Novel potassium channel inhibitor

Abstract

The present invention relates to novel compounds, pharmaceutical compositions containing such compounds and their use for treating, alleviating or preventing diseases or disorders associated with potassium channel activity.

Description

Technical Field

[0001] The present invention relates to novel compounds, pharmaceutical compositions containing such compounds, and their use for treating, alleviating or preventing diseases or disorders associated with the activity of potassium channels.

Background Art

[0002] Ion channels are transmembrane proteins that catalyze the transport of inorganic ions across cell membranes. Ion channels are involved in a very diverse range of processes such as the generation and timing of action potentials, synaptic transmission, hormone secretion, and muscle contraction.

[0003] All animal cells express potassium (K + ) channels in their cell membranes, and the channels play a major role in the regulation of membrane potential. In neurons and muscle cells, they affect the shape of action potentials, regulate the frequency and firing pattern of action potentials, neurotransmitter release, and the degree of bronchial and vascular dilation. In non-excitable cells, K + channels regulate cell proliferation and cell migration as well as cytokine secretion.

[0004] From a molecular and functional perspective, K + channels represent the largest and most diverse group among ion channels. It can be broadly divided into four families: · Voltage-activated K + channels (K v ), · Inwardly rectifying K + channels (KIR), · Two-pore K + channels (K2P), and · Calcium-activated K + channels (K Ca ) which can be divided into.

[0005] In K Ca channels, there are two main groups: · Small conductance (SK or K Ca 2.x) and intermediate conductance channels (IK or K Ca 3.1), as well as · Classical Ca 2+ and voltage-activated large conductance channels (BK, K Ca 1.1) and channels sensitive to other intracellular ions (K Ca 4.x; and K Ca 5.1) can be classified into the intracellular ligand-gated family to which it belongs.

[0006] K Ca 3.1 K Ca 3.1 is a Ca 2+ activated K + channel encoded by the human gene KCNN4. This channel is a tetramer consisting of four identical α subunits. At their interfaces, they form a transmembrane K + selective pore. On the cell side, incoming Ca 2+ binds to generate four calmodulins that open the pore for K + efflux. K Ca 3.1 is expressed in many immune cells including T and B lymphocytes, mast cells, neutrophils and macrophages, as well as erythrocytes, fibroblasts, epithelium and endothelium, but K Ca 3.1 is essentially absent from excitable cells such as cardiomyocytes, smooth muscle, and skeletal muscle, as well as neurons. Furthermore, since K Ca 3.1 is essentially absent from excitable cells, pharmacological modulation of this channel is not expected to cause related harmful effects on the cardiovascular system and CNS.

[0007] K Ca 3.1 K CaThe role of 3.1, which is described in this specification for T cells, is also effective for other immune cells and fibroblasts. Activated T cells (including Th0, Th1, and Th2) continuously require a highly and precisely regulated intracellular Ca 2+ concentration to regulate the activation of enzymes and nuclear transcription factors (such as the Ca 2+ -dependent calcineurin / NFAT system, etc.). The Ca 2+ in the cytosol is dynamically regulated via intracellular stores, but a long-term increase in Ca 2+ requires influx from the extracellular space. This causes membrane depolarization, reduces further influx, and, if not counteracted, rapidly terminates the process. This is achieved by the activation of 3.1 and the efflux of K Ca . To enhance the mechanism long-term, molecular adaptation occurs: the K + 3.1 channel is phosphorylated by the H kinase NDPK-B, increasing its maximum activity, and the expression of K Ca 3.1 is upregulated following the activation of NFAT. Both processes enhance the hyperpolarizing ability of Ca Ca -mediated K 2+ 3.1 activation. Ca The efficient maintenance of high levels of cytosolic Ca

[0008] homeostasis is beneficial in a controlled immune response but can become severely pathogenic if it becomes an uncontrolled autonomous process. 2+

[0009] K Ca 3.1 Red blood cells move between the lungs, which pick up O2 from alveolar air, and all tissues, which pass the O2 for use in oxidative phosphorylation. Gas exchange occurs in the smallest blood vessels, and red blood cells need to be flexible and sized to pass through the capillary bed.

[0010] In this process, K Ca ​3.1 is activated by the influx of Ca through the piezo 1, a Ca permeable channel, which is turned on by mechanical stress on the membrane during passage. Next, the efflux of K promotes the efflux of Cl and water, resulting in a rapid and transient contraction, allowing for smooth passage. On the opposite side where the blood vessel dilates again, it is safe, both channels close, and the gradients of salts (K, Cl, Ca) and water are rapidly restored by active transport processes, preparing the red blood cells for the next passage. 2+ through the piezo 1, a Ca permeable channel 2+ Thus, compounds that act as potassium channel modulators may be very useful in the treatment, alleviation, and / or prevention of diseases such as inflammatory bowel disease (IBD), xerocytosis erythrocytes, and acute respiratory distress syndrome (ARDS). + and water, resulting in a rapid and transient contraction, allowing for smooth passage. On the opposite side where the blood vessel dilates again, it is safe, both channels close, and the gradients of salts (K, Cl, Ca) and water are rapidly restored by active transport processes, preparing the red blood cells for the next passage. - and water, resulting in a rapid and transient contraction, allowing for smooth passage. On the opposite side where the blood vessel dilates again, it is safe, both channels close, and the gradients of salts (K, Cl, Ca) and water are rapidly restored by active transport processes, preparing the red blood cells for the next passage. + Cl - Ca 2+ ) and water are rapidly restored by active transport processes, preparing the red blood cells for the next passage.

[0011] Potassium channel modulator Thus, compounds that act as potassium channel modulators may be very useful in the treatment, alleviation, and / or prevention of diseases such as inflammatory bowel disease (IBD), xerocytosis erythrocytes, and acute respiratory distress syndrome (ARDS).

[0012] WO 2014 / 001363 discloses tetrazole derivatives that function as potassium channel modulators suitable for use in the treatment of diseases and disorders related to the activity of potassium channels.

[0013] WO 2013 / 191984 discloses fused thiazine-3-ones suitable for the treatment of diseases related to K3.1. Ca WO 2013 / 191984 discloses fused thiazine-3-ones suitable for the treatment of diseases related to K3.1.

[0014] WO 2014 / 067861 discloses 3,4-disubstituted oxazolidinone derivatives and their use as inhibitors of calcium-activated potassium channels.

[0015] Strobaek et al. (2013) disclose the K(Ca)3.1 channel inhibitor 4-[[3-(trifluoromethyl)-phenyl]methyl]-2H-1,4-benzothiazin-3(4H)-one (NS6180).

[0016] K Ca 3.1 is known to play an important role in diseases such as IBD, hereditary spherocytosis, and ARDS, and thus, K Ca 3.1 is a promising target for the treatment of these diseases. Thus, K Ca There is a need to provide 3.1 modulators.

[0017] Many known potassium channel modulators are poorly soluble in water. Thus, there is a further need for potassium channel modulators such as K Ca 3.1 modulators that are more soluble in water. SUMMARY OF THE INVENTION

[0018] In one aspect, the present invention provides a compound of formula (XVI):

[0019]

Chemical formula

[0020] (wherein, R 14 is selected from the group consisting of -C(O)-C 1-8 alkyl; -C(O)-O-C 1-8 alkyl; -C 2-8 alkyl; -H and -S(O)2-C 1-8 alkyl; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 6 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 7 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O 1-8 alkyl; R 8 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O 1-8 alkyl; R 3 R 4 R 5 R 6 R 7 and R 8 any one of may optionally combine together to form a ring; A is phenyl or pyridinyl, and phenyl or pyridinyl is optionally halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -CN, NO2, -SO2CH3, and -SF5, and is substituted by one or more substituents R 13 selected individually from the group consisting of; and X is halogen) or a pharmaceutically acceptable salt thereof.

[0021] In one aspect, the present invention relates to a compound of formula (I):

[0022]

Chemical formula

[0023] (wherein, R 1 is optionally -OH, or -OC 1-8 alkyl substituted by H, -C 1-8 alkyl; R2 is a bond, -C(O)-, -S(O)2-, or -C(H)2-; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 6 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 7 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O; R 8 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 any one of which optionally combines together to form a ring; R 9 is -C(H)- or -N-; R 10 is H or halogen; R 11 is H or halogen; R 12 is -CX3, -OCX3, H or halogen; and X is halogen) or a pharmaceutically acceptable salt thereof.

[0024] In a further aspect, the present invention relates to a pharmaceutical composition comprising a compound as disclosed herein.

[0025] The compounds of the present invention have high solubility in aqueous media. Furthermore, the compounds of the present invention are active as potassium channel modulators. Therefore, they are of great interest for the treatment, alleviation and / or prevention of diseases associated with potassium channels. Accordingly, the present invention also relates to the use of the compounds as disclosed herein as medicaments. In one aspect, the compounds disclosed herein are used for the treatment of inflammatory bowel disease (IBD). In another aspect, the compounds disclosed herein are used for the treatment of hereditary spherocytosis. In yet another aspect, the compounds disclosed herein are used for the treatment of acute respiratory distress syndrome (ARDS).

Embodiments for Carrying Out the Invention

[0026] Compound In one aspect, the present invention relates to a compound of formula (VII):

[0027]

Chemical Formula

[0028] (wherein, R 1 is optionally -OH, or -OC 1-8 alkyl substituted with H, -C 1-8 alkyl; R 2 is a bond, -C(O)-, -S(O)2-, or -C(H)2-; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 6 is H, a bond, or C in which one methylene group is optionally replaced by -O- 1-8 alkyl; R 7 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O 1-8 alkyl; R 8 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O 1-8 alkyl; R 3 R 4 R 5 R 6 R 7 and R 8 any one of which optionally combines together to form a ring; A is phenyl or pyridinyl, and phenyl or pyridinyl is optionally substituted with one or more substituents R individually selected from the group consisting of halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -CN, NO2, -SO2CH3, and -SF5; and 13 X is halogen) or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof.

[0029] In one embodiment, the compound is of formula (XVI):

[0030]

Chemical formula

[0031] (wherein, R 14is -C(O)-C 1-8 alkyl; -C(O)-O-C 1-8 alkyl; -C 2-8 alkyl; -H and -S(O)2-C 1-8 selected from the group consisting of; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 6 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 7 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O; R 8 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O; R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 any one of which optionally combines together to form a ring; A is phenyl or pyridinyl, and phenyl or pyridinyl is optionally halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7One or more substituents R individually selected from the group consisting of cycloalkyl, -CN, NO2, -SO2CH3, and -SF5 13 substituted with; and X is halogen) or a pharmaceutically acceptable salt thereof.

[0032] In one embodiment, A is a moiety of formula (IX):

[0033]

Chemical formula

[0034] (wherein R 9 is -C(H)-, -N-, or -C(R 13 )-; R 13 is halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -CN, NO2, -SO2CH3, and -SF5 individually selected from the group consisting of; n is an integer from 0 to 4; and X is halogen) is.

[0035] Thus, in one embodiment, the compound is of formula (VIII):

[0036]

Chemical formula

[0037] (wherein R 14 is -C(O)-C 1-8 alkyl; -C(O)-O-C 1-8 alkyl; -C 2-8Alkyl; -H and -S(O)2-C 1-8 Selected from the group consisting of alkyl; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C in which one methylene group is optionally replaced by -O- 1-8 alkyl; R 6 is H, a bond, or C in which one methylene group is optionally replaced by -O- 1-8 alkyl; R 7 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O 1-8 alkyl; R 8 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O 1-8 alkyl; R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Any one of which is optionally joined together to form a ring; and R 9 is -C(H)-, -N-, or -C(R 13 )-; R 13 is halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -CN, NO2, -SO2CH3, and -SF5, individually selected from the group consisting of; n is an integer from 0 to 4; and X is halogen) or a pharmaceutically acceptable salt thereof.

[0038] In one embodiment, A is a moiety of formula (X):

[0039]

Chemical formula

[0040] (wherein, R 9 is -C(H)-, -N-, or -C(R 13 )-; R 10 , R 11 , R 12 , and R 13 are each independently selected from the group consisting of H, halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -CN, NO2, -SO2CH3, and -SF5; and X is halogen) .

[0041] Thus, in one embodiment, the compound is of formula (I):

[0042]

Chemical formula

[0043] (wherein, R 1 is optionally -OH, or -OC 1-8 alkyl, -C 1-8 alkyl substituted with H; R 2 is a bond, -C(O)-, -S(O)2-, or -C(H)2-; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 6 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 7 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are each optionally replaced by -O- and / or replaced by =O; R 8 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are each optionally replaced by -O- and / or replaced by =O; R 3 R 4 R 5 R 6 R 7 R 8 and any one of R R 9 is -C(H)-, -N-, or -C(R 13 )-; R 10 R 11 R 12 R 13 is independently selected from the group consisting of H, halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -CN, NO2, -SO2CH3, and -SF5; and X is a halogen) or a pharmaceutically acceptable salt thereof.

[0044] In one embodiment, the present invention relates to a compound of formula (I):

[0045] [Chemical formula]

[0046] (wherein R 1 is optionally -OH, or -OC 1-8 alkyl substituted with H, -C 1-8 alkyl; R 2 is a bond, -C(O)-, -S(O)2-, or -C(H)2-; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 6 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 7 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are optionally individually replaced by -O- and / or substituted by =O; R 8 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are optionally individually replaced by -O- and / or substituted by =O; R 3 , R 4 , R 5 , R 6 , R7 and R 8 Any one of them is optionally joined together to form a ring; R 9 is -C(H)- or -N-; R 10 is H or halogen; R 11 is H or halogen; R 12 is -CX3, -OCX3, H or halogen; and X is halogen) or a pharmaceutically acceptable salt thereof.

