O (0.04% HCl)-ACN]; gradient: 10%-40% B, 8.0 min) to give a yellow oily 3-(1-((2-aminoethyl)(cyclopropyl)amino)-3,3,3-trifluoropropyl)-2-fluorobenzonitrile hydrochloride (27.7 mg, 78.4 μmol, yield 93.0%, purity 99.7%, HCl). MS (ESI): m / z=316.2 [M+H] + , retention time: 1.638min, 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).

[0722] Example 50: N'-[1-(3-bromo-2-fluorophenyl)-2-methyl-propyl]-N'-cyclopropyl-ethane-1,2-diamine Synthesis of TFA salt (Compound 294)

[0723] 1) 1-(3-bromo-2-fluorophenyl)-2-methyl-propan-1-ol

[0724]

[0725] To a solution of 3-bromo-2-fluorobenzaldehyde (6.8 g, 33.50 mmol, 1 eq) in THF (50 mL) was added i-PrMgBr (1 M, 40.20 mL, 1.2 eq) dropwise. The mixture was stirred at 0 °C for 2 h. TLC showed that 1 was completely consumed and a major new spot was formed. 4 The reaction was quenched with aqueous Cl solution and extracted with ethyl acetate (3*30 mL). The combined organic phases were washed with Na 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-3% ethyl acetate / petroleum ether gradient elution, 100 mL / min) to obtain 1-(3-bromo-2-fluoro-phenyl)-2-methyl-propan-1-ol (1.9 g, 6.91 mmol, yield 20.62%, purity 89.84%) as a light yellow oil. 1 H NMR (400 MHz, DMSO-d 6)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).

[0726] 2) 1-(3-bromo-2-fluorophenyl)-2-methyl-propan-1-one

[0727]

[0728] To a solution of 1-(3-bromo-2-fluorophenyl)-2-methyl-propan-1-ol (1.9 g, 7.69 mmol, 1 eq) in DCM (20 mL) was added Dess-Martin (6.52 g, 15.38 mmol, 4.76 mL, 2 eq). The mixture was stirred at 20 °C for 2 h. LC-MS showed no 2 residue and ~20% of the desired compound was 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 gel flash column, 0-0% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to give 1-(3-bromo-2-fluorophenyl)-2-methyl-propan-1-one (1.3 g, 5.09 mmol, yield 66.16%, purity 95.91%) as a yellow solid.

[0729] 3) N-[1-(3-bromo-2-fluoro-phenyl)-2-methyl-propyl]cyclopropylamine

[0730]

[0731] To a solution of 1-(3-bromo-2-fluoro-phenyl)-2-methyl-propan-1-one (1.2 g, 4.90 mmol, 1 eq) in MeOH (10 mL) was added cyclopropylamine (419.32 mg, 7.34 mmol, 508.88 μL, 1.5 eq) and Ti(i-PrO) 4 (4.17 g, 14.69 mmol, 4.34 mL, 3 eq). The mixture was stirred at 60 °C for 12 h, and then NaBH 3 CN (1.23 g, 19.58 mmol, 4 eq), the mixture was stirred at 60 °C for 2 h. LC-MS showed no 3 remained, and ~47% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 20 mL of H 2 O and extracted with ethyl acetate (15 mL*3). The combined organic layers were washed with Na 2 SO 4The mixture was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (12 g silica gel flash column, 0-3% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain colorless oily N-[1-(3-bromo-2-fluoro-phenyl)-2-methyl-propyl]cyclopropylamine (1.2 g, 3.69 mmol, yield 75.45%, purity 88.10%).

[0732] 4) N-[2-[[1-(3-bromo-2-fluorophenyl)-2-methyl-propyl]-cyclopropyl-amino]ethyl]carbamic acid tert-butyl ester

[0733]

[0734] To a solution of N-[1-(3-bromo-2-fluoro-phenyl)-2-methyl-propyl]cyclopropylamine (600 mg, 2.10 mmol, 1 eq) and tert-butyl N-(2-oxoethyl)carbamate (1.33 g, 8.39 mmol, 4 eq) in MeOH (8 mL) was added NaBH 3 CN (263.50 mg, 4.19 mmol, 2 eq) and ZnCl 2 (571.52 mg, 4.19 mmol, 196.60 μL, 2 eq). The mixture was stirred at 20 °C for 12 h. LC-MS showed no 4 remained and ~84% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with 10 mL of H 2 O and extracted with ethyl acetate (5 mL*3). The combined organic layers were washed with Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave tert-butyl N-[2-[[1-(3-bromo-2-fluoro-phenyl)-2-methyl-propyl]-cyclopropyl-amino]ethyl]carbamate (300 mg, crude) as a colorless oil.

