Arylcyclobutylamines and other modulators of NMDA receptor-mediated toxicity

Abstract

The present invention relates to compounds inhibiting the toxic activity of extrasynaptic NMDA receptors, in particular by inhibiting the formation of NMDA receptor / TRPM4 complexes. In particular, the present invention relates to diamine-based compounds according to general formula I and their use in medicine, in particular for treating neurological diseases such as neurodegenerative diseases.

Description

[0001] New International Patent Application 24 Feburary 2026 Applicant: FundaMental Pharma GmbH

[0002] Our Ref: FMP-006PCT2

[0003] Arylcyclobutylamines and other modulators of NMDA receptor-mediated toxicity

[0004] The present invention relates to the field of neurodegenerative processes and means to provide protection against the same. In particular, the present invention relates to compounds inhibiting 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 compounds according to general formula I and their use in medicine, in particular for treating neurological diseases such as neurodegenerative diseases.

[0005] Neurodegenerative diseases are devastating diseases involving the progressive loss of structure or function of neurons and eventual death of neurons. Neurodegeneration may be acute or slowly progressive, but both types of neurodegeneration often involve increased death signalling 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 for calcium. They can be categorized according to their subcellular location as synaptic and extrasynaptic NMDA receptors. The subunit composition of the receptors within and outside synaptic contacts is similar, although, in addition to carrying the common Glutamate Ionotropic Receptor NMDA Type Subunit 1 (GluNl) subunit, extrasynaptic NMDA receptors contain preferentially the GluN2B subunit, whereas GluN2A is the predominant subunit in synaptic NMDA receptors. The cellular consequences of synaptic versus extrasynaptic NMDA receptor stimulation are dramatically different. Synaptic NMDA receptors are essential for synaptic transmission and maintain their physiological functions by allowing calcium signalling pathways to the cell nucleus, which triggers the expression of key genes that are critical for the long-term implementation of virtually all behavioural adaptations. Most importantly, synaptic NMDA receptors, acting via nuclear calcium, are strong activators of neuronal structure-protective and survival-promoting genes. In striking contrast, extrasynaptic NMDA receptors trigger cell death pathways. Within minutes after extrasynaptic NMDA receptor activation, the mitochondrial membrane potential breaks down, followed by the opening of mitochondrial permeability transition pore that eventually led to mitochondrial dysfunction and cell death. Extrasynaptic NMDA receptors also strongly antagonize excitation-transcription couplingand disrupt nuclear calcium-driven adaptogenomics because they trigger a cyclic adenosine monophosphate (cAMP)-responsive element-binding protein (CREB) shutoff pathway, inactivate extracellular signal-regulated kinase (ERK)-MAPK signalling, and lead to nuclear import of class Ila histone deacetylases (HDACs) and the pro-apoptotic transcription factor Foxo3A. This affects activity regulation of many genes, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor D (VEGFD), that are vital for the maintenance of complex dendritic architecture and synaptic connectivity as well as the buildup of a neuroprotective shield. In addition, given the short reach of activated ERK1 / 2, their shut-off by extrasynaptic NMDA receptors disrupts important local signalling events including dendritic mRNA translation and AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor trafficking that controls the efficacy of synaptic transmission. Thus, extrasynaptic NMDA receptor signalling is characterized by the initiation of a pathological triad with mitochondrial dysfunction, deregulation of transcription, and loss of integrity of neuronal structures and connectivity (Bading, J Exp Med. 2017 Mar 6;214(3):569-578, incorporated herein by reference).

[0006] Several attempts have been made to use blockers of NMDA receptors for treatments of neurological conditions. In general, the results of clinical studies were disappointing, largely because of serious side effects caused by interference of the blockers with the physiological function of synaptically localized NMDA receptors (Ogden and Traynelis, 2011). One notable exception is the NMDA receptor antagonist memantine (Bormann, 1989). Beneficial effects of low-dose treatments with memantine have been observed in several animal models of neurodegeneration, which include Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and the experimental autoimmune encephalomyelitis (EAE) model of MS. Moreover, memantine is approved since 2002 by the European Medicines Agency and the US Food and Drug Administration (FDA) for the treatment of moderate-to- severe AD.

[0007] It was only recently discovered, that excitotoxicity requires physical coupling of toxic extrasynaptic NMDA receptors and TRPM4, a transient receptor potential channel (Yan et al., Science, 2020 Oct 9;370(6513):eaay3302; see also see WO 2020 / 079244, both incorporated herein by reference). The NMDA receptor / TRPM4 interaction is mediated by a 57-amino acid intracellular domain of TRPM4, that is positioned just beneath the plasma membrane. Yan et al. also discovered that said interaction can be inhibited by various means and thatthese provide protection against excitotoxic cell death in cultured neurons and in vivo in many mouse models of neurodegeneration while not interfering with synaptic NMDA receptor activity (Yan et al., Science, 2020 Oct 9;370(6513):eaay3302; Yan et al., Cell Reports Medicine, 2024 Feb 20;5(2): 101413, both incorporated herein by reference). The means suggested by Yan et al. included peptide derived inhibitors of NMDA receptor / TRPM4 interaction as well as small molecule compounds.

[0008] Additional compounds having such inhibitory activity have been disclosed in WO 2023 / 203254 and WO 2024 / 223617, all incorporated herein by reference.

[0009] However, while the compounds identified by Yan et al. and subsequent applications exhibit good neuroprotective activity, there is still room for an increase in potentcy, for example to facilitate oral application in vivo. Moreover, many of the compounds identified previously are cost-intensive in terms of synthesis due to stereochemical aspects which need to be considered. Therefore, there is a need in the art for further compounds suitable of selectively inhibiting the NMDA receptor / TRPM4 interaction, wherein said compounds are preferably highly potent or stereochemical less challenging in terms of synthesis or are ideally both. The problem to be solved by the present invention was thus to provide such new, preferably improved means to attenuate extrasynaptic toxic NMDA receptor activity.

[0010] This problem is solved by the subject-matter as set forth in the appended claims and in the description below.

[0011] As will be shown in the following, the inventors of the present invention have identified a new class of compounds, which surprisingly inhibit NMDA receptor mediated toxicity very effectively and are thus particularly useful candidates for treatment and prevention of diseases involving NMDA receptor mediated neuronal death. These compounds differ from compounds previously disclosed in the prior art by having an additional cyclic element. This additional cyclic element potentiates the activity and facilitates synthesis of said compounds.

[0012] Therefore, the present invention relates in a first aspect to a compound according to the following general formula I:

[0013]

[0014] wherein:

[0015] X is selected from

[0016]

[0017] wherein:

[0018] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0019] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0020] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3;

[0021] Z is selected from

[0022]

[0023]

[0024] wherein:

[0025] Re is selected from hydrogen, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl; and

[0026] Raand Rb are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, or Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused, bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), hydroxyl, oxo, and options provided above for Re (e.g. Raand Rb may form together with the nitrogen in between a substituted or unsubstituted 4-membered, 5-membered or 6-membered heterocycloalkyl);

[0027] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)- or (S)-enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any one of the above-mentioned compounds.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, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups -CH3 (Me), -CH2CH3 (Et), -CH2CH2CH3 (n Pr or propyl), -CH(CH3)2(i Pr, iPr or isopropyl), -CH2CH2CH2CH3 (n Bu), -CH(CH3)CH2CH3 (sec-butyl), -CH2CH(CH3)2 (isobutyl), -C(CH3)3 (tert-butyl, t butyl, t Bu or tBu), and -CH2C(CH3)3 (neo-pentyl) are non-limiting examples of alkyl groups. When “alkyl” is used with the “substituted” modifier, and unless specified otherwise, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -OCH3, -SCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2CH3, or -S(O)2NH2. Preferably, only one hydrogen atom has been replaced. Most preferably, only one hydrogen atom at a terminal carbon atom has been replaced. “Fluoro-substituted” alkyl refers to an alkyl group where one or more hydrogen atoms have been independently replaced by -F. In the case of fluoro-substituted alkyl it is preferred if more than one hydrogen atom has been replaced by -F. Even more preferably, more than two hydrogen atoms have been replaced by -F. Particularly preferred embodiments of fluoro-substituted alkyl are -CF3, -CHF2, -CH2CF3, -CF2CH3, and -CF2CF3. In the case of fluoro-substituted alkyl it is further preferred that the substitution with fluor is not adjacent to a nitrogen atom.

[0028] 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, a linear or branched, acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2(allyl), -CH2CH=CHCH3, and -CH=CHCH=CH2. Preferably, the structure contains only one nonaromatic carbon-carbon double bond, preferably at the terminal end of the structure as in allyl. When “alkenyl” is used with the “substituted” modifier, and unless specified otherwise, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -OCH3, -SCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -0C(0)CH3, -NHC(0)CH3, -S(O)2CH3, or -S(O)2NH2. Preferably, only one hydrogen atom has been replaced. Most preferably, only one hydrogen atom at a terminal carbon atom has been replaced. In the case of fluoro-substituted alkenyl it is preferred if more than onehydrogen atom has been replaced by -F. Even more preferably, more than two hydrogen atoms (e.g. 3) have been replaced by -F. For fluoro-substituted alkenyl it is further preferred that the substitution with fluor is not adjacent to a nitrogen atom.

[0029] As used herein, the term “unsubstituted cycloalkyl” or “cycloalkyl”, when used without the “substituted” modifier, refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forming part of a single non-aromatic ring structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl. When “cycloalkyl” is used with the “substituted” modifier, and unless specified otherwise, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -OCH3, -SCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -0C(0)CH3, -NHC(0)CH3, -S(O)2CH3, or -S(O)2NH2. Preferably, only one hydrogen atom has been replaced. “Fluoro-substituted” cycloalkyl refers to a cycloalkyl group where one or more hydrogen atoms have been independently replaced by -F. In the case of fluoro-substituted cycloalkyl, such as fluoro-substituted cyclobutyl, it is preferred if one hydrogen atom has been replaced by -F. For fluoro-substituted cycloalkyl it is further preferred that the substitution with fluor is not adjacent to a nitrogen atom.

[0030] 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, said carbon atom forming part of two non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. A non-limiting example is bicyclo [l.l.l]pentanyl. When “bicycloalkyl” is used with the “substituted” modifier, and unless specified otherwise, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -OCH3, -SCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2CH3, or -S(O)2NH2. Preferably, only one hydrogen atom has been replaced. For fluoro-substituted bicycloalkyl it is further preferred that a substitution with fluor is not adjacent to a nitrogen atom.

[0031] As used herein, the term “unsubstituted alkylcycloalkyl”, or “alkylcycloalkyl”, when used without the “substituted” modifier, refers to an alkyl group as defined above with at least twocarbon atoms and with a first carbon atom as the point of attachment, wherein a further, terminal carbon atom of the alkyl group forms part of one non-aromatic ring structure. Nonlimiting examples include: -CH2-CH(CH2)2 (cyclopropylmethyl), cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl. When “alkylcycloalkyl” is used with the “substituted” modifier, and unless specified otherwise, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -OCH3, -SCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2CH3, or -S(O)2NH2. Preferably, only one hydrogen atom has been replaced. Most preferably, only one hydrogen atom at a carbon atom of the non-aromatic ring structure has been replaced. In case alkylcycloalkyl is substituted with -F, it is preferred if one hydrogen atom has been replaced by -F. For fluoro-substituted alkylcycloalkyl it is further preferred that a substitution with fluor is not adjacent to a nitrogen atom.

[0032] The term “Ar”, as used herein, refers to a mono- or polycyclic aromatic hydrocarbon systems having 3 to 14, preferably 3-12, more preferably 4 to 12, even more preferably 5 to 10, most preferably 6 to 8 carbon atoms, which can be optionally substituted. The term “Ar” also includes systems in which the aromatic cycle is part of a bi- or polycyclic saturated, partially unsaturated and / or aromatic system, such as where the aromatic cycle is fused to an aryl, cycloalkyl or heteroaryl group via any desired and possible ring member of the aryl radical. The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the aryl radical. Examples of suited aryl radicals are phenyl, biphenyl, naphthyl, 1 -naphthyl, 2-naphthyl and anthracenyl, but likewise indanyl, indenyl or 1,2,3,4-tetrahydronaphthyl. Preferred groups Ar are optionally substituted naphthyl and biphenyl, more preferably optionally substituted monocylic aryl having 6-8 C atoms. The group “Ar” may be unsubstituted or substituted by one or more groups which may be the same or different. In particularly preferred embodiments of the sixt aspect the substitutents are selected from those as set out for Ri, R2, R3, R4 or R5 of the first aspect of the invention.

[0033] The term “Het”, as used herein, denotes a hetero-atom containing carbocyclic ring, such as heteroaryl, preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazo-, -4- or -5-yl, 1 ,2,4-triazo-, -3- or 5-yl, 1- or 5-tetrazolyl, 1 ,2,3-oxadiazol-4- or -5-yl, l,2,4-oxadiazol-3- or -5-yl, 1 ,3,4- thiadiazol-2- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl, 1 ,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso-5i-ndolyl, indazolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzo- pyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,l ,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-l ,4- oxazinyl, further preferably 1 ,3-benzodioxol-5-yI, l,4-benzodioxan-6-yl, 2,1 ,3-benzothiadiazol-4-, -5-yl or 2,1 ,3-benzoxadiazol-5-yl, azabicyclo- [3.2.1]octyl or dibenzofuranyl. The group “Het” may be unsubstituted or substituted by one or more groups which may be the same or different. In particularly preferred embodiments of the sixt aspect the substitutents are selected from those as set out for Ri, R2, R3, R4 or R5 of the first aspect of the invention.

[0034] The term “Aik”, as used herein, and in contrast to “alkyl” defined above, refers to a linear chain or branched alkyl group having 1 to 12 carbon atoms, wherein 1 to 3 CH2-groups may be replaced by a group selected from O, NRC, S, SO, SO2, S(O)(NRC), CO, COO, OCO, CONRc and NRcCO, and wherein 1 to 5 hydrogen atoms may be independently replaced by halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), NRcRd, CN or NO2. Rc and Rd are each independently selected from the group consisting of H, unsubstituted branched or linear Ci-Ce alkyl and C3-C6 cycloalkyl.

[0035] As used herein, a wavy line,

[0036]

[0037] , when positioned in a 90° angle to another bond line, indicates the point of attachment of a moiety like the phenyl or thiophen moiety of the X moiety to the rest of formula I.

[0038] As mentioned above, the compounds according to formula (I) have a cyclic element as defined above which distinguishes them from other compounds previously suggested in the prior art. The cyclic element is a non-aromatic ring, the size of which is determined by Y. Y is selected from the group consisting of (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7 is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O and S, and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3. In cases where Y is linear alkyl in the form of (CH2)n, the ring will be a four- (n=l), five- (n=2), six- (n=3) or seven-membered(n=4) ring. Preferably, when Y is (CH2)n, n is 1, 2 or 3. Even more preferably, n is 1 or 2 when Y is (CH2)n. Most preferably n is 1 when Y is (CH2)n. In cases where Y is CH-CH3, C=CH2, CHF, or CF2, the cyclic element is a substituted cyclobutyl ring, substituted with methyl or 1 or 2 fluoro substituents, or has a methylene substituent. In embodiments where Y is O or S, the ring element is a four- membered, heterocyclic ring (oxetane or thietane). In some embodiments, Y will be (CH2)m-R7-(CH2)i, wherein R7 is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O and S, and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3. Due to m+1 being selected from 1, 2 or 3, the ring will be in this case a five (m+1 =1), six- (m+1 =2), or seven-membered (m+1 =3) ring. Preferably, m+1 is 1 or 2. Most preferably, m+1 is 1. According to the present invention the choice of Y leads preferably to four, five or six-membered rings, i.e. is selected from the group consisting of (CH2)n, with n being 1, 2, or 3, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7 is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S, and wherein m and 1 are selected from 0, 1, and 2 and wherein m+1 is 1 or 2. In some embodiments, Y is selected from the group consisting of (CH2)n, with n being 1, 2, or 3, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O and S. In some embodiments, Y is selected from (CH2)n, with n being 1, 2, or 3, CHF and CF2. In some embodiments Y is CHF. In some embodiments Y is (CH2)n, with n being 1, 2, or 3, preferably wherein n is 1 or 2. Most preferably, Y is CH2.

[0039] In the compounds according to formula (I), X is selected from

[0040]

[0041]

[0042] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, F, Cl, Br, I, -CN and ethynyl. It will be understood by the skilled person that when X is thiophen any reference herein to R3, R4 and R5 in the context of X is obsolete, as there is no R3, R4 and R5 in thiophen. In preferred embodiments of the invention, Ri, R2, R4 and R5 of the inventive compounds are each independently selected from H, F, Cl, Br, I and -CN. In some embodiments of the inventive compounds of formula (I), at least one of Ri, R2, R4 and R5 isethynyl, preferably R2. In some embodiments of formula (I), one of R2 and R4 is selected from H, F, Cl, Br, I, -CN and ethynyl, while the other is H. In further embodiments of formula (I), at least two of Ri, R2, R4 and R5 are H and one of R2 and R4 is Cl. In some embodiments, Ri is H or F, preferably F, and R2 is selected from F, Cl, Br, I, CN and ethynyl, preferably from Cl, Br, CN and ethynyl. In some embodiments of formula (I), R5 is H or F, preferably F, and R4 is selected from F, Cl, Br, I, CN and ethynyl, preferably from Cl, Br, CN and ethynyl. In some embodiments of formula (I), Ri is F, R2 is Cl and R4 and R5 are H, or Ri and R2 are H, R4 is Cl and R5 is F. R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I). However, preferably R3 is selected from the group consisting of H and F and is still most preferably H. In some embodiments of the invention where X is

[0043]

[0044] (in the following termed X is thiophen), Ri and R2 are selected from H, F and -CN. In some embodiments, where X is thiophen, Ri is F. In some embodiments, where X is thiophen, R2 is -CN. In some embodiments, where X is thiophen, Ri is F and R2 is -CN. In

[0045] some embodiments X is

[0046]

[0047] (in the following termed X is phenyl). In some embodiments, where X is phenyl, Ri is F. In some embodiments, where X is phenyl, R2 is selected from -CN, Br and Cl. In some embodiments, where X is phenyl, R3 is H. In some embodiments, where X is phenyl, R4 is H. In some embodiments, where X is phenyl, R5 is H or F. In some embodiments, where X is phenyl, R3 and R4 are H. In some embodiments, where X is phenyl, R3 and R5 are H. In some embodiments, where X is phenyl, R4 and R5 are H. In some embodiments, where X is phenyl, R3, R4, and R5 are H. In some embodiments, where X is phenyl, Ri is F and R3 is H. In some embodiments, where X is phenyl, Ri is F and R2 is -CN. In some embodiments, where X is phenyl, Ri is F, R2 is -CN, Cl or Br and R3 and R4 are H. In some embodiments, where X is phenyl, Ri is F, R2 is -CN, Cl or F, and R3, R4 and R5 are H. In some embodiments, where X is phenyl, Ri is F, R2 is -CN, and R3, R4 and R5 are H.

[0048]

[0049] each independently selected from H, methyl and ethyl. More preferably, Raand / or Rb are H.

[0050] Most preferably, Raand Rb are H. When

[0051]

[0052] then preferably at at least one of Ri, R2, R3, R4 and R5 is not H, more preferably at least one of Ri, R2, R4 and R5 is selected from the group consisting of F, Cl, Br, I, -CN and ethynyl. Alternatively, when Z is

[0053]

[0054] , it is also preferred that Y is selected from the group consisting of (CH2)n, with n being 1, 2 or 4 , CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R?-(CH2)I, wherein R? is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S, and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is1, 2 or 3. Alternatively, when

[0055]

[0056] then it is also preferred that Raand Rb are not a combination of H and ethyl. Preferably, Z is selected from the group consisting of

[0057]

[0058] selected from the group consisting of

[0059]

[0060]

[0061] Even more preferably, Z is selected from the

[0062] group consisting

[0063]

[0064] more preferably, Z is selected from the group consisting

[0065]

[0066]

[0067] and even more preferably

[0068]

[0069] When Z is selected

[0070]

[0071] selected from unsubstituted branched or linear C2-C6 alkyl, substituted branched or linear C2-Ce 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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl. When R is substituted branched or linear C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 bicycloalkyl, substituted C4-C7 alkylcycloalkyl, substituted C3-C6 alkenyl and substituted C3-C6 alkynyl, the substituents of substituted branched or linear C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 bicycloalkyl, substituted C4-C7 alkylcycloalkyl, substituted C3-C6 alkenyl alkenyl and substituted C3-C6 alkynyl are preferably each independently selected from F, Cl, CN, OH, alkylthio, and alkoxy. Even more preferably, the substituents are each independently selected from the group consisting of F, Cl, CN, and OH. Preferably, Re of the compounds of the present invention according to formula I are 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. In cases where Re of the compounds of the present invention according to formula I 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, the substituents of substituted branched or linear C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted bicycloalkyl, substituted C4-C7 alkylcycloalkyl, and substituted C3-C6 alkenyl are each independently selected from halogen, CN, OH, alkylthio, and alkoxy. Preferably, the substituents of substituted branched or linear C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted bicycloalkyl, substituted C4-C7 alkylcycloalkyl, and substituted C3-C6 alkenyl are each independently selected from F, Cl, CN, -SCH3 and OH. Re may in some partocularlyl preferred embodiments be selected from the group consisting of cyclopropylmethyl,cyclobutylmethyl, cyclopropyl, cyclobutyl, fluoro-substituted cyclobutyl, methyl -substituted cyclobutyl, cyclopentyl, bicyclo[l.l.l]pentan-l-yl-, allyl, -CH2CH2-S-CH3, -CH2CF2H, -CH2CF3, -CH2CH2CN and -CH2CCH. Even more preferably, Re is selected from the group consisting of cyclopropyl, fluoro-substituted cyclopropyl, cyclobutyl , fluoro-substituted cyclobutyl, methyl -substituted cyclobutyl, propyl, isopropyl or allyl. In some embodiments, Re is cyclopropyl. In some embodiments, Re is fluoro-substituted cyclobutyl, in particular mono or difluoro-substituted cyclobutyl. In some embodiments, Re is n-propyl. Preferably, no substituent is present on the carbon atom forming the point of attachment of Re to the nitrogen of formula I.

[0072] When

[0073]

[0074] are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl. Raand Rb may be the same or different. Alternatively, Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused, bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), hydroxyl, oxo, and options provided above for Re In some embodiments, Raand Rb taken together with the nitrogen atom to which they are attached represent a substituted or unsubstituted 4-membered, 5-membered or 6-membered heterocycloalkyl, such as (optionally substituted) azetidine, pyrrolidine or piperidine. The above disclosure regarding potential substituents of “substituted cycloalkyl” is analogously applicable to “substituted heterocycloalkyl”. Preferably, such substituents such as fluor are not positioned in proximity of the nitrogen atom of the heterocyclic ring. Preferably, Raand Rb are each independently selected from H, methyl and ethyl. In particularly preferred embodiments, Raand / or Rb are H, and are most preferably both H, i.e. Z is

[0075]

[0076] In some embodiments of the invention, the compound according to the first aspect of the invention is selected from the group consisting of:

[0077]

[0078] wherein:

[0079] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0080] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0081]

[0082]

[0083] wherein:

[0084] Re is selected from unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl; and

[0085] Raand Rb are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, or Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused, bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), hydroxyl, oxo, and options provided above for Re (e.g. Raand Rb may form together with the nitrogen in between a substituted or unsubstituted 4-membered, 5-membered or 6-membered heterocycloalkyl), preferably wherein Raand Rb are each independently selected from H, methyl and ethyl, more preferably wherein Raand / or Rb are H and most preferably Raand Rb are both H;

[0086] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds. Options and substituent combinations discussed abovefor X (including options and substituent combinations for Ri, R2, R3, R4, and R5) and Z (including options and substituent combinations for Re, Raand Rb) in the context of general formula (I) are equally suited in the context of these more limited embodiments.

[0087] In some embodiments of the invention, the compound according to the first aspect of the invention is a compound selected from the group consisting of:

[0088]

[0089] wherein:

[0090] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0091] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0092] Z is selected from

[0093]

[0094] wherein:

[0095] Re is selected from unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl; and

[0096] Raand Rb are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, or Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused, bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferablyselected from F and Cl), hydroxyl, oxo, and options provided above for Re (e.g. Raand Rb may form together with the nitrogen in between a substituted or unsubstituted 4-membered, 5-membered or 6-membered heterocycloalkyl), preferably wherein Raand Rb are each independently selected from H, methyl and ethyl, more preferably Raand / or Rb are H and most preferably Raand Rb are both H;

[0097] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds. Options and combinations discussed above for Ri, R2, R3, R4 Rs and Z (including options for Re, Raand Rb) in the context of general formula (I) are equally suited in the context of these more limited embodiments.

[0098] In some embodiments of the invention, the compound according to the first aspect of the invention is a compound selected from the group consisting of:

[0099]

[0100] wherein:

[0101] Ri, and R2 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0102] Z is selected from

[0103]

[0104] wherein:

[0105] Re is selected from unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl; and

[0106] Raand Rb are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, or Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused, bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), hydroxyl, oxo, and options provided above for Re (e.g. Raand Rb may form together with the nitrogen in between a substituted or unsubstituted 4-membered, 5-membered or 6-membered heterocycloalkyl), preferably wherein Raand Rb each independently selected from H, methyl and ethyl, more preferably Raand / or Rb are H and most preferably Raand Rb are both H;

[0107] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds. Options and substituent combinations discussed above for Ri and R2 and Z (including options for Re, Raand Rb) in the context of general formula (I) are equally suited in the context of these more limited embodiments.

[0108] In some embodiments of the invention, the compound according to the first aspect of the invention is a compound selected from the group consisting of:

[0109]

[0110] wherein:

[0111] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3;

[0112] Z is selected from

[0113]

[0114] wherein:

[0115] Re is selected from hydrogen, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl; and

[0116] Raand Rb are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, or Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused, bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), hydroxyl, oxo, and options provided above for Re (e.g. Raand Rb may form together with the nitrogen in between a substituted or unsubstituted 4-membered, 5-membered or 6-membered heterocycloalkyl), preferably wherein Raand Rb each independently selected from H, methyl and ethyl, more preferably wherein Raand / or Rb are H and most preferably Raand Rb are both H;

[0117] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds. Options and substituent combinations discussed above for Y and Z (including options for Re, Raand Rb) in the context of general formula (I) are equally suited in the context of these more limited embodiments.

[0118] In some embodiments of the invention, the compound according to the first aspect of the invention is compound selected from the group consisting of:

[0119]

[0120]

[0121] wherein:

[0122] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0123] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0124] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3;

[0125] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds. Options and substituent combinations discussed above for X (including options and substituent combinations for Ri, R2, R3, R4 and R5) and Y in the context of general formula I are equally suited in the context of embodiments discussed here.

[0126] In some embodiments of the invention, the compound according to the first aspect of the invention is compound selected from the group consisting of:

[0127]

[0128]

[0129] wherein:

[0130] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), and ethynyl;

[0131] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0132] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3;

[0133] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds. Options and substituent combinations discussed above for Ri, R2, R3, R4 and R5 and Y in the context of general formula (I) are equally suited in the context of embodiments discussed here.In some embodiments of the invention, the compound according to the first aspect of the invention is compound selected from the group consisting of:

[0134]

[0135] wherein:

[0136] Ri, and R2 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0137] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selectedfrom the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3;

[0138] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds. Options and substituent combinations discussed above for Ri and R2 and Y in the context of general formula (I) are equally suited in the context of embodiments discussed here.

[0139] In some embodiments of the invention, the compound according to the first aspect of the invention is compound selected from the group consisting of:

[0140]

[0141]

[0142]

[0143]

[0144]

[0145] wherein:

[0146] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3;

[0147] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds. Specific options and substituent combinations discussed above for Y in the context of general formula (I) are equally suited in the context of embodiments discussed here.

[0148] In some embodiments of the invention, the compound according to the first aspect of the invention is compound selected from the group consisting of:

[0149]

[0150] wherein:

[0151] Z is selected from

[0152]

[0153] wherein:

[0154] Re is selected from unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl; and

[0155] Raand Rb are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, or Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused, bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferablyselected from F and Cl), hydroxyl, oxo, and options provided above for Re (e.g. Raand Rb may form together with the nitrogen in between a substituted or unsubstituted 4-membered, 5-membered or 6-membered heterocycloalkyl), preferably wherein Raand Rb each independently selected from H, methyl and ethyl, more preferably wherein Raand / or Rb are H, and most preferably Raand Rb are both H;

[0156] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds. Specific options and substituent combinations discussed above for Z in the context of general formula (I) are equally suited in the context of embodiments discussed here.

[0157] In some embodiments of the invention, the compound according to the first aspect of the invention is compound selected from the group consisting of:

[0158]

[0159]

[0160] wherein:

[0161] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0162] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0163] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds. Specific options and substituent combinations discussed above for X (including options and substituent combinations discussed above for Ri, R2, R3, R4 and R5) in the context of general formula I are equally suited in the context of embodiments discussed here.In some embodiments of the invention, the compound according to the first aspect of the invention is compound selected from the group consisting of:

[0164]

[0165] wherein:

[0166] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;R? is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0167] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)- or (S)-enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds. Specific options and substituent combinations discussed above for X (including options and substituent combinations discussed above for Ri and R2) in the context of general formula (I) are equally suited in the context of embodiments discussed here.

[0168] Preferred examples of compounds according to formula (I) are selected from the group consisting of the following compounds:

[0169]

[0170]

[0171]

[0172]

[0173]

[0174] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any of the above-mentioned compounds.

[0175] Preferably, the compound of formula (I) is not a compound of the following structure:

[0176]

[0177] In some embodiments of the invention, compounds of formula (I) are preferred, wherein one or more H atoms are replaced by D (deuterium). Alternatively, one or more H atoms may be replaced by T (tritium).In embodiments where the compound according to the present invention is a pharmaceutically acceptable salt, the pharmaceutically acceptable salt is preferably a salt formed with an inorganic or organic acid. Pharmaceutically acceptable salts of a compound according to the invention may be salts of the compounds according to the first aspect of the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, p-toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic 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, formiates and trifluoroacetates.

[0178] A compound according to the first aspect of the invention is capable of inhibiting extrasynaptic toxic NMDA receptor activity. Suitable tests for assessing NMDA receptor activity have been disclosed in the prior art. A preferred test of assessing inhibition of extrasynaptic toxic NMDA receptor activity is to study said activity in primary neuronal cultures as set out further down below. Preferably, a compound according to the present invention achieves at a concentration of 10 pM least the same level of inhibitory activity (i.e. the same index rating) as (2-aminoethyl)[(3-chlorophenyl)methyl]ethylamine (compound P401 of WO 2020 / 079244) at 10 pM. Preferably, the inhibitory activity is even greater than the one of compound P401. This is in particular the case where a compound of the first aspect of the invention achieves the same inhibitory activity at a lower concentration than compound P401 (e.g. at 3.0 pM or lower, e.g. at a concentration of 1.0 pM, 0.3 pM, 0.1 pM, or even 0.03 pM). It is also preferred if a compound according to the first aspect of the invention interferes with NMDA receptor / TRPM4 complex formation. A suitable method to assess the capability of disrupting the complex is the co-immunoprecipitation and Western Blot detection method is disclosed in WO 2023 / 203254.

[0179] A compound according to the present invention may be part of a composition according to the present invention. A composition according the present invention comprises at least one compound according to the first aspect of the invention and a suitable pharmaceutical carrier, excipient or diluent.

[0180] In a second aspect, the present invention relates to a compound for use in a method for treating or preventing a disease of the human or animal body, wherein the compound is a compound according the first aspect of the invention.In a third aspect, the present invention relates to a method of treating a disease in a subject, the method comprising administering an effective amount of a compound to a subject in need thereof, wherein the compound is a compound according the first aspect of the invention. As already mentioned above for the compounds according to the first aspect of the invention: In embodiments where the compound for use according to the second aspect of the invention or the compound to be used in the method of the third aspect of the invention is a pharmaceutically acceptable salt, then the pharmaceutically acceptable salt is preferably a salt formed with an inorganic or organic acid. Pharmaceutically acceptable salts of a compound according to the invention may be salts of the compounds according to the first aspect of the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, p-toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic 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, formiates and trifluoroacetates.

[0181] Compounds according to the first aspect of the invention or for use according to the second aspect of the invention or used in the context of the third aspect of the invention can be produced for example, and without being limited thereto, as set out in the examples and figures of the present application.

[0182] The disease to be treated according to the second or third aspect of the invention is preferably a neurological disease, in particular a neurodegenerative disease, or diseases potentially leading to or involving neurodegenerative events, for example infections leading to neurodegenerative events, in particular in the brain. The neurological or neurodegenerative disease may in some embodiments have an inflammatory component, i.e., is a neuroinflammatory disease. The neurodegenerative disease may by 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, post traumatic brain injury, absent-mindedness, age-related loss of memory, aging-related memory decline, progressive nuclear palsy, multiple sclerosis, thalamic degeneration, glutamate induced excitotoxicity, dystonia, epilepsy, optic nerve disease, diabetic retinopathy, glaucoma, pain, particularly neuropathic pain, anti-NMDA receptorencephalitis, dementia, such as post stroke dementia, HIV dementia, Creutzfeldt- Jakob dementia, dementia with Lewy bodies (DLB), dementia with degeneration of the frontal lobes including Pick's disease, dementia with corticobasal degeneration, vascular dementia, microangiopathy, Binswanger’s disease, cerebral ischemia, hypoxia, Parkinson's disease, Batten disease, schizophrenia, in particular schizophrenia with dementia, Korsakoff's psychosis, depression, cerebral malaria, toxoplasmosis (due to the risk of toxoplasmosis -associated brain damage), HIV infection / AIDS (due to the risk of HIV)-associated brain damage, and Zika virus infection (due to the possibility of Zika virus-associated brain damage), or any other viral infection potentially leading to neurodegenerative events and corresponding neuronal or brain damage, respectively, such as viral encephalopathy, viral meningitis or SARS-C0V2 virus induced encephalitis. In a further embodiment the disease may be a brain tumour, in particular a glioblastoma. Three papers published recently in Nature (see Barria, Nature, 2019, Vol 573 pages 499-501) show that glioblastoma cells express NMD A receptors and that their growth is enhanced / stimulated by the activation of NMD A receptors. Therefore, the growth of glioblastoma cells may be inhibited when NMD A receptor signalling is blocked, e.g. by compounds as described herein. In contrast thereto, conventional blockers of NMDA receptors cannot be used in this case because they interfere with the physiological role of NMDA receptors in normal synaptic transmission and cognitive functions such as memory. Due to the general relevance of extrasynaptic NMDA receptor signalling, the compounds disclosed herein are also suitable to treat diseases of the central nervous system such as states of anxiety, tension and depression, sexual dysfunction disorders, and sleep disorders. They may also be used for controlling pathological disturbances of the intake of food, stimulants and addictive substances. Particularyl preferred disease states to to be treated with the compounds according to the present inventiona are ALS, Alzheimer’s disease, Huntington’s disease, depression (such as treatment-resistant depression (TRD), major depressive disorder (MDD), juvenile depression or postpartum depression) and glaucoma. When the compound according to formula (I) is used to treat a disease, the compound will typically be administered as a monotherapy. However, the inventors also contemplate to administer the compound in combination with at least one further active substance. For example, in case the disease to be treated should be depression, then it would be possible to combine the compound for example with an antidepressant (e.g. SSRI or atypical antidepressant), a psychedelic drug, or esketamine. A combination of a compound according to formula (I) with esketamine is particularly preferred. The at least onefurther active substance may be administered prior, in parallel to or after the compound is administered to the patient in need thereof.