[0047] In one embodiment, the compound is of formula (XVII):

[0048]

Chemical formula

[0049] (wherein, R 14 is -C(O)-C 1-8 alkyl; -C(O)-O-C 1-8 alkyl; -C 2-8 alkyl; -H and -S(O)2-C 1-8 alkyl selected from the group consisting of; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 6 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 7is C where H, a bond, -OH, or one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O 1-8 alkyl; R 8 is C where H, a bond, -OH, or one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O 1-8 alkyl; R 3 R 4 R 5 R 6 R 7 and R 8 any one of which optionally combines together to form a ring; R 9 is -C(H)- or -N-; R 10 is H or halogen; R 11 is H or halogen; R 12 is -CX3, -OCX3, H or halogen; and X is halogen) or a pharmaceutically acceptable salt thereof.

[0050] The term "C 1-10 alkyl" including C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, and C 10 alkyl is well understood. The alkyl can be straight-chain, branched and / or cyclic. Thus, the alkyl can be partially cyclic. For example, "C1-C6-alkyl" refers to an alkyl group containing 1 to 6 carbon atoms which can be straight-chain or branched such as methyl, ethyl, propan-1-yl, propan-2-yl, isopropyl, tert-butyl, butan-1-yl, butan-2-yl, pentan-1-yl, pentan-2-yl, pentan-3-yl, 2-methylbutan-1-yl, 3-methylbutan-1-yl), hexan-1-yl or 2,3-dimethylbutan-1-yl.

[0051] For example, "C3-C7-cycloalkyl" represents a saturated monocyclic carbocyclic ring containing 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0052] For example, "C1-C6-alkoxy" represents an -O-C1-C6-alkyl group such as methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy, 3-methyl-1-butoxy, 2-pentoxy, 2-methyl-2-butoxy, 1-hexoxy, or 3-hexoxy.

[0053] In one embodiment, R 1 is -OC 1-7 alkyl, etc., -OC 1-6 alkyl, etc., -OC 1-5 alkyl, etc., -OC 1-4 alkyl, etc., -OC 1-3 alkyl, etc., -OC 1-2 alkyl, etc., -OC1 alkyl, etc., -OC 1-8 alkyl. The alkyl can be linear, branched, cyclic, or partially cyclic. In one embodiment, R 1 is -OC 1-4 alkyl.

[0054] In one embodiment, R 1 is -C 1-7 alkyl, etc., -C 1-6 alkyl, etc., -C 1-5 alkyl, etc., -C 1-4 alkyl, etc., -C 1-3 alkyl, etc., -C 1-2 alkyl, etc., -C1 alkyl, etc., -C 1-8 alkyl. The alkyl can be linear, branched, cyclic, or partially cyclic. In one embodiment, the alkyl is substituted with -OH. In one embodiment, R 1 is -C 1-4 alkyl. In one embodiment, R 1is a cyclic alkyl such as cyclopropyl or cyclobutyl.

[0055] In one embodiment, R 1 is H.

[0056] In one embodiment, R 2 is a bond. In one embodiment, R 2 is -C(O)-. In one embodiment, R 2 is -S(O)2. In one embodiment, R 2 is -C(H)2-.

[0057] In one embodiment, R 2 is -C(O)- and R 1 is -OC 1-4 alkyl. In one embodiment, R 2 is -C(O)- and R 1 is -OC 1-3 alkyl. In one embodiment, R 2 is -C(O)- and R 1 is -OCH3. In one embodiment, R 2 is -C(O)- and R 1 is -OCH2CH3. In one embodiment, R 2 is -C(O)- and R 1 is -OC3 alkyl such as -OCH2(CH3)2 or -O-cyclopropyl.

[0058] In one embodiment, R 2 is -C(O)- and R 1 is -C 1-3 alkyl. In one embodiment, R 2 is -C(O)- and R 1 is -C3 alkyl such as cyclopropyl.

[0059] In one embodiment, R 2 is a bond and R 1 is C 3-4 alkyl and R 2is -C(H)2-, and R 1 is C 2-3 corresponds to being alkyl.

[0060] In one embodiment, R 2 is -C(H)2-, and R 1 is -C3 alkyl such as cyclopropyl. In one embodiment, R 2 is -C(H)2-, and R 1 is -C3 alkyl such as n-propyl substituted with -OH.

[0061] In one embodiment, R 2 is -C(H)2-, and R 1 is cyclic alkyl such as cyclopropyl or cyclobutyl.

[0062] In one embodiment, R 2 is a bond, and R 1 is cyclic alkyl such as cyclopropyl or cyclobutyl.

[0063] In one embodiment, R 2 is -S(O)2-, and R 1 is -C 1-3 alkyl. In one embodiment, R 2 is -S(O)2-, and R 1 is methyl.

[0064] In one embodiment, -R 1 -R 2 is not -CH3, for example, when R 2 is a bond, R 1 is not C1 alkyl.

[0065] In one embodiment, -R 2 -R 1 is -R 14 .

[0066] In one embodiment, R 14 is -C(O)-C 1-8is alkyl. In one embodiment, R 14 is -C(O)-C 1-3 alkyl. In one embodiment, R 14 is -C(O)-C3 alkyl such as -C(O)-cyclopropyl.

[0067] In one embodiment, R 14 is -C(O)-O-C 1-8 alkyl. In one embodiment, R 14 is -C(O)-O-C 1-3 alkyl. In one embodiment, R 14 is -C(O)-OCH3. In one embodiment, R 14 is -C(O)-OCH2CH3. In one embodiment, R 14 is -C(O)-OC3 alkyl such as -OCH2(CH3)2 or -O-cyclopropyl.

[0068] In one embodiment, R 14 is C 3-4 alkyl such as -C 2-8 alkyl. In one embodiment, R 14 is -C(H)2-cycloalkyl such as -C(H)2-cyclopropyl or -C(H)2-cyclobutyl. 3-7 In one embodiment, R 14 is -cycloalkyl such as -cyclopropyl or -cyclobutyl. 3-7 In one embodiment, R 14 is -C alkyl substituted with one or more -OH. 3-4 alkyl such as -C 2-8 alkyl. In one embodiment, R 14 is isopropyl substituted with -OH.

[0069] In one embodiment, R 14 is -H.

[0070] In one embodiment, R 14 is -S(O)2-C 1-8is alkyl. In one embodiment, R 14 is -S(O)2-CH3.

[0071] In one embodiment, R 3 is H. In another embodiment, R 3 is a bond. In one embodiment, R 3 is C 1-4 alkyl such as C 1-3 alkyl such as C 1-2 alkyl such as C1 alkyl and the like, C 1-5 alkyl. The alkyl can be linear, branched, cyclic or partially cyclic. In one embodiment, R 3 is C 1-3 alkyl.

[0072] In one embodiment, R 4 is H. In another embodiment, R 4 is a bond. In one embodiment, R 4 is C 1-4 alkyl such as C 1-3 alkyl such as C 1-2 alkyl such as C1 alkyl and the like, C 1-5 alkyl. The alkyl can be linear, branched, cyclic or partially cyclic. In one embodiment, R 4 is C 1-3 alkyl.

[0073] In one embodiment, R 3 and R 4 are both H. In another embodiment, only one of R 3 and R 4 is H, while the other is a bond or C 1-5 alkyl.

[0074] In one embodiment, R 5 is H. In one embodiment, R 5 is a bond. In one embodiment, R 5 is C 1-7 alkyl such as C 1-6 alkyl such as C1-5 C such as alkyl 1-4 C such as alkyl 1-3 C such as alkyl 1-2 C such as C1 alkyl etc. of alkyl etc. 1-8 is alkyl. In one embodiment, one of the methylene groups in the alkyl is replaced by -O-, thus forming an ether moiety. In one embodiment, R 5 is C 1-4 alkyl.

[0075] In one embodiment, R 6 is H. In one embodiment, R 6 is a bond. In one embodiment, R 6 is C 1-7 C such as alkyl 1-6 C such as alkyl 1-5 C such as alkyl 1-4 C such as alkyl 1-3 C such as alkyl 1-2 C such as C1 alkyl etc. of alkyl etc. 1-8 is alkyl. In one embodiment, one of the methylene groups in the alkyl is replaced by -O-, thus forming an ether moiety. In one embodiment, R 6 is C 1-4 alkyl.

[0076] In one embodiment, R 5 and R 6 are H. In one embodiment, R 5 and R 6 are -CH3. In one embodiment, R 5 and R 6 are joined together to form a ring. The ring can be a 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, or 7-membered ring. In one embodiment, the ring is a 3-membered ring. In another embodiment, only one of R 5 and R 6 is H, while the other is a bond or C 1-8 alkyl. In one embodiment, R 5 and R 6Combine together to form a ring such as formula (II), formula (XV) or formula (XXII).

[0077]

Chemical formula

[0078] In one embodiment, R 7 is H. In one embodiment, R 7 is a bond. In one embodiment, R 7 is -OH. In one embodiment, R 7 is C 1-7 alkyl such as C 1-6 alkyl such as C 1-5 alkyl such as C 1-4 alkyl such as C 1-3 alkyl such as C 1-2 alkyl such as C1 alkyl etc. is C 1-8 alkyl. In one embodiment, one or more methylene groups of the alkyl are replaced by -O-. In one embodiment, the alkyl is substituted with =O, for example, R 7 is acetyl. In one embodiment, R 7 is -C(O)-CH3. In one embodiment, the alkyl is substituted with =O, one or more methylene groups of the alkyl are replaced by -O-, for example, R 7 is methoxycarbonyl. In one embodiment, R 7 is -C(O)-O-CH3. In one embodiment, R 7 is C 1-4 alkyl. In one embodiment, R 7 is methyl.

[0079] In one embodiment, R 8 is H. In one embodiment, R 8 is a bond. In one embodiment, R 8 is -OH. In one embodiment, R 8 is C 1-7C such as alkyl 1-6 C such as alkyl 1-5 C such as alkyl 1-4 C such as alkyl 1-3 C such as alkyl 1-2 C such as C1 alkyl such as alkyl 1-8 is alkyl. In one embodiment, one or more methylene groups of the alkyl are replaced by -O-. In one embodiment, the alkyl is substituted with =O, for example, R 8 is acetyl. Thus, in one embodiment, R 8 is -C(O)-CH3. In one embodiment, the alkyl is substituted with =O, one or more methylene groups of the alkyl are replaced by -O-, for example, R 8 is methoxycarbonyl. Thus, in one embodiment, R 8 is -C(O)-CH3. In one embodiment, R 8 is C 1-4 alkyl. In one embodiment, R 8 is methyl.

[0080] In one embodiment, R 5 or R 6 is such that R 5 is bonded to R 7 and is bonded to R 7 or R 8 to form a ring. In one embodiment, when R 5 is bonded to R 7 , R 6 and R 8 are H. In one embodiment, when R 5 is bonded to R 7 , R 6 is H and R 8 is methyl. In one embodiment, R 5 is such that it is bonded to R 7 and is bonded to R 7 or R 8 to which R 5 or R 6The ring formed thereby is a 4-membered ring, 5-membered ring, 6-membered ring, 3-membered ring or 7-membered ring. In one embodiment, R 5 when bonded to R 7 as in the case where R 5 or R 6 is bonded to R 7 or R 8 the ring formed is azetidine. In one embodiment, R 5 when bonded to R 7 as in the case where R 5 or R 6 is bonded to R 7 or R 8 the ring formed is pyrrolidine. In one embodiment, R 5 when bonded to R 7 as in the case where R 5 or R 6 is bonded to R 7 or R 8 the ring formed is morpholine. In one embodiment, R 5 when bonded to R 7 as in the case where R 5 or R 6 is bonded to R 7 or R 8 the ring formed is piperidine. In one embodiment, R 5 is bonded to R 7 as in formula (III), formula (XI) or formula (XVIII).

[0081]

Chemical formula

[0082] In one embodiment, the compound is the (S)-enantiomer of formula (III).

[0083] In one embodiment, R 5 when bonded to R 7 as in the case where R 5 or R 6 is bonded to R 7 or R 8The ring formed when combined is pyrrolidine as in the case of formula (IV), formula (XII) or formula (XIX).

[0084]

Chemical formula

[0085] In one embodiment, the compound is the (S)-enantiomer of formula (IV). In one embodiment, the compound has the formula (IV), and R 9 is -C(H)-, and R 10 is -H. In one embodiment, the compound has the formula (IV), and R 9 is -C(H)-, and R 10 is -H, and R 8 is C 1-3 alkyl such as -H or methyl.

[0086] In one embodiment, R 3 or R 4 is such that R 3 is combined with R 7 to form a ring by combining with R 7 or R 8 In one embodiment, when R 3 is combined with R 7 , R 4 and R 8 are H. In one embodiment, the ring formed by combining R 3 with R 7 by combining R 7 or R 8 with R 3 or R 4 is a 4-membered ring, 5-membered ring, 6-membered ring, 3-membered ring or 7-membered ring. In one embodiment, the ring formed when R 5 is combined with R 7 as in the case when R 3 or R 4 is combined with R 7 or R 8 is a 4-membered ring. In one embodiment, when R 3 is combined with R 7When combined with R 3 or R 4 is R 7 or R 8 The ring formed when combined with R is azetidine. In one embodiment, R 3 is combined with R as in formula (V), formula (XIV) or formula (XXI) 7 .