[0735] 5) N'-[1-(3-bromo-2-fluorophenyl)-2-methyl-propyl]-N'-cyclopropyl-ethane-1,2-diamine TFA salt

[0736]

[0737] 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 eq) in DCM (2 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 38.54 eq). The mixture was stirred at 20°C for 1 h. LC-MS showed that no 5 remained, and ~60% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-HPLC (TFA conditions; chromatographic column: Phenomenex luna C18 100*40mm*5μm; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 25%-55% B, 8.0 min) to obtain colorless oily N'-[1-(3-bromo-2-fluoro-phenyl)-2-methyl-propyl]-N'-cyclopropyl-ethane-1,2-diamine TFA salt (32.96 mg, 74.27 μmol, yield 21.26%, purity 99.88%, 1TFA). MS (ESI): m / z=328.1 [M+H] + , retention time: 1.878min, 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).

[0738] Example 51: LCMS method description

[0739] The above LCMS method is as follows:

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746] Example 52: Primary Neuronal Culture and Excitotoxic Cell Death

[0747] Mouse hippocampal primary neurons were prepared as described previously (Bading & Greenberg, Science, 1991; 253:912-914; Zhang et al., Neuron, 2007, 53:549-562) and maintained in Neurobasal-A medium supplemented with 2% B27, 5 mM L-Glutamax, and 0.5% penicillin / streptomycin until day in vitro (DIV) 10, when they were stimulated with NMDA. The S3 live cell analysis system (Sartorius AG, Germany) monitored nuclear localization of mCherry for real-time analysis of glutamate-induced cell death. Primary neurons were cultured in 24-well plates, infected with rAAV-hSyn-mCherry at DIV3, and stimulated with 10 μM or 20 μM glutamate at DIV10. All compounds were added to the cultures 30 min before glutamate / NMDA action. Images were acquired at 2 h intervals within 24 h after glutamate application, and 9-16 images were collected at each time point under each condition using a 20x objective. BasicAnalyzer of 2021 software analyzed the presence of mCheery in the nuclear region to quantify cell death, and used size and mean intensity as exclusion criteria.

[0748] Compound Rating

[0749] To evaluate the protective effects of various compounds, a quantitative method was developed to determine the protective index for each compound. The protective index (ranging from 0.0 to 10.0) was calculated based on the area above the curve (AAC) during 24 h of excitotoxic stimulation according to the following equation, where cell viability was normalized to that at 0 h ( Figure 2 ):

[0750]

[0751] Among them, AAC represents each compound, AAC 本底 indicates background conditions without excitotoxicity, AAC 溶媒 Represents a vehicle control with excitotoxic injury. According to this equation, the protection index of the vehicle (DMSO) is 0.0, while the protection index of compound P401 in WO2020 / 079244 is 6.0 (10 μM). Therefore, the inventors of the present invention divide the compounds into groups A, B, C and D, where:

[0752] A. The protection index exceeded 7.0, providing significantly better protection than compound P401 (10 μM) at 10 μM.

[0753] B. Protection index ranged from 5.0 to 7.0, providing protection comparable to compound P401 (10 μM) at 10 μM.

[0754] C. Protection index ranged from 3.0 to 5.0, providing significantly lower protection at 10 μM compared to compound P401 (10 μM).

[0755] D. The protection index is lower than 3.0, and there is no significant protection at 10 μM.

[0756] The inventors of the present invention also tested the compounds of Group A at lower concentrations in a 3-fold dilution format (μM: 3.0, 1.0, 0.3, 0.1, 0.03) and were able to achieve a similar protective effect as 10 μM compound P401, but at a lower concentration. These compounds are divided into A+, A++, A+++ and A++++ compounds:

[0757] The A+ protection index ranged from 5.0 to 7.0, and at a concentration of 3.0 μM, it provided protection comparable to that of compound P401 (10 μM).