[0183] Typically, the method of treatment (in the context of the second or third aspect of the invention) will focus on stopping or slowing down the progression of the disorder. In the alternative, such compound can also be administered in a preventive manner, e.g. in situations where the subject is at (an increased) risk of suffering from a neurological and / or neurodegenerative disease. This includes an acute (increase in) risk (e.g. a thrombotic stroke after surgery) as well as a continuous risk (e.g. due to a genetic and / or familial predisposition for a given neurological and / or neurodegenerative disorder).

[0184] The subject to be treated is preferably a mammal, preferably selected from the group consisting of human, mouse, rat, dog, cat, cow, monkey, horse, hamster, guinea pig, pig, sheep, goat, rabbit etc. Most preferably, the subject is a human being.

[0185] For the purposes of the second and third aspect of the invention, the person skilled in the art will be readily capable of selecting an appropriate route of administration, depending on the specific disease to be treated or prevented and / or body part to be treated. The route of administration may be, for example, oral, topical, intranasal, parenteral, intravenous, rectal, pulmonal, sublingual, lingual, buccal, transdermal, conjunctival or any other route of administration suitable in the specific context. The compound can also be administered by using an implant releasing the compound over time. For example, if the disease is a cerebrovascular disease, e.g. stroke, then intranasal administration is a preferred route of administration. Intranasal administration is known to the skilled person as being particularly suitable for administering neuroprotective compounds in general, for example in the context of treatment of stroke and stroke induced brain damage. For oral administration, known forms of administration that deliver the active substance rapidly and / or in a modified form are suitable, such as tablets (uncoated and coated tablets, e.g. tablets with enteric coatings or film-coated tablets), capsules, granules, pellets, powders, emulsions, suspensions, solutions and aerosols. Parenteral administration can be carried out bypassing a resorption step (intravenous, intra-arterial, intra-cardiac, intraspinal or intralumbar) or involving resorption (intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). For parenteral administration, suitable forms of administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates and sterile powders. For the other routes of administration, suitable forms include inhalation medicines (e.g. powder inhalers,nebulisers), 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, powder or implants such as stents. The active substances can be transferred to the above-mentioned forms of application in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients. These include excipients (e.g. microcrystalline cellulose), solvents (e.g. polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulphate), dispersants (e.g. polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), stabilisers (e.g. antioxidants such as ascorbic acid), colourants (e.g. inorganic pigments such as iron oxides) or taste and / or odour correctors. The active ingredient may also be present in microencapsulated form in one or more of the excipients listed above, if desired. In general, in both human and veterinary medicine, it has been found advantageous to administer the active ingredient of the invention in total amounts of about 0.001 preferably up to about 60, 0.001 up to 40 mg / kg body weight per 24 hours, optionally in the form of several single administrations, to achieve the desired results. A single dose preferably contains the active ingredient of the invention in amounts of about 0.001 to about 30, in particular 0.001 to 20 mg / kg body weight.

[0186] In a further, fourth aspect, the present invention relates to a a compound selected from the group consisting of:

[0187]

[0188]

[0189] In a fifth aspect, the present invention relates to a compound selected from the group consisting of:

[0190]

[0191]

[0192] wherein:

[0193] X is selected from

[0194]

[0195] wherein:

[0196] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0197] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F; and is most preferably H;

[0198] Y is selected from the group consisting of (CFDn, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7 is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S, and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3; and

[0199] Re is selected from unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0200] These compounds according to the fifth aspect of the invention are direct precursors in the production of inventive compounds according to the first aspect of the invention and be used to produce the same. Therefore, specific options and substituent combinations discussed above for X (including options and substituent combinations discussed above for Ri, R2, R3,R4 and R5) or Y in the context of general formula (I) are equally suited in the context of the intermediated compounds discussed here. In the examples section of the present invention, various direct precursors in the synthesis of a compound according to the first aspect of the invention or of a compound for use according to the second or third aspect of the invention are illustrated in more detail. All these intermediates are specifically contemplated as preferred embodiments of the fifth aspect of the present invention.

[0201] In a sixth aspect, the present invention relates to a compound according to the following general formula I:

[0202]

[0203] wherein:

[0204] X is selected from Ar or Het,

[0205] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3;

[0206]

[0207]

[0208] wherein:

[0209] Re is selected from hydrogen, Aik, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl; and

[0210] Raand Rb are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, or Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused, bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), hydroxyl, oxo, and options provided above for Re (e.g. Raand Rb may form together with the nitrogen in between a substituted or unsubstituted 4-membered, 5-membered or 6-membered heterocycloalkyl);

[0211] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)- or (S)-enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any one of the above-mentioned compounds of the sixth aspect.Specific options and substituent combinations discussed above in the context of compounds according to the first aspect of the invention for X (including options and substituent combinations discussed above for Ri, R2, R3, R4 and R5), Y or Z (including options and substituent combinations discussed above for Re, Ra, Rb) in the context of general formula (I) are specifically contemplated by the inventors to be equally suited in the context of compounds according to the sixth aspect of the invention.

[0212] In a seventh aspect, the present invention relates to further intermediate compounds for synthesis of compounds to the first aspect of the invention (for example a compound as set out in general in the synthesis schemes illustrated in the figures) but not yet reflected by any of the other aspects of the present invention. In this context, the present invention relates to a compound according to the following general formula

[0213]

[0214] wherein:

[0215] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0216] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F; and

[0217] Y is selected from the group consisting of linear (CFDn, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3.

[0218] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0219]

[0220] wherein:

[0221] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl; and

[0222] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3.

[0223] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0224]

[0225] wherein:

[0226] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0227] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0228] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, andX is selected from COOH, CONH2, CO(NHOH) and CON3.

[0229] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0230]

[0231] wherein:

[0232] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0233] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and.

[0234] X is selected from COOH, CONH2, CO(NHOH) and CON3.

[0235] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0236]

[0237] wherein:

[0238] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;Ra is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F; and

[0239] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3.

[0240] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0241]

[0242] wherein:

[0243] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl; and

[0244] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3.

[0245] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0246]

[0247] wherein:Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0248] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0249] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0250] Re is selected from hydrogen, unsubstituted branched or linear C2-Ce alkyl, substituted branched or linear C2-Ce alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7alkylcycloalkyl, substituted C4-C7alkylcycloalkyl, unsubstituted C3-C6 alkenyl, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0251] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0252]

[0253] wherein:

[0254] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0255] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, andRe is selected from hydrogen, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0256] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0257]

[0258] wherein:

[0259] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0260] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0261] Y is selected from the group consisting of linear (CFDn, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0262] Re is selected from hydrogen, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0263] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0264]

[0265] wherein:

[0266] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0267] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0268] Re is selected from hydrogen, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0269] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0270]

[0271] wherein:

[0272] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;Ra is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0273] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3,

[0274] Re is selected from hydrogen, unsubstituted branched or linear C2-Ce alkyl, substituted branched or linear C2-Ce alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7alkylcycloalkyl, substituted C4-C7alkylcycloalkyl, unsubstituted C3-C6 alkenyl, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl, and

[0275] Hal is selected from F, Cl, Br, and I, preferably selected from F and Cl.

[0276] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0277]

[0278] wherein:

[0279] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0280] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3,

[0281] Re is selected from hydrogen, unsubstituted branched or linear C2-Ce alkyl, substituted branched or linear C2-Ce 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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl, and

[0282] Hal is selected from F, Cl, Br, and I, preferably selected from F and Cl.

[0283] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0284]

[0285] wherein:

[0286] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0287] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0288] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0289] Re is selected from hydrogen, unsubstituted branched or linear C2-Ce alkyl, substituted branched or linear C2-Ce 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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0290] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0291]

[0292] wherein:

[0293] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0294] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0295] Re is selected from hydrogen, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0296] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0297]

[0298] wherein:

[0299] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;Ra is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0300] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0301] Re is selected from hydrogen, unsubstituted branched or linear C2-Ce alkyl, substituted branched or linear C2-Ce alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7alkylcycloalkyl, substituted C4-C7alkylcycloalkyl, unsubstituted C3-C6 alkenyl, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0302] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0303]

[0304] wherein:

[0305] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0306] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0307] Re is selected from hydrogen, unsubstituted branched or linear C2-Ce alkyl, substituted branched or linear C2-Ce alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0308] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0309]

[0310] wherein:

[0311] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0312] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0313] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0314] Re is selected from hydrogen, unsubstituted branched or linear C2-Ce alkyl, substituted branched or linear C2-Ce alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7alkylcycloalkyl, substituted C4-C7alkylcycloalkyl, unsubstituted C3-C6 alkenyl, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0315] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0316]

[0317] wherein:

[0318] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0319] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0320] Re is selected from hydrogen, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0321] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0322]

[0323] wherein:

[0324] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;Ra is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0325] Y is selected from the group consisting of linear (CFDn, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0326] Re is selected from hydrogen, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0327] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0328]

[0329] wherein:

[0330] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0331] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0332] Re is selected from hydrogen, unsubstituted branched or linear C2-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-C7alkylcycloalkyl, substituted C4-C7 alkylcycloalkyl, unsubstituted C3-C6 alkenyl, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0333] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0334]

[0335] wherein:

[0336] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0337] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0338] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0339] Re is selected from hydrogen, unsubstituted branched or linear C2-Ce alkyl, substituted branched or linear C2-Ce alkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C4-C8 bicycloalkyl, substituted C4-C8 bicycloalkyl, unsubstituted C4-C7alkylcycloalkyl, substituted C4-C7alkylcycloalkyl, unsubstituted C3-C6 alkenyl, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0340] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0341]

[0342] wherein:

[0343] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0344] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3, and

[0345] Re is selected from hydrogen, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

[0346] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0347]

[0348] wherein:

[0349] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;Ra is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F; and

[0350] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3.

[0351] In another embodiment of the seventh aspect of the invention, the present invention relates to a compound according to the following general formula

[0352]

[0353] wherein:

[0354] Ri and R2, are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl; and

[0355] Y is selected from the group consisting of linear (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3.

[0356] For each of the above mentioned embodiments of the seventh aspect of the invention the inventors consider the specific options and substituent combinations discussed further above in the context of compounds according to the first aspect of the invention for Ri, R2, R3, R4, Rs, Y or Re, in the context of general formula (I), to be equally suited in the context of compounds according to the seventh aspect of the invention and Ri, R2, R3, R4, Rs, Y or Re of formulas (II B), (II B’), (II C), (II C’), (II D), (II L), (II N), (II N’), (II O), (II O’), (II P), (II P’), (II Q), (II Q’), (II R), (II R’), (II S), (II S’), (II V), (II V’), (II W), (II W’), (II Ya) and (II Ya’), respectively.In an eighth aspect, the present invention relates to a compound for use in a method of treating or preventing a disease of the human or animal body, wherein the disease is selected from treatment-resistant depression (TRD), major depressive disorder (MDD), juvenile depression and postpartum depression, wherein the compound is a compound according to the following general formula (III):

[0357]

[0358] wherein:

[0359] Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;

[0360] R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;

[0361]

[0362]

[0363] wherein:

[0364] Re is selected from hydrogen, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl; and

[0365] Raand Rb are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, or Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused, bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), hydroxyl, oxo, and options provided above for Re (e.g. Raand Rb may form together with the nitrogen in between a substituted or unsubstituted 4-membered, 5-membered or 6-membered heterocycloalkyl);

[0366] either i) at least one of Rs and R9 is H, while the other is selected from the group consisting of H, unsubstituted branched or linear C1-C4 alkyl, fluoro-substituted branched or linear C1-C4 alkyl, unsubstituted propenyl, unsubstituted C3-C6 cycloalkyl, and fluorosubstituted C3-C6 cycloalkyl; or ii) Rs and R9 taken together with the carbon atom to which they are attached represent a 3-7 membered monocyclic saturated ring, optionally containingone heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from methyl, methylene, halogen (selected from F, Cl, Br, and I, preferably F), O and hydroxy,

[0367] or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof. Most preferred is a pharmaceutically acceptable salt of any one of the above-mentioned compounds.

[0368] In a preferred embodiment of the eighth aspect of the invention, Rs and R9 taken together with the carbon atom to which they are attached form a ring to yield a compound according to formula (I) of the invention. Preferably, the compound for use according to the eighth aspect of the invention is thus a compound according to the first aspect of the present invention.

[0369] The disease to be treated according to the eighth aspect of the invention can be treatmentresistant depression (TRD). As used herein, the term "treatment-resistant depression" and the abbreviation "TRD" shall be defined as depressive disorder, in particular a major depressive disorder, in a patient that does not respond adequately to at least one, preferably at least two different antidepressants, preferably between two and five antidepressants, in the current depressive episode. In other embodiments, TRD is defined as (e.g. major) depressive disorder in a patient that has not responded to at least one, preferably at least two different oral antidepressants of adequate dose and duration in the current depressive episode. One skilled in the art will recognize that the failure to respond to an adequate course of a given antidepressant may be determined retrospectively or prospectively. In an embodiment, at least one of the failures to respond to an adequate course of antidepressant is determined prospectively. In another embodiment, at least two of the failures to respond to an adequate course of antidepressant are determined prospectively. In another embodiment, at least one of the failures to respond to an adequate course of antidepressant is determined retrospectively. In another embodiment, at least two of the failures to respond to an adequate course of antidepressant are determined retrospectively in a current depressive episode. The "at least one (e.g. oral) antidepressant" or "at least two different (e.g. oral) antidepressants" has been administered to the patient at an adequate dose which may be determined by the attending physician. Similarly, the antidepressant has been administered for a suitable duration, asdetermined by the attending physician. Preferably, the antidepressant is selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI), a serotoninnorepinephrine reuptake inhibitor (SNRIs), a tricyclic antidepressant (TCA), a monoamine oxidase inhibitors (MAOI), an atypical antidepressant, a psychedelic drug, a selective 5HT receptor agonist and esketamine. In one embodiment the patient does not respond adequately to a treatment with a selective serotonin reuptake inhibitor (SSRI) in the current depressive episode, in particular not to an SSRI selected from the group consisting of fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro), and paroxetine (Paxil). In one embodiment the patient does not respond adequately to a treatment with a serotonin-norepinephrine reuptake inhibitor (SNRI) in the current depressive episode, in particular not to an SNRI selected from the group consisting of venlafaxine (Effexor), duloxetine (Cymbalta) and des venlafaxine (Pristiq). In one embodiment the patient does not respond adequately to a treatment with a tricyclic antidepressant (TCA) in the current depressive episode, in particular not to a TCA selected from the group consisting of amitriptyline, nortriptyline (Pamelor) and imipramine. In one embodiment the patient does not respond adequately to a treatment with a monoamine oxidase inhibitors (MAOI) in the current depressive episode, in particular not to a MAOI selected from the group consisting of phenelzine (Nardil) and tranylcypromine (Parnate). In one embodiment the patient does not respond adequately to a treatment with an atypical antidepressant in the current depressive episode, in particular not to an atypical antidepressant selected from the group consisting of bupropion (Wellbutrin), mirtazapine (Remeron), and trazodone. In one embodiment the patient does not respond adequately to a treatment with a psychedelic drug in the current depressive episode. In one embodiment the patient does not respond adequately to a treatment with a selective 5HT receptor agonist in the current depressive episode. In one embodiment the patient does not respond adequately to a treatment with esketamine in the current depressive episode.

[0370] Preferably, treatment according to the eighth aspect of the invention comprises administering the compound orally to the subject in need thereof. The method of treatment may involve administering the compound as monotherapy. However, the inventors also contemplate administering the compound in combination with at least one further active substance such as an antidepressant. Preferably, the antidepressant is selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRIs), a tricyclic antidepressant (TCA), a monoamine oxidase inhibitors(MAOI), an atypical antidepressant, a psychedelic drug, a selective 5HT receptor agonist and esketamine. Preferably, the SSRI is selected from the group consisting of fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro), and paroxetine (Paxil). Preferably, the SNRI is selected from the group consisting of venlafaxine (Effexor), duloxetine (Cymbalta) and des venlafaxine (Pristiq). Preferably, the TCA is selected from the group consisting of amitriptyline, nortriptyline (Pamelor) and imipramine. Preferably, the MAOI is selected from the group consisting of phenelzine (Nardil) and tranylcypromine (Parnate). Preferably, the atypical antidepressant is selected from the group consisting of bupropion (Wellbutrin), mirtazapine (Remeron), and trazodone. A combination of a compound for use according to the eighth aspect of the invention with esketamine is particularly preferred. The at least one further active substance may be administered prior, in parallel to or after the compound of formula III is administered to the patient in need thereof.

[0371] In a ninth aspect, the present invention relates to a compound for use in a method of treating or preventing a disease of the human or animal body, wherein the disease is selected from treatment-resistant depression (TRD), major depressive disorder (MDD), juvenile depression and postpartum depression, and wherein the compound is capable to bind to NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site and is capable of dissociating the NMDAR / TRPM4 complex. As used herein, a compound is considered to be capable of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site if it can replace the [3H]TCP or similar radioligand for at least 30%, preferably at least 40%, even more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%. Preferably, said replacement of [3H]TCP or similar radioligand is achieved at a concentration of 10 pM or lower, even more preferably at a concentration of 1 pM or lower, even more preferably at a concentration of 100 nM or lower. Most preferably the compound achieves replacement of [3H]TCP or similar radioligand of at least 50% at a concentration of 100 nM. A method for assessing whether or not a compound is capable of binding to NMDA receptor is the [3H]TCP binding assay disclosed in the examples section of the present invention. As used herein, a compound is capable of dissociating the NMDAR / TRPM4 complex if it reduces the Glu2B-TRPM4 interaction by at least 15%, preferably at least 20%, even more preferably at least 30%, even more preferably at least 40% in a TRPM4 co-IP assay as disclosed in the examples section of the present invention as compared to a vehicle control. Preferably, said dissociation of the NMDAR / TRPM4 complex is achieved at a concentration of 10 pM or lower, even morepreferably at a concentration of 1 pM or lower, even more preferably at a concentration of 100 nM or lower. Most preferably the compound achieves a dissociation of the NMDAR / TRPM4 complex of at least 30% at a concentration of 100 nM.

[0372] In a tenth aspect, the present invention relates to a method of identifying a compound capable of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site and capable of dissociating the NMDAR / TRPM4 complex, wherein the method comprises one of the following steps:

[0373] a) determining for a compound known to be capable of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site its capability of dissociating the NMDAR / TRPM4 complex,

[0374] b) determining for a compound known to be capable of dissociating the NMDAR / TRPM4 complex its capability of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site, or

[0375] c) determining for a compound of interest i) its capability of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site and ii) its capability of dissociating the NMDAR / TRPM4 complex.

[0376] Determining the capability of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site can be done by way of an [3H]TCP binding assay as disclosed in the examples section of the present invention. As defined above, a compound is considered to be capable of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site if it can replace at least 30% of [3H]TCP. Determining the capability of dissociating the NMDAR / TRPM4 complex can be done by way of a co-IP assay as disclosed in the examples section of the present invention. As defined above, a compound is considered to be capable of dissociating the NMDAR / TRPM4 complex if it can reduce the total Glu2B-TRPM4 interaction in a co-IP assay by at least 15% as compared to a vehicle control. Compounds positively identified in the method of the tenth aspect of the invention as being capable of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site as well as capable of dissociating the NMDAR / TRPM4 complex can, for example, be used in the context of the ninth aspect of the invention for the treatment of treatment-resistant depression (TRD), major depressive disorder (MDD), juvenile depression and postpartum depression.The term "comprising", as used herein, shall not be construed as being limited to the meaning "consisting of" (i.e. excluding the presence of additional other matter). Rather, "comprising" implies that optionally additional matter may be present. The term "comprising" encompasses as particularly envisioned embodiments falling within its scope "consisting of" (i.e. excluding the presence of additional other matter) and "comprising but not consisting of" (i.e. requiring the presence of additional other matter), with the former being more preferred.

[0377] Figures

[0378] In the following a brief description of the appended figures will be given. The figures are intended to illustrate aspects of the present invention in more detail. However, they are not intended to limit the scope of the invention.

[0379] Fig. 1 provides a synthetic scheme (scheme 1) to illustrate synthesis of intermediate compounds useful for producing phenyl-based compounds according to the present invention (arylcyclobutylamines or derivatives thereof)

[0380] Fig. 2 A) provides a synthetic scheme (scheme 2) to illustrate synthesis of arylacetonitriles (educt for scheme 1). B) provides a synthetic scheme to illustrate synthesis of intermediate compounds useful for producing thiophene-based compounds according to the present invention (scheme 3).

[0381] Fig. 3 provides a synthetic scheme to illustrate synthesis of compounds according to the present invention (amines) and intermediates thereof (scheme 4).

[0382] Fig. 4 provides a synthetic scheme to illustrate synthesis of compounds according to the present invention (aminoacetamides; scheme 5).

[0383] Fig. 5 provides a synthetic scheme to illustrate synthesis of 3 -aminopiperidine- and 2- aminomethylpyrrolidine compounds according to the present invention (scheme 6).

[0384] Fig. 6 provides an analysis of RNA-binding protein with multiple splicing (RBPMS) in flat mount retina using a representative compound according to the present invention,which is disclosed in this application and abbreviated for the purpose here “REP- CPD” in a mouse model of retinal ganglion cell (RGC) degeneration. N = 12 mice per group and results were expressed as mean ± SEM. Statistical analysis was performed using one-way ANOVA followed by post-hoc Dunnett’s test. ** P < 0.01, **** P < 0.0001. mpk: mg / kg BID: bidaily administration.

[0385] Fig. 7 illustrates the effects of REP-CPD on immobility time in a forced swim test (FST) depression model. Mice were administered either vehicle (Naive), ketamine (20 mg / kg, i.p.; positive control), or REP-CPD orally at 0.5, 1.5, or 5.0 mg / kg. Immobility time (in seconds) was measured as an indicator of antidepressant- like behavior. Ketamine, serving as the gold standard positive control, and REP-CPD at 1.5 mg / kg and 5 mg / kg significantly reduced immobility compared to the Vehicle group. N = 20 mice per group and data are shown as mean + SEM with individual values overlaid. Statistical analysis was performed using one-way ANOVA followed by Dunnett’s post hoc comparisons (*p < 0.05; ***p < 0.0001).

[0386] Fig. 8 illustrates the effects of REP-CPD in three different tests in a chronic unpredicted mild stress (CUMS) depression model. Mice were administered either vehicle (Naive), ketamine (20 mg / kg, i.p.; positive control), or REP-CPD orally at 2.0 or 5.0 mg / kg. A) Immobility time (in seconds) was measured as an indicator of antidepressant-like behavior. Ketamine served as the gold standard positive control. N = 12 mice per group and data are shown as mean + SEM with individual values overlaid. Statistical analysis was performed using one-way ANOVA followed by Sidak’s post hoc comparisons (*p < 0.05; ****p < 0.0001). B) Center entries were measured during the open field test (OFT) as an index of exploratory behavior and anxiety- like responses. N = 12 mice per group and data are shown as mean + SEM with individual values plotted. Statistical comparisons were made using ANOVA followed by Sidak’s post hoc comparisons (*ns = not significant; ***p < 0.001; ****p < 0.0001). C) The sucrose preference ratio was calculated as an indicator of anhedonia-like behaviour (sucrose preference test, SPT). N = 12 mice per group and data are presented as mean + SEM with individual values overlaid. Statistical comparisons were performed using ANOVA followed by Sidak’s post hoc comparisons (*p < 0.05; **p < 0.01; ***p < 0.0001).Fig. 9 illustrates the effects of REP-CPD on motor coordination and balance in the rotarod test. Mice were treated with ketamine (20mg / kg, i.p.) or REP-CPD orally at 1.5, 5, 7.5, or lOmg / kg. First latency to fall (in seconds) was measured using the accelerating rotarod test as an indicator of motor coordination. N = 12 per goup, data are shown as mean ± SEM with individual values overlaid. Statistical significance was assessed using ANOVA followed by Dunnett’s post hoc comparisons (**p < 0.01; ***p < 0.0001).

[0387] Fig. 10 shows the dose-dependent disruption of NMDAR / TRPM4 interaction by REP-CPD in mouse cortex tissue. TRPM4 was immunoprecipitated from mouse cortex lysates were treated with increasing concentrations of REP-CPD, or fixed concentrations of typical NMD AR antagonists memantine or MK-801. Co-immunoprecipitated GluN2B (subunit of NMDAR) was detected by immunoblotting, and the GluN2B / TRPM4 ratio was quantified in comparison to the vehicle control (dashed line). Data represent mean ± SD from n = 3 independent experiments.

[0388] Fig. 11 illustrates that REP-CPD inhibits [3H]TCP binding in a concentration-dependent manner. Membrane preparations were incubated with 6.5 nM [3H]TCP in the presence of increasing concentrations of REP-CPD. Binding was measured and expressed as percentage inhibition relative to control (no compound). The inhibition curve was fitted using nonlinear regression, yielding an EC so value of 23 nM. Data represent mean ± SEM from n = 1 independent experiments performed in duplicate.

[0389] Fig. 12 shows that a low dose of REP-CPD renders non-effective ketamine efficacious in a FST test. Mice were treated with ketamine (1, 2, or 20 mg / kg, i.p.), REP-CPD (0.5 mg / kg), or the combination (ketamine at 1 mg / kg, i.p. and REP-CPD at 0.5 mg / kg, PO). Data are expressed as mean ± SD. n = 12-28 per group. *p < 0.05, ****p < 0.0001 versus vehicle; One-way ANOVA followed by LSD post hoc test.

[0390] Examples

[0391] In the following, specific examples illustrating embodiments and aspects of the invention are presented. However, the present invention shall not to be limited in scope by the specificexamples described herein. Indeed, various modifications of the invention in addition to those described herein will become readily apparent to those skilled in the art from the foregoing description and the example below. All such modifications fall within the scope of the appended claims.

[0392] Example 1: General synthetic schemes

[0393] Compounds used in the context of the present invention for attenuation of extrasynaptic toxic NMD A receptor activity have been prepared in general as follows.

[0394] WO 2022 / 063767 describes compounds like A-[(pyrrolidin-2-yl)methyl]-l-[3-(trifhioromethyl)phenyl]cyclobutan-l-amine as potassium channel inhibitors. (l-(3-Bromo-2-fhiorophenyl)cyclobutanamine: CAS 1314744-00-7 ; l-(3-Chloro-2-fluorophenyl) cyclobutanamine: CAS1314765-37-1, Hydrochloride : CAS2095319-36-9).

[0395] The synthesis of intermediate arylcyclobutanamines is illustrated in scheme 1 (Fig. 1). Briefly, arylcyclobutanamines or derivatives D can be synthesized from known arylacetonitriles A by cyclisation with dihalo-compounds like 1,3-dibromopropane, saponification of the nitrile B to the carboxylic acid Ca or amide Cb and subsequent Curtins or Hofmann degradation resp. Use of dihalogenated alkanes like l,3-dibromo-2-methyl-propane (CAS28148-04-1), 1,4-dibromobutane or 1,5-dibromopentane instead of 1,3-dibromopropane leads to the corresponding 1- aryl-3-methyl-cyclobutane-l -carbonitrile, 1-aryl-cyclopentanecarbonitrile (see for example Chi, H. et al., Science (2019), 21, 650) or 1-arylcyclohexanecarbonitrile.

[0396] The carboxylic acid azides Cd required as starting materials for the Curtins reaction are usually synthesized from carboxylic acids Ca or carboxylic acid derivatives (carboxylic acid chlorides or carboxylic acid hydrazides). Alternatively, carboxylic acid azides Cd can be obtained by reacting the carboxylic acid with diphenylphosphoryl azide (DPPA) or with ethyl chloroformate via a mixed anhydride. Carboxylic acids Ca can also be converted to hydroxamic acids Cc using e.g., hydroxylamine hydrochloride, BOP / DIEA / DMF which subsequently can be converted into amines D via isocyanates by a Lossen-degradation using e.g., K2CO3 / DMSO and BOC2O followed by HCl / EtOAc. WO 2017 / 065473 describes the synthesis of l-(3-chloro-2-fluorophenyl)cyclobutanamine which is representative for a general access.In case of substituted arylcyclobutanamines and starting from arylacetonitriles A, epichlorohydrine or epibromohydrine can be used as cyclisation reagent to give l-aryl-3-hydroxycyclobutane- 1 -carbonitrile Bb. This can be fluorinated by DAST / DCM or other fluorinating agents to the l-aryl-3-fluorocyclobutane-l -carbonitrile Bd.

[0397] On the other hand, l-aryl-3-hydroxycyclobutane-l -carbonitrile Bb can be oxidized to the corresponding ketone Be which can be converted by DAST / DCM or other fluorinating agents to the l-aryl-3,3-difhiorocyclobutane-l-carbonitrile Be. Reaction of Be with methylenating reagents like e.g., methylenetriphenylphosphorane, which can be made from the precursor Ph3PCH3Br with strong bases like KOtBut, leads to methylene-derivative Bi.

[0398] Another route to amines D starts with ortho-metalation of appropriately substituted benzenes E, reaction with t-butylsulfinamides of structure (I) and hydrolysis to the free amine D by using acids like HC1 in EtOAc. For example, arylcyclobutanamines Da can be prepared using A-cyclobutylidene-2-methyl-2-propanesulfinamide (CAS 1191456-53-7) or its enantiomers. In close analogy, compounds Df (like e.g., 3-(3-bromo-2-fluorophenyl)oxetan-3-amine (CAS2153897-77-7)) can be prepared according to a sequence described in WO2012078545 using 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (CAS1158098-73-7).

[0399] An alternative route for the preparation of arylacetonitriles A is illustrated in scheme 2 (Fig. 2). Briefly, arylacetonitriles A can be prepared from arylmethanols H by cyanation e.g. with acetonecyanhydrine, n-Bu3P / ADDP in THF. Arylacetonitriles A can also be prepared from toluenes F, converting them into benzylhalogenides G using halogenating reagents like NBS in solvents like MeCN followed by cyanation using cyanating reagents like TMSCN / TBAF in solvents like MeCN.

[0400] The methods described above can be equally used for the preparation of thiophene derivatives L (see scheme 3, Fig. 2). The corresponding thiophen-2-yl)cyclobutan- 1 -amines can be prepared in an analogous manner. The synthesis of 4-bromo-3-fluoro-2-thiophenemethanol (CAS 1628447-67-5) is described in WO 2014 / 140078.

[0401] Starting from amines D (see product of scheme 1), compounds of general structure (I) and N (see scheme 4, Fig. 3) can be synthesized by consecutive reductive aminations and / or alkylations similar to those described in WO 2023 / 203254. Amines N can be reacted with halogenoacetamide like e.g. bromoacetamide in solvents like MeCN, butyronitrile, DMF,DMAC, TAME in the presence of a base like potash, soda, TEA or DIPEA to give substituted aminoacetamides O which can be reduced by appropriate reduction reagents like LiAlH4, BH3*Me2S, BH3*THF in solvents like THF or 2-methyl-THF to the desired compound (I).

[0402] Another route goes by reacting amine N with haloacylhalides like bromoacetylbromide or chloroacetylchloride to give haloacetamides P. These can be aminated either by using potassiumphthalamide yielding protected amines V that can be deprotected to give substituted aminoacetamides T with hydrazine hydrate or methylamine in methanol, ethanol and / or water or using NaBH4 / 2 -propanol, then acetic acid (J. O. Osby, M. G. Martin, B. Ganem, Tetrahedron Lett., 1984, 25, 2093-2096). Haloacetamides P can also be converted to the corresponding azidoacetamides Q using sodiumazide in DMF or DMAC. Azides Q can then be reduced to acetamides T using triphenylphosphine in THF / water. These compounds T can be reduced by appropriate reduction reagents like LiAlH4, BH3*Me2S, BH3*THF in solvents like THF or 2-methyl-THF, to the desired compound (I). In some cases it can be necessary to introduce protecting groups like BOC (cpd. S) or trifluoroacetyl (cpd. R). These intermediates can be preferentially used for manipulations at groups R1-R5, Re and A. It is understood that while Fig. 1 illustrates synthesis routes for compounds according to formula la, such procedures can be used in analogous manner to generate thiophene compounds according to formula lb as used herein.

[0403] Aminoacetamides O (see scheme 5, Fig. 4) can be reacted with thiation reagents like Fa wesson's reagent to give thioamide W. This can be alkylated, for example with a methylating agent like MeBr, to give S-alkylthioamide X, which in turn can be reacted with ammonia or ammonium salts like ammoniumchloride to provide amidine (Ic).

[0404] To get compounds (I) with at least one of R1-R5 is cyano, at any step, exchange of Ri -R5, preferably if one of them is bromine or iodine, can be accomplished with cyananating agents like e.g., Zn(CN)2 and a system of catalyst, precatalyst and a ligand like Brettphos / Brettphos Pd G3 or Pdi(dba)3 (0.1 eq) and s-Phos in a solvent like DMF.

[0405] Reaction of 2-(3-bromopropyl)oxirane with amines D (see scheme 6, Fig. 5) gives piperidinealkoholes Ya, which in a Mitsunobu-reaction with phthalimide, DEAD, ADDP or DIAD and a phosphine like PPh3 or Bu3P can be converted to a mixture of phthalimido-piperidines Yb and phthalimido-pyrrolidines Zb. Removal of the protecting group with hydrazinegives the corresponding 3 -aminopiperidine- and 2-aminomethylpyrrolidine compounds Y and Z.Fluorinated compounds like fluorocyclobutyl-derivatives can be prepared either directly by performing reductive aminations with the appropriate 2-fluorocyclobutanones or 3-fluorocyclobutanones or by using hydroxy-cyclobutanones protected by groups like e.g., benzyl or nitrobenzoyl and converting the hydroxy-group or the the protected hydroxy group into the fluoro compound at a later step. Introduction of the 4-nitrobenzoylgroup via a Mitsunobu-Reaction (PPh3 / DEAD / THF) can give rise to the inversion of the stereochemistry at the respective carbon. Removal of the protecting group with TiC14 / DCM (benzyl) or ammonia / methanol (4-nitrobenzoyl) or other appropriate reagents liberates the free hydroxyfunction. By using fluorinating agents like DAST / DCM this can be converted to the fluoro-derivative.