[0087] [Chemical formula]

[0088] In one embodiment, R 3 or R 4 is R 3 is combined with R 5 such that R 5 or R 6 combines with R 3 to form a ring. In one embodiment, when R 5 is combined with R 4 and R 6 are H. In one embodiment, R 3 is combined with R 5 such that R 5 or R 6 combined with R 3 or R 4 forms a ring that is a 5-membered ring, 4-membered ring, 6-membered ring, 3-membered ring or 7-membered ring. In one embodiment, when R 3 is combined with R 5 as in the case where R 3 or R 4 is combined with R 5 or R 6 the ring formed is a 5-membered ring. In one embodiment, when R 3 is combined with R 5 as in the case where R 3 or R 4 is combined with R 5 or R 6 the ring formed is a 4-membered ring. In one embodiment, when R 3 is combined with R 5 as in the case where R3 or R 4 is R 5 or R 6 When combined with R, the formed ring is cyclopentyl. In one embodiment, R 3 is combined with R as in formula (VI), formula (XIII) or formula (XX). 5

[0089]

Chemical formula

[0090] In one embodiment, R 3 and R 4 are -H, R 5 and R 6 are methyl, and R 7 and R 8 are -H.

[0091] In one embodiment, five or fewer of R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are H.

[0092] In one embodiment, R 9 is -C(H)-, thus forming a benzene ring. In one embodiment, R 9 is -N-, thus forming a pyridine ring. In one embodiment, R 9 is -C(R 13 )-.

[0093] In one embodiment, R 10 is H. In another embodiment, R 10 is a halogen such as Cl.

[0094] In one embodiment, R 11 is H. In another embodiment, R 11 is a halogen such as F. ​

[0095] In one embodiment, R 12 is -CX3, where X is halogen. In one embodiment, the halogen is F, and thus R 12 is -CF3. In one embodiment, R 12 is -OCX3, where X is halogen. In one embodiment, the halogen is F, and thus R 12 is -OCF3. In one embodiment, R 12 is H. In one embodiment, R 12 is halogen. In one embodiment, R 12 is Cl. In one embodiment, R 12 is Br.

[0096] In one embodiment, R 11 is F, and R 12 is -CF3. In one embodiment, R 10 is H, and R 11 is X, and R 12 is -CX3, where X is individually halogen. In one embodiment, R 10 is H, and R 11 is F, and R 12 is -CF3. In one embodiment, R 9 is -C(H)-, and R 10 is H, and R 11 is X, and R 12 is -CX3, where X is individually halogen. In one embodiment, R 9 is -C(H)-, and R 10 is H, and R 11 is F, and R 12 is -CF3. In one embodiment, R 10 is H, and R 11 is X, and R 12 is -OCX3, where X is individually halogen. In one embodiment, R 10 is H, and R 11 is F, and R 12is -OCF3. In one embodiment, R 9 is -C(H)-, R 10 is H, R 11 is X, R 12 is -OCX3, wherein X is individually a halogen. In one embodiment, R 9 is -C(H)-, R 10 is H, R 11 is F, R 12 is -OCF3. In one embodiment, R 9 is -C(H)-, R 10 is H, R 11 is F, R 12 is -CF3 or -OCF3.

[0097] In one embodiment, R 9 is -N-, R 10 is H, R 11 is X, R 12 is -CX3, wherein X is individually a halogen. In one embodiment, R 9 is -N-, R 10 is H, R 11 is F, R 12 is -CF3.

[0098] In one embodiment, R 10 is H, R 11 is H. In one embodiment, R 9 is -C(H)-, R 10 is H, R 11 is H. In one embodiment, R 10 is H, R 11 is H, R 12 is a halogen, for example, R 10 is H, R 11 is H, R 12 is Br or Cl. In one embodiment, R 9 is -C(H)-, R 10 is H, R 11 is H, R12 is a halogen, for example, R 9 is -C(H)-, R 10 is H, R 11 is H, R 12 is Br or Cl.

[0099] In one embodiment, R 10 is H, R 11 is H, R 12 is -CX3, where X is a halogen, for example, R 10 is H, R 11 is H, R 12 is -CF3. In one embodiment, R 9 is -C(H)-, R 10 is H, R 11 is H, R 12 is -CX3, where X is a halogen, for example, R 10 is H, R 11 is H, R 12 is -CF3.

[0100] In one embodiment, R 11 is H, R 10 and R 12 are each a halogen. In one embodiment, R 11 is H, R 10 and R 12 are Cl. In one embodiment, R 9 is -C(H)-, R 11 is H, R 10 and R 12 are each a halogen. In one embodiment, R 9 is -C(H)-, R 11 is H, R 10 and R 12 are Cl.

[0101] In one embodiment, R 10 , R 11 and R 12Two or less of them are H. In one embodiment, R 10 , R 11 and R 12 One or less of them is H.

[0102] In one embodiment, when R 11 and R 12 are H, R 10 is halogen.

[0103] In one embodiment, when R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are H, two or less of R 10 , R 11 and R 12 are H.

[0104] In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4.

[0105] In one embodiment, R 13 is -CX3, -OCX3, H or halogen. In one embodiment, R 13 is H or halogen.

[0106] In one embodiment, the compound is: N1-[1-(3-chlorophenyl)cyclopropyl]-N1-methyl-1,2-ethanediamine; N1-[1-(3-fluorophenyl)cyclopropyl]-N1-methyl-1,2-ethanediamine; N1-[1-(4-bromophenyl)cyclopropyl]-N1-methyl-1,2-ethanediamine; N1-[1-(4-fluorophenyl)cyclopropyl]-N1-methyl-1,2-ethanediamine; N1-methyl-N1-(1-phenylcyclopropyl)-1,2-ethanediamine; N-[1-(4-Fluorophenyl)cyclopropyl]-N-methyl-3-azetidinamine; N-[1-(4-Fluorophenyl)cyclopropyl]-N-methyl-3-pyrrolidinamine; N-[1-(3-Fluorophenyl)cyclopropyl]-N-methyl-3-pyrrolidinamine; N-[1-(3-Fluorophenyl)cyclopropyl]-N-methyl-3-azetidinamine; N-Methyl-N-(1-phenylcyclopropyl)-3-pyrrolidinamine; N-Methyl-N-(1-phenylcyclopropyl)-3-azetidinamine; N-Methyl-N-(1-phenylcyclopropyl)-3-piperidinamine; N-[1-(4-Chlorophenyl)cyclopropyl]-N-methyl-3-azetidinamine; N-[1-(3-Chlorophenyl)cyclopropyl]-N-methyl-3-azetidinamine; and N1-[1-(3-Bromophenyl)cyclopropyl]-N1-methyl-1,2-ethanediamine is not a compound selected from the group consisting of.

[0107] In one embodiment, the compound is methyl N-(2-(dimethylamino)ethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate.

[0108] In one embodiment, the compound is methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate.

[0109] In one embodiment, the compound is methyl ((1-aminocyclopropyl)methyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate.

[0110] In one embodiment, the compound is methyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)azetidine-1-carboxylate.

[0111] In one embodiment, the compound is methyl (azetidin-3-yl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate.

[0112] In one embodiment, the compound is N-(cyclopropylmethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)azetidin-3-amine.

[0113] In one embodiment, the compound is methyl (2-aminoethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate.

[0114] In one embodiment, the compound is N1-(cyclopropylmethyl)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-2-methylpropane-1,2-diamine.

[0115] In one embodiment, the compound is N-(2-amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopropanecarboxamide.

[0116] In one embodiment, the compound is N1-cyclopropyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine.

[0117] In one embodiment, the compound is methyl (2-amino-2-methylpropyl)(1-(3,5-dichlorophenyl)cyclopropyl)carbamate.

[0118] In one embodiment, the compound is methyl (2-amino-2-methylpropyl)(1-(3-bromophenyl)cyclopropyl)carbamate.

[0119] In one embodiment, the compound is methyl (2-amino-2-methylpropyl)(1-(3-chlorophenyl)cyclopropyl)carbamate.

[0120] In one embodiment, the compound is 1-((azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-ol.

[0121] In one embodiment, the compound is methyl (2-amino-2-methylpropyl)(1-(3-(trifluoromethyl)phenyl)cyclopropyl)carbamate.

[0122] In one embodiment, the compound is 1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)amino)-2-methylpropan-2-ol.

[0123] In one embodiment, the compound is methyl (2-amino-2-methylpropyl)(1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl)carbamate.

[0124] In one embodiment, the compound is N1-cyclobutyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine.

[0125] In one embodiment, the compound is ethyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate.

[0126] In one embodiment, the compound is methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate.

[0127] In one embodiment, the compound is N-(2-amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide.

[0128] In one embodiment, the compound is methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate.

[0129] In one embodiment, the compound is methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate.

[0130] In one embodiment, the compound is methyl (2-acetamido-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate.

[0131] In one embodiment, the compound is N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-2-methylpropane-1,2-diamine.

[0132] In one embodiment, the compound is methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate.

[0133] In one embodiment, the compound is methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)((1-methylpyrrolidin-2-yl)methyl)carbamate.

[0134] In one embodiment, the compound is methyl (S)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate.

[0135] In one embodiment, the compound is methyl (R)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate.

[0136] In one embodiment, the compound is methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)carbamate.

[0137] In one embodiment, the compound is methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamate.

[0138] In one embodiment, the compound is methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate.

[0139] In one embodiment, the compound is methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(2-(hydroxyamino)-2-methylpropyl)carbamate.

[0140] In one embodiment, the compound is ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate.

[0141] In one embodiment, the compound is ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamate.

[0142] In one embodiment, the compound is (S)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide.

[0143] In one embodiment, the compound is (S)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-((1-methylpyrrolidin-2-yl)methyl)methanesulfonamide.

[0144] In one embodiment, the compound is (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)ethyl carbamate.

[0145] In one embodiment, the compound is (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)methyl carbamate.

[0146] In one embodiment, the compound is (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)methyl carbamate.

[0147] In one embodiment, the compound is (R)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide.

[0148] In one embodiment, the compound is (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)methyl carbamate.

[0149] In one embodiment, the compound is (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)methyl carbamate.

[0150] In one embodiment, the compound is isopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate.

[0151] In one embodiment, the compound is cyclopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate.

[0152] In one embodiment, the compound is methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamate.

[0153] In one embodiment, the compound is N-((1-aminocyclopropyl)methyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine.

[0154] In one embodiment, the compound is cyclopropylmethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate.

[0155] In one embodiment, the compound is N-((1-aminocyclopropyl)methyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide.

[0156] In one embodiment, the compound is methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamate.

[0157] In one embodiment, the compound is (1S,2S)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopentane-1,2-diamine.

[0158] In one embodiment, the compound is (1R,2S)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopentane-1,2-diamine.

[0159] In one embodiment, the compound is methyl (S)-(azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate.

[0160] Solubility of the compound One of the advantages of the compounds of the present invention is that they have higher solubility than many other compounds known to modulate potassium channels such as K Ca 3.1. The compounds tested in Example

[54] have a solubility of 400 - 1700 μM in phosphate buffer at pH 7.4.

[0161] Pharmaceutically acceptable salts The compounds of the present invention can be provided in any form suitable for the intended administration, including pharmaceutically (i.e., physiologically) acceptable salts. Examples of pharmaceutically acceptable addition salts include, but are not limited to, addition salts of non-toxic inorganic acids and organic acids such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, etc. Such salts are well known in the art and can be formed by procedures described. Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates for obtaining the compounds of the present invention and their pharmaceutically acceptable addition salts.

[0162] Examples of pharmaceutically acceptable cation salts of the compounds of the present invention include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, aluminum salts, lithium salts, choline salts, lysinium salts, and ammonium salts of the compounds of the present invention containing anionic groups. Such cation salts are well known in the art and can be formed by the procedures described. In light of the present invention, "onium salts" of N-containing compounds are also contemplated as pharmaceutically acceptable salts. Preferred "onium salts" include alkyloonium salts, cycloalkyloonium salts, and cycloalkylalkyloonium salts. In one embodiment, the term "pharmaceutically acceptable salt" of a compound refers to any "onium" salt of an N-containing compound or any salt obtained by adding a mineral or organic acid from acetic acid, hydrochloric acid, cinnamic acid, citric acid, formic acid, hydrobromic acid, hydrolodic acid, hydrofluoric acid, malonic acid, methanesulfonic acid, oxalic acid, picric acid, maleic acid, lactic acid, nicotinic acid, phenylacetic acid, phosphoric acid, succinic acid, and tartaric acid, ammonium, diethylamine, piperazine, nicotinamide, urea, sodium, potassium, calcium, magnesium, zinc, lithium, methylamino, dimethylamino, trimethylamino, and tris(hydroxymethyl)aminomethane acid to the active ingredient.

[0163] Preparation of Compounds The compounds according to the present invention can be prepared according to any conventional method of chemical synthesis known to those skilled in the art, such as those described in the working examples. The starting materials for the processes described in this application are known or can be readily prepared by conventional methods known to those skilled in the art from commercially available chemicals.

[0164] The final products of the reactions described herein can be isolated by conventional techniques such as extraction, crystallization, distillation, chromatography, etc.