[0758] The A++ protection index ranged from 5.0 to 7.0, providing protection comparable to that of compound P401 (10 μM) at a concentration of 1.0 μM.

[0759] A+++ protection index ranged from 5.0 to 7.0, providing protection comparable to compound P401 (10 μM) at a concentration of 0.3 μM.

[0760] A++++ protection index ranged from 5.0 to 7.0, providing protection comparable to compound P401 (10 μM) at a concentration of 0.1 μM.

[0761] Example 53: Biological Activities of Various Compounds

[0762] Using the above assay for excitotoxic cell death in primary neuronal cultures, the first set of compounds received the following ranking results:

[0763]

[0764]

[0765] In another round of experiments, the second group of compounds received the following ranking results (using the above assay for excitotoxic cell death in primary neuronal cultures):

[0766]

[0767] In another round of experiments, the third group of compounds received the following ratings (using the above assay for excitotoxic cell death in primary neuronal cultures):

[0768]

[0769]

[0770] In the third set of experiments, the correlation between the biological activity level and IC50 (μM) of the compounds rated A++++ or above is as follows:

[0771]

[0772] Example 54: Reactive oxygen species (ROS) induce neuronal death

[0773] ROS is a common cause of damage to neurons; ROS accumulate in the brain and 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), so the inventors of the present invention tested whether NMDA receptor / TRPM4 interaction inhibitors can provide neuroprotection against ROS toxicity.

[0774] At DIV3, primary neurons cultured in 24-well plates were infected with rAAV-hSyn-mCherry and then treated with 300 μM HO at DIV10. 2 O 2 All compounds were stimulated in H 2 O 2 Add to the culture 30 min before treatment. Images were collected every 2 h for 24 h after glutamate administration, and 9-16 images were collected at each time point in each case using a 20x objective. The Basic Analyzer of 2021 software analyzed the presence of mCherry in the nuclear region to quantify cell death, using size and average intensity as exclusion criteria.

[0775] Using this detection method, the inventors of the present invention have demonstrated that 2 O 2The effect of the prior art compound P401 (WO2020 / 079244) provides better protection than the FDA-approved ALS drugs Riluzole and Edaravone. In addition, the compound of the present invention (Compound 220) provides even better protection than the prior art compound P401.

[0776] Example 55: Co-immunoprecipitation and disruption of NMDAR / TRPM4 complex formation

[0777] Co-immunoprecipitation

[0778] All co-immunoprecipitation steps were performed at 4°C. As described (Bauersachs HG et al, Neuroscience, 2022; 484: 83-97), Human iPSC-derived brain organoids were cultured in 6-well TC-treated cell culture plates until week 25, which resulted in high expression of GluN2A / GluN2B / TRPM4. Six brain organoids were cultured with 10 μM compound 120 for 30 min, washed twice with ice-cold PBS, and then lysed in 500 μL 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 rotated and incubated for 60 min and centrifuged at 1,200 × g for 12 min to remove cell debris and nuclei. 10% of the supernatant was boiled with Laemmli buffer for input sample analysis. The remaining supernatant was mixed with anti-TRPM4 antibody (1:200) overnight. The mixture was then incubated with Pierce Protein A magnetic beads for 12 h to adsorb the antibody complex and washed with immunoprecipitation buffer to remove any nonspecific binding. After the last wash, the supernatant was carefully removed and the pellet was boiled in Laemmli buffer. Both input and pellet samples were stored at -20 °C until Western blot analysis.

[0779] Western blotting

[0780] Input samples and / or immunoprecipitates were separated in 7.5% sodium dodecyl sulfate and polyacrylamide gel (SDS-PAGE), transferred to 0.45 μm nitrocellulose membranes, and finally blotted with the indicated antibodies. Running buffer (in mM: 190 glycine, 25 Tris, 0.1% SDS) and transfer buffer (in mM: 150 glycine, 20 Tris, 0.1% SDS, and 20% methanol) were diluted from 10× stock solutions.

[0781] Using this co-immunoprecipitation step, the present inventors demonstrated that compound 120 disrupts the NMDAR / TRPM4 complex.