[0406] Example 2: Synthesis of 5-(l-((2-aminoethyl)(propyl)amino)cyclobutyl)-4-fhiorothiophene -3-carbonitrile dihydrochloride (Compound 472)

[0407] 1) methyl 4-bromo-3-fluorothiophene-2-carboxylate

[0408]

[0409] To a solution of methyl 3-fluorothiophene-2-carboxylate (2.0 g, 12.5 mmol, 1.0 eq) in CHCh (15.0 mL) were added FeBn (369.1 mg, 1.3 mmol, 0.1 eq) and AlCh (10.0 g, 74.9 mmol, 6.0 eq). Then a solution of B (3.0 g, 18.7 mmol, 1.5 eq) in CHCh (5.0 mL) was added dropwise into the mixture. The reaction mixture was allowed to stir under N2 balloon at 20°C for 17 hr. TLC indicated reactant 1A was remained and two new spots formed. The reaction mixture was quenched by addition H2O 30.0 mL at 0°C, and then diluted with H2O 10.0 mL and extracted with DCM 90.0 mL (30.0 mL x 3). The combined organic layers were washed with sat. Na2SCh 30.0 mL (30.0 mL x 1) and brine 20.0 mL (20.0 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g, Eluent of 0~l% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give methyl 4-bromo-3-fluorothiophene-2-carboxylate (1.3 g, 5.3 mmol, 42.5% yield) as a white solid. ’H NMR (400 MHz, CHLOROEORM-d) 3 7.44 (d, J= 3.9 Hz, 1H), 3.93 (s, 3H).2) (4-bromo-3-fluorothiophen-2-yl)methanol

[0410]

[0411] To a solution of methyl 4-bromo-3-fluoro-thiophene-2-carboxylate (1.3 g, 5.3 mmol, 1.0 eq) in THF (15.0 mL) was degassed and purged with N2 for 3 times, and then added LiBH4 (2.0 M, 5.3 mL, 2.0 eq) in THF at 0°C. The mixture was stirred at 20°C for 12 hr under N2. TLC indicated reactant 1 was consumed completely and one new spot formed. The reaction mixture was quenched by addition sat.NH4Cl 20.0 mL at 0°C, and then extracted with ethyl acetate 60.0 mL (20.0 mL x 3). The combined organic layers were washed with sat. NaCl 20.0 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g, Eluent of 0~8% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give (4-bromo-3-fluorothiophen-2-yl)methanol (1.1 g, 5.2 mmol, 98.1% yield) as a colourless oil. ’H NMR (400 MHz, CHLOROFORM-d) 37.17 (d, J= 3.8 Hz, 1H), 4.85 - 4.76 (m, 2H), 1.88 - 1.77 (m, 1H).

[0412] 3) 2-(4-bromo-3-fluorothiophen-2-yl)acetonitrile

[0413]

[0414] To a solution of (4-bromo-3-fluoro-2-thienyl)methanol (1.0 g, 4.7 mmol, 1.0 eq) in THF (30.0 mL) was added 2-hydroxy-2-methyl-propanenitrile (725.8 mg, 8.5 mmol, 1.8 eq), tributylphosphane (1.7 g, 8.5 mmol, 1.8 eq) and ADDP (2.2 g, 8.5 mmol, 1.8 eq) at 0°C. The mixture was stirred at 20°C for 12 hr under N2. TLC indicated reactant 2 was consumed completely and one new spot formed. The reaction mixture was quenched by addition saturated sodium bicarbonate 15.0 mL at 20°C, and then extracted with ethyl acetate 30.0 mL (10.0 mL x 3). The combined organic layers were dried over NaiSCL, filtered and concentrated under reduced pressure to give a residue. The aqueous phase uses 20% sodiumhydroxide aqueous solution to adjust the system pH > 13. NaClO 20.0 mL was added to the aqueous phase mixture at 20°C for overnight. The residue was purified by flash silica gel chromatography (12 g Eluent of 0~8% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 2-(4-bromo-3-fluorothiophen-2-yl)acetonitrile (850.0 mg, 3.9 mmol, 81.5% yield) as a yellow oil. ’H NMR (400 MHz, CHLOROFORM-d) 37.21 (d, J= 4.0 Hz, 1H), 3.87 (d, J = 1.1 Hz, 2H).

[0415] 4) l-(4-bromo-3-fluorothiophen-2-yl)cyclobutane-l-carbonitrile

[0416]

[0417] 3 4

[0418] To a solution of 2-(4-bromo-3-fluoro-2-thienyl)acetonitrile (850.0 mg, 3.9 mmol, 1.0 eq) in Tol. (10.0 mL) and H2O (1.0 mL) was added 1,3-dibromopropane (779.8 mg, 3.9 mmol, 1.0 eq), KOH (1.1 g, 19.3 mmol, 5.0 eq) and TBAB (62.3 mg, 193.1 pmol, 0.05 eq). The mixture was stirred at 100 °C for 4hr. TLC indicated reactant 3 was consumed completely and one major new spot formed. The reaction mixture was diluted with H2O 15.0 mL and extracted with EtOAc 45.0 mL (15.0 mL x 3). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g, Eluent of 0~3% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to give l-(4-bromo-3-fluorothiophen-2-yl)cyclobutane-l-carbonitrile (364.0 mg, 1.4 mmol, 36.2% yield) as a yellow oil. ’H NMR (400 MHz, CHLOROFORM-d) 37.10 (d, J= 3.8 Hz, 1H), 2.86 - 2.77 (m, 2H), 2.69 - 2.58 (m, 2H), 2.32 (quind, J= 8.5, 11.7 Hz, 1H), 2.16 - 2.03 (m, 1H).

[0419] 5) l-(4-bromo-3-fluorothiophen-2-yl)cyclobutane-l-carboxylic acid

[0420]

[0421] 4 5To a solution of l-(4-bromo-3-fluoro-2-thienyl)cyclobutanecarbonitrile (364.0 mg, 1.4 mmol, 1.0 eq) in EtOH (4.0 mL) and H2O (4.0 mL) was added KOH (1.2 g, 21.0 mmol, 15.0 eq). The mixture was stirred at 100°C for 12 hr. LC-MS showed reactant 4 was consumed completely and 92.0% peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was acidified by HC1 (1.0 M) to adjust pH around 3, then extracted with EtOAc (25.0 mL x 2). The combined organic layers were washed with brine (25.0 mL), dried over NaiSO^ filtered and concentrated under reduced pressure to give compound l-(4-bromo-3-fluoro-2-thienyl)cyclobutanecarboxylic acid (370.0 mg, 1.3 mmol, 94.7% yield) as a yellow oil.

[0422] 6) l-(4-bromo-3-fluorothiophen-2-yl)cyclobutan-l -amine

[0423]

[0424] 5 6

[0425] A mixture of l-(4-bromo-3-fluoro-2-thienyl)cyclobutanecarboxylic acid (370.0 mg, 1.3 mmol, 1.0 eq), DPPA (547.2 mg, 2.0 mmol, 1.5 eq), and TEA (402.4 mg, 4.0 mmol, 3.0 eq) in DMF (7.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20°C for 2 hr under N2 atmosphere. HC1 (1.0 M, 8.0 mL, 6.0 eq) in H2O (3.5 mL) was added, after which the reaction mixture was stirred again at 100°C for 1 hr. LC-MS showed reactant 5 was consumed completely and 19.5% peak with desired m / z as detected. The reaction mixture was diluted with H2O 10.0 mL and extracted with EtOAc 15.0 mL. The aqueous phase was add sat. Na2COa (1.0 M) to adjust pH around 10, then extracted with EtOAc (15.0 mL x 2). The combined organic layers were washed with brine (10.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give l-(4-bromo-3-fluorothiophen-2-yl)cyclobutan-l-amine (230.0 mg, 919.5 pmol, 69.4% yield) as a yellow oil.7) 1 -(4-bromo-3-fluorothiophen-2-yl)-N-propylcyclobutan-l -amine

[0426]

[0427] To a solution of l-(4-bromo-3-fluoro-2-thienyl)cyclobutanamine (100.0 mg, 399.8 pmol, 1.0 eq) in MeOH (1.5 mL) was added AcOH (36.0 mg, 599.7 pmol, 1.5 eq), propanal (23.2 mg, 399.8 pmol, 1.0 eq) and NaBthCN (100.5 mg, 1.6 mmol, 4.0 eq). The mixture was stirred at 20°C for 12 hr. TLC indicated reactant 6 was consumed completely and two new spots formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 10.0 mL and extracted with EtOAc 45.0 mL (15.0 mL x 1). The combined organic layers dried over NaiSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate=3 / l) to give l-(4-bromo-3-fluorothiophen-2-yl)-N-propylcyclobutan-l-amine (40.0 mg, 136.9 pmol, 34.2% yield) as a yellow oil. ’H NMR (400 MHz, CHLOROFORM-d) 37.00 (d, J= 3.8 Hz, 1H), 2.48 - 2.35 (m, 2H), 2.28 (t, J= 7.3 Hz, 2H), 2.22 - 2.12 (m, 2H), 1.93 - 1.84 (m, 2H), 1.42 - 1.35 (m, 2H), 0.82 (t, 7 = 7.4 Hz, 3H).

[0428] 8) tert-butyl (2-((l-(4-bromo-3-fluorothiophen-2-yl)cyclobutyl)(propyl)amino)ethyl) carbamate

[0429]

[0430] To a solution of l-(4-bromo-3-fhioro-2-thienyl)-N-propyl-cyclobutanamine (40.0 mg, 136.9 pmol, 1.0 eq) in MeOH (1.0 mL) was added tert-butyl N-(2-oxoethyl)carbamate (65.4 mg, 410.7 pmol, 3.0 eq), AcOH (12.3 mg, 205.3 pmol, 1.5 eq) and NaBHaCN (34.4 mg, 547.6 pmol, 4.0 eq). The mixture was stirred at 60°C for 12 hr. LC-MS showed reactant 7 was consumed completely and 62.0% peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue waspurified by prep-TLC (S1O2, Petroleum ether / Ethyl acetate=3 / l) to give tert-butyl (2-((l-(4-bromo-3-fluorothiophen-2-yl)cyclobutyl)(propyl)amino)ethyl)carbamate (41.0 mg, 94.2 pmol, 68.8% yield) as a yellow oil.

[0431] 9) tert-butyl (2-((l-(4-cyano-3-fluorothiophen-2-yl)cyclobutyl)(propyl)amino)ethyl) carbamate

[0432]

[0433] A mixture of tert-butyl N-[2-[[l-(4-bromo-3-fluoro-2-thienyl)cyclobutyl]-propyl-amino] ethyl] carbamate (40.0 mg, 91.9 pmol, 1.0 eq), Zn(CN)2 (32.4 mg, 275.6 pmol, 3.0 eq), BrettPhos Pd G3 (8.3 mg, 9.2 pmol, 0.1 eq) and Brettphos (4.9 mg, 9.2 pmol, 0.1 eq) in DMF (3.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere. LC-MS showed reactant 8 was consumed completely and 2.8% peak with desired m / z was detected. The reaction mixture was quenched by addition saturated sodium bicarbonate 15.0 mL at 20°C, and then extracted with Ethyl acetate 30.0 mL (10.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate=3 / l) to give tert-butyl (2-((l-(4-cyano-3-fluorothiophen-2-yl)cyclobutyl)(propyl)amino)ethyl)carbamate (60.0 mg, 59.8 pmol, 65.1% yield, 38.0% purity) as a colourless oil.

[0434] 10) 5-(l-((2-aminoethyl)(propyl)amino)cyclobutyl)-4-fluorothiophene-3-carbonitrile dihydrochloride

[0435]

[0436] A solution of tert-butyl N-[2-[[l-(4-cyano-3-fluoro-2-thienyl)cyclobutyl]-propyl-amino] ethyl] carbamate (60.0 mg, 157.3 pmol, 1.0 eq) in 4M HCl / EtOAc (3.0 mL) was stirredat 20°C for 0.5 hr. LC-MS showed reactant 9 was consumed completely and 22% peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition; column: Phenomenex luna C18 100x40mmx5 um;mobile phase: [H20(0.04% HC1)-ACN]; gradient: l%-30% B over 8.0 min) to give 5-(l-((2-aminoethyl)(propyl)amino)cyclobutyl)-4-fluorothiophene-3-carbonitrile dihydrochloride (24.93 mg, 68.0 pmol, 43.2% yield, 96.6% purity, 2HC1) as a yellow oil. MS (ESI): m / z = 282.2 [M+H]+, retention time:0.936 min, method: B. ’H NMR (400 MHz, DMSO-t e) d 12.49 - 11.94 (m, 1H), 8.88 (br s, 1H), 8.52 (br s, 3H), 3.46 - 2.77 (m, 8H), 2.56 (br s, 2H), 1.93 - 1.61 (m, 4H), 0.87 (br t, J= 7.1 Hz, 3H).

[0437] Example 3: Synthesis of 5-(l-((2-aminoethyl)(cyclopropyl)amino)cyclobutyl)-4- fluorothio >hene-3-carbonitrile hydrochloride (Compound 473)

[0438] 1) 1 -(4-bromo-3-fluorothiophen-2-yl)-N-cyclopropylcyclobutan-l -amine

[0439]

[0440] 472 int.6 7

[0441] To a solution of l-(4-bromo-3-fhioro-2-thienyl)cyclobutanamine (130.0 mg, 519.7 pmol, 1.0 eq) in MeOH (2.0 mL) was added (l-ethoxycyclopropoxy)-trimethyl-silane (108.7 mg, 623.7 pmol, 125.4 pL, 1.2 eq), AcOH (46.8 mg, 779.6 pmol, 1.5 eq) and NaBHaCN (130.6 mg, 2.1 mmol, 4.0 eq). The mixture was stirred at 60°C for 12 hr. TLC indicated reactant 6 was consumed completely and two new spots formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 10.0 mL and extracted with EtOAc 45.0 mL (15.0 mL x 3). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate=5 / l) to give l-(4-bromo-3-fluorothiophen-2-yl)-N-cyclopropylcyclobutan-l-amine (47.0 mg, 162.0 pmol, 31.2% yield) as a yellow oil.2) tert-butyl (2-((l-(4-bromo-3-fluorothiophen-2-yl)cyclobutyl)(cyclopropyl)amino)ethyl) carbamate

[0442]

[0443] To a solution of l-(4-bromo-3-fluoro-2-thienyl)-N-cyclopropyl-cyclobutanamine (47.0 mg, 162.0 pmol, 1.0 eq) in MeOH (2.0 mL) was added tert-butyl N-(2-oxoethyl)carbamate (77.3 mg, 485.9 pmol, 3.0 eq), AcOH (14.6 mg, 242.9 pmol, 1.5 eq) and NaBPLCN (40.7 mg, 647.8 pmol, 4.0 eq). The mixture was stirred at 60°C for 12 hr. TLC indicated reactant 7 was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate=5 / l) to give tert-butyl (2-((l-(4-bromo-3-fluorothiophen-2-yl)cyclobutyl)(cyclopropyl)amino)ethyl)carbamat (37.0 mg, 85.4 pmol, 52.7% yield) as a white solid.

[0444] 3) tert-butyl (2-((l-(4-cyano-3-fluorothiophen-2-yl)cyclobutyl)(cyclopropyl)amino)ethyl) carbamate

[0445]

[0446] A mixture of tert-butyl N-[2-[[l-(4-bromo-3-fluoro-2-thienyl)cyclobutyl]-cyclopropyl-amino] ethyl] carbamate (30.0 mg, 69.2 pmol, 1.0 eq), Zn(CN)2 (24.4 mg, 207.7 pmol, 3.0 eq), BrettPhos (3.7 mg, 6.9 pmol, 0.1 eq) and BrettPhos Pd G3 (6.3 mg, 6.9 pmol, 0.1 eq) in DMF (3.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere. LC-MS showed reactant 8 was consumed completely and 3.1% peak with desired m / z was detected. The reaction mixture was quenched by addition saturated sodium bicarbonate 15.0 mL at 20°C, and then extracted with Ethyl acetate 30.0 mL (10.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered andconcentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiOi, Petroleum ether / Ethyl acetate=5 / l) to give tert-butyl (2-((l-(4-cyano-3-fluorothiophen-2-yl)cyclobutyl)(cyclopropyl)amino)ethyl)carbamate (26.0 mg, 68.5 pmol, 99.0% yield) as a white solid.

[0447] 4) 5-(l-((2-aminoethyl)(cyclopropyl)amino)cyclobutyl)-4-fluorothiophene-3-carbonitrile hydrochloride

[0448]

[0449] A solution of tert-butyl N-[2-[[l-(4-cyano-3-fluoro-2-thienyl)cyclobutyl]-cyclopropyl-amino] ethyl] carbamate (26.0 mg, 68.5 pmol, 1.0 eq) in 4M HCl / EtOAc (2.0 mL) was stirred at 20°C for 0.5 hr. LC-MS showed reactant 9 was consumed completely and 17.5% peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition; column: Phenomenex luna C18 100x40mmx5 um; mobile phase: [H20(0.04% HC1)-ACN]; gradient: l%-30% B over 8.0 min) to give 5-(l-((2-aminoethyl)(cyclopropyl)amino)cyclobutyl)-4-fluorothiophene-3-carbonitrile hydrochloride (11.95 mg, 35.79 pmol, 52.24% yield, 94.60% purity, HC1 salt) as a white solid. MS (ESI): m / z = 280.2 [M+H]+, retention time: 1.465 min, method: B.XH NMR (400 MHz, DMSO-t / d) d 8.80 (br s, 1H), 8.22 (br s, 3H), 3.33 - 2.69 (m, 8H), 1.82 - 1.56 (m, 3H), 1.12 - 0.82 (m, 2H), 0.67 (br s, 2H).

[0450] Example 4: Synthesis of 3-(l-((2-aminoethyl)(propyl)amino)cvclobutyl)-2- fluorobenzonitrile dihydrogen chloride (Compound 382)

[0451] 1) l-(3-bromo-2-fluorophenyl)cyclobutane-l-carbonitrile

[0452]

[0453] 1 2To a solution of 2-(3-bromo-2-fluoro-phenyl)acetonitrile (30.0 g, 140.0 mmol, 1.0 eq), 1,3-dibromopropane (29.7 g, 147.0 mmol, 1.05 eq) in Toluene (450.0 mL) and H2O (45.0 mL) was added KOH (39.3 g, 701.0 mmol, 5.0 eq) and TBAB (2.26 g, 7.0 mmol, 0.05 eq). The mixture was stirred at 100°C for 4 hrs (parallel in three batches). TLC indicated starting material was remained, and one major new spot with lower polarity was detected. The reaction mixture was concentrated under reduced pressure to remove Toluene. The reaction mixture was diluted with H2O (100.0 mL) and extracted with EtOAc (300.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product l-(3-bromo-2-fluorophenyl)cyclobutane-l-carbonitrile (100 g) as brown gum.

[0454] 2) l-(3-bromo-2-fluorophenyl)cyclobutane-l-carboxylic acid

[0455]

[0456] To a solution of l-(3-bromo-2-fhiorophenyl)cyclobutane-l -carbonitrile (33.3 g, 131.0 mmol, 1.0 eq) in EtOH (500.0 mL) and H2O (500.0 mL) was added NaOH (157.0 g, 3.9 mol, 30.0 eq) and KOH (221.0 g, 3.9 mol, 30.0 eq). The mixture was stirred at 110°C for 16 hrs (parallel in three batches). LC-MS showed -55% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove EtOH. Then the residue was diluted with H2O (500.0 mL) and extracted with EtOAc (500.0 mL x 3). Then combined organic layers were treated with con. HC1 to adjust pH~3, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (330 g SepaFlash® Silica Flash Column, Eluent of DCM @ 80 mL / min) to give l-(3-bromo-2-fluorophenyl)cyclobutane-l-carboxylic acid (50.0 g, 40.0% yield, 86.0% purity) as yellow solid.3) l-(3-bromo-2-fluorophenyl)cyclobutan-l -amine

[0457]

[0458] A mixture of l-(3-bromo-2-fluorophenyl)cyclobutane-l -carboxylic acid (10.0 g, 36.6 mmol, 1.0 eq), diphenylphosphoryl azide (DPPA) (12.1 g, 43.9 mmol, 9.5 mL, 1.2 eq) and TEA (11.1 g, 110.0 mmol, 15.3 mL, 3.0 eq) in DMF (200.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 3 hrs under N2 atmosphere. Then HC1 (1.0 M, 220.0 mL, 6.0 eq) was added dropwise to the above reaction mixture. After that, the reaction mixture was stirred at 100°C for 2 hrs (parallel in two batches). LC-MS showed starting material was consumed completely and -22% of desired compound was detected. The reaction mixture was diluted with H2O 100.0 mL and extracted with EtOAc (500.0 ml x 3). The aqueous phase was treated with sat. K2CO3 to adjust pH~10, then extracted with EtOAc (250.0 mL x 2). The combined organic layers were washed with brine (500.0 mL x 4), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give crude product l-(3-bromo-2-fluorophenyl)cyclobutan-l-amine (38.7 g) as yellow oil.

[0459] 4) tert-butyl (2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)amino)ethyl)carbamate

[0460] <

[0461]

[0462] 4 5

[0463] To a solution of l-(3-bromo-2-fluorophenyl)cyclobutan-l -amine (17.0 g, 69.6 mmol, 1.0 eq) in MeOH (255.0 mL) was added tert-butyl N-(2-oxoethyl)carbamate (10.0 g, 62.7 mmol, 0.9 eq), AcOH (6.3 g, 104.0 mmol, 6.0 mL, 1.5 eq) and NaBPLCN (17.5 g, 279.0 mmol, 4.0 eq). The mixture was stirred at 60°C for 16 hrs. LC-MS showed -35% of starting material remained and -37% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O100.0 mL and extracted with EtOAc 450.0 mL (150.0 mL x 3). The combined organic layers dried over NaiSCU, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, Eluent of 0-31% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give tert-butyl (2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)amino)ethyl)carbamate (17.0 g, 59.0% yield, 84.0% purity) as light-yellow oil.

[0464] 5) tert-butyl (2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)(propyl)amino)ethyl)carbamate

[0465]

[0466] 6 To a solution of tert-butyl (2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)amino)ethyl)carbamate (8.8 g, 22.6 mmol, 1.0 eq) in MeOH (110.0 mL) was added propanal (6.6 g, 113.0 mmol, 8.2 mL, 5.0 eq), AcOH (2.0 g, 33.9 mmol, 1.9 mL, 1.5 eq) and NaBFECN (5.7 g, 90.4 mmol, 4.0 eq). The mixture was stirred at 60°C for 16 hrs. LC-MS showed 86% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 200.0 mL and extracted with EtOAc 600.0 mL (200.0 mL x 3). The combined organic layers dried over NaiSO^ filtered and the filtrate was concentrated under reduced pressure to give crude product tert-butyl (2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)(propyl)amino)ethyl)carbamate (17.0 g) as yellow oil.

[0467] 6) tert-butyl (2-((l-(3-cyano-3-cyano-2- fluorophenyl)cyclobutyl)(propyl)amino)ethyl)carbamate

[0468]

[0469] DMF 6 7To a solution of tert-butyl (2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)(propyl)amino)ethyl)carbamate (15.0 g, 34.9 mmol, 1.0 eq) in DMF (150.0 mL) was added Zn(CN)2 (12.3 g, 105.0 mmol, 3.0 eq) under N2 atmosphere. Then the reaction mixture was degassed and purged with N2 for 3 times, BrettPhos Pd G3 (1.6 g, 1.7 mmol, 0.05 eq) and BrettPhos (937.0 mg, 1.7 pmol, 0.05 eq) was added to the above mixture. After addition, the reaction mixture was stirred at 90°C for 16 hrs under N2 atmosphere. LC-MS showed -51% of desired compound was detected. The reaction mixture was quenched by addition sat. NaHCOa 200.0 mL at 25°C, and then extracted with EtOAc 600.0 mL (200.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, Eluent of 0-6% Ethyl acetate (0.1% TEA) / Petroleum ether gradient @ 100 mL / min) to give compound tert-butyl (2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)ethyl)carbamate (10.8 g, 25.0 mmol, 72.0 % yield, 87.0% purity) as white solid.

[0470] 7) 3-(l-((2-aminoethyl)(propyl)amino)cyclobutyl)-2-fluorobenzonitrile dihydrogen chloride

[0471]

[0472] 7 382

[0473] A mixture of tert-butyl (2-((l-(3-cyano-2-fluoro-phenyl)cyclobutyl)(propyl)amino)ethyl)carbamate (10.8 g, 28.8 mmol, 1.0 eq) in HCl / EtOAc (160 mL) (4M) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 1.5 hrs under N2 atmosphere. LC-MS showed -53% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: CD27-Phenomenex luna Cl 8 250*70mm,10 um;mobile phase: [H20(0.05%HCl)-ACN];gradient:l%-30% B over 20.0 min) to give compound 3-(l-((2-aminoethyl)(propyl)amino)cyclobutyl)-2-fluorobenzonitrile dihydrogen chloride (7.5 g, 21.4 mmol, 75.0% yield, 99.6% purity, 2HC1 salt) as white solid. MS (ESI): m / z = 276.2 [M+H]+, retention time: 1.772 min, method: FXH NMR (400 MHz,DMSO-de) 38.29 (br s, 3H), 7.94 (br s, 2H), 7.49 (br t, J= 7.8 Hz, 1H), 3.30 - 2.52 (m, 10H), 2.02 (tq, J= 5.0, 9.8 Hz, 1H), 1.71 - 1.40 (m, 3H), 0.85 (t, J= 7.3 Hz, 3H).

[0474] Example 5: Synthesis of N -(3-bronK)-2-fluorophcnyl )cyclobutyl )-N I -propylcthanc- 1 ,2-

[0475]

[0476] diamine (Compound 373)

[0477] 1) (R )-N-cyclobutylidene-2-methylpropane-2-sulfinamide

[0478]

[0479] 1A 1B

[0480] To a solution of cyclobutanone (1.0 g, 14.3 mmol, 1.1 mL, 1.0 eq) in THF (12.0 mL) was added Ti(i-PrO)4 (8.1 g, 28.5 mmol, 8.4 mL, 2.0 eq) and (R)-2-methylpropane-2-sulfinamide (2.1 g, 17.1 mmol, 1.2 eq). The mixture was stirred at 20°C for 12 hrs. LC-MS showed one main peak with desired m / z was detected. The reaction mixture was poured into sat. NaHCOa (30.0 mL) and filtered through kieselguhr and washed with EtOAc 60.0 mL (30.0 mL x 2). The filtrate was concentrated under reduced pressure and extracted with EtOAc 60.0 mL (30.0 mL x 2). The combined organic layers were washed with brine 30.0 mL (15.0 mL x 2), dried over NaiSO4, filtered and concentrated under reduced pressure to give compound (R)-N-cyclobutylidene-2-methylpropane-2-sulfinamide (2.1 g, 12.2 mmol, 85.8% yield) as a yellow oil.

[0481] 2) (R)-N-(l -( 3-bromo-2-fluorophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide

[0482]

[0483] 1 2

[0484] To a solution of l-bromo-2-fluoro-benzene (2.0 g, 11.4 mmol, 1.0 eq) in THF (25.0 mL) was added a solution of LDA (2 M, 6.3 mL, 1.1 eq, in THF) drop-wise at -70°C over a period of 0.1 hr under N2. The reaction mixture was stirred at -70°C for 0.2 hr. (R)-N-cyclobutyl idcnc-2-mcthyl-propanc-2-sulfinamidc (2.0 g, 11.4 mmol, 1.0 eq) was added dropwise at -70°C. The reaction mixture was warmed to 20°C and stirred for 12 hrs under N2. LC-MS showed reactant 1 was consumed completely and one main peak with desired m / z was detected. The reaction was quenched with saturated aqueous NH4CI 30.0 mL and extracted with ethyl acetate (3 x 30.0 mL). The combined organic phases were dried over NaiSCU, filtered and concentrated under reduced pressure to give crude product (R)-N-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide (2.6 g, 7.5 mmol, 65.3% yield) as a red oil.

[0485] 3) l-(3-bromo-2-fluorophenyl)cyclobutan-l -amine

[0486]

[0487] 2 3

[0488] A solution of (R)-N-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide (2.6 g, 7.5 mmol, 1.0 eq) in 4 M HCl / EtOAc (20.0 mL) was stirred at 20°C for 1 hr. LC-MS showed reactant 2 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was concentrated to give a residue. The residue was diluted with H2O (15.0 mL) and extracted with EtOAc (45.0 mL). The aqueous phase was adjusted to pH=8 by saturated NaHCOa solution and the aqueous phase was extracted with EtOAc 45.0 mL (15.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give crude product l-(3-bromo-2-fluorophenyl)cyclobutan-l-amine (462.0 mg, 1.9 mmol, 25.4% yield) as a yellow oil.

[0489] 4) 1 -(3-bromo-2-fluoropheny l)-N-propy Icy clobutan- 1 -amine

[0490]

[0491] 3 4To a solution of l-(3-bromo-2-fluorophenyl)cyclobutan-l -amine (462.0 mg, 1.9 mmol, 1.0 eq) in MeOH (6.0 mL) was added propanal (98.9 mg, 1.7 mmol, 124.0 pL, 0.9 eq), AcOH (113.7 mg, 1.7 mmol, 108.3 pL, 1.0 eq) and NaBthCN (356.8 mg, 5.7 mmol, 3.0 eq). The mixture was stirred at 60°C for 12 hrs. LC-MS showed reactant 3 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 10.0 mL and extracted with EtOAc 30.0 mL (10.0 mL x 3). The combined organic layers dried over NaiSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~6% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound l-(3-bromo-2-fluorophenyl)-N-propylcyclobutan-l-amine (157.0 mg, 548.6 pmol, 29.0% yield) as a yellow oil.

[0492] 5) tert-butyl (2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)(propyl)amino)ethyl)carbamate

[0493]

[0494] 4 5

[0495] To a solution of l-(3-bromo-2-fluorophenyl)-N-propylcyclobutan-l -amine (147.0 mg, 513.7 pmol, 1.0 eq) in MeOH (3.0 mL) was added tert-butyl N-(2-oxoethyl)carbamate (327.1 mg, 2.2 mmol, 4.0 eq), ZnCh (140.0 mg, 1.0 mmol, 48.2 pL, 2.0 eq) and NaBHaCN (96.8 mg, 1.5 mmol, 3.0 eq). The mixture was stirred at 20°C for 12 hrs. LC-MS showed reactant 4 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 10.0 mL and extracted with EtOAc 30.0 mL (10.0 mL x 3). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate=5 / l) to give compound tert-butyl (2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)(propyl)amino)ethyl)carbamate (162.0 mg, 377.3 pmol, 73.5% yield) as a white solid.6) A l-( l-{ 3-bromo-2-J luoropheny I )cyclobuty I)- N 1 -propylethane- 1 ,2-diamine

[0496]

[0497] 5 373

[0498] A solution of tert-butyl (2-((l-(3-bromo-2- fluorophenyl)cyclobutyl)(propyl)amino)ethyl)carbamate (50.0 mg, 116.5 pmol, 1.0 eq) in 4 M HCl / EtOAc (3.0 mL) was stirred at 20°C for 0.5 hr. LC-MS showed reactant 5 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition, column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H20(0.04% HC1)-ACN]; gradient:5%-35% B over 8.0 min) to give compound N1-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-N1-propylethane-l,2-diamine (43.9 mg, 108.6 pmol, 93.3% yield, 99.4% purity, 2HC1) as a yellow oil. MS (ESI): m / z = 329.2 [M+H]+, retention time: 1.499 min, method:B.!H NMR (400 MHz, DMSO-d6) 3 11.90 (br d, J = 1.8 Hz, 1H), 8.53 (br s, 3H), 7.98 - 7.72 (m, 2H), 7.33 (br t, J = 7.7 Hz, 1H), 3.44 - 2.56 (m, 10H), 2.01 - 1.72 (m, 2H), 1.63 - 1.36 (m, 2H), 0.83 (t, 7 = 7.3 Hz, 3H).

[0499] Example 6: Synthesis of Compounds 410A and 410

[0500] In analogous manner as set out above for Compound 373, Compounds 410A and 410 have been prepared: 410 was prepared from the BOC-protected 410A via Pd-catalyzed cyanation using Zn(CN)2 (3 eq), Pdi(dba)3 (0.1 eq) and s-Phos (0.2 eq) in DMF followed by deprotection.

[0501]

[0502]

[0503] Example 7 : Synthesis of N I -( I -(3-bromo-2.6-difluorophcnyl )cyclobutyl )-N I -propylcthanc- E2-diamine.hydrogen chloride (Compound 516)

[0504] 1) l-bromo-3-(bromomethyl)-2,4-difluorobenzene

[0505]

[0506] Solution 1: l-bromo-2,4-difluoro-3-methyl-benzene (15.0 g, 72.5 mmol, 1.0 eq) in ACN (260.0 mL) and added NBS (14.2 g, 79.7 mmol, 1.1 eq). The solution 1 was pumped by Pump 1 {Si, Pi, 8.007 mL / min}to flow reactor 1 {FLRi, FEP, Coils reactor, 3.175 (1 / 8”) mm, 80.1 mF, 450 nm, 600 W, 40°C}. The residence time of flow reactor 1 was {FERI, 10 min}. TEC (PE:EA=20:l, Rf=0.53) showed the starting material was consumed completely and desired spot was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (80 g Silica Flash Column, Eluent of 0 ~ 1% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give l-bromo-3-(bromomethyl)-2,4-difluorobenzene (19.0 g, 66.5 mmol, 91.7% yield) as a colorless oil. ’H NMR (400 MHz, DMSO-tfe) b 7.75 - 7.84 (m, 1 H) 7.20 (td, 7=9.04, 1.69 Hz, 1 H) 4.68 (s, 2 H).2) 2-(3-bromo-2,6-difluorophenyl)acetonitrile

[0507]

[0508] To a solution of l-bromo-3-(bromomethyl)-2,4-difluoro-benzene (16.0 g, 55.9 mmol, 1.0 eq) in ACN (230.0 mL) was added trimethylsilylformonitrile (7.5 g, 75.6 mmol, 9.5 mL, 1.3 eq) under N2 atmosphere. Then added TBAF (1.0 M, 83.9 mL, 1.5 eq) to the mixture. The mixture was stirred at 80°C for 3 hr under N2 atmosphere. TLC showed no Reactant 1 remained and three new spot was formed. The reaction mixture was quenched by addition saturated sodium bicarbonate 400.0 mL at 20°C, and then extracted with ethyl acetate 600.0 mL (200.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (80 g Silica Flash Column, Eluent of 0 ~ 2% Ethyl acetate / Petroleum ether gradient @150 mL / min) to give 2-(3-bromo-2,6-difluorophenyl)acetonitrile (12.0 g, 51.7 mmol, 92.4% yield) as a white solid. ’H NMR (400 MHz, DMSO-tfe) d 7.86 - 7.76 (m, 1H), 7.28 - 7.19 (m, 1H), 4.12 (s, 2H).