[0165] The compounds of the present invention can exist in a non-solvated form and a solvated form with a pharmaceutically compatible solvent such as water or ethanol. Generally, the solvated form is considered equivalent to the non-solvated form for the purposes of the present invention.

[0166] Pharmaceutical composition The present invention also relates to a pharmaceutical composition comprising, for example, a pharmaceutically effective amount of a compound as disclosed herein as an active ingredient. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier, excipient or diluent.

[0167] While the compounds as disclosed herein for use in therapy can be administered in the form of the raw material compound, it is preferred to introduce the active ingredient into a pharmaceutical composition in the form of an optionally pharmaceutically acceptable salt, together with one or more adjuvants, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical aids.

[0168] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as disclosed herein or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or prophylactic agents known and used in the art. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to its recipient. The pharmaceutical compositions of the present invention are suitable for oral, rectal, bronchial, nasal, pulmonary, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including skin, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or perfusion) administration, or in a form suitable for administration by inhalation or insufflation, including powder and liquid aerosol administration, or by a sustained release system. Suitable examples of sustained release systems include a semipermeable matrix of a solid hydrophobic polymer containing a compound of the present invention, which matrix can be in the form of a shaped article, for example, a film or a microcapsule.

[0169] Thus, compounds as disclosed herein can be formulated into pharmaceutical compositions and their unit dosage forms together with conventional adjuvants, carriers, or diluents. Such forms can be solid, particularly tablets, filled capsules, powders, and pellet forms, as well as liquids, particularly aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled therewith, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and their unit dosage forms can contain conventional ingredients in conventional proportions, with or without the use of additional active compounds or active ingredients, and such unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be used. Compounds as disclosed herein can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms can contain either the compound of the invention or a pharmaceutically acceptable salt of the compound of the invention as an active ingredient.

[0170] Unlike many known KCa3.1 inhibitors, the compounds of the present invention have high solubility in aqueous media, making them suitable for liquid drug administration such as intravenous or infusion administration.

[0171] To prepare pharmaceutical compositions from compounds as disclosed herein, the pharmaceutically acceptable carrier can be either solid or liquid. Solid formulating agents include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizing agents, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0172] The pharmaceutical product can be in unit dosage form. In such a form, the formulation is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged formulation, the package containing individual amounts of the formulation such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or troche of its own, or can be an appropriate number of any of these in a package form.

[0173] A therapeutically effective dose refers to the amount of the active ingredient that improves the symptoms or condition. The therapeutically effective amount and toxicity, e.g., ED 50 can be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between the therapeutic effect and the toxic effect is the therapeutic index, which can be represented by the ratio between the plasma level that brings about the therapeutic effect and the plasma ratio that brings about the toxic effect. Pharmaceutical compositions showing a large therapeutic index are preferred.

[0174] The dose to be administered, of course, needs to be carefully adjusted for the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and dosing schedule, and the desired result, and the exact dosage will, of course, be determined by the practicing physician.

[0175] The actual dose administered depends on the nature and severity of the disease being treated, is within the discretion of the physician, and can be varied by titration of the dosage for the particular situation of the present invention in order to produce the desired therapeutic effect. However, at present, pharmaceutical compositions containing from about 0.1 to about 10000 mg of the active ingredient per individual dose, e.g., 0.5 to 2000 mg, preferably from about 1 to about 1000 mg, most preferably from about 10 to about 500 mg, are considered suitable for therapeutic treatment. The active ingredient can be administered in one or several doses per day.

[0176] Biological activity The compounds of the present invention are active as potassium channel modulators. All of the compounds of the present invention tested in Example

[55] inhibit K Ca 3.1.

[0177] Treatment method K Ca The compounds of the present invention, which are modulators of potassium ion channels such as 3.1, are useful in the treatment of diseases and disorders of living organisms including humans. As used herein, the term "treatment" also includes the prevention and / or alleviation of diseases and disorders. In one aspect, the compounds as described herein are for use in medicine. In one aspect, the present invention relates to a method for the treatment of IBD, hereditary spherocytosis or ARDS, comprising administration of a compound as described herein, or a pharmaceutical composition comprising said compound, to a subject in need thereof.

[0178] Inflammatory bowel disease (IBD) Inflammatory bowel disease (IBD) is a chronic autoimmune disease that affects the gastrointestinal tract with symptoms of abdominal pain, vomiting, diarrhea, bloody stools, and weight loss. IBD has two main forms: ulcerative colitis (UC) and Crohn's disease (CD). UC affects only the colon and rectum, while CD can affect the entire gastrointestinal tract. Histologically, UC is characterized by inflammation of the enlarged mucosa, in contrast to CD, where deep punctate lesions affect all layers of the intestinal wall. In industrialized societies (USA, Japan; the five major EU countries), it is estimated that approximately 2.5 million patients are diagnosed with IBD (1 million with colitis and 1.5 million with Crohn's disease). The incidence is increasing, especially in emerging industrialized countries, presumably related to changes in lifestyle.

[0179] Currently used anti-IBD agents are anti-inflammatory agents (5-ASA, steroids), generally immunosuppressive agents (azathioprine, 6-mercaptopurine), or biological single cytokine / integrin neutralizing agents (e.g., infliximab, ustekinumab, vedolizumab). Despite these options and carefully optimized clinical procedures, patients still face the round of bowel resection surgery (many Crohn's disease patients experience at least one surgery in their lifetime), and patients with ulcerative colitis may develop proctitis after colectomy. The next-best medical disease management regarding maintenance of long-term remission, fighting recurrence, and especially avoiding the occurrence of irreversible structural changes due to intractable intestinal fibrosis represents a profound unmet need for IBD patients.

[0180] Many of the drugs used today to treat IBD are associated with side effects. For example, side effects of steroids include increased susceptibility to infections; 5-aminosalicylic acid such as the form of sulfasalazine is associated with a significant proportion of non-responders among UC patients, decreased renal function, and high doses and frequent administration, causing a decrease in compliance. The drawbacks of the TNF-alpha inhibitor infliximab include high cost, inconvenience of application (injection), waning effectiveness, and induction of an increased risk of infection as a result of immunosuppressive properties; immunosuppressive agents such as azathioprine, 6-mercaptopurine, and methotrexate increase the risk of infections and some types of cancer as well as liver toxicity. Therefore, there is still a large unmet need for novel treatments for inflammatory bowel disease.

[0181] K as a target for IBD Ca 3.1 T cells play an important role in IBD. The IBD process (immune cell proliferation, homing, and cytokine release), excessive fibroblast-mediated collagen secretion can lead to fibrosis that causes strictures and intestinal obstruction, and excessive water transport across the epithelium can lead to diarrhea. All of these pathological processes are related to K Ca3.1 can be attenuated by inhibition.

[0182] As shown herein, the compounds of the invention inhibit K Ca 3.1, and thus, in one aspect, the invention relates to compounds as described herein for use in the treatment, alleviation and / or prevention of inflammatory bowel disease (IBD). In one embodiment, the IBD is a colitis such as ulcerative colitis (UC). In one embodiment, the IBD is Crohn's disease (CD).

[0183] Hereditary xerocytosis Hereditary xerocytosis, also known as dehydrated hereditary stomatocytosis, is characterized by increased erythrocyte fragility and hemolysis, resulting in either fully compensated or mild to severe anemia. Increased reticulocytosis (to compensate for erythrocyte loss), ion overload and jaundice (due to increased hemoglobin breakdown) are characteristic in adults. Neonates may be troubled by transient edema / ascites and rarely develop life-threatening fetal hydrops. The disease is very heterogeneous but is classically identified from a combination of clinical symptoms such as fatigue, splenomegaly, gallstones, thrombotic events, pulmonary hypertension. Microscopic examination may reveal erythrocytes with abnormal shapes and analysis of hematological parameters reveals erythrocytes that have shrunk due to salt and water loss. The pathophysiology of hereditary xerocytosis has long been known to be fundamentally different from other hereditary anemias such as hemoglobinopathies (e.g., sickle cell anemia and thalassemia) or glycolytic enzyme disorders (e.g., glucose-6-phosphate deficiency) in that it is due to a primary membrane permeability defect. The molecular targets involved in this defect have only recently been identified.

[0184] K Ca 3.1 Recent scientific investigations have shown that hereditary xerocytosis is associated with K CaIt is shown to be due to gain-of-function mutations in either Piezo1 or KCNN4, genes encoding 3.1. Both mutations essentially result in the same phenotype: in the case of the Piezo1 mutation, Ca 2+ enters the erythrocytes through channels that are always open and thus activates K Ca 3.1, resulting in permanently dehydrated erythrocytes; in the case of the KCNN4 mutation, K Ca 3.1 is constitutively open, thereby regulating erythrocyte dehydration even in the absence of Ca 2+ signals from the Piezo1 channels. A clear definition of the genes and mutations causing hereditary xerocytosis enables an easy diagnosis of which patients will benefit from treatment and which patients should not be treated.

[0185] Inhibition of the erythrocyte K Ca 3.1 channel counteracts unintended dehydration and probably prevents hemolysis of xerocytosis erythrocytes in hereditary xerocytosis, thereby improving the patient's clinical condition. Importantly, the binding site for K Ca 3.1 inhibitors does not overlap with known gain-of-function mutations of K Ca 3.1. This identifies K Ca 3.1 as a highly important target for all known causes of hereditary xerocytosis.

[0186] The compounds of the present invention inhibit K Ca 3.1. Thus, in one aspect, the present invention relates to the compounds described herein for use in the treatment, alleviation and / or prevention of hereditary xerocytosis. Hereditary xerocytosis is one of the most frequent variants of hereditary stomatocytoses, a group of rare diseases characterized by the leakage of monovalent cations such as K + from erythrocyte cells (RBC).

[0187] Acute respiratory distress syndrome (ARDS) Acute respiratory distress syndrome is a serious and often fatal complication of lung infections, such as those caused by the SARS, MERS, or Covid-19 virus. The infection can spread across the very thin barrier between air-filled alveoli and blood-filled alveolar blood vessels, filling the alveoli with fluid, which can lead to overall lung inflammation that impedes the life-essential oxygen / carbon dioxide gas exchange between the lungs and blood vessels. Thus, ARDS is a complex condition involving both components of the immune system and the air / blood barrier function. Currently, there is no medical treatment that specifically blocks ARDS (general immunosuppressive treatment with steroids is not effective), so the only option for patients is mechanical ventilation in the intensive care unit.

[0188] K as a target for ARDS Ca 3.1 K Ca Since the 3.1 channel is expressed in both epithelial and endothelial cells and in inflammatory cells such as neutrophils involved in lung inflammation, inhibition of K Ca 3.1 can attenuate both basic inflammations and, if possible, protect the air / blood barrier function. Experiments using a mouse model of ARDS have recently shown that K Ca 3.1 knockout mice had improved gas exchange, and this improvement was also demonstrated by treatment with the classical K Ca 3.1 inhibitors, senicapoc and TRAM-34. In the clinical situation of patients on mechanical ventilation, oral drug administration is not optimal, but intravenous bolus or infusion administration is preferred. Classical K Ca 3.1 inhibitors, such as triarylmethanes (exemplified by senicapoc and TRAM-34), are extremely poorly water-soluble, making it very difficult to formulate IV preparations. The same drawback applies to known K Ca 3.1 inhibitors based on other chemical scaffolds.

[0189] The compounds of the present invention are K CaInhibits 3.1. Furthermore, the compounds of the present invention have high solubility in aqueous media. Therefore, the compounds of the present invention are very suitable for use in the treatment of ARDS. For this reason, in one aspect, the present invention relates to compounds as described herein for use in the treatment, alleviation and / or prevention of ARDS.

[0190] Clause 1. A compound of formula (VII):

[0191] [Chemical formula]

[0192] (wherein, R 1 is optionally -OH, or -OC 1-8 alkyl, -C 1-8 alkyl; R 2 is a bond, -C(O)-, -S(O)2-, or -C(H)2-; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C in which one methylene group is optionally replaced by -O- 1-8 alkyl; R 6 is H, a bond, or C in which one methylene group is optionally replaced by -O- 1-8 alkyl; R 7 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or =O 1-8 alkyl; R 8 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or =O1-8 is alkyl; R 3 、R 4 、R 5 、R 6 、R 7 、and R 8 any one of which is optionally joined together to form a ring; A is phenyl or pyridinyl, and phenyl or pyridinyl is optionally substituted with one or more substituents R individually selected from the group consisting of halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -CN, NO2, -SO2CH3, and -SF5; and 13 X is halogen) or a pharmaceutically acceptable salt thereof.

[0193] 2. The compound is of formula (XVI):

[0194]

Chemical formula

[0195] (wherein, R 14 is selected from the group consisting of -C(O)-C 1-8 alkyl; -C(O)-O-C 1-8 alkyl; -C 2-8 alkyl; -H and -S(O)2-C 1-8 alkyl; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C in which one methylene group is optionally replaced by -O-​1-8 is alkyl; R 6 is H, a bond, or C in which one methylene group is optionally replaced by -O- and is 1-8 alkyl; R 7 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or are replaced by =O and is 1-8 alkyl; R 8 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or are replaced by =O and is 1-8 alkyl; R 3 R 4 R 5 R 6 R 7 and R 8 any one of which optionally combines together to form a ring; A is phenyl or pyridinyl, and phenyl or pyridinyl is optionally substituted with one or more substituents R individually selected from the group consisting of halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -CN, NO2, -SO2CH3, and -SF5; and 13 X is halogen) (or a pharmaceutically acceptable salt thereof), a compound according to clause 1. or a pharmaceutically acceptable salt thereof, a compound according to clause 1.