[0782] Example 56: Protection of Human iPSC-Derived Organoids

[0783] In order to explore the therapeutic effects of the compounds of the present invention on various neurodegenerative diseases, several in vitro models based on human induced pluripotent stem cells (iPSCs) have been or will be used.

[0784] Human iPSC-derived prefrontal cortex organoids

[0785] Prefrontal cortical organoids were prepared according to published literature (Bauersachs HG et al, Neuroscience, 2022; 484: 83-97). Around week 20, organoids were pre-incubated with compound 120 for 30 min and then stimulated with 200 μM NMDA for 24 h, and 80% of neurons underwent necrosis. The luciferase was detected using a plate reader (RealTime-Glo) according to the manufacturer's instructions. TM MT cell viability detection kit (RealTime-Glo TM MT Cell Viability Assay, Promega, G9711) was used to monitor and analyze cell death. Cell viability (%) can be calculated using the following equation:

[0786]

[0787] Among them, F t is the luciferase intensity at each time point, F 本底 is the background luciferase intensity before glutamate / NMDA treatment to reduce the difference between different organoids. 对照 and F 对照本底 Represents the same value in untreated organoids, so cell death can be calculated by normalization to healthy organoids.

[0788] Through this experiment, the inventors of the present invention demonstrated that compared with compound P401 known in the prior art (WO2020 / 079244), compound 120 can improve the cell survival rate after glutamate / NMDA treatment in human iPSC-derived prefrontal cortex organoids.

[0789] Human iPSC-derived motor neurons

[0790] According to publications (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), human iPSC-derived motor neuron cultures will be generated from healthy sporadic ALS, SOD1&TDP43&C9orf72 mutation-associated ALS. iPSCs are cultured and differentiated into motor neurons, and glutamate neurotoxicity and cell death are induced with 10 μM glutamate on day 17 of differentiation, with or without the use of compounds of the present invention. Neuronal survival will be tracked by Incucyte expressing mCherry-NLS in the cell nucleus. When the mCherry fluorescence in the cell nucleus can no longer detect dead neurons, the survival rate of the neurons will be calculated.

[0791] Example 57: ALS Mouse Model

[0792] This study will use 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(Pt12): 3335-47). Heterozygosity will be maintained by mating heterozygous transgenic males with C57BL / 6 wild-type females. They will be group-housed (up to three mice / cage) and housed in standard cages (15×21×13.5 cm) with a 12:12 h light-dark cycle and free access to food, water and nesting materials. Animals will be randomly assigned to treatment groups. The compounds of the invention will be administered to animals at different doses (in mg / kg body weight / day: 0.1, 0.3, 1, 3, 10, 30) before and after the onset of disease. The humane endpoint is defined as the inability of mice to self-right within 30 seconds and will be examined daily after the onset of paralysis, but blinded to the treatment group.

[0793] Example 58: Mouse Model of Retinal Ganglion Cell (RGC) Degeneration

[0794] C57BL / 6J mice will receive intraperitoneal injections of vehicle (40% propylene glycol) or compounds of the invention (40 mg / kg body weight, dissolved in 40% propylene glycol) at -16h, -3h, 0h (intravitreal injection of NMDA / saline), +3h and +24h, with each injection dose of 50μL. At 0h, 20nmol NMDA / sodium glutamate (total volume 2.0μL) was injected intravitreally into the left eye of the mouse, and saline (total volume 2.0μL) was injected into the right eye. Seven days after the intravitreal injection, both eyes were removed from the euthanized mice, fixed in formalin for 15min, and the retinas were dissected and subjected to whole-mount immunohistochemistry. The retinas will be incubated in blocking solution (10% normal donkey serum and 1% Triton-X 100 in PBS) for 6h, and then incubated with anti-Brn3a antibody in blocking solution at 4°C for 24h. The retinas will then be washed three times with PBS and incubated with donkey anti-rabbit AlexaFluor-594 for 24 h at room temperature. The retinas will be washed again, cut and mounted on slides. For each retina, images will be acquired from eight areas (554 μm × 554 μm) surrounding the peripheral retina (two per quadrant, located at ∼600 μm and ∼1400 μm from the macular hole) to minimize the impact of position-related changes in RGC density on cell counts. All images will be acquired with a HC PL APO 20× objective on a Leica TCS SP8LIA in a DM6CFS upright confocal microscope using LasX software. Brn3a-positive cells will be identified and counted using macros in Cell Profiler. Data analysis will be performed blindly without knowledge of the subjects.