[0509] 3) l-(3-bromo-2, 6-difluorophenyl)cyclobutane-l-carbonitrile

[0510]

[0511] To a solution of 2-(3-bromo-2,6-difluoro-phenyl)acetonitrile (2.0 g, 8.6 mmol, 1.0 eq) and 1,3-dibromopropane (2.0 g, 9.9 mmol, 1.0 mL, 1.2 eq) in Tol. (40.0 mL) and H2O (4.0 mL) was added KOH (2.4 g, 43.1 mmol, 5.0 eq) and TBAB (166.7 mg, 517.2 pmol, 0.1 eq). The mixture was stirred at 100°C for 3 hr. TLC showed no Reactant 1 remained and one new spot was formed. The reaction mixture was partitioned between H2O 60.0 mL and ethyl acetate (60.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (12 g Silica Flash Column, Eluent of 0 ~ 4% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give l-(3-bromo-2,6-difluorophenyl)cyclobutane-l -carbonitrile (1.3 g, 4.8 mmol, 55.4% yield) as a white solid. ’H NMR (400 MHz, DMSO-tfe) d 7.81 (td, J=8.41, 5.94 Hz, 1 H) 7.16 - 7.25 (m, 1 H) 2.69 -2.88 (m, 4 H) 2.32 - 2.43 (m, 1 H) 1.92 - 2.02 (m, 1 H).

[0512] 4) l-(3-bromo-2,6-difluorophenyl)cyclobutane-l-carboxylic acid

[0513]

[0514] 2 3

[0515] To a solution of l-(3-bromo-2,6-difluoro-phenyl)cyclobutanecarbonitrile (1.3 g, 4.8 mmol, 1.0 eq) in EtOH (13.0 mL) and H2O (13.0 mL) was added KOH (4.0 g, 71.7 mmol, 15.0 eq). The mixture was stirred at 100°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was partitioned between H2O 60.0 mL and ethyl acetate (60.0 mL x 3). The aqueous phase was acidified by HC1 (IM) to adjust pH around 3, then extracted with EtOAc (60.0 mL x 2). The combined organic layers were washed with brine (60.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give l-(3-bromo-2,6-difluorophenyl)cyclobutane-l -carboxylic acid (1.3 g, crude) as a yellow solid.

[0516] 5) l-(3-bromo-2,6-difluorophenyl)cyclobutan-l -amine

[0517]

[0518] A mixture of l-(3-bromo-2,6-difluoro-phenyl)cyclobutanecarboxylic acid (1.3 g, 4.5 mmol, 1.0 eq), diphenylphosphoryl azide (DPPA) (1.8 g, 6.7 mmol, 1.5 mL, 1.5 eq), and TEA (1.4 g, 13.4 mmol, 1.8 mL, 3.0 eq) in DME (13.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20°C for 12 hr under N2 atmosphere. HC1 (1.0 M, 26.8 mL, 6.0 eq) was added, after which the reaction mixture was stirred again at 100°C for 2hr. LC-MS showed desired compound was detected. The reaction mixture was diluted with H2O 60.0 mL and extracted with EtOAc 60.0 mL. The aqueous phase was added sat. NaiCOa to adjust pH around 10, then extracted with EtOAc (60.0 mL x 2). The combined organic layers were washed with brine (80.0 mL), dried over NaiSO^ filtered and concentrated under reduced pressure to give l-(3-bromo-2,6-difluorophenyl)cyclobutan-l-amine (750.0 mg, crude) as a yellow liquid.

[0519] 6) l-(3-bromo-2, 6-difluorophenyl)-N-propylcyclobutan-l -amine

[0520]

[0521] To a solution of l-(3-bromo-2,6-difluoro-phenyl)cyclobutanamine (240.0 mg, 915.7 pmol, 1.0 eq) in MeOH (2.5 mL) was added AcOH (82.5 mg, 1.4 mmol, 78.6 pL, 1.5 eq), propanal (53.2 mg, 915.7 pmol, 66.6 pL, 1.0 eq) and NaBHaCN (287.7 mg, 4.6 mmol, 5.0 eq). The mixture was stirred at 60°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 30.0 mL and ethyl acetate (30.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Elash Column, Eluent of 0 ~ 3% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give l-(3-bromo-2,6-difluorophenyl)-N-propylcyclobutan-l-amine (80.0 mg, 263.0 pmol, 28.7% yield) as a yellow oil.

[0522] 7) tert-butyl (2-((l-(3-bromo-2,6-difluorophenyl)cyclobutyl)(propyl)amino)ethyl) carbamate

[0523]

[0524] To a solution of l-(3-bromo-2,6-difluoro-phenyl)-N-propyl-cyclobutanamine (60.0 mg, 197.3 pmol, 1.0 eq) in MeOH (1.0 mL) was added AcOH (17.8 mg, 295.9 pmol, 16.9 pL, 1.5eq), tert-butyl N-(2-oxoethyl)carbamate (90.0 mg, 565.4 pmol, 2.8 eq) and NaBthCN (61.9 mg, 986.3 pmol, 5.0 eq). The mixture was stirred at 60°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give tert-butyl (2-((l-(3-bromo-2,6-difluorophenyl)cyclobutyl)(propyl)amino)ethyl) carbamate (60.0 mg, crude) as a yellow oil.

[0525] 8) 2V l-( l-( 3 -bromo-2,6-difluorophenyl)cyclobuty I)- N 1 -propylethane- 1 ,2-diamine hydrogen chloride

[0526]

[0527] To a solution of tert-butyl N-[2-[[l-(3-bromo-2,6-difluoro-phenyl)cyclobutyl]-propyl-amino] ethyl] carbamate (60.0 mg, 134.1 pmol, 1.0 eq) in MeOH (1.0 mL) was added HCI / EtOAc (4.0 M, 1.0 mL, 29.8 eq). The mixture was stirred at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2<D(0.04% HC1) -ACN]; gradient: 20% - 50% B over 8.0 min) to give Nl-(l-(3-bromo-2,6-difluorophenyl)cyclobutyl)-Nl-propylethane-l,2-diamine.hydrogen chloride (8.2 mg, 20.8 pmol, 15.5% yield, 97.9% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 347.0 [M+H]+, retention time: 1.802 min, method:B.XH NMR (400 MHz, DMSO-tfe) b 8.41 - 7.81 (m, 3H), 7.78 - 7.64 (m, 1H), 7.16 - 7.03 (m, 1H), 3.02 - 2.89 (m, 4H), 2.68 - 2.52 (m, 6H), 2.34 - 2.19 (m, 1H), 1.88 - 1.74 (m, 1H), 1.55 - 1.41 (m, 2H), 0.86 (t, 7 = 7.3 Hz, 3H).

[0528] Example 8: Synthesis of Compound 518

[0529] In analogous manner as set out above for Compound 516, Compound 518 has been prepared:

[0530]

[0531] Example 9: Synthesis of Nl-(l-(2,6-difhioro-3-cyanophenyl)cyclobutyl)-Nl-propylethane- 1,2-diamine hydrochloride (Compound 466)

[0532] 1) tert-butyl (2-((l-(3-bromo-2,6-difluorophenyl)cyclobutyl)(propyl)amino)ethyl) carbamate

[0533]

[0534] To a solution of l-(3-bromo-2,6-difhioro-phenyl)-N-propyl-cyclobutanamine (600.0 mg, 1.9 mmol, 1.0 eq) in MeOH (6.0 mL) was added AcOH (177.7 mg, 2.9 mmol, 169.4 pL, 1.5 eq) tert-butyl N-(2-oxoethyl)carbamate (900.0 mg, 5.6 mmol, 2.8 eq) and NaBHaCN (619.8 mg, 9.8 mmol, 5.0 eq). The mixture was stirred at 60°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0 ~ 3% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tertbutyl (2-((l-(3-bromo-2,6-difluorophenyl)cyclobutyl)(propyl)amino)ethyl)carbamate (250.0 mg, 558.8 pmol, 28.3% yield) as a yellow oil.2) tert-butyl (2-((l-(2,6-difluoro-3-cyanophenyl)cyclobutyl)(propyl)amino)ethyl) carbamate

[0535]

[0536] 6 7

[0537] To a solution of tert-butyl N-[2-[[l-(3-bromo-2,6-difluoro-phenyl)cyclobutyl]-propyl-amino] ethyl] carbamate (100.0 mg, 223.5 pmol, 1.0 eq) in DMF (2.0 mL) was added Zn(CN)2 (100.0 mg, 851.6 pmol, 54.1 pL, 3.8 eq), BrettPhos Pd G3 (20.3 mg, 22.4 pmol, 0.1 eq) and brettphos (12.0 mg, 22.4 pmol, 0.1 eq). The mixture was stirred at 90°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture was quenched by addition saturated NaHCOa (10.0 mL) at 25°C, and then extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL x 2) dried over NaiSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate = 6:1) to give tertbutyl (2-((l-(3-cyano-2,6-difluorophenyl)cyclobutyl)(propyl)amino)ethyl)carbamate (80.0 mg, 203.3 pmol, 90.9% yield) as a white solid.

[0538] 3) A l-( l-(3-cyano-2,6-difluorophenyl)cyclobutyl)-N 1 -propylethane- 1 ,2-diamine hydrochloride

[0539]

[0540] To a solution of tert-butyl N-[2-[[l-(3-cyano-2,6-difluoro-phenyl)cyclobutyl]-propyl-amino] ethyl] carbamate (80.0 mg, 203.3 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl / EtOAc (4.0 M, 888.9 pL, 17.5 eq) at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex Luna C1875 x 30mm x 3um; mobile phase: [HiO( 0.04%HCl)-ACN]; gradient: 10% - 45% B over 8.0 min) to give Nl-(l-(3-cyano-2,6-difluoro-phenyl)cyclobutyl)-Nl-propylethane-l,2-diamine hydrochloride (38.4 mg, 116.5 pmol, 57.3% yield, 100% purity, HC1) as a yellowoil. MS (ESI): m / z = 294.1 [M+H]+, retention time: 1.547 min, method:B.!H NMR (400 MHz, DMSO-76) 38.09 (br s, 3H), 7.99 - 7.89 (m, 1H), 7.32 (t, J= 9.7 Hz, 1H), 2.92 (br d, J = 18.1 Hz, 4H), 2.54 (br s, 6H), 2.34 - 2.18 (m, 1H), 1.88 - 1.74 (m, 1H), 1.56 - 1.37 (m, 2H), 0.86 (t, 7 = 7.3 Hz, 3H).

[0541] Example 10: Synthesis of Compound 469

[0542] In analogous manner as set out above for Compound 466, Compound 469 has been prepared:

[0543]

[0544] Example 11: Synthesis _ of _ Nl-(l-(2,6-difluoro-3-cyanophenyl)cyclobutyl)-Nl- isopropylethane-l,2-diamine dihydrochloride (Compound 468) and of Nl-(1- (3-bromo-2,6-difhiorophenyl)cyclobutyl)-Nl-isopropylethane-l,2-diamine hydrochloride (Compound 517)

[0545] 1) l-(3-bromo-2, 6-difluorophenyl)-N-isopropylcyclobutan-l -amine

[0546]

[0547] 466 int.4 5

[0548] To a solution of l-(3-bromo-2,6-difluoro-phenyl)cyclobutanamine (0.5 g, 1.9 mmol, 1.0 eq) in MeOH (5.0 mL) was added acetone (166.2 mg, 2.9 mmol, 210.4 pL, 1.5 eq), AcOH (229.1 mg, 3.8 mmol, 218.4 pL, 2.0 eq) and NaBHaCN (479.5 mg, 7.6 mmol, 4.0 eq). The mixture was stirred at 60°C for 12 hrs. LC-MS showed Reactant 466 int.4 was consumed completely and -91% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The reaction mixture was diluted with H2O 5.0 mL and extracted with ethyl acetate 15.0 mL (5.0 mL x 3). The combined organic layers were washed with sat. NaCl 10.0 mL, dried over NaiSO^ filtered and concentrated under reducedpressure to give compound l-(3-bromo-2,6-difluorophenyl)-N-isopropylcyclobutan-l-amine (0.6 g, 1.9 mmol, 97.2% yield, 93.8% purity) as a colorless oil and used into the next step without further purification.

[0549] 2) 2-bromo-N-( l-(3-bromo-2,6-difluorophenyl)cyclobutyl)-N-isopropylacetamide

[0550]

[0551] To a solution of l-(3-bromo-2,6-difluorophenyl)-N-isopropylcyclobutan-l -amine (0.6 g, 1.9 mmol, 1.0 eq) in DCM (10.0 mL) and H2O (10.0 mL) was added K2CO3 (2.1 g, 14.8 mmol, 8.0 eq) and 2-bromoacetyl bromide (748.2 mg, 3.7 mmol, 322.9 pL, 2.0 eq) at 0°C. The mixture was stirred at 25 °C for 12 hrs. LC-MS showed -7% of Reactant 5 remained. Several new peaks were shown on LC-MS and -59% of desired compound was detected. The reaction mixture was diluted with H2O 5.0 mL and extracted with DCM 15.0 mL (5.0 mL x 3). The combined organic layers were washed with sat. NaCl 10.0 mL, dried over NaiSCL, filtered and concentrated under reduced pressure to give compound 2-bromo-N-(l-(3-bromo-2,6-difluorophenyl)cyclobutyl)-N-isopropylacetamide (0.8 g, 1.1 mmol, 60.7% yield, 59.1% purity) as a yellow oil and used into the next step without further purification.

[0552] 3) 2-azido-N-( l-(3-bromo-2,6-difluorophenyl)cyclobutyl)-N-isopropylacetamide

[0553]

[0554] To a solution of 2-bromo-N-(l-(3-bromo-2,6-difluorophenyl)cyclobutyl)-N-isopropylacetamide (0.8 g, 1.9 mmol, 1.0 eq) in DMSO (10.0 mL) was added NaNa (136.2 mg, 2.1 mmol, 1.1 eq). The mixture was stirred at 25°C for 12 hrs. LC-MS showed Reactant 6 was consumed completely and -35% of desired mass was detected. The reaction mixture was quenched by addition water 10.0 mL at 0°C, and then extracted with ethyl acetate 30.0 mL (10.0 mL x 3). The combined organic layers were dried over NaiSCL, filtered and concentrated under reduced pressure to give compound 2-azido-N-(l-(3-bromo-2,6-difluorophenyl)cyclobutyl)-N-isopropylacetamide (0.8 g, 1.4 mmol, 74.9% yield, 71.4% purity) as a brown oil and used into the next step without further purification.

[0555] 4) tert-butyl (2-((l-(3-bromo-2,6-difluorophenyl)cyclobutyl)(isopropyl)amino)-2- oxoethyl )carbamate

[0556]

[0557] To a solution of 2-azido-N-(l-(3-bromo-2,6-difluorophenyl)cyclobutyl)-N-isopropylacetamide (0.8 g, 2.0 mmol, 1.0 eq) in THF (15.0 mL) and H2O (5.0 mL) was added PPI13 (785.0 mg, 3.0 mmol, 1.5 eq) and BOC2O (1.3 g, 6.0 mmol, 1.4 mL, 3.0 eq). The mixture was stirred at 25 °C for 12 hrs. LC-MS showed Reactant 7 was consumed completely and -34% of desired mass was detected. The reaction mixture was diluted with H2O 5.0 mL and extracted with ethyl acetate 15.0 mL (5.0 mL x 3). The combined organic layers were washed with sat. NaCl 10.0 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give compound tert-butyl (2-((l-(3-bromo-2,6-difluorophenyl)cyclobutyl)(isopropyl)amino)-2-oxoethyl)carbamate (0.3 g, 614.4 pmol, 30.8% yield, 86.1% purity) as a yellow oil.

[0558] 5) tert-butyl (2-((l-(3-bromo-2,6-difluorophenyl)cyclobutyl)(isopropyl)amino)ethyl)

[0559] carbamate

[0560]

[0561] difluorophenyl)cyclobutyl)(isopropyl)amino)-2-oxoethyl)carbamate (0.3 g, 713.8 pmol, 1.0 eq) in THF (10.0 mL) was degassed and purged with N2 for 3 times and then added BH3.THF (1.0 M, 7.1 mL, 10.0 eq) in THF at 0°C. The mixture was stirred at 25°C for 3 hrs under N2.LC-MS showed reactant 8 was consumed completely and -65% of desired mass was detected. The reaction mixture was quenched by addition MeOH 2.0 mL at 0°C and then stirred at 60°C for 2hrs. The mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0-3% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give compound tert-butyl (2-((l-(3-bromo-2,6-difluorophenyl)cyclobutyl)(isopropyl)amino) ethylcarbamate (0.2 g, 342.3 pmol, 48.0% yield, 87.6% purity) as a colorless oil.

[0562] 6) tert-butyl (2-((l-(3-cyano-2,6-difluoro-phenyl)cyclobutyl)(isopropyl)amino)

[0563] ethyl )carbamate

[0564]

[0565] A mixture of tert-butyl (2-((l-(3-bromo-2,6-difhiorophenyl)cyclobutyl)(isopropyl)amino) ethyl)carbamate (0.2 g, 390.7 pmol, 1.0 eq), Zn(CN)2 (137.6 mg, 1.2 mmol, 74.4 pL, 3.0 eq), BRETTPHOS (21.0 mg, 39.1 pmol, 0.1 eq) and BrettPhos Pd G3 (35.4 mg, 39.1 pmol, 0.1 eq) in DMF (10.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hrs under N2 atmosphere. LC-MS showed Reactant 9 was consumed completely and -10% of desired mass was detected. The reaction mixture was quenched by addition saturated sodium bicarbonate 10.0 mL at 20°C, and then extracted with Ethyl acetate 15.0 mL (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Elash Column, Eluent of 0-2% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound tert-butyl (2-((l-(3-cyano-2,6-difluorophenyl)cyclobutyl)(isopropyl)amino)ethyl)carbamate (0.2 g, 68.2% purity) as a colorless oil.7) A l-( l-(3-cyano-2,6-difluorophenyl)cyclobutyl)-N 1 -isopropylethane- 1 ,2-diamine dihydrochloride

[0566]

[0567] 10 468

[0568] A solution of tert-butyl N-[2-[[l-(3-cyano-2,6-difluoro-phenyl)cyclobutyl]-isopropyl-amino] ethyl] carbamate (0.2 g, 420.1 pmol, 1.0 eq) in HCl / EtOAc (10.0 mL) (4mol / L) was stirred at 25°C for 1 hr. LC-MS showed reactant 10 was consumed completely and 35% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HC1 condition)(column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H20(0.04% HC1)- ACN];gradient:l%-35% B over 8.0 min) to give compound N1-(l-(3-cya«o-2,6-difluorophenyl)cyclobutyl)-N1-isopropylethane-l,2-diamine dihydrochloride (93.8 mg, 248.9 pmol, 59.2% yield, 97.2% purity, 2HC1) as a white solid. MS (ESI): m / z = 294.1 [M+H]+; retention time:2.581 min, method: C!H NMR (400 MHz, DMSO-tTs) 3 8.11 (br s, 3H), 7.96 - 7.85 (m, 1H), 7.35 - 7.26 (m, 1H), 3.53 - 3.35 (m, 1H), 3.10 - 2.84 (m, 4H), 2.58 (br s, 2H), 2.53 (br s, 1H), 2.49 (br d, J = 1.9 Hz, 1H), 2.28 - 2.11 (m, 1H), 1.88 - 1.74 (m, 1H), 0.90 (br d, J = 6.6 Hz, 6H).

[0569] 8) A l-( l-{ 3-bromo-2, 6-difluoropheny I )cyclobuty I)- N 1-isopropylethane-l ,2-diamine

[0570] hydrochloride

[0571]

[0572] 6 517

[0573] A solution of tert-butyl N-[2-[[l-(3-bromo-2,6-difluoro-phenyl)cyclobutyl]-isopropyl-amino] ethyl] carbamate (0.04 g, 99.0 pmol, 1.0 eq) in HCl / EtOAc (5.0 mL) (4.0 mol / L) was stirred at 25 °C for 1 hr. LC-MS showed Reactant 6 was consumed completely and -12% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HC1 condition)(column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H20(0.04% HC1)-ACN];gradient:5%-45% B over 8.0 min) to give compound N1-(l-(3-bromo-2,6-difluorophenyl)cyclobutyl)-N1-isopropylethane-l,2-diamine hydrochloride (24.6 mg, 63.9 pmol, 64.5% yield, 99.8% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 347.1 [M+H]+; retention time:2.313 min, method: A.XH NMR (400 MHz, DMSO-tTs) 3 8.21 - 7.74 (m, 3H), 7.71 - 7.58 (m, 1H), 7.11 - 7.00 (m, 1H), 3.50 - 3.34 (m, 1H), 3.06 - 2.81 (m, 4H), 2.52 (br d, J = 2.0 Hz, 1H), 2.49 - 2.37 (m, 3H), 2.25 - 2.14 (m, 1H), 1.85 - 1.73 (m, 1H), 0.87 (br d, J = 6.6 Hz, 6H).

[0574] Example 12: Synthesis of NMlA3-bromo-2,4-difhioromhenyl)cvclobutyl]-N'-propyl-ethane- 1,2-diamine.dihydrogen chloride (Compound 519)

[0575] 1) l-(3-bromo-2,4-difluoro-phenyl)cyclobutanecarbonitrile

[0576]

[0577] To a solution of 2-(3-bromo-2,4-difluoro-phenyl)acetonitrile (5.4 g, 23.2 mmol, 1.0 eq) and 1,3-dibromopropane (5.2 g, 25.6 mmol, 2.6 mL, 1.1 eq) in Tol. (70.0 mL) and H2O (7.0 mL) was added KOH (6.5 g, 116.3 mmol, 5.0 eq) and TBAB (462.8 mg, 1.4 mmol, 0.6 eq). The mixture was stirred at 100°C for 8 hr. TLC indicated Reactant 1 was consumed completely and new spot formed. The reaction mixture was partitioned between H2O (50.0 mL) and ethyl acetate (60.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~4% Tetrahydrofuran / Petroleum ether gradient @ 120 mL / min) to give compound l-(3-bromo-2,4-difluoro-phenyl)cyclobutanecarbonitrile (2.6 g, 9.5 mmol, 41.0% yield) as a brown oil.

[0578] 2) l-(3-bromo-2,4-difluoro-phenyl)cyclobutanecarboxylic acid

[0579]

[0580] 2 3To a solution of l-(3-bromo-2,4-difluoro-phenyl)cyclobutanecarbonitrile (2.5 g, 9.2 mmol, 1.0 eq) in EtOH (25.0 mL) and H2O (25.0 mL) was added KOH (7.7 g, 137.8 mmol, 15.0 eq) at 0°C. The mixture was stirred at 100°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove EtOH. The aqueous phase was acidified by HC1 (6.0 M) adjust to pH = 3.0, then extracted with EtOAc (80.0 mLx 3). The combined organic layers were washed with brine (80.0 mL x 1), dried over NaiSO^ filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~4% Tetrahydrofuran / Petroleum ethergradient @ 120 mL / min) to give compound l-(3-bromo-2,4-difluoro-phenyl)cyclobutanecarboxylic acid (2.4 g, 6.9 mmol, 75.7% yield, 84.4% purity) as a yellow oil.

[0581] 3) l-(3-bromo-2,4-difluoro-phenyl)cyclobutanamine

[0582]

[0583] 3 4

[0584] To a solution of l-(3-bromo-2,4-difluoro-phenyl)cyclobutanecarboxylic acid (2.4 g, 8.2 mmol, 1.0 eq) in DMF (50 mL) was added diphenylphosphoryl azide (DPPA) (2.7 g, 9.9 mmol, 2.1 mL, 1.2 eq) and TEA (2.5 g, 24.7 mmol, 3.4 mL, 3.0 eq). The mixture was stirred at 25°C for 3 hr under N2. Then HC1 (1.0 M, 48.0 mL, 5.8 eq) in H2O (25.0 mL) was added to the mixture at 0°C, the mixture was stirred at 100°C for 1.5 hr under N2. LC-MS showed desired compound was detected. The reaction mixture was diluted with 1.0 M HC1 (50.0 mL) and extracted with ethyl acetate (150.0 mL x 1). The aqueous phase was basified by 20% NaOH adjust to pH = 10, then extracted with ethyl acetate (150.0 mL x3). The combined organic layers were washed with sat. NaHCOa (120.0 mL x 2) and brine (120 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound l-(3-bromo-2,4-difluoro-phenyl)cyclobutanamine (1.4 g, crude) as a yellow oil.4) l-(3-bromo-2,4-difluoro-phenyl)-N-propyl-cyclobutanamine

[0585]

[0586] To a solution of l-(3-bromo-2,4-difluoro-phenyl)cyclobutanamine (300.0 mg, 1.1 mmol, 1.0 eq) in MeOH (6.0 mL) was added AcOH (103.1 mg, 1.2 mmol, 98.3 pL, 1.5 eq), propanal (66.4 mg, 1.1 mmol, 83.3 pL, 1.0 eq) and NaBthCN (215.8 mg, 3.4 mmol, 3.0 eq). The mixture was stirred at 60°C for 4 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0~4% Ethyl acetate / Petroleum ethergradient @ 70 mL / min) to give compound l-(3-bromo-2,4-difluoro-phenyl)-N-propyl-cyclobutanamine (270.0 mg, 887.6 pmol, 77.5% yield) as a yellow oil.

[0587] 5) tert-butyl N-[2-[[l-(3-bromo-2,4-difluoro-phenyl)cyclobutyl]-propyl-amino]ethyl] carbamate

[0588]

[0589] To a solution of l-(3-bromo-2,4-difluoro-phenyl)-N-propyl-cyclobutanamine (50.0 mg, 164.3 pmol, 1.0 eq) and tert-butyl N-(2-oxoethyl)carbamate (52.3 mg, 328.7 pmol, 2.0 eq) in MeOH (1.0 mL) was added AcOH (14.8 mg, 246.5 pmol, 14.1 pL, 1.5 eq) and NaBHaCN (31.0 mg, 493.1 pmol, 3.0 eq). The mixture was stirred at 60°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give compound tert-butyl N-[2-[[l-(3-bromo-2,4-difluoro-phenyl)cyclobutyl]-propyl-amino]ethyl]carbamate (70.0 mg, crude) as a white solid.6) N'-[ l-(3-bromo-2,4-difluoro-phenyl)cyclobutyl]-N'-propyl-ethane-l,2- diamine.dihydrogen chloride

[0590]

[0591] 6 519

[0592] A mixture of tert-butyl N-[2-[[l-(3-bromo-2,4-difluoro-phenyl)cyclobutyl]-propyl-amino] ethyl] carbamate (70.0 mg, 156.4 pmol, 1.0 eq) in EtOAc (0.5 mL) and HCl / EtOAc (1.0 mL) (4.0 M) was stirred at 25°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HC1 condition, column: Phenomenex luna C18 100 x 40mm x 5 um; mobile phase: [H20(0.04% HC1)-ACN]; gradient: l%-35% B over 8.0 min) to give compound N'-[l-(3-bromo-2,4-difluoro-phenyl)cyclobutyl]-N'-propyl-ethane-l,2-diamine.dihydrogen chloride (23.5 mg, 55.4 pmol, 35.4% yield, 98.9% purity, 2HC1 salt) as a white solid. MS (ESI): m / z = 347.0 [M+H]+, retention time: 1.557 min, method: EXH NMR (400 MHz, DMSO-tfe) <5 = 11.89 (br d, J= 1.8 Hz, 1H), 8.54 (br s, 3H), 7.90 (br d, J= 1.4 Hz, 1H), 7.46 (br d, J = 7.5 Hz, 1H), 3.38 - 2.88 (m, 6H), 2.77 (br s, 4H), 2.07 - 1.76 (m, 2H), 1.57 (qd, J= 9.1, 18.7 Hz, 2H), 0.84 (t, J= 7.3 Hz, 3H).

[0593] Example 13: Synthesis of Nl-(l-(2,4-difhioro-3-cyanophenyl)cyclobutyl)-Nl-propylethane- 1,2-diamine dihydrochloride (Compound 465)

[0594] 1) tert-butyl N-[2-[[l-(3-cyano-2,4-difluorophenyl)cyclobutyl]-propyl-amino]ethyl] carbamate

[0595]

[0596] 6 7

[0597] To a solution of tert-butyl N-[2-[[l-(3-bromo-2,4-difluoro-phenyl)cyclobutyl]-propyl-amino] ethyl] carbamate (120.0 mg, 268.2 pmol, 1.0 eq) in DMF (2.0 mL) was added Zn(CN)2 (94.5 mg, 804.7pmol, 51.1 pL, 3.0 eq) , Brettphos (28.8 mg, 53.6 pmol, 0.2 eq) and BrettPhos Pd G3 (24.3 mg, 26.8 pmol, 0.1 eq) under N2. The mixture was stirred at 90°C for 12 hr underNi atmosphere. LC-MS showed desired compound was detected. The reaction mixture was partitioned between NaHCOa (10.0 mL) and ethyl acetate (10.0 mL x 3). The organic phase was separated, washed with brine (10.0 mL x 3), dried over NaiSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether : Ethyl acetate = 3:1) to give compound tert-butyl N-[2-[[l-(3-cyano-2,4-difluoro-phenyl)cyclobutyl]-propyl-amino]ethyl]carbamate (70.0 mg, 177.9 pmol, 66.3% yield) as a light yellow oil.

[0598] 2) A l-( l-(3-cyano-2,4-difluorophenyl)cyclobutyl)-N 1 -propylethane- 1 ,2-diamine dihydrochloride

[0599]

[0600] To a solution of tert-butyl N-[2-[[l-(3-cyano-2,4-difluoro phenyl)cyclobutyl] -propylamino] ethyl] carbamate (70.0 mg, 177.9 pmol, 1.0 eq) in EtOAc (0.5 mL) was added HCl / EtOAc (4.0 M, 0.5 mL, 11.2 eq). The mixture was stirred at 25°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HC1 condition, column: Phenomenex luna Cis 100 x 40mm x 5 um; mobile phase: [H2<D(0.04% HC1)-ACN]; gradient: l%-30% B over 8.0 min) to give compound Nl-(l-(3-cyano-2,4-difluoroophenyl)cyclobutyl)-Nl-propylethane-l,2-diamine dihydrochloride (25.8 mg, 70.4 pmol, 39.5% yield, 100% purity, 2HC1 salt) as a yellow oil. MS (ESI): m / z = 294.1 [M+H]+, retention time: 1.451 min, method: EXH NMR (400 MHz, DMSO-tfe) b 12.55 - 11.40 (m, 1H), 8.48 (br s, 3H), 8.23 (br s, 1H), 7.60 (br t, J= 8.1 Hz, 1H), 3.42 - 2.91 (m, 6H), 2.89 - 2.54 (m, 4H), 1.93 (q, J = 9.9 Hz, 1H), 1.58 (td, J= 9.1, 18.6 Hz, 3H), 0.85 (t, J= 7.3 Hz, 3H).Example 14: Synthesis of Nl-(l-(3-cyano-2,4-difluoro-phenyl)cyclobutyl)-Nl- isopropylethane- E2-diamine dihydrochloride (Compound 467) and of Nl-(1- (3-bromo-2.4-difluorophcn yl )c yclobutyl )-N 1 -isopropylethane- 1 ,2-diam i nc dihydrochloride (Compound 520)

[0601] 1) 1 -(3-bromo-2,4-difluorophenyl)-N-isopropylcyclobutan-l -amine

[0602]

[0603] 465 int.4 5

[0604] To a solution of l-(3-bromo-2,4-difluoro-phenyl)cyclobutanamine (500.0 mg, 1.9 mmol, 1.0 eq) and acetone (166.2 mg, 2.9 mmol, 210.4 pL, 1.5 eq) in MeOH (5.0 mL) was added AcOH (171.8 mg, 2.8 mmol, 163.8 pL, 1.5 eq) and NaBthCN (359.6 mg, 5.72 mmol, 3.0 eq). The mixture was stirred at 60°C for 12 hr. LC-MS showed reactant 1 was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4.0 g Silica Elash Column, Eluent of 0 ~ 24% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give l-(3-bromo-2,4-difluorophenyl)-N-isopropylcyclobutan-l-amine (550.0 mg, 1.8 mmol, 94.8% yield) as a yellow oil.

[0605] 2) 2-bromo-N-( l-(3-bromo-2,4-difluorophenyl)cyclobutyl)-N-isopropylacetamide

[0606]

[0607] 5 6

[0608] To a solution of l-(3-bromo-2,4-difluoro-phenyl)-N-isopropyl-cyclobutanamine (550.0 mg, 1.8 mmol, 1.0 eq) in DCM (6.0 mL) and H2O (6.0 mL) was added K2CO3 (999.6 mg, 7.2 mmol, 4.0 eq) and 2-bromoacetyl bromide (729.9 mg, 3.6 mmol, 315.0 pL, 2.0 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 40 mL and ethyl acetate (40.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reducedpressure to give 2-bromo-N-(l-(3-bromo-2,4-difluorophenyl)cyclobutyl)-N-isopropylacetamide (800.0 mg, crude) as a yellow oil.

[0609] 3) 2-azido-N-(l-(3-bromo-2,4-difluorophenyl)cyclobutyl)-N-isopropylacetamide

[0610]

[0611] To a solution of 2-bromo-N-[l-(3-bromo-2,4-difluoro-phenyl)cyclobutyl]-N-isopropyl-acetamide (800.0 mg, 1.8 mmol, 1.0 eq) in DMSO (20.0 mL) was added NaNa (173.0 mg, 2.6 mmol, 1.4 eq). The mixture was stirred at 25°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between NaHCOa (30.0 mL) and ethyl acetate (30 mL x 3). The organic phase was separated, washed with brine (30 mL x 3), dried over NaiSCL, filtered and concentrated under reduced pressure to give 2-azido-N-(l-(3-bromo-2,4-difluorophenyl)cyclobutyl)-N-isopropylacetamide (800.0 mg, crude) as a yellow oil.

[0612] 4) tert-butyl (2-( (l-(3-bromo-2,4-difluorophenyl)cyclobutyl)(isopropyl)amino)-2- oxoethyl )carbamate

[0613]

[0614] To a solution of 2-azido-N-[l-(3-bromo-2,4-difluoro-phenyl)cyclobutyl]-N-isopropyl-acetamide (400.0 mg, 1.0 mmol, 1.0 eq) in THF (3.0 mL) and H2O (1.0 mL) was added PPh? (325.1 mg, 1.2 mmol, 1.2 eq) and BociO (450.9 mg, 2.1 mmol, 474.6 pL, 2.0 eq). The mixture was stirred at 25°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 30.0 mL and ethyl acetate (30.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (4 g Silica Flash Column, Eluent of 0 ~ 3% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give tert-butyl (2-((l-(3-bromo-2,4-difluorophenyl)cyclobutyl)(isopropyl)amino)-2-oxoethyl)carbamate (200.0 mg, 433.5 pmol, 41.9% yield) as a yellow solid.