[0196] 3. A compound is of formula (VIII):

[0197]

Chemical formula

[0198] (wherein R 14 is -C(O)-C 1-8 alkyl; -C(O)-O-C 1-8 alkyl; -C 2-8 alkyl; -H and -S(O)2-C 1-8 selected from the group consisting of; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 6 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 7 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O; R 8 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O; R 3 R 4 R 5 R 6 R 7 and R 8 any one of which optionally combines together to form a ring; and R 9 is -C(H)-, -N-, or -C(R 13 )-; R 13 is halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C3-7 Cycloalkyl, -OC 3-7 individually selected from the group consisting of cycloalkyl, -CN, NO2, -SO2CH3, and -SF5; n is an integer from 0 to 4; and X is halogen) or a pharmaceutically acceptable salt thereof, a compound according to any one of the preceding clauses.

[0199] 4. A compound is of formula (I):

[0200]

Chemical formula

[0201] (wherein, R 1 is optionally -OH, or -OC optionally substituted with H 1-8 alkyl, -C 1-8 alkyl; R 2 is a bond, -C(O)-, -S(O)2-, or -C(H)2-; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C where one methylene group is optionally replaced by -O- 1-8 alkyl; R 6 is H, a bond, or C where one methylene group is optionally replaced by -O- 1-8 alkyl; R 7 is H, a bond, -OH, or C where one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O 1-8 alkyl; R 8is C where H, a bond, -OH, or one or more methylene groups are each optionally replaced by -O- and / or replaced by =O 1-8 alkyl; R 3 R 4 R 5 R 6 R 7 and R 8 any one of which optionally joins together to form a ring; R 9 is -C(H)-, -N-, or -C(R 13 )-; R 10 R 11 R 12 and R 13 are each independently selected from the group consisting of H, halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -CN, NO2, -SO2CH3, and -SF5; and X is halogen) or a pharmaceutically acceptable salt thereof, a compound according to clause 1.

[0202] 5. A compound of formula (I):

[0203]

Chemical formula

[0204] (wherein, R 1 is optionally -OH or -OC 1-8 alkyl, -C 1-8 alkyl, each optionally substituted by H; R 2 is a bond, -C(O)-, -S(O)2-, or -C(H)2-; R 3 is H, C1-5 is alkyl or a bond; R 4 is H, C 1-5 is alkyl or a bond; R 5 is H, a bond, or C in which one methylene group is optionally replaced by -O- 1-8 alkyl; R 6 is H, a bond, or C in which one methylene group is optionally replaced by -O- 1-8 alkyl; R 7 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O 1-8 alkyl; R 8 is H, a bond, -OH, or C in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O 1-8 alkyl; R 3 R 4 R 5 R 6 R 7 and R 8 any one of which optionally combines together to form a ring; R 9 is -C(H)- or -N-; R 10 is H or halogen; R 11 is H or halogen; R 12 is -CX3, -OCX3, H or halogen; and X is halogen) or a pharmaceutically acceptable salt thereof, the compound according to clause 1.

[0205] 6. The compound is of formula (XVII):

[0206]

Chemical formula

[0207] (wherein, R 14 is selected from the group consisting of -C(O)-C 1-8 alkyl; -C(O)-O-C 1-8 alkyl; -C 2-8 alkyl; -H and -S(O)2-C 1-8 alkyl; R 3 is H, C 1-5 alkyl, or a bond; R 4 is H, C 1-5 alkyl, or a bond; R 5 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 6 is H, a bond, or C 1-8 alkyl in which one methylene group is optionally replaced by -O-; R 7 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O; R 8 is H, a bond, -OH, or C 1-8 alkyl in which one or more methylene groups are optionally individually replaced by -O- and / or replaced by =O; R 3 R 4 R 5 R 6 R 7 R 8 and any one of R R 9 is -C(H)- or -N-; R 10 is H or halogen; R 11 is H or halogen; R12 is -CX3, -OCX3, H or halogen; and X is halogen) or a pharmaceutically acceptable salt thereof, a compound according to clause 1.

[0208] 7.R 3 and R 4 are -H, R 5 and R 6 are methyl, R 7 and R 8 are -H, a compound according to any one of the preceding clauses.

[0209] 8. The compound is of formula (XI):

[0210]

Chemical formula

[0211] is a compound according to any one of the preceding clauses.

[0212] 9. The compound is of formula (XII):

[0213]

Chemical formula

[0214] is a compound according to any one of the preceding clauses.

[0215] 10. The compound is of formula (XIII):

[0216]

Chemical formula

[0217] is a compound according to any one of the preceding clauses.

[0218] 11. The compound is of formula (XIV):

[0219]

Chem.

[0220] a compound as described in any one of the preceding clauses.

[0221] 12. The compound is of formula (XV):

[0222]

Chem.

[0223] a compound as described in any one of the preceding clauses.

[0224] 13. The compound is of formula (III):

[0225]

Chem.

[0226] a compound as described in any one of the preceding clauses.

[0227] 14. The compound is of formula (IV):

[0228]

Chem.

[0229] a compound as described in any one of the preceding clauses.

[0230] 15. The compound is of formula (VI):

[0231]

Chem.

[0232] a compound as described in any one of the preceding clauses.

[0233] 16. The compound is of formula (V):

[0234]

Chem.

[0235] The compound according to any one of the preceding clauses.

[0236] 17. The compound is of formula (II):

[0237]

Chem.

[0238] The compound according to any one of the preceding clauses.

[0239] 18. The compound is of formula (XVIII):

[0240]

Chem.

[0241] The compound according to any one of the preceding clauses.

[0242] 19. The compound is of formula (XIX):

[0243]

Chem.

[0244] The compound according to any one of the preceding clauses.

[0245] 20. The compound is of formula (XX):

[0246]

Chem.

[0247] The compound according to any one of the preceding clauses.

[0248] 21. The compound is of formula (XXI):

[0249]

Chemical formula

[0250] The compound according to any one of the preceding clauses.

[0251] 22. The compound is of formula (XXII):

[0252]

Chemical formula

[0253] The compound according to any one of the preceding clauses.

[0254] 23. A is the moiety of formula (IX):

[0255]

Chemical formula

[0256] (wherein, R 9 is -C(H)-, -N-, or -C(R 13 )-; R 13 is individually selected from the group consisting of halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -CN, NO2, -SO2CH3, and -SF5; n is an integer from 0 to 4; and X is halogen) The compound according to any one of the preceding clauses.

[0257] 24. A is a moiety of formula (X):

[0258]

Chemical formula

[0259] (wherein, R 9 is -C(H)-, -N-, or -C(R 13 )-; R 10 , R 11 , R 12 , and R 13 are each independently selected from the group consisting of H, halogen, -CX3, -OCX3, -CHX2, -OCHX2, -CH2X, -OCH2X, -CH2CX3, OCH2CX3, -C 1-8 alkyl, -OC 1-8 alkyl, -C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -CN, NO2, -SO2CH3, and -SF5; and X is halogen) The compound according to any one of the preceding clauses.

[0260] 25. R 9 is -C(H)- or -N-; R 10 is H or halogen; R 11 is H or halogen; R 12 is -CX3, -OCX3, H or halogen; and X is halogen, The compound according to any one of the preceding clauses.

[0261] 26. -R 2 -R 1 is -R 14 and R 14 is -C(O)-C 1-8Alkyl; -C(O)-O-C 1-8 Alkyl; -C 2-8 Alkyl; -H and -S(O)2-C 1-8 The compound according to any one of the preceding clauses, selected from the group consisting of alkyl.

[0262] 27. The compound according to any one of the preceding clauses, wherein the compound is the (S)-enantiomer.

[0263] 28. R 1 is -OC 1-7 Alkyl etc., -OC 1-6 Alkyl etc., -OC 1-5 Alkyl etc., -OC 1-4 Alkyl etc., -OC 1-3 Alkyl etc., -OC 1-2 Alkyl etc., -OC1 alkyl etc. of -OC 1-8 Alkyl, the compound according to any one of the preceding clauses.

[0264] 29. R 1 is -C 1-7 Alkyl etc., -C 1-6 Alkyl etc., -C 1-5 Alkyl etc., -C 1-4 Alkyl etc., -C 1-3 Alkyl etc., -C 1-2 Alkyl etc., -C1 alkyl etc. of -C 1-8 Alkyl, the compound according to any one of the preceding clauses.

[0265] 30. R 1 is -C substituted with -OH 1-8 Alkyl, the compound according to any one of the preceding clauses.

[0266] 31. R 1 is -H, the compound according to any one of the preceding clauses.

[0267] 32. R 2 is a bond, the compound according to any one of the preceding clauses.

[0268] 33.R 2 The compound according to any one of the preceding clauses, wherein R is -C(O)-.

[0269] 34.R 2 The compound according to any one of the preceding clauses, wherein R is -C(H)2-.

[0270] 35.R 2 The compound according to any one of the preceding clauses, wherein R is -S(O)2-.

[0271] 36.R 2 is -C(O)-, and R 1 is -OC 1-4 alkyl, the compound according to any one of the preceding clauses.

[0272] 37.R 2 is -C(O)-, and R 1 is -OC 1-3 alkyl, the compound according to any one of the preceding clauses.

[0273] 38.R 2 is a bond, and R 1 is -OC 3-4 alkyl, the compound according to any one of the preceding clauses.

[0274] 39.R 14 is -C(O)-C 1-8 alkyl, for example, R 14 is -C(O)-C 1-3 alkyl, for example, R 14 is -C(O)-C3 alkyl such as -C(O)-cyclopropyl, the compound according to any one of the preceding clauses.

[0275] 40.R 14 is -C(O)-O-C 1-8 alkyl, for example, R 14 is -C(O)-O-C 1-3 alkyl, for example, R 14The compound according to any one of the preceding clauses, wherein R is selected from the group consisting of -C(O)-OCH3, -C(O)-OCH2CH3, -OCH2(CH3)2 and -O-cyclopropyl.

[0276] 41.R 14 is -C 3-4 -C such as alkyl 2-8 The compound according to any one of the preceding clauses, wherein R is alkyl.

[0277] 42.R 14 is -C(H)2-cyclopropyl or -C(H)2-cyclobutyl etc. -C(H)2-C 3-7 The compound according to any one of the preceding clauses, wherein R is cycloalkyl.

[0278] 43.R 14 is -cyclopropyl or -cyclobutyl etc. -C 3-7 The compound according to any one of the preceding clauses, wherein R is cycloalkyl.

[0279] 44.R 14 is -C substituted with one or more -OH 3-4 -C such as alkyl 2-8 is alkyl, for example, R 14 The compound according to any one of the preceding clauses, wherein R is isopropyl substituted with -OH.

[0280] 45.R 14 The compound according to any one of the preceding clauses, wherein R is -H.

[0281] 46.R 14 is -S(O)2-C 1-8 is alkyl, for example, R 14 The compound according to any one of the preceding clauses, wherein R is -S(O)2-CH3.

[0282] 47.R 14 The compound according to any one of the preceding clauses, wherein R is not -CH3.

[0283] 48.R3 is -C 1-4 such as -C alkyl 1-3 such as -C alkyl 1-2 such as -C alkyl, -C1 alkyl, etc., -C 1-5 The compound according to any one of the preceding clauses, wherein it is alkyl.

[0284] 49. R 4 is -C 1-4 such as -C alkyl 1-3 such as -C alkyl 1-2 such as -C alkyl, -C1 alkyl, etc., -C 1-5 The compound according to any one of the preceding clauses, wherein it is alkyl.

[0285] 50. R 3 and R 4 The compound according to any one of the preceding clauses, wherein they are H.

[0286] 51. R 5 is -C 1-7 such as -C alkyl 1-6 such as -C alkyl 1-5 such as -C alkyl 1-4 such as -C alkyl 1-3 such as -C alkyl 1-2 such as -C alkyl, -C1 alkyl, etc., -C 1-8 The compound according to any one of the preceding clauses, wherein it is alkyl.

[0287] 52. R 6 is -C 1-7 such as -C alkyl 1-6 such as -C alkyl 1-5 such as -C alkyl 1-4 such as -C alkyl 1-3 such as -C alkyl 1-2 such as -C alkyl, -C1 alkyl, etc., -C 1-8 The compound according to any one of the preceding clauses, wherein it is alkyl.

[0288] 53. R 5 and R 6 The compound according to any one of the preceding clauses, wherein they are H.

[0289] 54.R 5 and R 6 is -CH3, the compound according to any one of the preceding clauses.

[0290] 55.R 5 and R 6 are joined together to form a ring, the compound according to any one of the preceding clauses.

[0291] 56.R 7 is, -C 1-7 alkyl, etc., -C 1-6 alkyl, etc., -C 1-5 alkyl, etc., -C 1-4 alkyl, etc., -C 1-3 alkyl, etc., -C 1-2 alkyl, etc., -C1 alkyl, etc. of -C 1-8 is alkyl, the compound according to any one of the preceding clauses.

[0292] 57.R 7 is H, the compound according to any one of the preceding clauses.

[0293] 58.R 7 is, -C(O)-O-CH3 or -C(O)-CH3, the compound according to any one of the preceding clauses.

[0294] 59.R 8 is, -C 1-7 alkyl, etc., -C 1-6 alkyl, etc., -C 1-5 alkyl, etc., -C 1-4 alkyl, etc., -C 1-3 alkyl, etc., -C 1-2 alkyl, etc., -C1 alkyl, etc. of -C 1-8 is alkyl, the compound according to any one of the preceding clauses.