[0795] Example 59: More compounds

[0796] In the next round of synthesis, the inventors of the present invention will synthesize the following inventive compounds and evaluate their activities:

[0797]

Claims

1. A compound having the following general formula I: in: R7 is selected from R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and wherein 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 the group consisting of 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, if R5 is methyl, R7 is 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 linear C3-C6 alkyl, unsubstituted branched C4-C6 alkyl, substituted branched or linear 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; Provided further that, if R5 is methyl, R7 is Two of R1, R2, R3 and R4 are Cl and the other two are H, wherein R1 and R2, R3 and R4, R1 and R3, or R2 and R4 are 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; Provided that, if R5 is methyl, R7 is 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 chain 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; Provided further that, if R5 is ethyl, R7 is 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 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; Provided further that, if R5 is H, R7 is The compound then has one of the following formulae: and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers of any of these compounds.

2. The compound according to claim 1, wherein R7 is 3. The compound according to claim 1, wherein R7 is 4. The compound according to any one of claims 1-3, wherein R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I and -CN.

5. The compound according to any one of claims 1 to 3, wherein at least one of R1, R2, R3 and R4 is ethynyl, preferably wherein R2 is ethynyl.

6. A compound according to any one of claims 1-3 and 5, wherein two of R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl.

7. A compound according to any one of claims 1, 5 and 6, wherein R7 is And wherein one of R2 and R3 is selected from H, F, Cl, Br, I, -CN and ethynyl, and the other is H.

8. A compound according to any one of claims 1 and 5-7, wherein R7 is wherein at least two of R1, R2, R3 and R4 are H, and one of R2 and R3 is Cl.

9. A compound according to any one of claims 1 to 3, wherein R1 is H or F, and wherein R2 is selected from F, Cl, Br, I, CN and ethynyl.

10. The compound of claim 9, wherein R1 is F, and wherein R2 is selected from Cl, Br, CN and ethynyl.

11. The compound of claim 2, wherein R4 is H or F, and wherein R3 is selected from F, Cl, Br, I, CN and ethynyl.

12. The compound of claim 11, wherein R4 is F, and wherein R3 is selected from Cl, Br, CN and ethynyl.

13. The compound of claim 2, wherein i) R1 is F, R2 is Cl, and R3 and R4 are H, or wherein ii) R1 and R2 are H, R3 is Cl, and R4 is F.

14. The compound according to any one of claims 1 to 13, wherein 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.

15. The compound according to claim 14, wherein 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.

16. The compound of claim 14, wherein R5 is H.

17. The compound of claim 15, wherein R5 is methyl.

18. A compound according to any one of claims 1 to 13, wherein R5 is selected from ethyl, isopropyl, -CH2CF3, -CF2CF3, -CF2CH3, -CHF2, -CF3, cyclopropyl, fluorine-substituted isopropyl, propenyl, cyclopropyl, cyclobutyl, fluorine-substituted cyclobutyl and cyclopentyl.

19. The compound according to any one of claims 1 to 18, wherein R6 is selected from unsubstituted branched or linear C3-C6 alkyl, substituted branched or linear 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 wherein the substituents of the substituted branched or linear C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 bicycloalkyl, substituted C4-C7 cycloalkyl and substituted C3-C6 alkenyl are preferably each independently selected from F, Cl, CN, OH, alkylthio and alkoxy, more preferably each independently selected from F, Cl, CN and OH.

20. The compound according to any one of claims 1 to 18, wherein R6 is selected from substituted branched or linear C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 bicycloalkyl, substituted C4-C7 alkylcycloalkyl and substituted C3-C6 alkenyl, and wherein the substituents of the substituted branched or linear C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 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 and OH.

21. The compound according to claim 19, wherein R6 is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl-, allyl, -CH2CH2-S-CH3, -CH2CF2H, -CH2CF3 and -CH2CH2CN, in particular wherein R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl- and allyl.