[0615] 5) tert-butyl (2-( (l-(3-bromo-2,4-difluorophenyl)cyclobutyl)(isopropyl)amino)

[0616] ethyl )carbamate

[0617]

[0618] To a solution of tert-butyl N-[2-[[l-(3-bromo-2,4-difluoro-phenyl)cyclobutyl]-isopropyl-amino]-2-oxo-ethyl]carbamate (200.0 mg, 433.5 pmol, 1.0 eq) in THF (2.0 mL) was added BH3-Me2S (10.0 M, 0.1 mL, 3.2 eq) at 0°C under N2. The mixture was stirred at 25°C for 6 hr under N2. LC-MS showed desired compound was detected. The reaction mixture was quenched by addition MeOH 5.0 mL at 0°C under N2, the mixture was stirred at 25°C for 1 hr and 60°C for 1 hr under N2. The mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 3:1) to give tert-butyl (2-((l-(3-bromo-2,4-difluorophenyl)cyclobutyl)(isopropyl)amino)ethyl) carbamate (100.0 mg, 223.5 pmol, 51.6% yield) as a yellow solid.

[0619] 6) tert-butyl (2-((l-(3-cyano-2,4-difluorophenyl)cyclobutyl)(isopropyl)amino)

[0620] ethyl )carbamate

[0621]

[0622] To a solution of tert-butyl N-[2-[[l-(3-bromo-2,4-difluoro-phenyl)cyclobutyl]-isopropyl-amino] ethyl] carbamate (70.0 mg, 156.5 pmol, 1.0 eq) in DMF (1.5 mL) was added Zn(CN)2(75 mg, 638.7 pmol, 40.5 pL, 4.1 eq), BrettPhos Pd G3 (14.2 mg, 15.7 pmol, 0.1 eq) andBRETTPHOS (8.4 mg, 15.7 pmol, 0.1 eq). The mixture was stirred at 90°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture was quenched by addition sat.NaHCO, 10 mL at 25 °C, and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over NaiSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate = 3:1) to give tert-butyl (2-((3-cyano-l-(2,4-difluorophenyl)cyclobutyl)(isopropyl)amino)ethyl)carbamate (100.0 mg, 106.7 pmol, 68.2% yield, 42.0% purity) as a yellow solid.

[0623] 7) A l-( l-(3-cyano-2,4-difluorophenyl)cyclobutyl)-N 1 -isopropylethane- 1 ,2-diamine dihydrochloride

[0624]

[0625] To a solution of tert-butyl N-[2-[[l-(3-cyano-2,4-difluorophenyl)cyclobutyl]-isopropyl-amino] ethyl] carbamate (100.0 mg, 254.2 pmol, 1.0 eq) in EtOAc (0.5 mL) was added HCI / EtOAc (4.0 M, 0.5 mL, 7.8 eq) at 0°C. The mixture was stirred at 20°C for 2 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100 x 40mm x 5 um; mobile phase: [H2O (0.04% HC1) -ACN]; gradient: 5% - 40% B over 8.0 min) to give Nl-(l-(3-cyano-2,4-difluorophenyl)cyclobutyl)-Nl-isopropylethane-l,2-diamine dihydrochloride (29.26 mg, 78.3 pmol, 30.8% yield, 98.1% purity, 2HC1 salt) as a yellow oil. MS (ESI): m / z = 294.2 [M+H]+, retention time: 1.449 min, method:B.XH NMR (400 MHz, DMSO-tfe) d 12.01 -10.98 (m, 1H), 8.78 - 8.06 (m, 4H), 7.68 - 7.50 (m, 1H), 3.66 - 3.43 (m, 2H), 3.20 (br d, J = 1.4 Hz, 4H), 2.99 - 2.79 (m, 1H), 2.75 - 2.51 (m, 2H), 1.93 - 1.76 (m, 1H), 1.67 - 1.00 (m, 4H), 0.72 (br s, 3H).8) A l-( l-(3-bromo-2,4-difluorophenyl)cyclobutyl)-N 1-isopropylethane-l ,2-diamine dihydrochloride

[0626]

[0627] 9 520

[0628] To a solution of tert-butyl N-[2-[[l-(3-bromo-2,4-difluoro-phenyl)cyclobutyl]-isopropyl-amino] ethyl] carbamate (30.0 mg, 67.1 pmol, 1.0 eq) in EtOAc (0.3 mL) was added HCl / EtOAc (4.0 M, 0.7 mL, 41.75 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100 x 40mm x5 um;mobile phase: [H20(0.04% HC1) - ACN]; gradient: 5% - 40% B over 8.0 min) to give Nl-(l-(3-bromo-2,4-difluorophenyl)cyclobutyl)-Nl-isopropylethane-l,2-diamine dihydrochloride (23.46 mg, 55.8 pmol, 83.3% yield, 100.0% purity, 2HC1 salt) as a yellow oil. MS (ESI): m / z = 347.1 [M+H]+, retention time: 1.492 min, method:B.XH NMR (400 MHz, DMSO-tfe) b 11.66 - 11.05 (m, 1H), 8.71 - 8.20 (m, 3H), 8.11 - 7.74 (m, 1H), 7.54 - 7.28 (m, 1H), 3.97 - 3.68 (m, 1H), 3.66 - 3.58 (m, 1H), 3.52 - 3.37 (m, 2H), 3.35 - 3.23 (m, 1H), 3.12 (br s, 2H), 3.01 - 2.77 (m, 1H), 2.65 (br d, J = 15.0 Hz, 1H), 1.94 - 1.78 (m, 1H), 1.71 - 0.99 (m, 4H), 0.86 - 0.47 (m, 3H).

[0629] Example 15: Synthesis of Nl-(l-(3-cyano-2-fluorophenyl)cyclobutyl)-Nl-((ls,3s)-3- fluorocyclobutyl)ethane-E2-diamine hydrochloride (Compound 470) and of Nl-(l-(3-bromo-2-fhiorophenyl)cvclobutyl)-N 1 -(( lr,3r)-3- fluorocvclobutyl)ethane-E2-diamine hydrochloride (Compound 500)

[0630] 1) N-(3-(benzyloxy )cyclobutyl)~ 1 -(3-bromo-2-fluorophenyl)cyclobutan-l -amine

[0631]

[0632] 4 5To a solution of l-(3-bromo-2-fluoro-phenyl)cyclobutanamine (7.0 g, 28.7 mmol, 1.0 eq) in MeOH (100.0 mL) was added 3-benzyloxycyclobutanone (10.0 g, 56.8 mmol, 1.9 eq), Ti(i-PrO)4 (12.2 g, 43.0 mmol, 12.7 mL, 1.5 eq) and AcOH (3.4 g, 57.4 mmol, 3.3 mL, 2.0 eq). The mixture was stirred at 20°C for 1 hr. Then added NaBtLCN (7.2 g, 114.7 mmol, 4.0 eq) to the mixture at 20°C. The mixture was stirred at 20°C for 2 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 60.0 mL and ethyl acetate (60.0 mL x 3). The organic phase was separated, dried over NaiSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0 ~ 13% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give N-(3-(benzyloxy)cyclobutyl)-l-(3-bromo-2-fluorophenyl)cyclobutan-l-amine (7.0 g, 4.5 mmol, 15.7% yield, 26.0% purity) as a yellow oil.

[0633] 2) N-(3-(benzyloxy)cyclobutyl)-2-bromo-N-(l-(3-bromo-2-fluorophenyl)cyclobutyl) acetamide

[0634]

[0635] To a solution of N-(3-benzyloxycyclobutyl)-l-(3-bromo-2-fluoro-phenyl)cyclobutanamine (7.0 g, 17.3 mmol, 1.0 eq) in DCM (70.0 mL) and H2O (70.0 mL) was added K2CO3 (9.6 g, 69.3 mmol, 4.0 eq) and 2-bromoacetyl bromide (8.8 g, 43.4 mmol, 3.8 mL, 2.5 eq) at 0°C. The mixture was stirred at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 100.0 mL and ethyl acetate (200.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (80 g Silica Flash Column, Eluent of 0 ~ 12% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give N-(3-(benzyloxy)cyclobutyl)-2-bromo-N-(l-(3-bromo-2-fluorophenyl)cyclobutyl) acetamide (3.0 g, 5.7 mmol, 32.9% yield) as a yellow oil.3) 2-azido-N-( 3-(benzyloxy)cyclobutyl)-N-(l -( 3-bromo-2-fluorophenyl)cyclobutyl) acetamide

[0636]

[0637] To a solution of N-(3-benzyloxycyclobutyl)-2-bromo-N-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl] acetamide (3.0 g, 5.7 mmol, 1.0 eq) in DMSO (60.0 mL) was added NaNa (480.0 mg, 7.4 mmol, 1.3 eq). The mixture was stirred at 25°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between NaHCOa (60.0 mL) and ethyl acetate (120.0 mL x 3). The organic phase was separated, washed with brine (120.0 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-azido-N-(3-(benzyloxy)cyclobutyl)-N-(l-(3-bromo-2-fluorophenyl)cyclobutyl) acetamide (3.2 g, crude) as a yellow oil.

[0638] 4) 2-amino-N-(3-(benzyloxy)cyclobutyl)-N-(l-(3-bromo-2-fluorophenyl)cyclobutyl) acetamide

[0639]

[0640] To a solution of 2-azido-N-(3-benzyloxycyclobutyl)-N-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl] acetamide (1.1 g, 2.3 mmol, 1.0 eq) in THF (9.0 mL) and H2O (3.0 mL) was added PPh? (710.4 mg, 2.7 mmol, 1.2 eq). The mixture was stirred at 25°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O (200.0 mL) and ethyl acetate (200.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-amino-N-(3-(benzyloxy)cyclobutyl)-N-(l-(3-bromo-2-fluorophenyl)cyclobutyl) acetamide (2.2 g, crude) as a yellow oil.5) N-(2-((3-(benzyloxy)cyclobutyl)(l-(3-bromo-2-fluorophenyl)cyclobutyl)amino)-2- oxoethyl)-2,2,2-trifluoroacetamide

[0641]

[0642] To a solution of 2-amino-N-(3-benzyloxycyclobutyl)-N-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl] acetamide (2.2 g, 4.8 mmol, 1.0 eq) in DCM (22.0 mL) was added TFAA (1.2 g, 5.7 mmol, 795.4 pL, 1.2 eq) and TEA (965.0 mg, 9.6 mmol, 1.3 mL, 2.0 eq) at 0°C. The mixture was stirred at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 100.0 mL and ethyl acetate (100.0 mL x 3). The organic phase was separated, dried over NaiSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Elash Column, Eluent of 0 ~ 8% Ethyl acetate / Petroleum ether gradient @120 mL / min) to give N-(2-((3-(benzyloxy)cyclobutyl)(l-(3-bromo-2-fluorophenyl)cyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (800.0 mg, 1.1 mmol, 23.2% yield, 77.0% purity) as a yellow oil.

[0643] 6) N-(2-(( l-(3-bromo-2-fluorophenyl)cyclobutyl)(3-hydroxycyclobutyl)amino)-2- oxoethyl)-2,2,2-trifluoroacetamide

[0644]

[0645] To a solution of N-[2-[(3-benzyloxycyclobutyl)-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]amino]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (1.0 g, 1.8 mmol, 1.0 eq) in DCM (20.0 mL) was added BB13 (1.6 g, 6.2 mmol, 0.6 mL, 3.5 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hr. LC-MS showed desired compound was detected. The reaction mixture was quenched by addition NH3.H2O 15.0 mL at -78°C, and then diluted with H2O 40.0 mL and extracted with Ethyl acetate 60.0 mL (30.0 mL x 2). The combined organiclayers were dried over NaiSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0 ~ 36% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give N- (2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)(3-hydroxycyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (0.9 g, 1.7 mmol, 94.5% yield, 88.0% purity) as a yellow oil.

[0646] 7) N-(2-(( l-(3-bromo-2-fluorophenyl)cyclobutyl)(3-fluorocyclobutyl)amino)-2-oxoethyl)- 2,2,2-trifluoroacetamide

[0647]

[0648] To a solution of N-[2-[[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-(3-hydroxycyclobutyl)amino]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (700.0 mg, 1.5 mmol, 1.0 eq) in DCM (14.0 mL) was added DAST (341.6 mg, 2.1 mmol, 280.0 pL, 1.4 eq) at -78°C. The mixture was stirred at -78°C for 1 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture was partitioned between NaHCOa 40.0 mL and ethyl acetate (50.0 mL x 3). The organic phase was separated, dried over NaiSCC filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0 ~ 6% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give N-(2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)(3-fluorocyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (130.0 mg, 277.0 pmol, 18.5% yield) as a yellow solid.

[0649] 8) 2-amino-N-( 1 -(3-bromo-2-fluorophenyl)cyclobutyl)-N-(3-fluorocyclobutyl) acetamide

[0650]

[0651] To a solution of N-[2-[[l-(3-bromo-2-fhioro-phenyl)cyclobutyl]-(3-fluorocyclobutyl)amino]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (50.0 mg, 106.6 pmol, 1.0 eq)in MeOH (0.6 mL) and H2O (0.2 mL) was added NaOH (21.3 mg, 532.8 pmol, 5.0 eq). The mixture was stirred at 20°C for 2 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 10.0 mL and ethyl acetate (10.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-amino-N-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-N-(3-fluorocyclobutyl) acetamide (50.0 mg, crude) as a yellow oil.

[0652] 9) Nl-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-N l-(3-fluorocyclobutyl)ethane-l,2- diamine

[0653]

[0654] To a solution of 2-amino-N-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-N-(3-fluorocyclobutyl)acetamide (75.0 mg, 200.9 pmol, 1.0 eq) in THF (1.5 mL) was added BH3.THF (1.0 M, 602.8 pL, 3.0 eq) at 0°C. The mixture was stirred at 25°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture was quenched by addition MeOH 5.0 mL at 0°C under N2, the mixture was stirred at 25°C for 1 hr and 60°C for 1 hr under N2. The mixture was concentrated under reduced pressure to remove solvent to give Nl-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-Nl-(3-fluorocyclobutyl)ethane-l,2-diamine (70.0 mg, crude) as a yellow solid.

[0655] 10) tert-butyl (2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)(3-fluorocyclobutyl)amino)ethyl) carbamate

[0656]

[0657] To a solution of N'-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-N'-(3-fluorocyclobutyl)ethane-l,2-diamine (70.0 mg, 194.9 pmol, 1.0 eq) in DCM (1.5 mL) was added TEA (39.4 mg, 389.7 pmol, 54.2 pL, 2.0 eq) and BOC2O (42.5 mg, 194.9 pmol, 44.8pL, 1.0 eq). The mixture was stirred at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 20.0 mL and ethyl acetate (20.0 mL x 3). The organic phase was separated, dried over NaiSC , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate = 3:1) to give tert-butyl (2-((l-(3-bromo-2-fluorophenyl)cyclobutyl)(3-fluorocyclobutyl)amino)ethyl)carbamate (40.0 mg, 87.1 pmol, 44.7% yield) as a yellow solid.

[0658] 11) tert-butyl (2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(3-fluorocyclobutyl)amino) ethyl )carbamate

[0659]

[0660] To a solution of tert-butyl N-[2-[[l-(3-bromo-2-fhioro-phenyl)cyclobutyl]-(3-fluorocyclobutyl)amino]ethyl]carbamate (40.0 mg, 87.1 pmol, 1.0 eq) in DMF (1.0 mL) was added Zn(CN)2 (40.0 mg, 340.7 pmol, 21.6 pL, 3.9 eq), BrettPhos Pd G3 (7.9 mg, 8.7 pmol, 0.1 eq) and BRETTPHOS (4.7 mg, 8.7 pmol, 0.1 eq). The mixture was stirred at 90°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture was quenched by addition sat. NaHCOa 10.0 mL at 25°C, and then extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 3:1) to give tert-butyl (2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(3-fluorocyclobutyl)amino) ethyl)carbamate (30.0 mg, 73.9 pmol, 84.9% yield) as a yellow solid.12) A l-(l-(3-cyano-2-fluorophenyl3-cyano-2-fluorophenyl)cyclobutyl)-N l-((ls,3s)-3- fluorocyclobutyl) ethane-l,2-diamine hydrochloride

[0661]

[0662] 15 470

[0663] To a solution of tert-butyl N-[2-[[l-(3-cyano-2-fluoro-phenyl)cyclobutyl]-(3-fluorocyclobutyl)amino]ethyl]carbamate (30.0 mg, 73.9 pmol, 1.0 eq) in EtOAc (0.3 mL) was added HCl / EtOAc (4.0 M, 0.3 mL, 16.2 eq) at 0°C. The mixture was stirred at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100 x 40mm x 5 um; mobile phase: [H20(0.04% HC1) - ACN]; gradient: 5% - 40% B over 8.0 min) to give Nl-(l-(3-cyano-2-fluorophenyl3-cyano-2-fluorophenyl)cyclobutyl)-Nl-((ls,3s)-3-fluorocyclobutyl)ethane-l,2-diamine hydrochloride (9.25 mg, 27.06 pmol, 36.58% yield, 100% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 306.3 [M+H]+, retention time: 1.552 min, method:E.!H NMR (400 MHz, DMSO-tfe) d 8.26 - 7.97 (m, 3H), 7.94 - 7.82 (m, 2H), 7.48 - 7.39 (m, 1H), 5.19 - 4.93 (m, 1H), 3.86 (br d, J= 8.1 Hz, 1H), 2.93 (br s, 4H), 2.71 - 2.56 (m, 2H), 2.51 (br s, 2H), 2.44 -2.25 (m, 2H), 2.22 - 2.04 (m, 2H), 1.96 - 1.84 (m, 1H), 1.57 (quind, J= 8.1, 10.6 Hz, 1H).

[0664] 13) Nl-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-Nl-((lr,3r)-3-fluorocyclobutyl)ethane-l,2- diamine hydrochloride

[0665]

[0666] To a solution of 2-amino-N-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-N-(3-fhiorocyclobutyl)acetamide (25.0 mg, 66.9 pmol, 1.0 eq) in THF (0.5 mL) was added BH3.THF (1.0 M, 200.9 pL, 3.0 eq) at 0°C. The mixture was stirred at 25°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture wasquenched by addition MeOH 2.0 mL at 0°C under N2, the mixture was steirred at 25°C for 1 hr and 60°C for 1 hr under N2. The mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100 x 40mm x5 um;mobile phase: [H20(0.04% HC1) - ACN]; gradient: 5% - 45% B over 8.0 min) to give Nl-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-Nl-((lr,3r)-3-fluorocyclobutyl)ethane-l,2-diamine hydrochloride (6.07 mg, 14.8 pmol, 22.2% yield, 96.8% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 359.2 [M+H]+, retention time: 1.696 min, method:B.XH NMR (400 MHz, DMSO-tfe) d 8.28 - 7.88 (m, 3H), 7.70 (br t, J = 7.0 Hz, 1H), 7.54 (br t, J = 7.2 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 5.20 - 4.95 (m, 1H), 3.96 - 3.79 (m, 1H), 2.96 (br s, 4H), 2.68 (br d, J = 2.1 Hz, 2H), 2.57 - 2.52 (m, 2H), 2.46 - 2.28 (m, 2H), 2.26 - 2.08 (m, 2H), 1.92 (tq, J= 4.7, 9.6 Hz, 1H), 1.67 - 1.47 (m, 1H).

[0667] Example 16: Synthesis of 3-(l-((2-aminoethyl)((lR,2R)-2-fluorocvclobutyl)amino) cyclobutyl)-2-fluorobenzonitrile hydrochloride (Compound 491) and of 3-(l- ((2-aminoethyl)((lS,2S)-2-fhiorocyclobutyl)amino)cyclobutyl)-2-fluorobenzo nitrile hydrochloride (Compound 492)

[0668] 1) tert-butyl N-[2-[[l-(3-cyano-2-fluoro-phenyl)cyclobutyl]-[(lR,2R)-2- fluorocyclobutyl]amino]ethyl]carbamate and tert-butyl N-[2-[[l-(3-cyano-2-fluoro- phenyl)cyclobutyl]-[(lS,2S)-2-fluorocyclobutyl]amino]ethyl]carbamate

[0669]

[0670] To a solution of 3-[l-[2-aminoethyl-(2-fhiorocyclobutyl)amino]cyclobutyl]-2-fluoro-benzonitrile (36.0 mg, 105.3 pmol, 1.0 eq, HC1) in DCM (1.0 mL) was added TEA (31.9 mg, 315.9 pmol, 43.9 pL, 3.0 eq) and BociO (27.5 mg, 126.3 pmol, 29.0 pL, 1.2 eq). The mixture was stirred at 25 °C for 2 hr. LC-MS showed desired compound was detected. The residue was purified by prep-HPLC (HC1 condition, column: Phenomenex luna C18 100 x 40mm x 5 um; mobile phase: [H20(0.04% HCl)-ACN];gradient:30%-60% B over 8.0 min ) to give compound 12 (18 mg) as a light yellow solid, which was further separated by SFC (condition, column: DAICEL CHIRALPAK IC(250mm*30mm,10um); mobile phase: [CO2-IPA(0.1%NH3H2O)]; B%:25%, isocratic elution mode) to give compound tert-butyl N-[2-[[l-(3-cyano-2-fluoro-phenyl)cyclobutyl]-[(lR,2R)-2-fluorocyclobutyl]amino]ethyl] carbamate (8.0 mg, 19.7 pmol, 18.7% yield) and tert-butyl N-[2-[[l-(3-cyano-2-fluoro-phenyl)cyclobutyl]-[(lS,2S)-2-fluorocyclobutyl]amino]ethyl]carbamate (8.0 mg, 19.7 pmol, 18.7% yield) as a light yellow solid.

[0671] 2) 3-(l-((2-aminoethyl)((lR,2R)-2-fluorocyclobutyl)amino)cyclobutyl)-2- fluorobenzonitrile hydrochloride

[0672] < > < >

[0673]

[0674] 12A 491

[0675] A mixture of tert-butyl N-[2-[[l-(3-cyano-2-fhioro-phenyl)cyclobutyl]-[(lR,2R)-2-fluorocyclobutyl] amino] ethyl] carbamate (8.0 mg, 19.7 pmol, 1.0 eq) in HCI / EtOAc (0.2 mL) (4 M) was stirred at 25 °C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give compound 3-(l-((2-aminoethyl)((lR,2R)-2-fluorocyclobutyl)amino)cyclobutyl)-2-fluorobenzonitrile hydrochloride (5.85 mg, 100% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 306.2 [M+H]+, retention time: 1.625 min, method: BXH NMR (400 MHz, DMSO-tfe) <5 8.19 - 7.86 (m, 3H), 7.85 - 7.76 (m, 2H), 7.40 (t, J = 7.8 Hz, 1H), 4.95 - 4.67 (m, 1H), 3.43 - 3.20 (m, 1H), 2.97 - 2.73 (m, 4H), 2.58 - 2.51 (m, 1H), 2.44 - 2.37 (m, 1H), 2.04 - 1.91 (m, 2H), 1.65 - 1.50 (m, 3H), 1.30 - 1.19 (m, 3H).3) 3-(l-((2-aminoethyl)((lS,2S)-2-fluorocyclobutyl)amino)cyclobutyl)-2- fluorobenzonitrile hydrochloride

[0676] < > < >

[0677]

[0678] <12B 492

[0679] A mixture of tert-butyl N-[2-[[l-(3-cyano-2-fluoro-phenyl)cyclobutyl]-[(lS,2S)-2-fluorocyclobutyl] amino] ethyl] carbamate (8.0 mg, 19.7 pmol, 1.0 eq) in HCI / EtOAc (0.2 mL) (4 M) was stirred at 25 °C for 1 hr. LC-MS showed desired compound was detected. The mixture was filtered and concentrated under reduced pressure to give compound 3-(l-((2-aminoethyl)((lS,2S)-2-fluorocyclobutyl)amino)cyclobutyl)-2-fluorobenzonitrile hydrochloride (4.85 mg, 98.4% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 306.2 [M+H]+, retention time: 1.598 min, method: EXH NMR (400 MHz, DMSO-tfe) 5 8.02 (br s, 3H), 7.85 - 7.76 (m, 2H), 7.40 (t, J= 7.7 Hz, 1H), 4.94 - 4.74 (m, 1H), 3.41 - 3.24 (m, 1H), 2.99 - 2.77 (m, 4H), 2.55 (br s, 1H), 2.45 - 2.39 (m, 1H), 2.04 - 1.87 (m, 2H), 1.65 - 1.49 (m, 3H), 1.34 - 1.17 (m, 3H).

[0680] Example 17: Synthesis of trans-3-l-((2-aminoethyl)(propyl)amino)-3-fhiorocyclobutyl)-2- fluorobenzonitrile (Compound 413), of cis-3- l-((2- aminoethyl)(propyl)amino)-3-fluorocyclobutyl)-2-fluorobenzonitrile (Compound 413A) and of trans-Nl-(l-(3-bromo-2-fhioro >henyl)-3- fluorocyclobutyl)-Nl -propylethane- 1,2-diamine (Compound 413B)

[0681] 1) l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutane-l-carbonitrile

[0682]

[0683] To a solution of l-(3-bromo-2-fluoro-phenyl)-3-hydroxy-cyclobutanecarbonitrile (1.0 g, 3.7 mmol, 1.0 eq) in DCM (30.0 mL) was added DAST (1.8 g, 11.1 mmol, 1.5 mL, 3.0 eq). The mixture was stirred at 20°C for 12 hrs. TLC indicated 414 int.2 was consumedcompletely and one major new spot formed. The reaction mixture was quenched by addition sat. NaHCO? 15.0 mL at 0°C, and then diluted with H2O 10.0 mL and extracted with DCM 45.0 mL (15.0 mL x 3). The combined organic layers dried over NaiSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~8% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutane-l-carbonitrile (290.0 mg, 1.1 mmol, 28.8% yield) as a colorless oil.

[0684] 2) l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutane-l-carboxylic acid

[0685]

[0686] To a solution of l-(3-bromo-2-fhiorophenyl)-3-fluorocyclobutane-l -carbonitrile (400.0 mg, 1.5 mmol, 1.0 eq) in MeOH (4.0 mL) and H2O (16.0 mL) was added NaOH (1.8 g, 44.1 mmol, 30.0 eq). The mixture was stirred at 110°C for 12 hrs. LC-MS showed reactant 3 was consumed completely and 74.4% peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was acidified by HC1 (1 M) to adjust pH around 3, then extracted with EtOAc (15.0 mL x 2). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutane-l-carboxylic acid (384.0 mg, crude) as a yellow oil.

[0687] 3) l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutan-l -amine

[0688]

[0689] 4 5A mixture of l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutane-l -carboxylic acid (384.0 mg, 1.3 mmol, 1.0 eq), DPPA (435.7 mg, 1.6 mmol, 341.7 pL, 1.2 eq), and TEA (400.5 mg, 4.0 mmol, 550.9 pL, 3.0 eq) in DMF (15.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20°C for 12 hrs under N2 atmosphere. HC1 (1 M, 7.9 mL, 6.0 eq) and H2O (15.0 mL) was added, after which the reaction mixture was stirred again at 100°C for 2 hrs. LC-MS showed reactant 4 was consumed completely and 4.5% peak with desired m / z was detected. The reaction mixture was diluted with H2O 5.0 mL and extracted with EtOAc 15.0 mL. The aqueous phase was add sat. Na2COa to adjust pH around 10, then extracted with EtOAc (25.0 mL x 2). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutan-l-amine (210.0 mg, crude) as a yellow oil.

[0690] 4) tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)amino)ethyl)carbamate

[0691] >

[0692]

[0693] 5 6

[0694] To a solution of l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutan-l-amine (190.0 mg, 724.9 pmol, 1.0 eq) in MeOH (1.5 mL) was added tert-butyl N-(2-oxoethyl)carbamate (80.8 mg, 507.5 pmol, 0.7 eq), AcOH (65.3 mg, 1.1 mmol, 62.3 pL, 1.5 eq) and NaBHaCN (136.7 mg, 2.2 mmol, 3.0 eq). The mixture was stirred at 60°C for 1 hr. LC-MS showed reactant 5 was consumed completely and 42.0% peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 10.0 mL and extracted with EtOAc 30.0 mL (15.0 mL x 2). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate=2 / l) to give compound tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)amino)ethyl) carbamate (260.0 mg, 384.9 pmol, 53.1% yield, 60.0% purity) as a colorless oil.5) tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(propyl)amino) ethyl )carbamate

[0695]

[0696] To a solution of tert-butyl (2-((l-(3-bromo-2-fhiorophenyl)-3-fluorocyclobutyl) amino)ethyl)carbamate (94.0 mg, 139.2 pmol, 1.0 eq) in MeOH (1.0 mL) was added propanal (161.7 mg, 2.8 mmol, 202.6 pL, 20.0 eq), AcOH (16.7 mg, 278.3 pmol, 15.9 pL, 2.0 eq) and NaBHaCN (35.0 mg, 556.7 pmol, 4.0 eq). The mixture was stirred at 60°C for 12 hrs. LC-MS showed 43.0% reactant 6 was remained and 26.0% peak with desired m / z was detected. The reaction mixture was diluted with H2O 15.0 mL and extracted with EtOAc 45.0 mL (15.0 mL x 3). The combined organic layers were washed with brine 30.0 mL (10.0 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate=3 / l) to give compound tertbutyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(propyl)amino)ethyl) carbamate (36.0 mg, 51.5 pmol, 37.0% yield) as a white solid.

[0697] 6) tert-butyl (2-((l-(3-cyano-2-fluorophenyl)-3-fluorocyclobutyl)(propyl)amino)ethyl) carbamate

[0698]

[0699] A mixture of tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(propyl)amino)ethyl)carbamate (50.0 mg, 111.8 pmol, 1.0 eq) , Zn(CN)2 (39.4 mg, 335.3 pmol, 21.3 pL, 3.0 eq), BrettPhos Pd G3 (10.1 mg, 11.2 pmol, 0.1 eq) and BrettPhos (6.0 mg, 11.2 pmol, 0.1 eq) in DMF (3.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hrs under N2 atmosphere. LC-MS showed reactant 7 was consumed completely and 13.0% peak with desired m / z was detected.The reaction mixture was quenched by addition saturated sodium bicarbonate 10.0 mL at 20°C, and then extracted with ethyl acetate 15.0 mL (5.0 mL x 3). The combined organic layers were dried over NaiSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate=3 / l) to give compound tert-butyl (2-((l-(3-cyano-2-fluorophenyl)-3-fluorocyclobutyl)(propyl)amino)ethyl)carbamate (40.0 mg, 101.7 pmol, 91.0% yield) as a colourless oil.

[0700] 7) Trans-3-l-((2-aminoethyl)(propyl)amino)-3-fluorocyclobutyl)-2-fluorobenzonitrile &

[0701] cis-3-l-((2-aminoethyl)(propyl)amino)-3-fluorocyclobutyl)-2-fluorobenzonitrile

[0702]

[0703] A solution of tert-butyl (2-((l-(3-cyano-2-fluorophenyl)-3-fluorocyclobutyl)(propyl)amino)ethyl)carbamate (40.0 mg, 101.7 pmol, 1.0 eq) in 4 M HCl / EtOAc (3.0 mL) was stirred at 20°C for 0.5 hr. LC-MS showed reactant 8 was consumed completely and 35% peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H20(0.04% HC1)-ACN]; gradient: l%-35% B over 8.0 min) to give compound trans-3-l-((2-aminoethyl)(propyl)amino)-3-fluorocyclobutyl)-2-fluorobenzonitrile (413) (15.4 mg, 45.7 pmol, 44.8% yield, 97.8% purity, HC1 salt) as a white solid. MS (ESI): m / z 294.2 [M+H]+, retention time: 1.620 min, method:B.!H NMR (400 MHz, DMSO-d6) 3 8.16 (br s, 3H), 7.87 (br t, J = 6.5 Hz, 1H), 7.74 (br t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 5.45 -5.41 (m, 0.5H), 5.28 (br s, 0.5H), 3.18 (br s, 2H), 3.01 - 2.77 (m, 4H), 2.63 - 2.53 (m, 2H), 2.48 (br d, J = 7.6 Hz, 2H), 1.51 - 1.37 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H) and compound cis-3-l-((2-aminoethyl)(propyl)amino)-3-fluorocyclobutyl)-2-fluorobenzonitrile (413A) (5.41 mg, 16.34 pmol, 16.07% yield, 99.61% purity, HC1 salt) as a white solid. MS (ESI): m / z = 294.2 [M+H]+, retention time: 1.557 min, method:B. ’H NMR (400 MHz, DMSO-d6) 3 8.19 -7.82 (m, 5H), 7.45 (t, J = 7.8 Hz, 1H), 4.81 (br t, J = 6.7 Hz, 0.5H), 4.67 (br d, J = 6.8 Hz,0.5H), 3.30 - 3.08 (m, 2H), 3.02 - 2.69 (m, 6H), 2.38 (br s, 2H), 1.50 - 1.34 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H).

[0704] 8) Trans-N l-( l-{ 3-bromo-2-J luoropheny I )-3-fluorocyclobuty I )-N 1 -propylethane- 1 ,2- diamine

[0705]

[0706] A solution of tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(propyl)amino)ethyl)carbamate (36.0 mg, 80.5 pmol, 1.0 eq) in 4 M HCl / EtOAc (3.0 mL) was stirred at 20°C for 0.5 hr. LC-MS showed reactant 7 was consumed completely and 43% peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (NH4HCO3 condition, column: WePure Biotech XP tC18 150 x 40 x 7um; mobile phase: [HiOQOmM NH4HCO3)-ACN]; gradient: 35%-65% B over 8.0 min) to give compound trans-N1-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N1-propylethane-1,2-diamine (5.0 mg, 13.5 pmol, 16.8% yield, 94.4% purity) as a colorless oil. MS (ESI): m / z = 347.1 [M+H]+, retention time: 1.794 min, method:B. ’H NMR (400 MHz, DMSO-d6) 3 7.61 - 7.53 (m, 1H), 7.23 - 7.10 (m, 2H), 5.31 - 5.05 (m, 1H), 3.02 - 2.85 (m, 4H), 2.42 - 2.15 (m, 6H), 1.39 - 1.24 (m, 2H), 0.80 (t, J= 7.3 Hz, 3H).

[0707] Example 18: Synthesis of Compounds 463, 525 and 526

[0708] 1) l-(3-bromo-2-fluorophenyl)-3-fluoro-N-(2-fluorocyclobutyl)cyclobutan-l-amine

[0709]

[0710] To a solution of l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutanamine (2.0 g, 7.6 mmol, 1.0 eq) in MeOH (20.0 mL) was added AcOH (916.5 mg, 15.3 mmol, 873.7 pL, 2.0eq) and 2-fluorocyclobutanone (672.1 mg, 7.6 mmol, 1.0 eq). The mixture was stirred at 20°C for 11 hr. Then added NaBFLCN (1.9 g, 30.5 mmol, 4.0 eq) to the mixture. The mixture was stirred at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 30.0 mL and ethyl acetate (30.0 mL x 3). The organic phase was separated, dried over NaiSC , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0 ~ 5% Ethyl acetate / Petroleum ether gradient @80 mL / min) to give l-(3-bromo-2-fluorophenyl)-3-fluoro-N-(2-fluorocyclobutyl)cyclobutan-l-amine (900.0 mg, 2.7 mmol, 35.3% yield) as a yellow solid.