[0295] 60.R 8 is H, the compound according to any one of the preceding clauses.

[0296] 61.R 5and R 6 is R 7 or R 8 combines with to form a ring, for example, R 5 is R 7 combines with, the compound according to any one of the preceding clauses.

[0297] 62. R 5 is R 7 combines with to form a 4-membered, 5-membered or 6-membered ring, the compound according to any one of the preceding clauses.

[0298] 63. R 3 and R 4 is R 5 or R 6 combines with to form a ring, for example, R 3 is R 5 combines with, the compound according to any one of the preceding clauses.

[0299] 64. R 3 is R 5 combines with to form a 4-membered or 5-membered ring, the compound according to any one of the preceding clauses.

[0300] 65. R 3 and R 4 is R 7 or R 8 combines together with to form a ring, for example, R 3 is R 7 combines with, the compound according to any one of the preceding clauses.

[0301] 66. R 3 is R 7 combines with to form a 4-membered ring, the compound according to any one of the preceding clauses.

[0302] 67. R 9 is -C(H)-, the compound according to any one of the preceding clauses.

[0303] 68. R 10 is H, the compound according to any one of the preceding clauses.

[0304] 69. R 10 is Cl, the compound according to any one of the preceding clauses.

[0305] 70. R 11 is F, the compound according to any one of the preceding clauses.

[0306] 71. R 12 is -CF3, the compound according to any one of the preceding clauses.

[0307] 72. R 12 is -OCF3, the compound according to any one of the preceding clauses.

[0308] 73. R 12 is Cl or Br, the compound according to any one of the preceding clauses.

[0309] 74. R 11 is F, and R 12 is -CF3, the compound according to any one of the preceding clauses.

[0310] 75. R 9 is -C(H)-, and R 10 is H, and R 11 is F, and R 12 is -CF3 or -OCF3, the compound according to any one of the preceding clauses.

[0311] 76. R 9 is -C(H)-, and R 10 is H, and R 11 is F, and R 12 is -CF3, the compound according to any one of the preceding clauses.

[0312] 77. R 9 is -C(H)-, and R 10 is H, and R 11 is F, and R 12 is -OCF3, the compound according to any one of the preceding clauses.

[0313] 78. -R1 -R 2 A compound according to any one of the preceding clauses, wherein -R is not -CH3.

[0314] 79. R 10 , R 11 and R 12 A compound according to any one of the preceding clauses, wherein two or less of R

[0315] 80. R 10 , R 11 and R 12 A compound according to any one of the preceding clauses, wherein one or less of R

[0316] 81. R 11 and R 12 are H, and R 10 is halogen. A compound according to any one of the preceding clauses.

[0317] 82. R 3 , R 4 , R 5 , R 6 , R 7 and R 8 A compound according to any one of the preceding clauses, wherein five or less of R

[0318] 83. R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are H, and R 10 , R 11 and R 12 A compound according to any one of the preceding clauses, wherein two or less of R

[0319] 84. The compound is N1-[1-(3-chlorophenyl)cyclopropyl]-N1-methyl-1,2-ethanediamine; N1-[1-(3-fluorophenyl)cyclopropyl]-N1-methyl-1,2-ethanediamine; N1-[1-(4-Bromophenyl)cyclopropyl]-N1-methyl-1,2-ethanediamine; N1-[1-(4-Fluorophenyl)cyclopropyl]-N1-methyl-1,2-ethanediamine; N1-Methyl-N1-(1-phenylcyclopropyl)-1,2-ethanediamine; N-[1-(4-Fluorophenyl)cyclopropyl]-N-methyl-3-azetidinamine; N-[1-(4-Fluorophenyl)cyclopropyl]-N-methyl-3-pyrrolidinamine; N-[1-(3-Fluorophenyl)cyclopropyl]-N-methyl-3-pyrrolidinamine; N-[1-(3-Fluorophenyl)cyclopropyl]-N-methyl-3-azetidinamine; N-Methyl-N-(1-phenylcyclopropyl)-3-pyrrolidinamine; N-Methyl-N-(1-phenylcyclopropyl)-3-azetidinamine; N-Methyl-N-(1-phenylcyclopropyl)-3-piperidinamine; N-[1-(4-Chlorophenyl)cyclopropyl]-N-methyl-3-azetidinamine; N-[1-(3-Chlorophenyl)cyclopropyl]-N-methyl-3-azetidinamine; and N1-[1-(3-Bromophenyl)cyclopropyl]-N1-methyl-1,2-ethanediamine A compound according to any one of the preceding clauses, which is not selected from the group consisting of.

[0320] 85. The compound is Methyl N-(2-(dimethylamino)ethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; Methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; ((1-Aminocyclopropyl)methyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamic acid methyl; Methyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)azetidine-1-carboxylate; Methyl azetidin-3-yl(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; N-(Cyclopropylmethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)azetidin-3-amine; (2-Aminoethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamic acid methyl; N1-(Cyclopropylmethyl)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-2-methylpropane-1,2-diamine; N-(2-Amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopropanecarboxamide; N1-Cyclopropyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine; (2-Amino-2-methylpropyl)(1-(3,5-dichlorophenyl)cyclopropyl)carbamic acid methyl; (2-Amino-2-methylpropyl)(1-(3-bromophenyl)cyclopropyl)carbamic acid methyl; (2-Amino-2-methylpropyl)(1-(3-chlorophenyl)cyclopropyl)carbamic acid methyl; 1-((Azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-ol; (2-Amino-2-methylpropyl)(1-(3-(trifluoromethyl)phenyl)cyclopropyl)carbamic acid methyl; 1-((1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)amino)-2-methylpropan-2-ol; (2-Amino-2-methylpropyl)(1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl)carbamic acid methyl; N1-Cyclobutyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine; (2-Amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamic acid ethyl; (2-Amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamic acid methyl; N-(2-Amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide; (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid methyl; (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid methyl; (2-Acetamido-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamic acid methyl; N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-2-methylpropane-1,2-diamine; (Azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamic acid methyl; (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamic acid methyl; (S)-(1-(4-Fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid methyl ester; (R)-(1-(4-Fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid methyl ester; (1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)carbamic acid methyl ester; (R)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamic acid methyl ester; (Azetidin-2-ylmethyl)(1-(4-Fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamic acid methyl ester; (1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(2-(hydroxyamino)-2-methylpropyl)carbamic acid methyl ester; (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid ethyl ester; (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamic acid ethyl ester; (S)-N-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide; (S)-N-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-((1-methylpyrrolidin-2-yl)methyl)methanesulfonamide; (R)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid ethyl ester; (R)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamic acid methyl ester; (R)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamic acid methyl; (R)-N-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide; (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamic acid methyl; (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamic acid methyl; (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid isopropyl; (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid cyclopropyl; (R)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamic acid methyl; N-((1-Aminocyclopropyl)methyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine; (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid cyclopropylmethyl; N-((1-Aminocyclopropyl)methyl)-N-(1-(4-fluoro-3-(trifluoromethyl)-phenyl)cyclopropyl)methanesulfonamide; (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamic acid methyl; (1S,2S)-N1-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopentane-1,2-diamine; (1R,2S)-N1-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopentane-1,2-diamine; and (S)-(Azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methyl carbamate A compound according to any one of the preceding clauses, selected from the group consisting of.

[0321] 86. A pharmaceutical composition comprising a compound according to any one of the preceding clauses.

[0322] 87. A compound or pharmaceutical composition according to any one of the preceding clauses for use in medicine.

[0323] 88. A compound according to any one of clauses 1 to 50 or a pharmaceutical composition according to clause 51 for use in the treatment of inflammatory bowel disease (IBD).

[0324] 89. A compound or pharmaceutical composition for use according to clause 88, wherein the IBD is colitis.

[0325] 90. A compound or pharmaceutical composition for use according to clause 88, wherein the IBD is ulcerative colitis.

[0326] 91. A compound or pharmaceutical composition for use according to clause 88, wherein the IBD is Crohn's disease.

[0327] 92. A compound according to any one of clauses 1 to 85 or a pharmaceutical composition according to clause 86 for use in the treatment of hereditary spherocytosis.

[0328] 93. A compound according to any one of clauses 1 to 85 or a pharmaceutical composition according to clause 86 for use in the treatment of acute respiratory distress syndrome (ARDS).

[0329] A method for the treatment of IBD, hereditary xerocytosis or ARDS, comprising administering to a subject in need thereof a compound defined in any one of clauses 1 to 85 or a composition described in clause 86.

[0330] Use of a compound defined in any one of clauses 1 to 85 or a composition described in clause 86 in the manufacture of a medicament for the treatment of IBD, hereditary xerocytosis or ARDS.

[0331] Examples Example [1] - Methyl N-(2-(dimethylamino)ethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

[0332] Step 1 To a solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (105.75 mmol) and titanium(IV) isopropoxide (116.33 mmol) in anhydrous diethyl ether, a 3M ethereal solution of ethylmagnesium bromide (222.09 mmol) was added at -78 °C. The resulting yellow solution was stirred for 10 minutes and gradually warmed to room temperature over 4 hours. Boron trifluoride diethyl etherate (211.51 mmol) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with 1.5N HCl solution and extracted with ethyl acetate. The aqueous phase was basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate to obtain a crude product, which was purified by flash chromatography using neutral silica gel in 10% TEA ethyl acetate solution. Petroleum ether was used as the eluent, giving 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] (LCMS: MH+: 220.1) as the product.

[0333] Step 2 To a stirred solution of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine [1.1] (0.2 g, 0.912 mmol) in dichloromethane (10 mL), N,N-diisopropylethylamine (0.35 mL, 2 mmol) was added followed by methyl chloroformate (0.122 g, 1.29 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by flash chromatography using ethyl acetate in hexane as eluent to afford methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [1.2] (0.19 g, 75%) as an off-white solid.

[0334] Step 3 To a solution of methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [1.2] (0.08 g, 0.29 mmol) in DMF (3 mL), sodium hydride (60%, 0.016 g, 0.32 mmol) was added. The reaction was stirred at 0 °C for 10 min, then 2-chloro-N,N-dimethylethan-1-amine hydrochloride (0.037 g, 0.26 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography using ethyl acetate in hexane to afford methyl (2-(dimethylamino)ethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [1] (0.012 g, 15%) as a yellow gum. 1 1H-NMR (400 MHz, DMSO-d6): δ 7.55 (bs, 1H), 7.45 - 7.35 (m, 2H), 3.55 (bs, 3H), 3.40 - 3.30 (m, 2H), 1.70 (bs, 2H), 2.05 (s, 6H), 1.48 - 1.18 (m, 4H). HRMS calculated for: [C 16 1 20 14H19F4N2O2+H]+ +349.1534; Measured value: 349.1526 (deviation 2.3).

[0335] Example [2] - Methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate Step 1 To a solution of tert-butyl (1-hydroxy-2-methylpropan-2-yl)carbamate (20 g, 105.7 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (55.4 g, 126.8 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was extracted with dichloromethane and washed with saturated sodium thiosulfate solution and 10% sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and dried under vacuum to give a crude product, which was purified by flash chromatography using ethyl acetate in petroleum ether as the solvent to give tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1] (19.5 g, 99%) as a white solid.

[0336] Step 2 To a stirred solution of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine [1.1] (0.05 g, 0.22 mmol) in IPA (5 mL) at 0 °C, tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1] (0.029 g, 0.16 mmol) and acetic acid (0.05 mL) were added. The reaction was stirred at room temperature for 1 h, then sodium cyanoborohydride (0.016 g, 0.26 mmol) was added at 0 °C and the reaction was then stirred at room temperature for 2 h. Saturated aqueous sodium bicarbonate was added and the reaction was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography using EtOAc in hexane as eluent to give tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] (0.03 g, 34%, LCMS MH + = 391.1) as a colorless liquid.

[0337] Step 3 Adapting the procedure used in Step 2 of Example [1], 16 g of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] was reacted to give methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [2.3] (14 g, 76%, LCMS MH + = 449.2) as a colorless liquid.

[0338] Step 4 A solution of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [2.3] (7.8 g, 17.4 mmol) in dioxane (10 mL) was stirred and dioxane.HCl (20 mL) was added at 0 °C. The reaction was stirred at room temperature for 12 h. The reaction was concentrated under reduced pressure and the residue was triturated in pentane to give methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [2] hydrochloride (6.5 g, 97%) as an off-white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 7.53 (s, 2H), 7.42 (t, J = 10.40 Hz, 1H), 3.57 (s, 3H), 3.32 (d, J = 16.80 Hz, 2H), 1.65 (bs, 4H), 1.31 (s, 2H), 0.93 (s, 6H). HRMS calculated value: [C 16 H 20 F4N2O2 + H] + 349.1534; found: 349.1521 (deviation 3.7 ppm).

[0339] Example [3]-Methyl ((1-aminocyclopropyl)methyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate Step 1 A solution of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine[1.1] (0.2 g, 0.91 mmol) and tert-butyl N-(1-formylcyclopropyl)carbamate (0.16 g, 0.91 mmol) in dichloromethane / isopropyl alcohol (3:2, 10 mL) was added with sodium triacetoxyborohydride (0.38 g, 1.82 mmol) at room temperature, and the reaction was stirred for 2 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by flash chromatography using ethyl acetate in petroleum ether as the solvent system to give tert-butyl (1-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)cyclopropyl)carbamate[3.1] (0.11 g, 31%, LCMS MH + = 389.2).