22. The compound of claim 21, wherein R6 is cyclopropyl.

23. The compound of claim 1, wherein the compound has one of the following formulas: and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers of any of these compounds.

24. The compound of claim 1, wherein the compound has one of the following formulas: and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers of any of these compounds.

25. The compound according to any one of claims 1-21, wherein the pharmaceutically acceptable salt is selected from the group consisting of a halide, a formates and a trifluoroacetate.

26. A compound for use in a method for treating or preventing a disease in the human or animal body, wherein the compound is a compound of the following general formula I: in: R7 is selected from in 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 linear C1-C4 alkyl, fluorine-substituted branched or linear C1-C4 alkyl, unsubstituted propenyl, unsubstituted C3-C6 cycloalkyl and fluorine-substituted C3-C6 cycloalkyl; R6 is selected from the group consisting of 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 if 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; with the further proviso that if 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; Or wherein the compound is a pharmaceutically acceptable salt, racemate, (R)- or (S)-enantiomer of a compound of formula I.

27. The compound for use according to claim 22, wherein R7 is 28. The compound for use according to claim 22, wherein R7 is 29. The compound for use according to any one of claims 26 to 28, wherein R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br and -CN.

30. A compound for use according to any one of claims 26 to 28, wherein at least one of R1, R2, R3 and R4 is ethynyl, preferably wherein R2 is ethynyl.

31. A compound for use according to any one of claims 26-28 and 30, wherein two of R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl.

32. A compound for use according to any one of claims 26, 30 and 31, wherein R7 is And wherein one of R2 and R3 is selected from H, F, Cl, Br, I, -CN and ethynyl, and the other is H.

33. A compound for use according to any one of claims 26 and 30-32, wherein R7 is wherein at least two of R1, R2, R3 and R4 are H, and one of R2 and R3 is Cl.

34. A compound for use according to any one of claims 26 to 28, wherein R1 is H or F, and wherein R2 is selected from F, Cl, Br, I, CN and ethynyl.

35. The compound for use according to claim 34, wherein R1 is F, and wherein R2 is selected from Cl, Br, CN and ethynyl.

36. The compound for use according to claim 27, wherein R4 is H or F, and wherein R3 is selected from F, Cl, Br, I, CN and ethynyl.

37. The compound for use according to claim 36, wherein R4 is F, and wherein R3 is selected from Cl, Br, CN and ethynyl.

38. A compound for use according to claim 31, wherein i) R1 is F, R2 is Cl, and R3 and R4 are H, or wherein ii) R1 and R2 are H, R3 is Cl, and R4 is F.

39. A compound for use according to any one of claims 26 to 38, wherein R5 is selected from H, unsubstituted branched or linear C1-C4 alkyl, fluorine-substituted branched or linear C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl and fluorine-substituted C3-C6 cycloalkyl.

40. The compound for use according to claim 39, wherein R5 is selected from unsubstituted branched or linear C1-C4 alkyl, fluorine-substituted branched or linear C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl and fluorine-substituted C3-C6 cycloalkyl.

41. A compound for use according to claim 39, wherein R5 is H.

42. A compound for use according to claim 32, wherein R5 is methyl.

43. A compound for use according to any one of claims 26 to 38, wherein R5 is selected from ethyl, isopropyl, -CH2CF3, -CF2CF3, -CF2CH3, -CHF2, -CF3, cyclopropyl, fluorine-substituted isopropyl, propenyl, cyclopropyl, cyclobutyl, fluorine-substituted cyclobutyl and cyclopentyl.

44. The compound for use according to any one of claims 26 to 43, wherein R6 is selected from unsubstituted branched or linear C3-C6 alkyl, substituted branched or linear 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; wherein the substituents of the substituted branched or linear C3-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 bicycloalkyl, substituted C4-C7 alkylcycloalkyl and substituted C3-C6 alkenyl are preferably each independently selected from F, Cl, CN, OH, alkylthio and alkoxy, more preferably each independently selected from F, Cl, CN and OH.

45. A compound for use according to any one of claims 26 to 44, wherein R6 is selected from substituted branched or linear C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 bicycloalkyl, substituted C4-C7 alkylcycloalkyl and substituted C3-C6 alkenyl, and wherein the substituents of the substituted branched or linear C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 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 and OH.