[0711] 2) 2-bromo-N-( l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(2- fluorocyclobutyl)acetamide

[0712]

[0713] To a solution of l-(3-bromo-2-fluoro-phenyl)-3-fluoro-N-(2-fluorocyclobutyl) cyclobutanamine (900.0 mg, 2.7 mmol, 1.0 eq) in DCM (9.0 mL) and H2O (9.0 mL) was added K2CO3 (1.5 g, 10.8 mmol, 4.0 eq) and 2-bromoacetyl bromide (1.6 g, 8.1 mmol, 703.9 pL, 3.0 eq) at 0°C. The mixture was stirred at 20°C for 3 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 60.0 mL and ethyl acetate (60.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-bromo-N-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(2-fluorocyclobutyl)acetamide (1.0 g, crude) as a yellow oil.

[0714] 3) 2-azido-N-( 1 -(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(2- fluorocyclobutyl)acetamide

[0715]

[0716] 7 8To a solution of 2-bromo-N-[l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutyl]-N-(2-fluorocyclobutyl)acetamide (1.0 g, 2.2 mmol, 1.0 eq) in DMSO (20.0 mL) was added NaN? (186.0 mg, 2.9 mmol, 1.3 eq). The mixture was stirred at 25°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between NaHCOa (40.0 mL) and ethyl acetate (60.0 mL x 3). The organic phase was separated, washed with brine (60.0 mL x 3), dried over NaiSCU, filtered and concentrated under reduced pressure to give 2-azido-N-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(2-fluorocyclobutyl)acetamide (1.0 g, crude) as a yellow oil.

[0717] 4) tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(2-fluorocyclobutyl) amino )-2-oxoethyl)carbamate

[0718]

[0719] To a solution of 2-azido-N-[l-(3-bromo-2-fhioro-phenyl)-3-fluoro-cyclobutyl]-N-(2-fluorocyclobutyl)acetamide (1.0 g, 2.4 mmol, 1.0 eq) in THF (9.0 mL) and H2O (3.0 mL) was added PPI13 (754.4 mg, 2.9 mmol, 1.2 eq) and BOC2O (1.1 g, 4.8 mmol, 1.1 mL, 2.0 eq). The mixture was stirred at 25°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 60.0 mL and ethyl acetate (60.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0 ~ 6% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(2-fluorocyclobutyl)amino)-2-oxoethyl)carbamate (320.0 mg, 651.3 pmol, 27.2% yield) as a yellow solid.5) tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(2-fluorocyclobutyl) amino )ethyl )carbamate

[0720]

[0721] To a solution of tert-butyl N-[2-[[l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutyl]-(2-fluorocyclobutyl)amino]-2-oxo-ethyl]carbamate (320.0 mg, 651.3 pmol, 1.0 eq) in THF (3.0 mL) was added BHa-MeiS (10.0 M, 0.2 mL, 3.1 eq) at 0°C under N2. The mixture was stirred at 25°C for 3 hr under N2. LC-MS showed desired compound was detected. The reaction mixture was quenched by addition MeOH 5.0 mL at 0°C under N2, the mixture was stirred at 25°C for 1 hr and 60°C for 1 hr under N2. The mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate = 3:1) to give tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(2-fluorocyclobutyl)amino)ethyl)carbamate (170.0 mg, 356.1 pmol, 54.7% yield) as a yellow solid.

[0722] 6) tert-butyl (2-( (l-(3-cyano-2-fluorophenyl)-3-fluorocyclobutyl)(2-fluorocyclobutyl) amino )ethyl)carbamate

[0723]

[0724] To a solution of tert-butyl N-[2-[[l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutyl]-(2-fluorocyclobutyl)amino]ethyl]carbamate (100.0 mg, 209.5 pmol, 1.0 eq) in DMF (2.0 mL) was added Zn(CN)2 (100.0 mg, 851.6 pmol, 54.1 pL, 4.1 eq), BrettPhos Pd G3 (19.0 mg, 20.9 pmol, 0.1 eq) and BRETTPHOS (11.2 mg, 20.9 pmol, 0.1 eq). The mixture was stirred at 90°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture was quenched by addition sat.NaHCOa 10.0 mL at 25°C, and then extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were washed with brine (10.0mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiOi. Petroleum ether / Ethyl acetate = 3:1) to give tert-butyl (2-((l-(3-cyano-2-fluorophenyl)-3-fluorocyclobutyl)(2-fluorocyclobutyl)amino)ethyl)carbamate (60.0 mg, 141.7 pmol, 67.6% yield) as a yellow solid.

[0725] 7) (cis, cis)-3-(l-((2-aminoethyl)(2-fluorocyclobutyl)amino)-3-fluorocyclobutyl)-2- fluorobenzonitrile.hydrogen chloride and (trans, cis)-3-(l-((2-aminoethyl)(2- fluorocyclobutyl)amino)-3-fluorocyclobutyl)-2-fluorobenzonitrile.hydrogen chloride and (cis, trans)-3-(l-((2-aminoethyl)(2-fluorocyclobutyl)amino)-3-fluorocyclobutyl)-2- fluorobenzonitrile.hydrogen chloride

[0726]

[0727] 525 526

[0728] To a solution of tert-butyl N-[2-[[l-(3-cyano-2-fhioro-phenyl)-3-fluoro-cyclobutyl]-(2-fluorocyclobutyl)amino]ethyl]carbamate (60.0 mg, 141.7 pmol, 1.0 eq) in EtOAc (0.6 mL) was added HCl / EtOAc (4.0 M, 0.6 mL, 16.9 eq). The mixture was stirred at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100 x 40mm x 5 um; mobile phase: [H2O (0.04% HC1) - ACN]; gradient: 5% - 40% B over 8.0 min) to give (cis, cis)-3-(l-((2-aminoethyl)(2-fluorocyclobutyl)amino)-3-fluorocyclobutyl)-2-fluorobenzonitrile.hydrogen chloride (463) (5.6 mg, 15.2 pmol, 10.7% yield, 97.6% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 324.1 [M+H]+, retention time: 1.523 min, method:B.XH NMR (400 MHz, DMSO-tfe) b 8.04 - 7.83 (m, 5H), 7.40 (t, J= 7.8 Hz, 1H), 5.04 - 4.83 (m, 1H), 4.77 - 4.55 (m, 1H), 3.21 -2.97 (m, 5H), 2.79 - 2.60 (m, 4H), 2.35 (quin, J = 9.8 Hz, 1H), 2.02 - 1.84 (m, 2H), 1.80 -1.61 (m, 1H). and (trans, cis)-3-(l-((2-aminoethyl)(2-fluorocyclobutyl)amino)-3-fluorocyclobutyl)-2-fluorobenzonitrile.hydrogen chloride (525) (15.8 mg, 42.0 umol.

[0729] 29.6% yield, 95.8% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 324.2 [M+H]+, retention time: 1.574 min, method:B. ’H NMR (400 MHz, DMSO-tfe) d 8.15 (br s, 3H), 7.98 -7.83 (m, 2H), 7.47 - 7.37 (m, 1H), 5.03 - 4.78 (m, 1H), 4.77 - 4.56 (m, 1H), 3.20 - 3.04 (m, 3H), 2.98 - 2.64 (m, 6H), 2.09 - 1.93 (m, 1H), 1.75 - 1.48 (m, 2H), 1.41 - 1.18 (m, 1H) and (cis, trans)-3-(l-((2-aminoethyl)(2-fluorocyclobutyl)amino)-3-fluorocyclobutyl)-2-fluorobenzonitrile.hydrogen chloride (526) (14.1 mg, 37.8 pmol, 26.7% yield, 96.3% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 324.1 [M+H]+, retention time: 1.638 min, method:B. ’H NMR (400 MHz, DMSO-tfe) d 8.11 (br s, 3H), 7.89 - 7.82 (m, 1H), 7.73 - 7.66 (m, 1H), 7.41 (t, J = 7.8 Hz, 1H), 5.39 - 5.11 (m, 1H), 4.95 - 4.68 (m, 1H), 3.51 - 3.34 (m, 1H), 3.18 - 2.99 (m, 2H), 2.96 - 2.70 (m, 4H), 2.49 - 2.34 (m, 2H), 2.04 - 1.89 (m, 1H), 1.65 -1.48 (m, 1H), 1.41 (quin, J= 10.2 Hz, 1H), 1.12 (quin, J= 9.8 Hz, 1H).

[0730] Example 19: Synthesis of Compounds 510, 511 and 512

[0731] 1) 1 -(3-bromo-2-fluorophenyl)-3-fluoro-N-(2-fluorocyclobutyl)cyclobutan-l -amine

[0732]

[0733] To a solution of l-(3-bromo-2-fhioro-phenyl)-3-fhioro-cyclobutanamine (580.0 mg, 2.2 mmol, 1.0 eq) in MeOH (6.0 mL) was added AcOH (265.8 mg, 4.4 mmol, 253.4 pL, 2.0 eq) and 2-fluorocyclobutanone (194.9 mg, 2.2 mmol, 1.0 eq). The mixture was stirred at 20°C for 1 hr. Then added NaBHaCN (556.3 mg, 8.8 mmol, 4.0 eq) to the mixture. The mixture was stirred at 20°C for 11 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 30.0 mL and ethyl acetate (30.0 mL x 3). The organic phase was separated, dried over NaiSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0 ~ 4% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give l-(3-bromo-2-fluorophenyl)-3-fluoro-N-(2-fluorocyclobutyl)cyclobutan-l-amine (330.0 mg, 987.5 pmol, 44.6% yield) as a yellow solid.2) 2-bromo-N-( l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(2- fluorocyclobutyl)acetamide

[0734]

[0735] To a solution of l-(3-bromo-2-fhioro-phenyl)-3-fluoro-N-(2-fluorocyclobutyl)cyclobutanamine (330.0 mg, 987.5 pmol, 1.0 eq) in DCM (3.0 mL) and H2O (3.0 mL) was added K2CO3 (545.9 mg, 3.9 mmol, 4.0 eq) and 2-bromoacetyl bromide (797.3 mg, 3.9 mmol, 344.1 pL, 4.0 eq) at 0°C. The mixture was stirred at 20°C for 3 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 20.0 mL and ethyl acetate (20.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-bromo-N-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(2-fluorocyclobutyl)acetamide (500.0 mg, crude) as a yellow oil.

[0736] 3) 2-azido-N-( 1 -(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(2-fluorocyclobutyl) acetamide

[0737]

[0738] To a solution of 2-bromo-N-[l-(3-bromo-2-fhioro-phenyl)-3-fluoro-cyclobutyl]-N-(2-fluorocyclobutyl)acetamide (500.0 mg, 1.1 mmol, 1.0 eq) in DMSO (10.0 mL) was added NaNa (93.0 mg, 1.4 mmol, 1.3 eq). The mixture was stirred at 25°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between NaHCCh (20.0 mL) and ethyl acetate (30.0 mL x 3). The organic phase was separated, washed with brine (30.0 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-azido-N-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(2-fluorocyclobutyl)acetamide (400.0 mg, crude) as a yellow oil.4) tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(2-fluorocyclobutyl) amino )-2-oxoethyl)carbamate

[0739]

[0740] To a solution of 2-azido-N-[l-(3-bromo-2-fhioro-phenyl)-3-fluoro-cyclobutyl]-N-(2-fluorocyclobutyl)acetamide (400.0 mg, 958.7 pmol, 1.0 eq) in THF (3.0 mL) and H2O (1.0 mL) was added PPI13 (301.7 mg, 1.2 mmol, 1.2 eq) and BOC2O (418.5 mg, 1.9 mmol, 440.5 pL, 2.0 eq). The mixture was stirred at 25°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O 30.0 mL and ethyl acetate (30.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate = 3:1) to give tert-butyl (2-((l-(3-bromo- 2-fluorophenyl)-3-fluorocyclobutyl)(2-fluorocyclobutyl)amino)-2-oxoethyl)carbamate (120.0 mg, 244.2 pmol, 25.4% yield) as a yellow solid.

[0741] 5) tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(2-fluorocyclobutyl) amino )ethyl)carbamate

[0742]

[0743] To a solution of tert-butyl N-[2-[[l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutyl]-(2-fluorocyclobutyl)amino]-2-oxo-ethyl]carbamate (60.0 mg, 122.1 pmol, 1.0 eq) in THF (1.0 mL) was added BHa-MeiS (10.0 M, 0.1 mL, 3.3 eq) at 0°C under N2. The mixture was stirred at 25°C for 3 hr under N2. LC-MS showed desired compound was detected. The reaction mixture was quenched by addition MeOH 2.0 mL at 0°C under N2, the mixture was stirred at 25°C for 1 hr and 60°C for 1 hr under N2. The mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiCL, Petroleumether / Ethyl acetate = 3:1) to give tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(2-fluorocyclobutyl)amino)ethyl)carbamate (44.0 mg, 92.1 umol. 37.7% yield) as a yellow solid.

[0744] 6) ( cis, cis )-Nl-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-Nl -( 2- fluorocyclobutyl)ethane-l,2-diamine.hydrogen chloride and (trans, cis)-Nl-(l-(3- bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N 1 -(2-fluorocyclobutyl)ethane-l ,2- diamine.hydrogen chloride and (cis, trans)-Nl-(l-(3-bromo-2-fluorophenyl)-3- fluorocyclobutyl)-N l-(2-fluorocyclobutyl)ethane-l ,2-diamine. hydrogen chloride

[0745]

[0746] 511 512

[0747] To a solution of tert-butyl N-[2-[[l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutyl]-(2-fluorocyclobutyl)amino]ethyl]carbamate (44.0 mg, 92.1 pmol, 1.0 eq) in EtOAc (0.5 mL) was added HCl / EtOAc (4.0 M, 0.5 mL, 21.7 eq). The mixture was stirred at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100x40mmx5 um; mobile phase: [H2O (0.04% HC1) - ACN]; gradient: 5% - 45% B over 8.0 min) to give (cis, cis)-Nl-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-Nl-(2-fluorocyclobutyl)ethane-l,2-diamine.hydrogen chloride (7.6 mg, 16.9 pmol, 18.4% yield, 92.9% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 377.0 [M+H]+, retention time: 1.731 min, method:B. ’H NMR (400 MHz, DMSO-tfe) d 7.92 - 7.68 (m, 3H), 7.67 - 7.60 (m, 1H), 7.57 - 7.46 (m, 1H), 7.23 - 7.10 (m, 1H), 5.07 - 4.82 (m, 1H), 4.80 - 4.57 (m, 1H), 3.41 - 3.29 (m, 1H), 3.10 - 2.96 (m, 4H), 2.86 - 2.75 (m, 2H), 2.69 - 2.56 (m, 2H), 2.41 - 2.29 (m, 1H), 2.05 - 1.84 (m, 2H), 1.82 - 1.65 (m, 1H). and (trans, cis)-Nl-(l- (3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-Nl-(2-fluorocyclobutyl)ethane-l,2-diamine.hydrogen chloride (20.8 mg, 47.6 pmol, 51.7% yield, 94.8% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 377.0 [M+H]+, retention time: 1.773 min, method:B. ’H NMR (400 MHz, DMSO-tfe) d 8.07 - 7.74 (m, 3H), 7.69 - 7.59 (m, 1H), 7.55 - 7.46 (m, 1H), 7.21 -7.11 (m, 1H), 4.91 - 4.75 (m, 1H), 4.74 - 4.58 (m, 1H), 3.16 - 2.99 (m, 3H), 2.91 - 2.74 (m, 4H), 2.73 - 2.56 (m, 2H), 2.07 - 1.95 (m, 1H), 1.70 - 1.48 (m, 2H), 1.33 - 1.15 (m, 1H). and (cis, trans)-Nl-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-Nl-(2-fluorocyclobutyl)ethane-l,2-diamine.hydrogen chloride (5.8 mg, 13.9 pmol, 15.1% yield, 98.5% purity, HC1) as a yellow oil. MS (ESI): m / z = 377.0 [M+H]+, retention time: 1.838 min, method:B. ’H NMR (400 MHz, DMSO-tfe) <58.11 - 7.76 (m, 3H), 7.61 (br

[0748]

[0749] Hz, 1H), 7.39 - 7.26 (m, 1H), 7.20 - 7.09 (m, 1H), 5.37 - 5.09 (m, 1H), 4.93 - 4.66 (m, 1H), 3.48 - 3.33 (m, 1H), 3.15 - 3.00 (m, 3H), 2.88 - 2.76 (m, 3H), 2.48 - 2.32 (m, 2H), 2.07 - 1.94 (m, 1H), 1.66 - 1.40 (m, 2H), 1.29 - 1.10 (m, 1H).

[0750] Example 20: Synthesis of Compounds 502, 503, 506 and 507

[0751] 1) N-(3-(benzyloxy )cyclobutyl)~ 1 -(3-bromo-2-fluorophenyl)-3-fluorocyclobutan- 1 -amine

[0752]

[0753] To a solution of l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutanamine (3.5 g, 13.3 mmol, 1.0 eq) in MeOH (35.0 mL) was added 3-benzyloxycyclobutanone (3.0 g, 17.3 mmol, 1.3 eq), AcOH (1.6 g, 26.7 mmol, 1.5 mL, 2.0 eq) and Ti(i-PrO)4 (5.6 g, 20.0 mmol, 5.9 mL, 1.5 eq). The mixture was stirred at 20°C for 1 hr. NaBHaCN (3.3 g, 53.4 mmol, 4.0 eq) was added the reaction and then stirred at 20°C for 2 hr. LC-MS showed desired compound 6 was detected. The combined reaction mixture was poured into water (100.0 mL) and extracted with ethyl acetate (60.0 mL x 2). The combined organic layers were washed with brine 50.0 mL, dried over NaiSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g, Eluent of 10-12% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound N-(3- (benzyloxy)cyclobutyl)-l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutan-l-amine (4.5 g, 10.2 mmol, 77.0% yield, 96.6% purity) as a colourless oil.2) N-(3-(benzyloxy)cyclobutyl)-2-bromo-N-( l-(3-bromo-2-fluorophenyl)-3- fluorocyclobutyl)acetamide

[0754]

[0755] To a solution of N-(3-benzyloxycyclobutyl)-l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutanamine (3.5 g, 8.2 mmol, 1.0 eq) in H2O (35.0 mL) and DCM (35.0 mL) was added K2CO3 (4.5 g, 33.1 mmol, 4.0 eq) and 2-bromoacetyl bromide (5.0 g, 24.8 mmol, 2.1 mL, 3.0 eq). The mixture was stirred at 20°C for 12 hr. LC-MS showed 21% reactant 6 was remained and 60% peak with desired mass was detected. The reaction mixture was diluted with H2O 100.0 mL and extracted with DCM 150.0 mL (50.0 mL x 3). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue to give compound N-(3-(benzyloxy)cyclobutyl)-2-bromo-N-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)acetamide (5.4 g, 60.2% purity) as a colourless oil.

[0756] 3) 2-azido-N-( 3-(benzyloxy)cyclobutyl)-N-(l -( 3-bromo-2-fluorophenyl)-3- fluorocyclobutyl)acetamide

[0757]

[0758] To a solution of N-(3-benzyloxycyclobutyl)-2-bromo-N-[l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutyl] acetamide (5.4 g, 9.9 mmol, 1.0 eq) in DMSO (54.0 mL) was added NaNa (581.6 mg, 8.9 mmol, 0.9 eq). The mixture was stirred at 20°C for 12 hr. LC-MS showed reactant 7 was consumed completely and desired mass was detected. The reaction mixture was quenched by addition water 162.0 mL at 0°C, and then extracted with ethyl acetate 200.0 mL (100.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g, Eluent of 10-15% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give compound 2-azido-N-(3-(benzyloxy)cyclobutyl)-N-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)acetamide (2.6 g, 3.8 mmol, 38.8% yield, 73.6% purity) as a colourless oil.

[0759] 4) tert-butyl (2-((3-(benzyloxy)cyclobutyl)(l-(3-bromo-2-fluorophenyl)-3- fluorocyclobutyl)amino)-2-oxoethyl)carbamate

[0760]

[0761] To a solution of 2-azido-N-(3-benzyloxycyclobutyl)-N-[l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutyl] acetamide (2.6 g, 5.2 mmol, 1.0 eq) in THF (27.0 mL) and H2O (9.0 mL) was added PPI13 (2.0 g, 7.8 mmol, 1.5 eq) and BOC2O (3.4 g, 15.7 mmol, 3.6 mL, 3.0 eq). The mixture was stirred at 20°C for 12 hr. LC-MS showed reactant 8 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 50.0 mL and extracted with EtOAc 60.0 mL (30.0 mL x 2). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g, Eluent of 15-50% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound tert-butyl (2-((3-(benzyloxy)cyclobutyl)(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)amino)-2-oxoethyl)carbamate (1.0 g, 1.0 mmol, 19.3% yield, 58.7% purity) as a colourless oil.

[0762] 5) 2-amino-N-( 1 -(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(3- hydroxycyclobutyl)acetamide

[0763]

[0764] To a solution of tert-butyl (2-((3-(benzyloxy)cyclobutyl)(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)amino)-2-oxoethyl)carbamate (180.0 mg, 310.6 pmol, 1.0 eq) in DCM (2.0 mL) was added TiCL (117.8 mg, 621.2 pmol, 2.0 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. LC-MS showed reactant 8A was consumed completely and new peak with desiredmass was detected. The reaction mixture was quenched by addition NaHCOa 10.0 mL at 0°C, and extracted with ethyl acetate 10.0 mL (5.0 mL x 2). The combined organic layers were washed with brine 5.0 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100x40mmx5 um; mobile phase: [H20(0.04% HCl)-ACN];gradient:l%-35% B over 8.0 min) to give compound 2-amino-N-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(-3-hydroxycyclobutyl)acetamide (20.0 mg, 17.6 pmol, 5.6% yield, 34.4% purity) as a white solid.

[0765] 6) cis-3-((2-aminoethyl)(cis-l-(3-bromo-2-fluorophenyl)-3- fluorocyclobutyl)amino)cyclobutan-l-ol hydrochloride & cis-3-((2-aminoethyl)(trans- l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)amino)cyclobutan-l-ol hydrochloride

[0766]

[0767] To a solution of 2-amino-N-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(-3-hydroxycyclobutyl)acetamide (20.0 mg, 51.3 pmol, 1.0 eq) in THF (1.0 mL) was added BH3-Me2S (10.0 M, 25.6 pL, 5.0 eq) at 0°C under N2 atmosphere. The mixture was stirred at 25°C for 2 hr under N2 atmosphere. Several new peaks were shown on LC-MS and 37.7% of desired compound was detected. The reaction mixture was quenched by addition MeOH 5.0 mL at 0°C under N2, the mixture was stirred at 25°C for 1 hr and 60°C for 1 hr under N2. The mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100x40mmx5 um; mobile phase:

[0768] [H20(0.04% HCl)-ACN];gradient:5%-40% B over 8.0 min) to give compound cis-3-((2-aminoethyl)(cis-l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)amino)cyclobutan-l-ol hydrochloride (502) (4.05 mg, 8.9 pmol, 17.3% yield, 90.68% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 375.2 [M+H]+, retention time: 1.517 min, method:G. ’H NMR (400 MHz, DMSO-de) d 7.77 - 8.11 (m, 3H) 7.64 - 7.73 (m, 1H) 7.45 - 7.55 (m, 1H) 7.12 - 7.22 (m, 1H) 4.53 - 4.80 (m, 1H) 3.62 - 3.73 (m, 1H) 3.01 - 3.15 (m, 6H) 2.63 - 2.80 (m, 3H) 2.14 -2.28 (m, 2H) 1.69 - 1.85 (m, 2H). and cis-3-((2-aminoethyl)(trans-l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)amino)cyclobutan-l-ol hydrochloride (503) (2.10 mg,5.0 pmol, 9.8% yield, 99.18% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 375.2 [M+H]+, retention time: 1.578 min, method:G. ’H NMR (400 MHz, DMSO-de) d 7.75 - 8.00 (m, 3H) 7.64 (br s, 1H) 7.24 - 7.34 (m, 1H) 7.10 - 7.22 (m, 1H) 5.07 - 5.34 (m, 1H) 3.62 -3.71 (m, 2H) 2.99 - 3.18 (m, 2H) 2.72 - 2.97 (m, 5H) 2.35 - 2.45 (m, 1H) 1.96 - 2.15 (m, 2H) 1.48 - 1.73 (m, 2H).

[0769] 7) 2-amino-N-(3-(benzyloxy)cyclobutyl)-N-(l-(3-bromo-2-fluorophenyl)-3- fluorocyclobutyl)acetamide

[0770] ><

[0771]

[0772] 8A 8B

[0773] A solution of tert-butyl (2-((3-(benzyloxy)cyclobutyl)(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)amino)-2-oxoethyl)carbamate (800.0 mg, 1.3 mmol, 1.0 eq) in HCI / EtOAc (4.0 M, 8.0 mL, 23.1 eq). The mixture was stirred at 20°C for 1 hr. LC-MS showed reactant 8A was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to give compound 2-amino-N-(3-(benzyloxy)cyclobutyl)-N-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)acetamide (780.0 mg, crude) as a yellow oil.

[0774] 8) N-(2-((3-(benzyloxy)cyclobutyl)(l-(3-bromo-2-fluorophenyl)-3- fluorocyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide

[0775]

[0776] To a solution of 2-amino-N-(3-benzyloxycyclobutyl)-N-[l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutyl] acetamide (780.0 mg, 1.6 mmol, 1.0 eq) in DCM (8.0 mL) was added TFAA (410.1 mg, 1.9 mmol, 271.4 pL, 1.2 eq) and TEA (329.3 mg, 3.2 mmol, 452.9 pL, 2.0 eq). The mixture was stirred at 20°C for 12 hr. LC-MS showed desired compound 9 was detected. The reaction mixture was diluted with H2O 10.0 mL and extracted with DCM 20.0 mL (10.0 mL x 2). The combined organic layers were dried over NaiSCC filtered andconcentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g, Eluent of 0~3% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to give compound N-(2-((3-(benzyloxy)cyclobutyl)(l-(3-bromo-2-fluorophenyl)- 3-fluorocyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (483.0 mg, 839.4 pmol, 51.5% yield) as a colourless oil.

[0777] 9) N-(2-(( l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(3-hydroxycyclobutyl)amino)-2- oxoethyl)-2,2,2-trifluoroacetamide

[0778]

[0779] To a solution of N-[2-[(3-benzyloxycyclobutyl)-[l-(3-bromo-2-fluoro-phenyl)-3-fluoro-cyclobutyl] amino] -2-oxo-ethyl] -2, 2, 2-trifhioro-acetamide (373.0 mg, 648.2 pmol, 1.0 eq) in DCM (2.0 mL) was added TiCU (245.9 mg, 1.3 mmol, 2.0 eq) at 0°C. The mixture was stirred at 0°C for 1 hr under N2 atmosphere. LC-MS showed 43.3% of desired compound 10 was detected. The reaction mixture was quenched by addition NaHCOa 20.0 mL at 0°C, and extracted with ethyl acetate 20.0 mL (5.0 mL x 4). The combined organic layers were washed with brine 10.0 mL, dried over NaiSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g, Eluent of 30-35% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound N-(2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(3-hydroxycyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (210.0 mg, crude) as a colourless oil.

[0780] 10) N-(2-((cis-l -(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(trans-3- fluorocyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide & N-(2-((trans-l-(3- bromo-2-fluorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl)amino)-2- oxoethyl)-2,2,2-trifluoroacetamide

[0781]

[0782] To a solution of N-[2-[[l-(3-bromo-2-fhioro-phenyl)-3-fluoro-cyclobutyl]-(3-hydroxycyclobutyl)amino]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (190.0 mg, 391.5 pmol, 1.0 eq) in DCM (1.0 mL) was added DAST (88.9 mg, 552.1 pmol, 72.9 pL, 1.4 eq) at -70°C. The mixture was stirred at -70°C for 6 hr under N2 atmosphere. Several new peaks were shown on LC-MS and 44.8% of desired mass was detected. The reaction mixture was partitioned between NaHCOa 10.0 mL and ethyl acetate (5.0 mL x 3). The organic phase was separated, dried over NaiSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate = 3:1) to give compound N-(2-((cis-l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (37.0 mg, 63.1 pmol, 16.1% yield, 83.2% purity) as a yellow oil and N-(2-((trans-l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (55.0 mg, 60.9 pmol, 15.5% yield, 54.0% purity) as a yellow oil.

[0783] 11) 2-amino-N-(cis- 1 -(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(trans-3- fluorocyclobutyl)acetamide

[0784]

[0785] 11 15

[0786] To a solution of N-(2-((cis-l-(3-bromo-2-fhiorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (37.0 mg, 75.9 pmol, 1.0 eq) in MeOH (0.6 mL) and H2O (0.2 mL) was added NaOH (15.1 mg, 379.6 pmol, 5.0 eq). The mixture was stirred at 20°C for 1 hr. LC-MS showed reactant 11 was consumed completely and one main peak with desired mass was detected. The reaction mixture was partitioned between H2O 10.0 mL and ethyl acetate (10.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 2-amino-N-(cis-l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(trans-3-fluorocyclobutyl)acetamide (20.0 mg, 51.1 pmol, 67.3% yield) as a yellow oil.12) Nl-( cis-1 -( 3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-Nl-( trans-3- fluorocyclobutyl)ethane-l,2-diamine hydrochloride

[0787]

[0788] 15 506

[0789] To a solution of 2-amino-N-(cis-l-(3-bromo-2-fhiorophenyl)-3-fluorocyclobutyl)-N-(trans-3-fluorocyclobutyl)acetamide (20.0 mg, 51.1 pmol, 1.0 eq) in THF (1.0 mL) was added BHa-MeiS (10.0 M, 15.3 pL, 3.0 eq) at 0°C under N2 atmosphere. The mixture was stirred at 25°C for 12 hr under N2 atmosphere. LC-MS showed reactant 15 was consumed completely and 14.5% of desired compound was detected. The reaction mixture was quenched by addition MeOH 5.0 mL at 0°C under N2, the mixture was steirred at 25°C for 1 hr and 60°C for 1 hr under N2. The mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100x40mmx5 um; mobile phase: [H20(0.04% HCl)-ACN];gradient:10%-60% B over 8.0 min) to give compound Nl-(cis-l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-Nl-(trans-3-fluorocyclobutyl)ethane-l,2-diamine hydrochloride (10.37 mg, 24.5 pmol, 47.9% yield, 97.84% purity, HC1 salt) as a white solid. MS (ESI): m / z = 377.2 [M+H]+, retention time:1.753 min, method:G. ’H NMR (400 MHz, DMSO-de) d 7.61 - 7.91 (m, 4H) 7.53 (br t, 7=7.25 Hz, 1H) 7.19 (t, 7=7.94 Hz, 1H) 4.89 - 5.14 (m, 1H) 4.53 - 4.79 (m, 1H) 3.56 - 3.72 (m, 1H) 2.98 - 3.16 (m, 2H) 2.69 - 2.85 (m, 4H) 2.56 - 2.65 (m, 2H) 1.93 - 2.27 (m, 4H).

[0790] 13) 2-amino-N-(trans-l -(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(trans-3- fluorocyclobutyl)acetamide

[0791]

[0792] To a solution of N-(2-((trans-l-(3-bromo-2-fhiorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (55.0 mg, 112.8 pmol, 1.0 eq) in MeOH (0.6 mL) and H2O (0.2 mL) was added NaOH (22.5 mg, 564.4 pmol, 5.0 eq). The mixture was stirred at 20°C for 1 hr. Several new peaks were shown on LC-MS and 56.9% ofdesired compound 15 A was detected. The reaction mixture was partitioned between H2O 10.0 mL and ethyl acetate (10.0 mL x 3). The organic phase was separated, dried over NaiSC , filtered and concentrated under reduced pressure to give compound 2-amino-N- (trans-l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(trans-3-fluorocyclobutyl)acetamide (30.0 mg, 76.6 pmol, 67.9% yield) as a yellow oil.

[0793] 14) A 1 -(trans- 1 -(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N 1 -(trans-3- fluorocyclobutyl)ethane-l,2-diamine hydrochloride hydrochloride

[0794]

[0795] To a solution of 2-amino-N-(trans-l-(3-bromo-2-fhiorophenyl)-3-fluorocyclobutyl)-N-(trans-3-fhiorocyclobutyl)acetamide (30.0 mg, 76.6 pmol, 1.0 eq) in THF (1.0 mL) was added BH3-Me2S (10.0 M, 23.0 pL, 3.0 eq) at 0°C under N2 atmosphere. The mixture was stirred at 25°C for 12 hr under N2 atmosphere. LC-MS showed 23.6% of reactant 15A remained. Then BH3-Me2S (10.0 M, 23.0 pL, 3.0 eq) was added to the mixture at 0°C under N2 atmosphere. The mixture was stirred at 25°C for 12 hr. LC-MS showed reactant 15A was consumed completely and 14.8% desired compound was detected. The reaction mixture was quenched by addition MeOH 5.0 mL at 0°C under N2, the mixture was stirred at 25 °C for 1 hr and 60°C for 1 hr under N2. The mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100x40mmx5 um; mobile phase: [H2<D(0.04% HC1)-ACN]; gradient: 10%-50% B over 8.0 min) to give compound Nl-(trans-l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-Nl-(trans-3-fluorocyclobutyl)ethane-l,2-diamine hydrochloride hydrochloride (4.26 mg, 9.7 pmol, 12.7% yield, 94.63% purity, HC1 salt) as a white solid. MS (ESI): m / z = 377.2 [M+H]+, retention time:1.785 min, mcthod:G.'H NMR (400 MHz, DMSO-tTs) 37.90 (br d, 7=1.13 Hz, 3H) 7.64 (t, 7=6.69 Hz, 1H) 7.25 - 7.35 (m, 1H) 7.13 - 7.22 (m, 1H) 5.09 - 5.34 (m, 1H) 4.86 -5.08 (m, 1H) 3.98 - 4.06 (m, 1H) 3.07 (br dd, 7=4.69, 1.94 Hz, 2H) 2.81 (br s, 4H) 2.30 - 2.46 (m, 2H) 1.87 - 2.17 (m, 4H).Example 21: Synthesis of 3-(trans-l-((2-aminoethyl)(trans-3-fluorocyclobutyl)amino)-3- fluorocyclobutyl)-2-fluorobenzonitrile hydrochloride (Compound 471)

[0796] 1) N-(2-(( l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl) amino)-2-oxoethyl)-2,2,2-trifluoroacetamide

[0797] <>

[0798]

[0799] 10 11

[0800] To a solution of N-(2-((l-(3-bromo-2-fhiorophenyl)-3-fluorocyclobutyl)(cis-3-hydroxycyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (600.0 mg, 1.2 mmol, 1.0 eq) in DCM (6.0 mL) was added DAST (281.0 mg, 1.7 mmol, 230.3 pL, 1.4 eq) at -70°C. The mixture was stirred at -70°C for 6 hrs under N2 atmosphere. LC-MS showed reactant 10 was consumed completely and 64.2% of desired compound 11 was detected. The reaction mixture was partitioned between NaHCOa 10.0 mL and ethyl acetate (5.0 mL x 3). The organic phase was separated, dried over NaiSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate = 3:1) to give compound N-(2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (166.0 mg, 281.4 uinol.