[0340] Step 2 Adapting the procedure used in Step 2 of Example [1], 0.11 g of tert-butyl (1-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)cyclopropyl)carbamate[3.1] and 0.073 g of methyl chloroformate were reacted to give methyl ((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate[3.2] (0.1 g, 80%, LCMS MH + = 447.2) as an off-white solid.

[0341] Step 3 Example [2]: Adapting the procedure used in Step 4, 0.1 g of methyl ((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [3.2] was reacted to give 0.055 g (55%) of methyl ((1-aminocyclopropyl)methyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [3] as a brown solid. 1 1H-NMR (400 MHz, DMSO-d6): δ 7.60 - 7.32 (m, 4H), 3.65 (s, 3H), 1.60 - 1.42 (m, 2H), 1.36 - 1.28 (m, 2H), 1.30 - 1.21 (m, 2H), 0.95 - 0.70 (m, 5H). HRMS calculated value: 16 1H 18 F4N2O2 + H] + 347.1377; found: 347.1369 (deviation 2.5 ppm).

[0342] Example [4] - Methyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)azetidine-1-carboxylate Step 1 Adapting the procedure used in Step 1 of Example [3], 0.5 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine and 0.117 g of tert-butyl 3-oxoazetidine-1-carboxylate were reacted to give 0.39 g (crude, LCMS MH + = 375.1) of tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)azetidine-1-carboxylate [4.1].

[0343] Step 2 Example [2], adapting the procedure used in Step 4, react 0.3 g of tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)azetidine-1-carboxylate [4.1] to give the product N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)azetidin-3-amine [4.2] (0.2 g, crude, LCMS MH + = 275.1).

[0344] Step 3 Example [1], adapting the procedure used in Step 2, react 0.2 g of N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)azetidin-3-amine and 0.2 mL of methyl carbonochloridate to give methyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)azetidine-1-carboxylate [4] (0.045 g, 30%). MS (M+1) + = 391.1. 1 1H-NMR (400 MHz, DMSO-d6): δ 7.45 (t, J = 8.80 Hz, 2H), 7.30 (d, J = 5.20 Hz, 1H), 4.40 (q, J = 6.80 Hz, 1H), 4.20 - 3.98 (m, 4H), 3.61 (s, 3H), 3.52 (s, 3H), 1.40 (s, 4H). HRMS calculated value: [C 17 1 18 H + 4F4N2O4 + H]

[0345] Example [5] - Methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate Step 1 Example [1], adapting the procedure used in Step 2, 0.3 g of tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)azetidine-1-carboxylate [4.1] and 0.226 g of methyl carbonochloridate were reacted to give the product tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)azetidine-1-carboxylate [5.1] (0.3 g, crude, LCMS MH + = 433.1).

[0346] Step 2 Example [2], adapting the procedure used in Step 4, 0.25 g of tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)azetidine-1-carboxylate [5.1] was reacted to give methyl azetidin-3-yl(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [5] (0.04 g, 40%). MS (M+1) + = 333.1. 1 H-NMR (400 MHz, CDCl3): δ 7.32 - 7.27 (m, 2H), 7.15 (t, J = 8.80 Hz, 1H), 4.60 - 4.50 (m, 1H), 4.50 - 4.20 (m, 4H), 3.82 (s, 3H), 1.32 - 1.25 (m, 4H). HRMS calculated value: [C 15 H 16 F4N2O2 + H] + 333.1221; found: 333.1215 (deviation 1.6 ppm).

[0347] Example [6] - N-(cyclopropylmethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)azetidin-3-amine Step 1 Example [3]: Adapting the procedure used in Step 1, 0.25 g of tert-butyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)azetidine-1-carboxylate [4.1] and 0.274 g of cyclopropanecarbaldehyde were reacted to give, as a colorless gum, the product tert-butyl 3-((cyclopropylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)azetidine-1-carboxylate (0.15 g, crude, LCMS MH + = 429.1).

[0348] Step 2 Adapting the procedure used in Step 4 of Example [2], 0.15 g of tert-butyl 3-((cyclopropylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)azetidine-1-carboxylate [6.1] was reacted to give, as a colorless gum, N-(cyclopropylmethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)azetidin-3-amine [6] (0.1 g, 87%). MS (M+1) + = 329.1. 1 1H-NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1H), 8.38 (s, 1H), 7.67 - 7.62 (m, 2H), 7.47 (t, J = 8.80 Hz, 1H), 3.95 - 3.82 (m, 3H), 3.79 (t, J = 8.00 Hz, 1H), 2.38 - 2.32 (m, 2H), 1.17 (q, J = 42.00 Hz, 2H), 0.96 (q, J = 11.60 Hz, 2H), 1.40 - 1.30 (m, 1H), 0.47 - 0.42 (m, 2H), 0.13 (q, J = 3.20 Hz, 2H). HRMS calculated value: [C 17 H 20 F4N2 + H] + 329.1635; found: 329.1624 (deviation 3.3 ppm).

[0349] Example [7] - Methyl (2-aminoethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate Project 1 In Example [3], adapting the procedure used in Project 1, 0.4 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine [1.1] and 0.29 g of tert-butyl (2-oxoethyl)carbamate were reacted to give the product tert-butyl (2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)ethyl)carbamate [7.1] (0.4 g, 60%, LCMS MH + = 363.2) as an off-white solid.

[0350] Project 2 In Example [1], adapting the procedure used in Project 2, 0.4 g of tert-butyl (2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)ethyl)carbamate [7.1] and 0.32 g of methyl chloroformate were reacted to give the product methyl (2-((tert-butoxycarbonyl)amino)ethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [7.2] (0.4 g, crude, LCMS MH + = 421.2) as an off-white solid.

[0351] Project 3 In Example [2], adapting the procedure used in Project 4, 0.4 g of methyl (2-((tert-butoxycarbonyl)amino)ethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [7.2] was reacted to give methyl (2-aminoethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [7] (0.011 g, 04%) as a yellow oil. 1 H-NMR (400 MHz, CDCl3): δ 7.4 (bs, 3H), 3.72 (s, 3H), 3.40 (s, 2H), 2.82 (s, 2H), 1.45 (s, 2H), 1.25 (s, 4H). HRMS calculated value: [C 14 H 16 F4N2O2 + H] +321.1221; Measured value: 321.1217 (deviation 1.1 ppm).

[0352] Example [8] - N1-(Cyclopropylmethyl)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-2-methylpropane-1,2-diamine Step 1 Adapting the procedure used in Example [3], Step 1, 0.22 g of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate and 0.047 g of cyclopropanecarbaldehyde were reacted to give, as a colorless gum, the product (1-((cyclopropylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [8.1] (0.2 g, 80%, LCMS MH + = 459.2).

[0353] Step 2 Adapting the procedure used in Example [2], Step 4, 0.2 g of tert-butyl (1-((cyclopropylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [8.1] was reacted to give, as a yellow oil, N1-(cyclopropylmethyl)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-2-methylpropane-1,2-diamine [8] (0.1 g, 66%). 1 1H-NMR (400 MHz, DMSO-d6): δ 7.70 - 7.60 (m, 2H), 7.45 (t, J = 40.00 Hz, 1H), 2.52 - 2.40 (m, 2H), 2.37 (d, J = 6.80 Hz, 2H), 1.40 - 1.20 (m, 4H), 1.10 - 1.00 (m, 2H), 1.00 - 0.88 (m, 7H), 0.45 (q, J = 1.20 Hz, 2H), 0.07 (t, J = 3.60 Hz, 2H). HRMS calculated value: [C 18 H 24 F4N2 + H] +345.1948; Measured value: 345.1937 (deviation 3.3 ppm).

[0354] Example [9] - N-(2-Amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopropanecarboxamide Step 1 To a stirred solution of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] (0.1 g, 0.256 mmol) and DIPEA (0.09 mL, 0.512 mmol) in DCM (5 mL), cyclopropanecarbonyl chloride (0.054 g, 0.512 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was diluted with water and extracted with DCM. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give, as a colorless liquid, tert-butyl (1-(N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopropanecarboxamide)-2-methylpropan-2-yl)carbamate [9.1] (0.1 g, 80%, LCMS MH + = 445.2). Step 2 Adapting the procedure used in Example [2], Step 4, 0.1 g of tert-butyl (1-(N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopropanecarboxamide)-2-methylpropan-2-yl)carbamate [9.1] was reacted to give a crude product, which was purified by preparative HPLC using 0.2% TFA in acetonitrile to give, as a light brown solid, the TFA salt of N-(2-amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopropanecarboxamide [9] (0.08 g, 80%). 11H-NMR (400 MHz, DMSO-d6): δ 7.76 (s, 3H), 7.52 (t, J = 11.60 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.27 (dd, J = 3.20, 8.40 Hz, 1H), 3.88 (d, J = 60.00 Hz, 1H), 3.30 (s, 1H), 2.15 - 1.95 (m, 1H), 1.95 - 1.80 (m, 1H), 1.80 - 1.65 (m, 1H), 1.65 - 1.50 (m, 1H), 1.50 - 1.35 (m, 1H), 1.22 (s, 4H), (s, 3H), 0.90 - 0.80 (m, 2H), 0.80 - 0.65 (m, 1H), 0.65 - 0.55 (m, 1H). HRMS calculated value: [C 18 H 22 F4N2O + H] + 359.1741; found: 359.1733 (deviation 2.2 ppm).

[0355] Example

[10] - N1-Cyclopropyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine Step 1 Adapting the procedure used in Step 1 of Example [1], 1.5 g of 3-(trifluoromethyl)benzonitrile was reacted to give 1-(3-(trifluoromethyl)phenyl)cyclopropane-1-amine [10.1] (0.5 g, 30%, LCMS MH + = 202.1).

[0356] Step 2 Adapting the procedure used in Step 1 of Example [3], 0.275 g of 1-(3-(trifluoromethyl)phenyl)cyclopropane-1-amine [10.1] was reacted to give (2-methyl-1-((1-(3-(trifluoromethyl)phenyl)cyclopropyl)amino)propan-2-yl)carbamic acid tert-butyl [10.2] (0.37 g, 73%, LCMS MH + = 373.2) as an off-white solid.

[0357] Step 3 Example [2], adapting the procedure used in Step 2, 0.270 g of tert-butyl (2-methyl-1-((1-(3-(trifluoromethyl)phenyl)cyclopropyl)amino)propan-2-yl)carbamate [2.2] was reacted with [(1-ethoxycyclopropyl)oxy]trimethylsilane to give tert-butyl (1-(cyclopropyl(1-(3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [10.3] (0.1 g, 36%, LCMS MH + = 413.4).

[0358] Step 4 Example [2], adapting the procedure used in Step 4, 0.06 g of tert-butyl (1-(cyclopropyl(1-(3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [10.3] was reacted to give N1-cyclopropyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine

[10] (0.025 g, 50%, LCMS MH + = 313.2). 1 1H-NMR (400 MHz, DMSO-d6): δ 7.88 (s, 2H), 7.71 - 7.59 (m, 4H), 2.91 (s, 2H), 1.57 (m, 1H), 1.25 (d, J = 5.68 Hz, 6H), 1.20 - 1.00 (m, 2H), 1.00 - 0.85 (m, 2H), 0.85 - 0.70 (m, 2H), 0.60 - 0.40 (m, 2H). HRMS calculated value: [C 17 1 23 H + F3N2 + H]

[0359] Example

[11] - Methyl (2-amino-2-methylpropyl)(1-(3,5-dichlorophenyl)cyclopropyl)carbamate Step 1 Example [1], adapting the procedure used in Step 1, 0.5 g of 3,5-dichlorobenzonitrile was reacted to give 1-(3,5-dichlorophenyl)cyclopropane-1-amine [11.1] (0.2 g, 34%, LCMS MH + = 203.1).

[0360] Step 2 Example [3], adapting the procedure used in Step 1, 0.2 g of 1-(3,5-dichlorophenyl)cyclopropane-1-amine [11.1] and 0.18 g of tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1] were reacted to give the product (1-((1-(3,5-dichlorophenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate tert-butyl [11.2] (0.2 g, 54%, LCMS MH + = 374.1) as a brown liquid.

[0361] Step 3 Example [1], adapting the procedure used in Step 2, 0.2 g of (1-((1-(3,5-dichlorophenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate tert-butyl [11.2] was reacted to give the product methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(3,5-dichlorophenyl)cyclopropyl)carbamate [11.3] (0.14 g, 60%, LCMS MH + = 432.2) as a colorless liquid.

[0362] Step 4 Example [2], adapting the procedure used in Step 4, 0.14 g of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(3,5-dichlorophenyl)cyclopropyl)carbamate [11.3] was reacted to give (2-amino-2-methylpropyl)(1-(3,5-dichlorophenyl)cyclopropyl)carbamate methyl

[11] (0.037 g, 31%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): δ 7.80 (bs, 3H), 7.48 (d, J = 1.20 Hz, 1H), 7.14 (bs, 1H), 3.65 (s, 3H), 3.56 (d, J = 2.40 Hz, 1H), 3.50 (s, 1H), 1.45 (s, 2H), 1.35 (s, 1H), 1.30 - 1.22 (m, 1H), 1.17 (bs, 6H). HRMS calculated value: [C 15 H 20 Cl2N2O2 + H] + 331.0975; found: 331.0966 (deviation 2.7 ppm).