46. ​​Compounds for use according to claim 44, wherein R6 is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl-, allyl, -CH2CH2-S-CH3, -CH2CF2H, -CH2CF3 and -CH2CH2CN, in particular wherein R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentan-1-yl- and allyl.

47. A compound for use according to claim 46, wherein R6 is cyclopropyl.

48. The compound for use according to claim 26, wherein the compound is a compound according to any one of claims 1-25.

49. The compound for use according to claim 26, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers of any of these compounds.

50. The compound for use according to claim 26, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts, racemates, (R)- or (S)-enantiomers of any of these compounds.

51. A compound for use according to any one of claims 26 to 50, wherein the pharmaceutically acceptable salt is selected from the group consisting of a halide, a formates and a trifluoroacetate.

52. A compound for use according to any one of claims 26 to 51, wherein the disease is a neurological disease.

53. A compound for use according to any one of claims 26 to 52, wherein the disease is a neurodegenerative disease.

54. A compound for use according to any one of claims 26 to 53, wherein the disease is treated by inhibiting the formation of the NMDA receptor / TRPM4 complex.

55. The compound for use according to any one of claims 26 to 54, wherein the disease is selected from the group consisting of: stroke, in particular ischemic stroke and hemorrhagic stroke, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), traumatic brain injury, sequelae of traumatic brain injury, mental confusion, age-related memory loss, memory decline associated with aging, progressive nuclear palsy, multiple sclerosis, thalamic degeneration, glutamate-induced excitotoxicity, dystonia, epilepsy, optic nerve diseases, diabetic retinopathy, glaucoma, pain, in particular neuropathic pain, anti-NMDA receptor encephalitis, viral encephalitis, dementia, for example post-stroke dementia, HIV dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), frontal lobe degeneration (including Pick's disease), corticobasal degeneration dementia, vascular dementia, microangiopathy, Binswanger's disease, cerebral ischemia, hypoxia, Parkinson's disease, Batten disease, schizophrenia, especially schizophrenia with dementia, Korsakov psychosis, depression, cerebral malaria, toxoplasmosis (due to the risk of toxoplasmosis-related brain damage), brain damage associated with HIV infection / AIDS (due to the risk of HIV), Zika virus infection (due to the possibility of Zika virus-related brain damage), other viral infections that may lead to neurodegenerative events and corresponding neuronal or brain damage, respectively, such as viral meningitis or SARS-COV2 virus-induced encephalitis; brain tumors, especially glioblastoma, central nervous system diseases, such as anxious, tense and depressive states, sexual dysfunction, sleep disorders and pathological disturbances in the intake of food, stimulants and addictive substances.

56. A compound having the following general formula II: in: R7 is selected from R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and wherein 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 linear C1-C4 alkyl, fluorine-substituted branched or linear 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, Provided that, if R5 is methyl, R7 is one of R2 and R3 is H and the other is Cl, and R1 and R4 are H, then R6 is selected from unsubstituted linear C3-C6 alkyl, unsubstituted branched C4-C6 alkyl, substituted branched or linear 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; Provided further that, if R5 is methyl, R7 is Two of R1, R2, R3 and R4 are Cl and the other two are H, wherein R1 and R2, R3 and R4, R1 and R3 or R2 and R4 are 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; Provided further that, if R5 is methyl, R7 is 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; Provided further that, if R5 is methyl, R7 is 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 further proviso that if 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 the group consisting of 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 further 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 the group consisting of unsubstituted straight chain C3-C6 alkyl, unsubstituted branched 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, Provided further that, if R5 is H, R7 is The compound then has one of the following formulae: and salts, racemates, (R)- or (S)-enantiomers, hydrates or isotopes of any of these compounds.

57. A compound having the following general formula III: in: R7 is selected from R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and wherein 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 linear C1-C4 alkyl, fluorine-substituted branched or linear 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, wherein the compounds are described.

58. A compound having the following general formula IV: in: R7 is selected from R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, -CN and ethynyl, and wherein 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 linear C1-C4 alkyl, fluorine-substituted branched or linear 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, wherein the compounds are described.

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