[0801] 22.7% yield, 82.6% purity) as a yellow oil.

[0802] 2) 2-amino-N-( 1 -(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(trans-3- fluorocyclobutyl)acetamide

[0803]

[0804] To a solution of N-(2-((l-(3-bromo-2-fhiorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide (166.0 mg, 340.7 pmol, 1.0 eq) in MeOH (3.0 mL) and H2O (1.0 mL) was added NaOH (68.1 mg, 1.7 mmol, 5.0 eq). The mixture was stirred at 20°C for 1 hr. LC-MS showed reactant 11 was consumed completely and 80.8% of desired compound 12 was detected. The reaction mixture was partitionedbetween H2O 10.0 mL and ethyl acetate (10.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue to give compound 2-amino-N-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(trans-3-fluorocyclobutyl)acetamide (140.0 mg, 301.6 pmol, 88.5% yield, 84.3% purity) as a yellow oil.

[0805] 3) Nl-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-Nl-(trans-3- fluorocyclobutyl)ethane-l,2-diamine

[0806]

[0807] To a solution of 2-amino-N-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-N-(trans-3-fluorocyclobutyl)acetamide (140.0 mg, 357.8 pmol, 1.0 eq) in THF (1.0 mL) was added BH3-Me2S (10.0 M, 357.8 pL, 10.0 eq) at 0°C under N2 atmosphere. The mixture was stirred at 35°C for 12 hrs under N2 atmosphere. LC-MS showed reactant 12 was consumed completely and 47.8% of desired compound 13 was detected. The reaction mixture was quenched by addition MeOH 5.0 mL at 0°C under N2, the mixture was stirred at 60°C for 1 hr under N2. The mixture was concentrated under reduced pressure to remove solvent to give compound Nl-(l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)-Nl-(trans-3-fluorocyclobutyl) ethane- 1,2-diamine (180.0 mg, crude) as a yellow oil.

[0808] 4) tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(trans-3- fluorocyclobutyl)amino)ethyl)carbamate

[0809]

[0810] To a solution of Nl-(l-(3-bromo-2-fhiorophenyl)-3-fluorocyclobutyl)-Nl-(trans-3-fluorocyclobutyl)ethane-l,2-diamine (180.0 mg, 477.1 pmol, 1.0 eq) in DCM (2.0 mL) was added Boc2O (156.2 mg, 715.7 pmol, 164.4 pL, 1.5 eq) and TEA (144.8 mg, 1.4 mmol, 199.2 pL, 3.0 eq). The mixture was stirred at 20°C for 1 hr. LC-MS showed reactant 13 wasconsumed completely and 42.1% of desired compound 14 was detected. The reaction mixture was partitioned between H2O 10.0 mL and ethyl acetate (10.0 mL x 3). The organic phase was separated, dried over NaiSC , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound tert-butyl (2-((l-(3-bromo-2-fluorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl)amino)ethyl)carbamate (60.0 mg, 86.6 pmol, 18.1% yield, 68.9% purity) as a yellow oil.

[0811] 5) tert-butyl (2-( (l-(3-cyano-2-fluorophenyl)-3-fluorocyclobutyl)(trans-3- fluorocyclobutyl)amino)ethyl)carbamate

[0812]

[0813] To a solution of tert-butyl (2-((l-(3-bromo-2-fhiorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl)amino)ethyl)carbamate (60.0 mg, 125.6 pmol, 1.0 eq) in DMF (2.0 mL) was added Zn(CN)2 (44.2 mg, 377.0 pmol, 23.9 pL, 3.0 eq), BRETTPHOS (13.4 mg, 25.1 pmol, 0.2 eq) and BrettPhos Pd G3 (22.7 mg, 25.1 pmol, 0.2 eq). The reaction mixture was stirred and degassed and purged with N2 for 3 times and stirred at 90°C for 12 hrs. LC-MS showed reactant 14 was consumed completely and 7.2% of desired compound 15 was detected. The reaction mixture was quenched by addition H2O 10.0 mL at 20°C, and then extracted with ethyl acetate 20.0 mL (10.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, commercial hexanes : ethyl acetate = 3:1) to give compound tert-butyl (2-((l-(3-cyano-2-fluorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl)amino)ethyl)carbamate (15.0 mg, 28.2 pmol, 22.4% yield, 79.6% purity) as a colourless oil.6) 3-(trans-l-((2-aminoethyl)(trans-3-fluorocyclobutyl)amino)-3-fluorocyclobutyl)-2- fluorobenzonitrile hydrochloride

[0814]

[0815] 15 471

[0816] A solution of tert-butyl (2-((l-(3-cyano-2-fhiorophenyl)-3-fluorocyclobutyl)(trans-3-fluorocyclobutyl)amino)ethyl)carbamate (15.0 mg, 35.4 pmol, 1.0 eq) in HCl / EtOAc (4.0 M, 1.0 mL, 112.9 eq) was stirred at 20°C for 1 hr. LC-MS showed reactant 15 was consumed completely and 88.7% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove HCl / EtOAc. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40mm x 5 um; mobile phase: [H20(0.04% HC1)-ACN]; gradient: l%-35% B over 8.0 min) to give compound 3-(trans-l-((2-aminoethyl)(trans-3-fluorocyclobutyl)amino)-3-fluorocyclobutyl)-2-fluorobenzonitrile hydrochloride (3.77 mg, 10.4 pmol, 29.5% yield, 99.86% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 324.1 [M+H]+, retention time: 1.580 min, method:B.XH NMR (400 MHz, DMSO-de) d 8.07 (br s, 3H) 7.94 (br t, 7=6.32 Hz, 1H) 7.76 (br t, 7=7.25 Hz, 1H) 7.49 (t, 7=7.75 Hz, 1H) 5.17 - 5.38 (m, 1H) 4.94 - 5.15 (m, 1H) 4.05 (quin, 7=8.25 Hz, 1H) 3.15 (br d, 7=2.25 Hz, 2H) 2.82 - 2.98 (m, 4H) 2.42 - 2.54 (m, 2H) 1.93 - 2.25 (m, 4H)

[0817] Example 22: Synthesis of Compounds 452, 453, 452A and 453A

[0818] 1) 1 -(3-bromo-2-fluoro-phenyl)-N-(2-fluorocyclobutyl)cyclobutanamine

[0819]

[0820] 374 int.4 5

[0821] To a solution of l-(3-bromo-2-fluoro-phenyl)cyclobutanamine (600.0 mg, 2.4 mmol, 1.0 eq) in MeOH (6.0 mL) was added 2-fluorocyclobutanone (216.5 mg, 2.4 mmol, 1.0 eq) and AcOH (221.4 mg, 3.6 mmol, 211.0 pL, 1.5 eq). The mixture was stirred at 25°C for 1 hr. Then NaBH.CN (463.3 mg, 7.3 mmol, 3.0 eq) was added to the mixture, the mixture was stirred at 25 °C for 24 hr. LC-MS showed desired compound was detected. The reactionmixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 70 mL / min) to give compound l-(3-bromo-2-fluoro-phenyl)-N-(2-fluorocyclobutyl)cyclobutanamine (220.0 mg, 695.8 pmol, 28.3% yield) as a colourless oil.

[0822] 2) 2-bromo-N-[ 1 -(3-bromo-2-fluoro-phenyl)cyclobutyl]-N-(2-fluorocyclobutyl) Acetamide

[0823]

[0824] 5 6

[0825] To a solution of l-(3-bromo-2-fluoro-phenyl)-N-(2-fluorocyclobutyl)cyclobutanamine (200.0 mg, 632.5 pmol, 1.0 eq) in DCM (2.5 mL) and H2O (2.5 mL) was added K2CO3 (349.6 mg, 2.5 mmol, 4.0 eq) and 2-bromoacetyl bromide (255.3 mg, 1.2 mmol, 110.2 pL, 2.0 eq) at 0°C. The mixture was stirred at 25 °C for 3 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O (10.0 mL) and dichloromethane (10.0 mL x 3). The organic phase was separated, washed with brine (10.0 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 2-bromo-N-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-N-(2-fluorocyclobutyl)acetamide (330.0 mg, crude) as a yellow oil.

[0826] 3) 2-azido-N-[ 1 -(3-bromo-2-fluoro-phenyl)cyclobutyl]-N-(2-fluorocyclobutyl) acetamide

[0827]

[0828] To a solution of 2-bromo-N-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-N-(2-fluorocyclobutyl)acetamide (330.0 mg, 754.9 pmol, 1.0 eq) in DMSO (6.0 mL) was added NaNa (58.0 mg, 892.1 pmol, 1.2 eq). The mixture was stirred at 25°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between NaHCCF (10.0 mL) and ethyl acetate (15.0 mL x 3). The organic phase was separated, washed with brine (15.0 mL x 3), dried over NaiSCL, filtered and concentrated under reducedpressure to give compound 2-azido-N-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-N-(2-fluorocyclobutyl)acetamide (350.0 mg, crude) as a white solid.

[0829] 4) tert-butyl N-[2-[[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-(2-fluorocyclobutyl)amino] -2- oxo-ethyl]carbamate

[0830]

[0831] -N-(2-fluorocyclobutyl)acetamide (300.0 mg, 751.4 pmol, 1.0 eq) in THF (5.4 mL) and H2O (1.8 mL) was added PPI13 (236.5 mg, 901.7 pmol, 1.2 eq) and BOC2O (328.0 mg, 1.5 mmol, 345.2 pL, 2.0 eq). The mixture was stirred at 25°C for 12 hr under N2. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O (20.0 mL) and ethyl acetate (20.0 mL x 3). The organic phase was separated, washed with brine (20.0 mL x 1), dried over NaiSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) and was purified by prep-TLC (SiOi, Petroleum ether : Ethyl acetate = 3:1) to give compound tert-butyl N-[2-[[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-(2-fluorocyclobutyl)amino]-2-oxo-ethyl]carbamate (140.0 mg, 295.7 pmol, 39.3% yield) as a yellow oil.

[0832] 5) tert-butyl N-[2-[[ l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-(2-fluorocyclobutyl) amino ]ethyl]carbamate

[0833]

[0834] To a solution of tert-butyl N-[2-[[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-(2-fluorocyclobutyl)amino]-2-oxo-ethyl]carbamate (140.0 mg, 295.7 pmol, 1.0 eq) in THF (4.0 mL) was added BH3-Me2S (10.0 M, 0.1 mL, 3.3 eq) at 0°C under N2. The mixture was stirred at 25°C for 3 hr under N2. LC-MS showed desired compound was detected. The reactionmixture was quenched by addition MeOH (2.0 mL) at 0 °C under N2, the mixture was stirred at 25 °C for 1 hr and 60°C for 1 hr. The mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (S i O2, Petroleum ether : Ethyl acetate = 3:1) to give compound tert-butyl N-[2-[[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-(2-fluorocyclobutyl)amino] ethyl] carbamate (90.0 mg, 162.6 pmol, 54.9% yield, 83.0% purity) as a light yellow oil.

[0835] 6) tert-butyl N-[2-[(2-fluorocyclobutyl)-[l-(2-fluoro-3-cyano-phenyl)cyclobutyl] amino ]ethyl]carbamate

[0836]

[0837] To a solution of tert-butyl N-[2-[[l-(3-bromo-2-fhioro-phenyl)cyclobutyl]-(2-fluorocyclobutyl)amino]ethyl]carbamate (90.0 mg, 195.9 pmol, 1.0 eq) in DMF (2.0 mL) was added Zn(CN)2 (80.0 mg, 681.2 pmol, 43.2 pL, 3.5 eq), Brettphos (21.0 mg, 39.1 pmol, 0.2 eq) and Brettphos Pd G3 (17.7 mg, 19.6 pmol, 0.1 eq) under N2. The mixture was stirred at 90°C for 12 hr under N2. LC-MS showed desired compound was detected. The reaction mixture was quenched by addition sat. NaHCOa (10.0 mL) at 25 °C, and then extracted with ethyl acetate (10.0 mL x 3). The organic phase was separated, washed with brine (10.0 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 3:1) to give compound tert-butyl N-[2-[(2-fluorocyclobutyl)-[l-(2-fluoro-3-cyano-phenyl)cyclobutyl] amino]ethyl]carbamate (70.0 mg, 100.1 pmol, 51.1% yield, 58.0% purity) as a light yellow oil.7) Cis-3-[l-[2-aminoethyl-(2-fluorocyclobutyl)amino]cyclobutyl]-2-fluoro-benzonitrile and trans-3-[l-[2-aminoethyl-(2-fluorocyclobutyl)amino]cyclobutyl]-2-fluoro-benzonitrile

[0838]

[0839] 453

[0840] A mixture of tert-butyl N-[2-[(2-fluorocyclobutyl)-[l-(2-fluoro-3-cyano-phenyl)cyclobutyl] amino] ethyl] carbamate (70.0 mg, 172.6 pmol, 1.0 eq) in HCI / EtOAc (1.0 mL) (4.0 M) and EtOAc (1.0 mL) was stirred at 25°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition, column: Phenomenex luna Cis 100 x 40 mm x 5 um; mobile phase: [H20(0.04% HC1)-ACN]; gradient: 10%-35% B over 8.0 min) to give compound cis-3-(452) [l-[2-aminoethyl-(2-fluorocyclobutyl)amino]cyclobutyl]-2-fluoro-benzonitrile (13.6 mg, 39.7 pmol, 23.0% yield, 99.7% purity, HC1 salt) as a light yellow oil. MS (ESI): m / z = 306.2 [M+H]+, retention time:1.626 min, method: B ’H NMR (400 MHz, DMSO-tfe) d 8.00 (br s, 3H), 7.91 - 7.76 (m, 2H), 7.40 (t, J = 7.7 Hz, 1H), 5.06 - 4.79 (m, 1H), 3.54 - 3.36 (m, 1H), 3.19 - 3.10 (m, 1H), 3.09 - 3.00 (m, 1H), 2.96 - 2.72 (m, 2H), 2.62 - 2.52 (m, 2H), 2.49 - 2.32 (m, 3H), 2.06 - 1.86 (m, 3H), 1.84 - 1.67 (m, 1H), 1.66 - 1.54 (m, 1H). and compound trans-3-[l-[2-aminoethyl-(2-fluorocyclobutyl)amino]cyclobutyl]-2-fluoro-benzonitrile (453) (45.5 mg, 130.6 pmol, 75.6% yield, 98.1% purity, HC1 salt) as a light yellow oil. MS (ESI): m / z = 306.1 [M+H]+, retention time:1.674 min, method: E ’H NMR (400 MHz, DMSO-tfe) d 8.19 (br s, 3H), 7.91 -7.77 (m, 2H), 7.42 (t, J= 7.8 Hz, 1H), 5.08 - 4.82 (m, 1H), 3.47 - 3.30 (m, 1H), 3.07 - 2.96 (m, 2H), 2.92 (br s, 2H), 2.64 (quin, J = 9.4 Hz, 2H), 2.54 (br d, J = 4.6 Hz, 1H), 2.49 - 2.41 (m, 1H), 2.13 - 1.98 (m, 1H), 1.98 - 1.86 (m, 1H), 1.72 - 1.51 (m, 3H), 1.48 - 1.30 (m, 1H).8) Cis-N'-[ l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-N'-(2-fluorocyclobutyl)ethane-l ,2- diamine and trans-N'-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-N'-(2- fluorocyclobutyl)ethane-l,2-diamine

[0841]

[0842] 453A

[0843] To a solution of tert-butyl N-[2-[[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-(2-fluorocyclobutyl)amino]ethyl]carbamate (80.0 mg, 174.1 pmol, 1.0 eq) in EtOAc (0.5 mL) was added HCl / EtOAc (4.0 M, 0.5 mL, 11.5 eq). The mixture was stirred at 25°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition, column: Phenomenex luna C18 100 x 40mm x 5 um; mobile phase: [H2<D(0.04% HCl)-ACN];gradient:5%-40% B over 8.0 min) to give compound cis-N'-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-N'-(2-fluorocyclobutyl)ethane-l,2-diamine (452A) (12.4 mg, 30.6 pmol, 17.6% yield, 97.4% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 359.1 [M+H]+, retention time:1.761 min, method: E ’H NMR (400 MHz, DMSO-tfe) d 8.11 - 7.73 (m, 3H), 7.60 (ddd, J= 1.5, 6.5, 8.0 Hz, 1H), 7.45 (dt, J= 1.5, 7.5 Hz, 1H), 7.14 (dt, J= 0.6, 7.9 Hz, 1H), 5.03 - 4.79 (m, 1H), 3.54 - 3.41 (m, 1H), 3.14 - 2.97 (m, 2H), 2.81 (br d, J= 4.1 Hz, 2H), 2.49 - 2.28 (m, 5H), 2.01 - 1.83 (m, 3H), 1.80 - 1.67 (m, 1H), 1.65 - 1.53 (m, 1H). And compound trans-N'-[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-N'-(2-fluorocyclobutyl)ethane-l,2-diamine (453A) (39.4 mg, 99.7 pmol, 57.2% yield, 99.2% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 359.1 [M+H]+, retention time: 1.821 min, method: E ’H NMR (400 MHz, DMSO-tfe) d 8.18 (br s, 3H), 7.73 - 7.57 (m, 1H), 7.50 (dt, J = 1.3, 7.5 Hz, 1H), 7.28 - 7.10 (m, 1H), 5.15 - 4.82 (m, 1H), 3.43 - 3.33 (m, 1H), 3.08 - 2.84 (m, 4H), 2.72 - 2.57 (m, 2H), 2.57 - 2.51 (m, 1H), 2.48 - 2.38 (m, 1H), 2.05 (dq, J= 4.0, 8.5 Hz, 1H), 1.99 - 1.83 (m, 1H), 1.71 - 1.53 (m, 3H), 1.51 - 1.28 (m, 1H) .Example 23: Synthesis of Compound 569 and 604

[0844] 1) tert-butyl (R)-2-(((l-(3-bromo-2-fluorophenyl)cyclobutyl)(propyl)amino)methyl) pyrrolidine-l-carboxylate

[0845]

[0846] To a solution of l-(3-bromo-2-fluoro-phenyl)cyclobutanamine (100.0 mg, 409.7 pmol, 1.0 eq) in MeOH (1.0 mL) was added tert-butyl (2R)-2-formylpyrrolidine-l -carboxylate (97.9 mg, 491.6 pmol, 1.2 eq), AcOH (49.2 mg, 819.3 pmol, 46.9 pL, 2.0 eq) and NaBHaCN (102.9 mg, 1.6 mmol, 4.0 eq). The mixture was stirred at 60°C for 12 hr. Then added propanal (118.9 mg, 2.1 mmol, 149.1 pL, 5.0 eq) to the mixture. The mixture was stirred at 60°C for 2 hr. LC-MS showed desired compound was detected. The reaction mixture was partitioned between H2O (30.0 mL) and ethyl acetate (30.0 mL x 3). The organic phase was separated, dried over NaiSO^ filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiOi, Petroleum ether / Ethyl acetate = 3:1) to give tertbutyl (R)-2-(((l-(3-bromo-2-fluorophenyl)cyclobutyl)(propyl)amino)methyl)pyrrolidine-1-carboxylate (100.0 mg, 213.0 pmol, 52.0% yield) as a yellow oil.

[0847] 2) tert-butyl (R)-2-(((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)methyl) pyrrolidine-l-carboxylate

[0848]

[0849] To a solution of tert-butyl (2R)-2-[[[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-propyl-amino]methyl]pyrrolidine-l-carboxylate (70.0 mg, 149.1 pmol, 1.0 eq) in DME (1.5 mL) was added Zn(CN)2 (120.0 mg, 1.0 mmol, 64.9 pL, 6.8 eq), BrettPhos Pd G3 (13.5 mg, 14.9 pmol, 0.1 eq) and Brettphos (8.0 mg, 14.9 pmol, 0.1 eq). The mixture was stirred at 90°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixturewas quenched by addition sat. NaHCOa (10.0 mL) at 25°C, and then extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL x 2), dried over NaiSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate = 3:1) to give tertbutyl (R)-2-(((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)methyl) pyrrolidine-1-carboxylate (60.0 mg, 144.4 pmol, 96.8% yield) as a yellow solid.

[0850] 3) (R)-2-fluoro-3-(l -(propyl(pyrrolidin-2-ylmethyl)amino )cyclobutyl)benzonitrile

[0851] dihydrochloride

[0852]

[0853] To a solution of tert-butyl (2R)-2-[[[l-(3-cyano-2-fluoro-phenyl)cyclobutyl]-propyl-amino]methyl]pyrrolidine-l-carboxylate (60.0 mg, 144.4 pmol, 1.0 eq) in EtOAc (0.5 mL) was added HCl / EtOAc (4.0 M, 0.5 mL, 13.8 eq). The mixture was stirred at 20°C for 2 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2<D(0.04% HC1) - ACN]; gradient: 10% - 40% B over 8.0 min) to give (R)-2-fluoro-3-(l-(propyl(pyrrolidin-2-ylmethyl)amino)cyclobutyl)benzonitrile dihydrochloride (35.43 mg, 89.5 pmol, 62.0% yield, 98.13% purity, 2HC1 salt) as a yellow oil. MS (ESI): m / z = 316.3 [M+H]+, retention time: 1.687 min, method:B.XH NMR (400 MHz, DMSO-tfe) b 12.33 -10.88 (m, 1H), 10.75 - 9.24 (m, 2H), 8.12 (br s, 2H), 7.67 - 7.42 (m, 1H), 3.97 - 3.88 (m, 1H), 3.81 - 3.65 (m, 2H), 3.44 - 3.28 (m, 1H), 3.26 - 3.08 (m, 3H), 3.02 - 2.64 (m, 4H), 2.25 - 2.01 (m, 1H), 2.00 - 1.76 (m, 4H), 1.57 (td, 7= 8.9, 18.3 Hz, 3H), 0.84 (br t, J = 7.1 Hz, 3H).4) (R)-l -(3-bromo-2-fluorophenyl)-N-propyl-N-(pyrrolidin-2-ylmethyl)cyclobutan- 1 -amine dihydrochloride

[0854]

[0855] 569 To a solution of tert-butyl (2R)-2-[[[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-propyl- amino]methyl]pyrrolidine-l-carboxylate (30.0 mg, 63.9 pmol, 1.0 eq) in EtOAc (0.5 mL) was added HCl / EtOAc (4.0 M, 0.3 mL, 18.8 eq). The mixture was stirred at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2<D(0.04% HC1) -ACN]; gradient: 10% - 50% B over 8.0 min) to give (R)-l-(3-bromo-2-fluorophenyl)-N-propyl-N-(pyrrolidin-2-ylmethyl)cyclobutan-l-amine dihydrochloride (14.94 mg, 33.0 pmol, 51.6% yield, 97.69% purity, 2HC1 salt) as a yellow oil. MS (ESI): m / z = 369.2 [M+H]+, retention time:1.853 min, method:B.!H NMR (400 MHz, DMSO-tfe) b 12.13 - 11.18 (m, 1H), 10.43 - 8.31 (m, 2H), 8.12 - 7.85 (m, 1H), 7.85 - 7.57 (m, 1H), 7.44 - 7.22 (m, 1H), 4.08 - 3.86 (m, 1H), 3.45 - 3.31 (m, 1H), 3.20 (br d, J= 5.9 Hz, 3H), 3.07 - 2.95 (m, 1H), 2.92 - 2.57 (m, 3H), 2.54 (br s, 1H), 2.45 - 2.27 (m, 1H), 2.18 - 2.03 (m, 1H), 2.02 - 1.73 (m, 4H), 1.67 - 1.18 (m, 3H), 0.84 (br s, 3H).

[0856] Example 24: Synthesis of Compounds 497 and 561

[0857] 1) tert-butyl ( S )-2-( ((!-( 3-bromo-2-fluorophenyl)cyclobutyl)(propyl)amino )methyl) pyrrolidine-l-carboxylate

[0858]

[0859] 434 int.4 6To a solution of l-(3-bromo-2-fluoro-phenyl)cyclobutanamine (100.0 mg, 409.7 pmol, 1.0 eq) in MeOH (2.0 mL) was added tert-butyl (2S)-2-formylpyrrolidine-l -carboxylate (97.9 mg, 491.6 pmol, 1.2 eq), AcOH (49.2 mg, 819.3 pmol, 46.9 pL, 2.0 eq) and NaBthCN (102.9 mg, 1.6 mmol, 4.0 eq). The mixture was stirred at 60°C for 12 hr. Then added propanal (118.9 mg, 2.1 mmol, 149.1 pL, 5.0 eq) to the mixture. The mixture was stirred at 60°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiOi, Petroleum ether / Ethyl acetate = 3:1) to give tert-butyl (S)-2-(((l-(3-bromo-2-fluorophenyl)cyclobutyl)(propyl)amino) methyl)pyrrolidine-l-carboxylate (100.0 mg, 213.0 pmol, 52.0% yield) as a white solid.

[0860] 2) tert-butyl ( S )-2-( (( / -( 3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino )methyl) pyrrolidine-l-carboxylate

[0861]

[0862] To a solution of tert-butyl (2S)-2-[[[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-propyl-amino]methyl]pyrrolidine-l-carboxylate (100.0 mg, 213.0 pmol, 1.0 eq) in DMF (2.0 mL) was added Zn(CN)2 (120.0 mg, 1.0 mmol, 64.9 pL, 4.8 eq), BrettPhos Pd G3 (19.3 mg, 21.3 pmol, 0.1 eq) and BrettPhos (11.4 mg, 21.3 pmol, 0.1 eq). The mixture was stirred at 90°C for 12 hr under N2 atmosphere. LC-MS showed desired compound was detected. The reaction mixture was quenched by addition sat. NaHCOa (10.0 mL) at 25°C, and then extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate = 3:1) to give tert-butyl (S)-2-(((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)methyl) pyrrolidine-l-carboxylate (100.0 mg, 163.6 pmol, 76.8% yield, 68.0% purity) as a yellow solid.3) (S)-2-fluoro-3-(l-(propyl(pyrrolidin-2-ylmethyl)amino)cyclobutyl)benzonitrile hydrochloride

[0863]

[0864] To a solution of tert-butyl (2S)-2-[[[l-(3-cyano-2-fluoro-phenyl)cyclobutyl]-propyl-amino]methyl]pyrrolidine-l-carboxylate (100.0 mg, 240.6 pmol, 1.0 eq) in EtOAc (0.5 mL) was added HCl / EtOAc (4.0 M, 1.0 mL, 16.6 eq). The mixture was stirred at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H20(0.04% HC1) - ACN]; gradient: 10% - 40% B over 8.0 min) to give (S)-2-fluoro-3-(l-(propyl(pyrrolidin-2-ylmethyl)amino)cyclobutyl)benzonitrile hydrochloride (35.98 mg, 102.0 pmol, 42.4% yield, 99.8% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 316.3 [M+H]+, retention time: 1.683 min, method:B.XH NMR (400 MHz, DMSO-tfe) b 10.39 - 9.09 (m, 2H), 8.09 - 7.91 (m, 2H), 7.51 (t, J= 7.8 Hz, 1H), 3.83 (br s, 1H), 3.58 - 3.40 (m, 1H), 3.38 - 3.28 (m, 1H), 3.26 - 3.15 (m, 1H), 3.09 - 2.87 (m, 3H), 2.73 (br s, 4H), 2.20 (br d, J = 7.0 Hz, 1H), 2.07 - 1.85 (m, 3H), 1.77 - 1.54 (m, 4H), 0.86 (t, J= 7.3 Hz, 3H).

[0865] 4) (S)- 1 -(3-bromo-2-fluorophenyl)-N-propyl-N-(pyrrolidin-2-ylmethyl)cyclobutan-l -amine hydrochloride

[0866]

[0867] A mixture of tert-butyl (2S)-2-[[[l-(3-bromo-2-fhioro-phenyl)cyclobutyl]-propyl-amino]methyl]pyrrolidine-l-carboxylate (70.0 mg, 149.1 pmol, 1.0 eq) in HCl / EtOAc (4.0 M, 0.8 mL, 21.5 eq) was stirred at 20°C for 1 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent.The residue was purified by prep-HPLC (HC1 condition column: Phenomenex luna C18 100 x 40 mm x5 um; mobile phase: [H20(0.04% HC1) - ACN]; gradient: 10% - 50% B over 8.0 min) to give (S)-l-(3-bromo-2-fluorophenyl)-N-propyl-N-(pyrrolidin-2- ylmethyl)cyclobutan-l-amine hydrochloride (27.20 mg, 67.0 pmol, 44.9% yield, 100% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 369.2 [M+H]+, retention time: 1.815 min, method:B.1H NMR (400 MHz, DMSO-tfe) d 9.76 (br s, 2H), 7.80 (br t, J = 6.5 Hz, 1H), 7.76 - 7.58 (m, 1H), 7.28 (t, J= 7.9 Hz, 1H), 3.86 (br d, J= 1.0 Hz, 1H), 3.15 (br s, 3H), 3.02 (br s, 3H), 2.86 - 2.66 (m, 4H), 2.20 (br s, 1H), 2.03 - 1.88 (m, 3H), 1.75 - 1.53 (m, 4H), 0.86 (t, J = 7.3 Hz, 3H).

[0868] Example 25: Synthesis of Compounds 570 and 605

[0869] 1) tert-butyl (3-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-3-((4-hydroxybutyl)amino) propyl )carbamate

[0870]

[0871] To a solution of l-(3-bromo-2-fhioro-phenyl)cyclobutanamine (0.2 g, 819.3 pmol, 1.0 eq) in MeOH (3.0 mL) was added tert-butyl 2-formylazetidine- 1 -carboxylate (303.5 mg, 1.6 mmol, 2.0 eq), AcOH (98.4 mg, 1.6 mmol, 2.0 eq) and NaBHaCN (206.0 mg, 3.3 mmol, 4.0 eq). The mixture was stirred at 60°C for 12 hrs. LC-MS showed reactant 434 int.4 was consumed completely and -80% of desired compound 5 was detected. And then propanal (95.2 mg, 1.6 mmol, 2.0 eq) was added to the reaction. The mixture was stirred at 60°C for 12 hrs. LC-MS showed -54% of compound 5 remained and -23% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The reaction mixture was diluted with H2O 5.0 mL and extracted with ethyl acetate 15.0 mL (5.0 mL x 3). The combined organic layers were washed with sat. NaCl 10.0 mL, dried overNaiSC , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0~8% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound tert-butyl (3-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-3-((4-hydroxybutyl)amino)propyl)carbamate (96.7 mg, 195.0 pmol, 23.8% yield, 91.8% purity) as a yellow oil.

[0872] 2) tert-butyl 2-(((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)methyl)azetidine-l- carboxylate

[0873]

[0874] A mixture of tert-butyl (3-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-3-((4-hydroxybutyl)amino)propyl)carbamate (0.07 g, 146.5 pmol, 1.0 eq), Zn(CN)2 (51.6 mg, 439.4 pmol, 27. 9 pL, 3.0 eq), BrettPhos (7.9 mg, 14.6 pmol, 0.1 eq) and BrettPhos Pd G3 (13.3 mg, 14.7 pmol, 0.1 eq) in DMF (5.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hrs under N2 atmosphere. LC-MS showed reactant 6 was consumed completely and -13% of desired mass was detected. The reaction mixture was quenched by addition saturated sodium bicarbonate 10.0 mL at 20°C, and then extracted with ethyl acetate 15.0 mL (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate=3 / l) to give compound tert-butyl 2-(((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)methyl)azetidine-l-carboxylate (0.06 g, 121.6 pmol, 83.1% yield, 85.7% purity) as a colorless oil.

[0875] 3) 3-(l-((azetidin-2-ylmethyl)(propyl)amino)cyclobutyl)-2-fluorobenzonitrile

[0876] dihydrochloride

[0877]

[0878] 7 605A solution of tert-butyl 2-(((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino) methyl)azetidine-l -carboxylate (0.05 g, 124.5 pmol, 1.0 eq) in HCl / EtOAc (5.0 mL) (4.0 mol / L) was stirred at 25 °C for 1 hr. LC-MS showed reactant 7 was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HC1 condition, column: Phenomenex luna C18 100x40mmx5 um;mobile phase: [H2O (0.04% HC1) - ACN] ;gradient: l%-35% B over 8.0 min) to give compound 3-(l-((azetidin-2-ylmethyl)(propyl)amino)cyclobutyl)-2-fluorobenzonitrile dihydrochloride (31.68 mg, 84.6 pmol, 68.0% yield, 100.0% purity, 2HC1 salt) as a white solid. MS (ESI): m / z = 302.1 [M+H]+, retention time: 1.946 min, method:G!H NMR (400 MHz, DMSO-tTs) 3 9.16 (br s, 2H), 7.93 (br d, J = 6.0 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 4.78 - 4.59 (m, 1H), 4.19 - 4.03 (m, 1H), 3.90 (br d, J= 8.1 Hz, 1H), 3.76 (br s, 1H), 3.61 - 3.21 (m, 1H), 3.00 (br d, J= 10.0 Hz, 1H), 2.77 (br d, J= 1.5 Hz, 2H), 2.68 - 2.54 (m, 3H), 2.48 - 2.40 (m, 1H), 2.38 - 2.12 (m, 1H), 1.99 (tt, J = 4.8, 9.8 Hz, 1H), 1.70 - 1.41 (m, 3H), 0.85 (t, J= 7.3 Hz, 3H).

[0879] 4) N-(azetidin-2-ylmethyl)-l -(3-bromo-2-fluorophenyl)-N-propylcyclobutan- 1 -amine dihydrochloride

[0880] >

[0881]

[0882] 570

[0883] A solution of tert-butyl (3-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-3-((4-hydroxybutyl)amino)propyl)carbamate (0.03 g, 65.9 pmol, 1.0 eq) in HCl / EtOAc (3.0 mL) (4.0 mol / L) was stirred at 25°C for 1 hr. LC-MS showed reactant 6 was consumed completely and ~9% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HCI condition, column: Phenomenex luna C18 100x40mmx5 um;mobile phase: [H20(0.04% HCl)-ACN];gradient:l%-35% B over 8.0 min) to give compound N-(azetidin-2-ylmethyl)-l-(3-bromo-2-fluorophenyl)-N-propylcyclobutan-l-amine dihydrochloride (9.67 mg, 22.4 pmol, 34.0% yield, 99.12% purity, 2HC1 salt) as a white solid. MS (ESI): m / z = 355.1 [M+H]+, retention time:2.103 min, method:G ’H NMR (400 MHz, DMSO-t / d) 3 9.90 - 9.32 (m, 1H), 9.17 (br d, J = 7.4 Hz, 1H), 7.78 (br t, J = 6.9 Hz, 1H), 7.64 (br s, 1H), 7.26 (t, J = 7.9 Hz, 1H), 4.76 (br d, J= 7.5 Hz, 1H), 4.03 - 3.81 (m, 3H), 3.15 - 2.82 (m, 3H), 2.67 (br d, J= 1.8 Hz, 4H), 2.49 - 2.41 (m, 1H), 2.39 - 2.26 (m, 1H), 2.08 - 1.85 (m, 1H), 1.60 (td, J= 8.5, 10.5 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H).

[0884] Example 26: Synthesis of Compound 606

[0885] In analogous manner as set out above for Compound 605, Compound 606 has been prepared:

[0886]

[0887] Example 27: Synthesis of l-(3-bromo-2-fluorophenyl)-N-(piperidin-2-ylmethyl)-N- propylcyclobutan-1 -amine hydrochloride (Compound 571)

[0888] 1) 1 -(3-bromo-2-fluoropheny l)-N-propy ley clobutan- 1 -amine

[0889]

[0890] 4 5

[0891] To a solution of l-(3-bromo-2-fluoro-phenyl)cyclobutanamine (200.0 mg, 819.3 pmol, 1.0 eq) in MeOH (3.0 mL) was added propanal (28.6 mg, 491.6 pmol, 0.6 eq), AcOH (73.8 mg, 1.2 mmol, 1.5 eq) and NaBHaCN (206.0 mg, 3.3 mmol, 4.0 eq). The mixture was stirred at 20°C for 12 hr. LC-MS showed 44% reactant 4 was remained and 22% peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (4 g, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give l-(3-bromo-2-fluorophenyl)- N-propylcyclobutan-1 -amine (64.0 mg, 223.6 pmol, 27.3% yield) as a yellow oil.2) tert-butyl 2-(((l-(3-bromo-2-fluorophenyl)cyclobutyl)(propyl)amino)methyl)piperidine- 1-carboxylate

[0892] Boc

[0893]

[0894] To a solution of l-(3-bromo-2-fluoro-phenyl)-N-propyl-cyclobutanamine (60.0 mg, 209.7 pmol, 1.0 eq) in MeOH (2.0 mL) was added tert-butyl 2-formylpiperidine- 1 -carboxylate (89.4 mg, 419.3 pmol, 2.0 eq), AcOH (18.9 mg, 314.5 pmol, 1.5 eq) and NaBthCN (52.7 mg, 838.6 pmol, 4.0 eq). The mixture was stirred at 60°C for 12 hr. LC-MS showed 36% reactant 5 was remained and 28% peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 15.0 mL and extracted with EtOAc 30.0 mL (15.0 mL x 2). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 2-(((l- (3-bromo-2-fluorophenyl)cyclobutyl)(propyl)amino)methyl)piperidine-l-carboxylate (70.0 mg, crude) as a yellow oil.

[0895] 3) 1 -(3-bromo-2-fluoropheny l)-N -(piperidin-2-ylmethy l)-N-propy ley clobutan- 1 -amine hydrochloride

[0896]

[0897] A solution of tert-butyl 2-[[[l-(3-bromo-2-fluoro-phenyl)cyclobutyl]-propyl-amino]methyl]piperidine-l-carboxylate (70.0 mg, 144.8 pmol, 1.0 eq) in 4M HCl / EtOAc (3.0 mL) was stirred at 20°C for 0.5 hr. LC-MS showed reactant 6 was consumed completely and 18% peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition; column: Phenomenex luna C18 100x40mmx5 um;mobile phase: [H20(0.04% HC1)-ACN]; gradient: 10%-50% B over 8.0 min) to give l-(3-bromo-2-fluorophenyl)-N-(piperidin-2-ylmethyl)-N-propylcyclobutan-l-amine hydrochloride (9.78 mg, 23.0 umol. 15.9% yield, 98.59% purity, HC1 salt) as a yellow oil. MS (ESI): m / z = 383.2 [M+H]+, retention time: 2.004 min, method: B.1H NMR (400 MHz, DMSO-de) d 9.89 - 8.33 (m, 1H), 8.04 - 7.34 (m, 2H), 7.34 - 7.11 (m, 1H), 3.40 - 2.54 (m, 9H), 2.49 - 2.23 (m, 2H), 2.10 - 1.37 (m, 10H), 0.83 (br t, 7 = 7.0 Hz, 3H).

[0898] Example 28: Synthesis of Compounds 434 and 529

[0899] 1) l-[l-(3-chloro-2-fluoro-phenyl)cyclobutyl]piperidin-3-ol

[0900]

[0901] 4 5

[0902] To a solution of 2-(3-bromopropyl)oxirane (500.0 mg, 3.0 mmol, 1.0 eq) in MeOH (2.5 mL) was added dropwise l-(3-chloro-2-fluoro-phenyl)cyclobutanamine (636.3 mg, 3.1 mmol, 1.0 eq) in MeOH (2.5 mL) at 60°C. After dropping, the mixture was stirred at 60°C for 12 hr. Then CS2CO3 (2.9 g, 9.1 mmol, 3.0 eq) was added to the mixture, the mixture was stirred at 60°C for 12 hr. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~4% Tetrahydrofuran / Petroleum ether gradient @ 100 mL / min) to give compound l-[l-(3-chloro-2-fluoro-phenyl)cyclobutyl]piperidin-3-ol (530.0 mg, 1.2 mmol, 38.4% yield, 62.2% purity) as a light yellow oil.

[0903] 2) 2-[[l-[l-(3-chloro-2-fluoro-phenyl)cyclobutyl]pyrrolidin-2-yl]methyl]isoindoline-l,3- dione and 2-[l-[l-(3-chloro-2-fluoro-phenyl)cyclobutyl]-3-piperidyl]isoindoline-l,3- dione

[0904]

[0905] 5 6

[0906]

[0907] 6A

[0908] To a solution of l-[l-(3-chloro-2-fluoro-phenyl)cyclobutyl]piperidin-3-ol (480.0 mg, 1.7 mmol, 1.0 eq) and isoindoline- 1,3-dione (273.7 mg, 1.8 mmol, 1.1 eq) in THF (8.0 mL) was added PPI13 (532.4 mg, 2.0 mmol, 1.2 eq) and DEAD (353.5 mg, 2.0 mmol, 368.9 pL, 1.2 eq). The mixture was stirred at 50°C for 12 hr under N2. LC-MS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~2% Tetrahydrofuran / Petroleum ether gradient @ 100 mL / min) to give compound 2-[[l-[l-(3-chloro-2-fluoro-phenyl)cyclobutyl]pyrrolidin-2-yl]methyl]isoindoline-l,3-dione (260.0 mg, 629.7 pmol, 37.2% yield) as a light yellow oil and compound 2-[l-[l-(3-chloro-2-fluoro-phenyl)cyclobutyl]-3-piperidyl]isoindoline-l, 3-dione (40.0 mg, 96.9 pmol, 5.7% yield) as a light yellow solid.

[0909] 3) l-(l-(3-chloro-2-fluorophenyl)cyclobutyl)piperidin-3-amine dihydrochloride

[0910]

[0911] To a solution of 2-[l-[l-(3-chloro-2-fluoro-phenyl)cyclobutyl]-3-piperidyl]isoindoline-1, 3-dione (40.0 mg, 96.8 pmol, 1.0 eq) in MeOH (1.0 mL) was added NH2NH2.H2O (18.2 mg, 290.6 pmol, 17.6 pL, 80.0% purity, 3.0 eq). The mixture was stirred at 60°C for 2 hr. LC-MS showed desired compound was detected. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HC1 condition, column: Phenomenex luna Cis 100 x 40 mm x 5 um; mobile phase: [H2<D(0.04% HCl)-ACN];gradient:l%-25% B over 8.0 min) to give compound l-(l-(3-chloro-2-fluorophenyl)cyclobutyl)piperidin-3-amine dihydrochloride (25.8 mg, 71.2 pmol, 73.5% yield, 98.2% purity, 2HC1 salt) as a yellow oil. MS (ESI): m / z = 283.2 [M+H]+, retention time:1.285 min, method: E ’H NMR (400 MHz, DMSO-tfe) d 13.15 - 11.18 (m, 1H), 8.45 (brs, 3H), 7.78 (br s, 1H), 7.57 (br s, 1H), 7.39 (br t, J = 7.8 Hz, 1H), 3.99 - 3.65 (m, 2H), 3.17 -2.97 (m, 2H), 2.74 (br s, 3H), 2.33 (br s, 1H), 2.23 - 1.93 (m, 4H), 1.83 (br d, J = 12.5 Hz, 1H), 1.69 - 1.58 (m, 1H), 1.43 - 1.28 (m, 1H).

[0912] 4) (l-(l-(3-chloro-2-fluorophenyl)cyclobutyl)pyrrolidin-2-yl)methanamine

[0913] dihydrochloride

[0914]

[0915] 6A 529

[0916] To a solution of 2-[[l-[l-(3-chloro-2-fluoro-phenyl)cyclobutyl]pyrrolidin-2-yl]methyl]isoindoline- 1,3-dione (100.0 mg, 242.2 pmol, 1.0 eq) in MeOH (2.0 mL) was added NH2NH2.H2O (46.0 mg, 735.1 pmol, 44.5 pL, 80.0% purity, 3.0 eq). The mixture was stirred at 60°C for 2 hr. LC-MS showed desired compound was detected. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HC1 condition, column: Phenomenex luna C18 100 x 40mm x 5 um;mobile phase: [H2<D(0.04% HC1)-ACN]; gradient: l%-25% B over 8.0 min) to give compound (1-(1-(3-chloro-2-fluorophenyl)cyclobutyl)pyrrolidin-2-yl)methanamine dihydrochloride (81.4 mg, 228.3 pmol, 94.2% yield, 99.7% purity, 2HC1 salt) as a yellow oil. MS (ESI): m / z = 283.2 [M+H]+, retention time: 1.229 min, method: E ’H NMR (400 MHz, DMSO-tfe) b 12.24 (br s, 1H), 8.69 (br s, 3H), 7.94 - 7.72 (m, 2H), 7.39 (t, J= 8.0 Hz, 1H), 3.87 (br s, 1H), 3.59 (br s, 1H), 3.37 (br s, 2H), 3.15 - 2.97 (m, 3H), 2.79 (br dd, J= 3.9, 7.3 Hz, 2H), 2.17 (tt, J = 5.0, 10.0 Hz, 1H), 2.02 - 1.83 (m, 2H), 1.73 - 1.47 (m, 3H).

[0917] Example 29: Synthesis of 2-((l-(3-cyano-2-fhiorophenyl)cyclobutyl)(propyl)amino) acetimidamide (Compound 412)

[0918] 1) N-( l-(3-bromo-2-fluorophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide

[0919]

[0920] 1 2To a solution of l-bromo-2-fluoro-benzene (10.0 g, 57.1 mmol, 6.3 mL, 1.0 eq) in THF (100.0 mL) was added a solution of LDA (2 M, 31.4 mL, 1.1 eq, in THF) drop-wise at -70°C over a period of 0.1 hr under N2. The reaction mixture was stirred at -70°C for 0.1 hr. N-cyclobutylidene-2-methyl-propane-2-sulfinamide (10.9 g, 62.9 mmol, 1.1 eq) was added at -70°C. The reaction mixture was warmed to 25°C and stirred for 12 hrs under N2. LC-MS showed 1 was consumed completely and desired mass was detected. The reaction was quenched with saturated aqueous NH4CI 150.0 mL and extracted with ethyl acetate 300.0 mL (100.0 x 3 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give compound N-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide (2.2 g, 4.4 mmol, 7.6% yield, 70.0% purity) as a yellow solid.

[0921] 2) N-(l-(3-cyano-2-fluorophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide

[0922]

[0923] 2 3 A mixture of N-(l-(3-bromo-2-fluorophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide (1.9 g, 5.5 mmol, 1.0 eq), Zn(CN)2 (1.3 g, 10.9 mmol, 692.5 pL, 2.0 eq), Pd2(dba)3 (499.6 mg, 545.5 pmol, 0.1 eq) and Sphos (224.0 mg, 545.5 pmol, 0.1 eq) in DMF (25.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120°C for 12 hrs under N2 atmosphere. LC-MS showed 2 was consumed completely and desired mass was detected. The reaction mixture was quenched by addition water 80.0 mL, and then extracted with ethyl acetate 300.0 mL (100.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give compound N-(l-(3-cyano-2-fluorophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide (1.0 g, 1.7 mmol, 31.7% yield, 52.0% purity) as a yellow oil.3) 3-(l-aminocyclobutyl)-2-fluorobenzonitrile

[0924]

[0925] A solution of N-(l-(3-cyano-2-fluorophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide (1.0 g, 3.3 mmol, 1.0 eq) in 4 M HCl / EtOAc (18.3 mL) was stirred at 25°C for 1 hr. LC-MS showed 3 was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HC1 condition, column: Phenomenex luna C18 100 x 40mm x 5 um; mobile phase:

[0926] [H2O (0.04% HC1)-ACN]; gradient: l%-20% B over 8.0 min) to give compound 3-(l-aminocyclobutyl)-2-fluorobenzonitrile (336.0 mg) as a yellow solid.

[0927] 4) 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)amino)acetamide

[0928]

[0929] To a solution of 3-(l-aminocyclobutyl)-2-fluorobenzonitrile (300.0 mg, 1.3 mmol, 1.0 eq, HC1) in ACN (6.0 mL) was added 2-bromoacetamide (547.8 mg, 4.0 mmol, 3.0 eq) and K2CO3 (731.6 mg, 5.3 mmol, 4.0 eq). The mixture was stirred at 80°C for 12 hrs. LC-MS showed 4 was consumed completely and 73% of desired compound was detected. The reaction mixture was added H2O 10 mL and extracted with ethyl acetate 30 mL (10 mL x 3). The combined organic layers were washed with brine 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Llash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give compound 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)amino)acetamide (276.0 mg, 96.0% purity) as a yellow solid.5) 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)acetamide

[0930]

[0931] To a solution of 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)amino)acetamide (388.0 mg, 1.6 mmol, 1.0 eq) in MeOH (4.0 mL) was added AcOH (188.5 mg, 3.1 mmol, 179.7 pL, 2.0 eq) to pH=5-6, then propanal (109.4 mg, 1.9 mmol, 137.0 pL, 1.2 eq) and NaBFECN (394.4 mg, 6.3 mmol, 4.0 eq) was added. The mixture was stirred at 60°C for 12 hrs. LC-MS showed 47% of 5 was remained and 45% of desired compound was detected. The reaction mixture was added H2O 10.0 mL and extracted with ethyl acetate 30.0 mL (10.0 mL x 3). The combined organic layers were washed with brine 10.0 mL, dried over NaiSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give compound 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)acetamide (151.0 mg, 495.8 pmol, 31.6% yield, 95.0% purity) as a yellow oil.

[0932] 6) 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)ethanethioamide

[0933]

[0934] A solution of 2-((l-(3-cyano-2-fhiorophenyl)cyclobutyl)(propyl)amino)acetamide (150.0 mg, 518.4 pmol, 1.0 eq) in THF (2.0 mL) was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-l,3,2,4dithiadiphosphetane (251.6 mg, 622.1 pmol, 1.2 eq). The mixture was stirred at 60°C for 12 hrs. LC-MS showed 5% of 6 was remained and 12% of desired compound was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0-75% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give compound 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)ethanethioamide (209.0 mg, 62.0% purity, 2 batchs) as a yellow oil.

[0935] 7) methyl 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)ethanimidothioate

[0936]

[0937] To a solution of 2-((l-(3-cyano-2-fhiorophenyl)cyclobutyl)(propyl)amino)ethanethioamide (209.0 mg, 684.3 pmol, 1.0 eq) in acetone (4.0 mL) was added K2CO3 (378.3 mg, 2.7 mmol, 4.0 eq) and CH3I (388.5 mg, 2.7 mmol, 170.4 pL, 4.0 eq). The mixture was stirred at 60°C for 12 hrs. LC-MS showed 7 was consumed completely and 46% of desired compound was detected. The reaction mixture was added H2O 5.0 mL and extracted with EtOAc 30.0 mL (10.0 mL x 3). The combined organic layers were washed with brine 10.0 mL (5.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give compound methyl 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)ethanimidothioate (48.0 mg, 127.7 pmol, 18.7% yield, 85.0% purity) as a yellow oil.

[0938] 8) 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)acetimidamide

[0939]

[0940] To a solution of methyl 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)ethanimidothioate (48.0 mg, 150.3 pmol, 1.0 eq) in EtOH (1.0 mL) was added NH4CI (16.1 mg, 300.5 pmol, 2.0 eq). The mixture was stirred at 60°C for 2 hrs. LC-MS showed 8 was consumed completely and 34% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition, column: Phenomenex LunaC18 100 x 30 mm x 5um; mobile phase: [H2O (0.1% TFA) - ACN]; gradient: 15%-40% B over 8.0 min) to give compound 2-((l-(3-cyano-2-fluorophenyl)cyclobutyl)(propyl)amino)acetimidamide (4.8 mg, 11.9 pmol, 7.9% yield, 99.1% purity, TFA salt) as a white solid. MS (ESI): m / z = 289.2 [M+H]+; retention time: 1.674 min, method: D ’H NMR (400 MHz, DMSO-d6) 39.08 - 8.94 (m, 2H), 8.63 (br s, 2H), 7.93 - 7.85 (m, 1H), 7.79 - 7.70 (m, 1H), 7.47 - 7.39 (m, 1H), 3.35 (s, 2H), 2.47 - 2.29 (m, 4H), 2.27 - 2.13 (m, 3H), 1.74 - 1.63 (m, 1H), 1.32 - 1.19 (m, 2H), 0.87 - 0.74 (m, 3H).

[0941] Example 30: Synthesis _ of 3-(3-((2-aminoethyl)(cvclopropyl)amino)oxetan-3-yl)-2- fluorobenzonitrile (Compound 417)

[0942] 1) N-(3-(3-bromo-2-fluorophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide

[0943]

[0944] A mixture of l-bromo-2-fluoro-benzene (4.5 g, 25.7 mmol, 2.8 mL, 1.0 eq) in THF (45.0 mL) was degassed and purged with N2 for 3 times, and then LDA (2 M, 14.1 mL, 1.1 eq, in THF) was added to the mixture at -78°C, the mixture was stirred at -78°C for 0.5 hr under N2 atmosphere. And then 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (5.0 g, 28.3 mmol, 1.1 eq) was added to the mixture at -78°C, the mixture was stirred at 25°C for 12 hrs under N2 atmosphere. TLC indicated reactant 1 was consumed completely and many new spots formed. The reaction mixture was quenched by addition sat. NH4CI 50.0 mL at 0°C, and then extracted with ethyl acetate 150.0 mL (50.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Elash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound N-(3-(3-bromo-2-fluorophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (3.2 g, 8.4 mmol, 32.5% yield, 92.4% purity) as a yellow solid.2) 3-(3-bromo-2-fliiorophenyl)oxetan-3-amine

[0945]

[0946] 2 3

[0947] A solution of N-(3-(3-bromo-2-fluorophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (0.5 g, 1.4 mmol, 1.0 eq) in 4 M HCl / EtOAc (2.0 mL) and EtOAc (10.0 mL) was stirred at 25 °C for 1 hr. LC-MS showed reactant 2 was consumed completely and -73% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give crude product 3-(3-bromo-2-fluorophenyl)oxetan-3-amine (0.6 g, 1.4 mmol, 98.2% yield, 72.6% purity, HC1) as a yellow solid.

[0948] 3) 3-(3-bromo-2-fluorophenyl)-N-cyclopropyloxetan-3-amine

[0949]

[0950] The pH of solution of 3-(3-bromo-2-fhiorophenyl)oxetan-3-amine (0.6 g, 1.4 mmol, 1.0 eq, HC1) in MeOH (5.0 mL) was adjusted with TEA to 8-9. And then the solution was adjusted pH~6 with AcOH, tert-butyl-(l-ethoxycyclopropoxy)-dimethyl-silane (1.5 g, 7.0 mmol, 5.0 eq) and NaBHaCN (264.3 mg, 4.2 mmol, 3.0 eq) was added to the solution. The mixture was stirred at 60°C for 12 hrs. LC-MS showed -39% of reactant 3 remained, several new peaks were shown on LC-MS and -22% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give compound 3-(3-bromo-2-fluorophenyl)-N-cyclopropyloxetan-3-amine (0.2 g, 549.0 pmol, 39.2% yield) as a colorless oil.4) tert-butyl (2-((3-(3-bromo-2-fluorophenyl)oxetan-3-yl)(cyclopropyl)amino)ethyl) carbamate

[0951]

[0952] 4 5

[0953] To a solution of 3-(3-bromo-2-fluorophenyl)-N-cyclopropyloxetan-3-amine (0.1 g, 443.8 pmol, 1.0 eq) in THF (5.0 mL) was added tert-butyl N-(2-oxoethyl)carbamate (353.3 mg, 2.2 mmol, 5.0 eq), AcOH (32.0 mg, 532.6 pmol, 30.5 pL, 1.2 eq) and NaBH(OAc)3 (282.2 mg, 1.3 mmol, 3.0 eq). The mixture was stirred at 25°C for 12 hrs. LC-MS showed reactant 4 was consumed completely and -64.0% of desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give compound tert-butyl (2-((3-(3-bromo-2-fluorophenyl)oxetan-3-yl)(cyclopropyl)amino)ethyl)carbamate (0.1 g, 272.8 pmol, 61.5% yield) as a colorless oil.

[0954] 5) tert-butyl (2-((3-(3-cyano-2-fluorophenyl)oxetan-3-yl)(cyclopropyl)amino)ethyl) carbamate

[0955]

[0956] 5 6

[0957] A mixture of tert-butyl (2-((3-(3-bromo-2-fluorophenyl)oxetan-3-yl)(cyclopropyl)amino)ethyl)carbamate (0.1 g, 249.2 pmol, 1.0 eq), Zn(CN)i (117.1 mg, 996.9 pmol, 63.3 pL, 4.0 eq), sPhos (10.2 mg, 24.9 pmol, 0.1 eq) and Pd2(dba)3 (22.8 mg, 24.9 pmol, 0.1 eq) in DMF (5.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120°C for 12 hrs under N2 atmosphere. LC-MS showed reactant 5 was consumed completely and -9.0% of desired mass was detected. The reaction mixture was quenched by addition water 10.0 mL, and then extracted with ethyl acetate 15.0 mL (5.0mL x 3). The combined organic layers were dried over NaiSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC , Petroleum ether / Ethyl acetate=3 / l) to give compound tert-butyl (2-((3-(3-cyano-2-fluorophenyl)oxetan-3-yl)(cyclopropyl)amino)ethyl)carbamate (0.04 g, 93.5 pmol, 37.5% yield) as a yellow oil.

[0958] 6) 3-(3-((2-aminoethyl)(cyclopropyl)amino)oxetan-3-yl)-2-fluorobenzonitrile

[0959]

[0960] 6 417

[0961] A solution of tert-butyl (2-((3-(3-cyano-2-fluorophenyl)oxetan-3-yl)(cyclopropyl)amino)ethyl)carbamate (0.04 g, 93.2 pmol, 1.0 eq) in TFA (0.2 mL) and DCM (2.0 mL) was stirred at 25°C for 1 hr. LC-MS showed reactant 6 was consumed completely and -47% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition, column: Phenomenex luna C18 100 x 40 mm x 3 um; mobile phase: [H2<D(0.1% TFA)-ACN];gradient:l%-28% B over 8.0 min) to give compound 3-(3-((2-aminoethyl)(cyclopropyl)amino)oxetan-3-yl)-2-fluorobenzonitrile (0.01 g, 45.8 pmol, 49.1% yield, TFA salt) as a yellow oil. MS (ESI): m / z = 276.3 [M+H]+, retention time:1.609 min, method:A. ’H NMR (400 MHz, DMSO-d6) 37.96 (dt, J = 1.4, 6.8 Hz, 1H), 7.90 - 7.71 (m, 4H), 7.48 (t, J = 7.8 Hz, 1H), 4.95 (d, J = 6.9 Hz, 2H), 4.86 (d, J = 6.4 Hz, 2H), 2.94 (br d, J= 5.4 Hz, 2H), 2.62 (br t, J= 6.4 Hz, 2H), 1.30 - 1.19 (m, 1H), 0.56 - 0.38 (m, 4H).

[0962] Example 31: Synthesis of 3-(3-((2-aminoethyl)(propyl)amino)oxetan-3-yl)-2-fluor...

Claims

Claims1. A compound according to the following general formula I:wherein:X is selected fromwherein:Ri, R2, R4 and R5 are each independently selected from the group consisting of H, F, Cl, Br, I, -CN and ethynyl;R3 is selected from the group consisting of H and F;Y is selected from the group consisting of (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7 is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S, and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3;Z is selected fromwherein:Re is selected from unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl; andRaand Rb are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl; or Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused, bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), hydroxyl, oxo, and options provided above for Re;or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)- or (S)-enantiomers of any of these compounds or prodrugs or metabolites thereof,with the proviso that the compound is not2. The compound according to claim 1, wherein Y is selected from the group consisting of (CH2)n, with n being 1, 2, or 3, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O and S.

3. The compound according to claim 2, wherein Y is selected from (CH2)n, CF2, and CHF, with n being 1, 2, or 3.

4. The compound according to claim 2, wherein Y is CHF.

5. The compound according to claim 2, wherein Y is (CH2)n, with n being 1, 2, or 3.

6. The compound according to claim 5, wherein Y is CH2.

7. The compound according to any one of claims 1 to 6, wherein Raand Rb are each independently selected from H, methyl and ethyl or Raand Rb form together to which they are attached a substituted or unsubstituted 4-membered, 5-membered or 6-membered heterocyclo alkyl .

8. The compound according to any one of the preceding claims, wherein Z is selected from the group consisting of9. The compound according to claim 8, wherein Z is selected from the group consisting of10. The compound according to claim 8, wherein Z is selected from the group consisting of11. The compound according to claim 8, wherein12. The compound according to claim 8, wherein13. The compound according to any one of claims 1 to 12, wherein Re is selected from substituted branched or linear C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 bicycloalkyl, substituted C4-C7 alkylcycloalkyl, substituted C3-C6 alkenyl and substituted C3-C6 alkynyl; and wherein the substituents of substituted branched or linear C2-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C4-C8 bicycloalkyl, substituted C4-C7 alkylcycloalkyl, substituted C3-C6 alkenyl alkenyl and substituted C3-C6 alkynyl are each independently selected from F, Cl, CN, OH, alkylthio, and alkoxy.

14. The compound according to claim 13, wherein the substituents are each independently selected from the group consisting of F, Cl, CN, and OH.

15. The compound according to any one of claims 1 to 12, wherein Reis selected from the group consisting of cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, cyclobutyl, fluoro-substituted cyclobutyl, methyl- substituted cyclobutyl, cyclopentyl, bicyclo[l.l.l]pentan-l-yl-, allyl, -CH2CH2-S-CH3, -CH2CF2H, -CH2CF3, -CH2CH2CN and -CH2CCH.

16. The compound according to any one of claims 1 to 12, wherein Re is cyclopropyl, fluoro- substituted cyclobutyl, methyl-substituted cyclobutyl, propyl, isopropyl or allyl.

17. The compound according to claim 16 wherein Re is cyclopropyl.

18. The compound according to claim 16, wherein Re is fluoro-substituted cyclobutyl.

19. The compound according to claim 16, wherein Re is n-propyl.

20. The compound according to any one of claims 1 to 19, wherein21. The compound according to any one of claims 1 to 19, wherein22. The compound according to claim 21, wherein R3 is H.

23. The compound according to claim 21 or 22, wherein R4 is H.

24. The compound according to any one of claims 21 to 23, wherein R5 is H or F.

25. The compound according to any one of claims 21 to 24, wherein R3 and R4 are H.

26. The compound according to any one of claims 21 to 25, wherein R3, R4, and R5 are H.

27. The compound according to any one of the preceding claims, wherein Ri is F.

28. The compound according to any one of the preceding claims, wherein R2 is selected from -CN, Br and Cl.

29. The compound according to claim 21, wherein Ri is F and R3 is H.

30. The compound according to any one of claims 1 to 28, wherein Ri is F and R2 is -CN.

31. The compound according to claim 21 or 22, wherein Ri is F, R2 is -CN and R4 and R5 are H.

32. The compound according to claim 1, wherein the compound has one of the following formulas:or a pharmaceutically acceptable salt, stereoisomer, diasteromer, (R)- or (S)- enantiomer of any of these compounds, a racemate thereof or any other mixture of the corresponding (R)- or (S) -enantiomers of any of these compounds or prodrugs or metabolites thereof.

33. The compound according to any one of the preceding claims, wherein the pharmaceutically acceptable salt is selected from halides, sulphates, sulfonates, fumarates, formiates and trifluoroacetates.

34. A compound for use in a method for treating or preventing a disease of the human or animal body, wherein the compound is a compound according to the following general formula I:wherein:X is selected fromwherein:Ri, R2, R4 and R5 are each independently selected from the group consisting of H, F, Cl, Br, I, -CN and ethynyl;R3 is selected from the group consisting of H and F;270Y is selected from the group consisting of (CH2)n, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7 is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S, and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3;Z is selected fromwherein:Re is selected from unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl; andRaand Rb are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl; or Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused,271bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), hydroxyl, oxo, and options provided above for Re;or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)- or (S)-enantiomers of any of these compounds or prodrugs or metabolites thereof.

35. The compound for use according to claim 34, wherein the compound is a compound according any one of claims 1 to 33.

36. The compound for use according to claim 34, wherein the disease is treated by inhibiting NMD A receptor / TRPM4 complex formation.

37. The compound for use according to claim 34 or claim 35, wherein the disease is a neurological disease.

38. The compound for use according to claim 34 or claim 35, wherein the disease is a neurodegenerative disease.

39. The compound for use according to claim 34 or claim 35, wherein the disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Huntington’s disease (HD), stroke, traumatic brain injury, post traumatic brain injury, absent-mindedness, age-related loss of memory, aging-related memory decline, progressive nuclear palsy, multiple sclerosis, thalamic degeneration, glutamate induced excitotoxicity, dystonia, epilepsy, optic nerve disease, diabetic retinopathy, glaucoma, pain, anti-NMDA receptor encephalitis, viral encephalopathy, dementia, microangiopathy, Binswanger’s disease, cerebral ischemia, hypoxia, Parkinson's disease, Batten disease, schizophrenia, Korsakoff's psychosis, depression, cerebral malaria, toxoplasmosis, HIV infection / AIDS, Zika virus infection, other viral infection potentially leading to neurodegenerative events and corresponding neuronal or brain damage,272respectively, brain tumour, diseases of the central nervous system, sexual dysfunction disorders, sleep disorders, pathological disturbances after the intake of food, stimulants and addictive substances.

40. The compound for use according to claim 34 or claim 35, wherein the disease is ALS.

41. The compound for use according to claim 34 or claim 35, wherein the disease is Alzheimer’s disease.

42. The compound for use according to claim 34 or claim 35, wherein the disease is Huntington’s disease.

43. The compound for use according to claim 34 or claim 35, wherein the disease is glaucoma.

44. The compound for use according to claim 34 or claim 35, wherein the disease is depression.

45. The compound for use according to claim 43, wherein the depression is selected from the group consisting of treatment-resistant depression (TRD), major depressive disorder (MDD), juvenile depression and postpartum depression.

46. A compound according to one of the following formulas:273wherein:X is selected fromwherein:Ri, R2, R4 and R5 are each independently selected from the group consisting of H, F, Cl, Br, I, -CN and ethynyl;R3 is selected from the group consisting of H and F;Y is selected from the group consisting of (CFDn, with n being 1, 2, 3 or 4, CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, S, and (CH2)m-R7-(CH2)i, wherein R7 is selected from the group consisting of CH-CH3, C=CH2, CHF, CF2, CO, CHOH, O, and S, and wherein m and 1 are selected from 0, 1, 2 and 3 and wherein m+1 is 1, 2 or 3; and274Re is selected from unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl.

47. A compound for use in a method for treating or preventing a disease of the human or animal body, wherein the disease is selected from treatment-resistant depression (TRD), major depressive disorder (MDD), juvenile depression and postpartum depression, and wherein the compound is a compound according to the following general formula (III):Ri, R2, R4 and R5 are each independently selected from the group consisting of H, halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), -CN and ethynyl;R3 is selected from the group consisting of H, Ci-Ce alkyl and halogen (selected from F, Cl, Br, and I, preferably selected from F and Cl), preferably from the group consisting of H and F;Z is selected from275wherein:Re is selected from hydrogen, unsubstituted branched or linear C2-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, substituted C3-C6 alkenyl; unsubstituted C3-C6 alkynyl, and substituted C3-C6 alkynyl; andRaand Rb are each independently selected from the group consisting of H, substituted or unsubstituted branched or linear C1-C4 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, or Raand Rb taken together with the nitrogen atom to which they are attached represent a 4-11 membered monocyclic or fused, bridged, or spiro bicyclic saturated ring, optionally containing one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from halogen (selected from F, Cl, Br, and I, preferably276selected from F and Cl), hydroxyl, oxo, and options provided above for Re (e.g. Raand Rb may form together with the nitrogen in between a substituted or unsubstituted 4-membered, 5-membered or 6-membered heterocycloalkyl);either i) at least one of Rs and R9 is H, while the other is selected from the group consisting of H, unsubstituted branched or linear C1-C4 alkyl, fluoro-substituted branched or linear C1-C4 alkyl, unsubstituted propenyl, unsubstituted C3-C6 cycloalkyl, and fluorosubstituted C3-C6 cycloalkyl; or ii) Rs and R9 taken together with the carbon atom to which they are attached represent a 3-7 membered monocyclic saturated ring, optionally containing one heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one, two, or three substituents independently selected from methyl, methylene, halogen (selected from F, Cl, Br, and I, preferably F), O and hydroxy,or a pharmaceutically acceptable salt, stereoisomer, diastereomer, (R)- or (S)-enantiomer of any of these compounds a racemate thereof or any other mixture of the corresponding (R)-or (S) -enantiomers of any of these compounds or prodrugs or metabolites (in particular N-carbamoylglucuronides) thereof.

48. A compound for use in a method of treating or preventing a disease of the human or animal body, wherein the disease is selected from treatment-resistant depression (TRD), major depressive disorder (MDD), juvenile depression and postpartum depression, and wherein the compound is capable to bind to NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site and is capable of dissociating the NMDAR / TRPM4 complex.

49. A method of identifying a compound capable of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site and capable of dissociating the NMDAR / TRPM4 complex, wherein the method comprises one of the following steps: a) determining for a compound known to be capable of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site its capability of dissociating the NMDAR / TRPM4 complex,277b) determining for a compound known to be capable of dissociating the NMDAR / TRPM4 complex its capability of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site, orc) determining for a compound of interest i) its capability of binding to the NMDA receptor at the phencyclidine / tenocyclidine (PCP / TCP) site and ii) its capability of dissociating the NMDAR / TRPM4 complex.

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