[0363] Example

[12] - Methyl (2-amino-2-methylpropyl)(1-(3-bromophenyl)cyclopropyl)carbamate Step 1 Adapting the procedure used in Example [1], Step 1, 3 g of 3-bromobenzonitrile was reacted to give 1-(3-bromophenyl)cyclopropane-1-amine [12.1] (1.3 g, 56%, LCMS MH + = 213.0).

[0364] Step 2 Adapting the procedure used in Example [3], Step 1, 1 g of 1-(3-bromophenyl)cyclopropane-1-amine [12.1] and 0.97 g of tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1] were reacted to give the product tert-butyl (1-((1-(3-bromophenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] (0.9 g, 67%, LCMS MH + = 384.2) as a yellow solid.

[0365] Step 3 Example [1], adapting the procedure used in Step 2, 0.5 g of tert-butyl (1-((1-(3-bromophenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] was reacted to give the product methyl (1-(3-bromophenyl)cyclopropyl)(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamate (0.4 g, 69%, LCMS MH + = 442.1) as a colorless liquid.

[0366] Step 4 Example [2], adapting the procedure used in Step 4, 0.1 g of methyl (1-(3-bromophenyl)cyclopropyl)(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamate [12.3] was reacted to give the TFA salt of methyl (2-amino-2-methylpropyl)(1-(3-bromophenyl)cyclopropyl)carbamate

[12] (purified by preparative HPLC using 0.1% TFA in ACN) (0.02 g, 26%) as a white solid. 1 1H-NMR (400 MHz, DMSO-d6): δ 7.67 (bs, 2H), 7.42 - 7.38 (m, 1H), 7.27 (t, J = 10.40 Hz, 2H), 7.10 (bs, 1H), 3.62 (s, 3H), 3.52 - 3.37 (m, 2H), 1.50 - 1.20 (m, 4H), 1.15 (s, 6H). HRMS calculated value: [C 15 H 21 BrN2O2 + H] + 341.0859; 343.0839; found: 341.0847; 343.0828 (deviation 3.5; 3.3 ppm).

[0367] Example

[13] - Methyl (2-amino-2-methylpropyl)(1-(3-chlorophenyl)cyclopropyl)carbamate Step 1 Example [1], adapting the procedure used in Step 1, 1 g of 3-bromobenzonitrile was reacted to give 1-(3-chlorophenyl)cyclopropane-1-amine [13.1] (0.4 g, 32%, LCMS MH +gave (yield = 168.5).

[0368] Step 2 In Example [3], adapting the procedure used in Step 1, 0.4 g of 1-(3-chlorophenyl)cyclopropane-1-amine [13.1] and 0.49 g of tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1] were reacted to give the product tert-butyl (1-((1-(3-chlorophenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [13.2] (0.25 g, 31%, LCMS MH + = 339.2).

[0369] Step 3 In Example [1], adapting the procedure used in Step 2, 0.2 g of tert-butyl (1-((1-(3-chlorophenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [13.2] was reacted to give methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(3-chlorophenyl)cyclopropyl)carbamate [13.3] (0.17 g, 72%, LCMS MH + = 397.1).

[0370] Step 4 In Example [2], adapting the procedure used in Step 4, 0.17 g of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(3-chlorophenyl)cyclopropyl)carbamate [13.3] was reacted to give the TFA salt of methyl (2-amino-2-methylpropyl)(1-(3-chlorophenyl)cyclopropyl)carbamate

[13] (0.1 g, 78%) (the compound was purified by preparative HPLC using 0.1% TFA in ACN) as a colorless gum. 1 1H-NMR (400 MHz, DMSO-d6): δ 7.59 (s, 2H), 7.36 - 7.24 (m, 2H), 7.33 (bs, 2H), 3.62 (s, 3H), 3.50 (bs, 2H), 1.35 (s, 4H), 1.15 (s, 6H). HRMS calculated value: [C15 H 21 ClN2O2+H] + 297.1364; Measured value: 297.1257 (deviation 2.5 ppm).

[0371] Example

[14] - 1 - ((azetidin - 2 - ylmethyl)(1 - (4 - fluoro - 3 - (trifluoromethyl)phenyl)cyclopropyl)amino)-2 - methylpropan - 2 - ol Step 1 To a stirred solution of 1 - (4 - fluoro - 3 - (trifluoromethyl)phenyl)cyclopropane - 1 - amine [1.1] (1.5 g, 6.84 mmol) and 1 - (tert - butoxycarbonyl)azetidine - 2 - carboxylic acid (1.23 g, 6.15 mmol) in DMF, Hatu (3.12 g, 8.21 mmol) was added followed by DIPEA (2.2 g, 17.10 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by flash chromatography using ethyl acetate in petroleum ether as the eluent to give tert - butyl 2 - ((1 - (4 - fluoro - 3 - (trifluoromethyl)phenyl)cyclopropyl)carbamoyl)azetidine - 1 - carboxylate [14.1] (2.3 g, 85%, LCMS MH + = 403.3).

[0372] Step 2 A solution of 2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamoyl)azetidine-1-carboxylic acid [14.1] (2.3 g, 5.72 mmol) in tetrahydrofuran was added with borane dimethyl sulfide complex (1.8 g, 22.86 mmol) at 0 °C, and the reaction was refluxed at 70 °C for 2 h. The reaction mixture was quenched with methanol at 0 °C until foaming ceased. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with water and aqueous salt solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by flash chromatography using ethyl acetate in petroleum ether as the solvent, to give tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [14.2] (1.45 g, 55%, LCMS M + = 389.4) as a colorless liquid.

[0373] Step 3 To a solution of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [14.2] (0.3 g, 0.77 mmol) and potassium carbonate (0.32 g, 2.31 mmol) in acetonitrile was added methyl bromoacetate (0.35 g, 2.31 mmol), and the reaction mixture was heated at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with water and aqueous salt solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by flash chromatography using ethyl acetate in petroleum ether as the solvent, to give tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(2-methoxy-2-oxoethyl)amino)methyl)azetidine-1-carboxylate [14.3] (0.25 g, 70%, LCMS MH + = 461.2) as a colorless liquid.

[0374] Step 4 A solution of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(2-methoxy-2-oxoethyl)amino)methyl)azetidine-1-carboxylate [14.3] (0.2 g, 0.43 mmol) in tetrahydrofuran (5 mL) at 0 °C was treated with methylmagnesium bromide (0.21 g, 1.74 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 2 h and then at room temperature for 1 h. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography using ethyl acetate / hexane as the eluent to afford tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(2-hydroxy-2-methylpropyl)amino)methyl)azetidine-1-carboxylate [14.4] (0.15 g, 75%, LCMS MH + = 461.2) as a colorless gum.

[0375] Step 5 Following the procedure used in Step 2 of Example [1], 0.12 g of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(2-hydroxy-2-methylpropyl)amino)methyl)azetidine-1-carboxylate [14.4] was reacted to give 1-((azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-ol

[14] (0.06 g, 66%, LCMS MH + = 361.2) as an off-white solid. 1 H-NMR (400 MHz, CDCl3): δ 7.52 - 7.45 (m, 2H), 7.07 (q, J = 62.80 Hz, 1H), 3.45 (q, J = 32.80 Hz, 1H), 3.01 (s, 1H), 2.60 (s, 2H), 2.58 - 1.87 (m, 4H), 1.60 - 1.40 (m, 2H), 1.30 - 1.22 (m, 2H), 1.20 (s, 6H), 0.95 - 0.90 (m, 2H). HRMS calculated value: [C18 H 24 F4N2O+H] + 361.1898; Measured value: 361.1889 (deviation 2.4 ppm).

[0376] Example

[15] - Methyl (2 - amino - 2 - methylpropyl)(1 - (3 - (trifluoromethyl)phenyl)cyclopropyl)carbamate Step 1 Adapting the procedure used in Example [3], Step 1, 0.4 g of 1 - (3 - (trifluoromethyl)phenyl)cyclopropan - 1 - amine [10.1] and 0.52 g of tert - butyl (2 - methyl - 1 - oxopropan - 2 - yl)carbamate were reacted to give the product tert - butyl (2 - methyl - 1 - ((1 - (3 - (trifluoromethyl)phenyl)cyclopropyl)amino)propan - 2 - yl)carbamate [15.1] (0.35 g, 69%, LCMS MH + = 373.3).

[0377] Step 2 Adapting the procedure used in Example [1], Step 2, 0.3 g of tert - butyl (2 - methyl - 1 - ((1 - (3 - (trifluoromethyl)phenyl)cyclopropyl)amino)propan - 2 - yl)carbamate [15.1] was reacted to give the product methyl (2 - ((tert - butoxycarbonyl)amino)-2 - methylpropyl)(1 - (3 - (trifluoromethyl)phenyl)cyclopropyl)carbamate [15.2] (0.2 g, 57%, LCMS MH + = 431.4) as a colorless liquid.

[0378] Step 3 Example [2], adapting the procedure used in Step 4, 0.2 g of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [15.2] was reacted to give 0.03 g (20%) of methyl (2-amino-2-methylpropyl)(1-(3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

[15] as an off-white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 7.85 (bs, 2H), 7.57 (t, J = 5.20 Hz, 2H), 7.40 (bs, 2H), 3.63 (s, 3H), 3.53 (s, 1H), 1.50 (bs, 2H), 1.37 (bs, 2H), 1.23 (bs, 1H), 1.18 (s, 6H). HRMS calculated value: [C 16 H 21 F3N2O2 + H] + 331.1628; found: 331.1620 (deviation 2.5 ppm).

[0379] Example

[16] - 1-((1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)amino)-2-methylpropan-2-ol Example [2], adapting the procedure used in Step 2, 0.09 g of 1-((azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-ol

[14] was reacted to give 0.02 g (21%, LCMS MH + = 375.2) of 1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)amino)-2-methylpropan-2-ol

[16] as a colorless gum. 11H-NMR (400 MHz, CDCl3): δ 7.46 - 7.43 (m, 2H), 7.14 (t, J = 9.20 Hz, 1H), 3.52 - 3.48 (m, 1H), 3.42 - 3.33 (m, 1H), 3.01 - 2.96 (m, 1H), 2.80 - 2.70 (m, 3H), 2.65 (d, J = 13.20 Hz, 1H), 2.41 (s, 3H), 2.15 - 2.12 (m, 1H), 1.80 - 1.70 (m, 2H), 1.30 - 1.23 (m, 2H), 1.21 - 1.19 (m, 3H), 1.90 - 1.30 (m, 3H), 1.08 - 0.80 (m, 1H), 0.30 - 0.20 (m, 1H). HRMS calculated value: [C 19 H 26 F4N2O + H] + 375.2054; found: 375.2044 (deviation 2.6 ppm).

[0380] Example

[17] - Methyl (2 - amino - 2 - methylpropyl)(1 - (5 - fluoro - 4 - (trifluoromethyl)pyridin - 2 - yl)cyclopropyl)carbamate Step 1 Adapting the procedure used in Step 1 of Example [3], 0.054 g of 1 - (5 - fluoro - 4 - (trifluoromethyl)pyridin - 2 - yl)cyclopropan - 1 - amine [36.6] was reacted to give (1 - ((1 - (5 - fluoro - 4 - (trifluoromethyl)pyridin - 2 - yl)cyclopropyl)amino)-2 - methylpropan - 2 - yl)carbamic acid tert - butyl [17.1] (0.052 g, 54%, LCMS MH + = 392.2) as an off - white solid.

[0381] Step 2 Example [1], adapting the procedure used in Step 2, 0.05 g of tert-butyl (1-((1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [17.1] was reacted to give methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl)carbamate [17.2] (0.042 g, 73%, LCMS MH + = 450.2) as an off-white solid.

[0382] Step 3 Example [2], adapting the procedure used in Step 4, 0.04 g of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl)carbamate was reacted to give methyl (2-amino-2-methylpropyl)(1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl)carbamate

[17] (0.021 g, 61%, LCMS MH + = 350.2) as an off-white solid. 1 1H-NMR (400 MHz, DMSO-d6): δ 8.81 (s, 1H), 7.80 (s, 2H), 7.33 (s, 1H), 3.58 (s, 3H), 3.26 - 3.25 (m, 2H), 1.58 - 1.54 (m, 4H), 1.24 - 1.21 (m, 6H). HRMS calculated value: [C 15 1 19 9H4F4N3O2 + H] + 350.1486; found: 350.1483 (deviation 0.9 ppm).

[0383] Example

[18] - N1-Cyclobutyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine A solution of 2-(cyclobutyl(1-(3-(trifluoromethyl)phenyl)cyclopropyl)amino)acetonitrile

[82] (0.25 g, 0.85 mmol) in toluene (3 mL) was added with titanium(IV) isopropoxide (0.26 mL, 0.85 mmol) at -40 °C, and the reaction was stirred for 15 minutes. Methylmagnesium bromide solution (7.2 mmol) was added dropwise over 10 minutes, and then the reaction was stirred at room temperature for 18 hours. The reaction was quenched with ammonium chloride solution and extracted with DCM (3 × 50 mL). The organic layers were combined and concentrated under vacuum, and purified by flash column chromatography using 15% EtOAc / petroleum ether as the eluent to give N1-cyclobutyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine

[18] (0.05 g, 18%, LCMS MH + = 327.1) as a pale brown rubber. 1 1H-NMR (400 MHz, DMSO-d6): δ 7.60 - 7.54 (m, 5H), 3.45 - 3.43 (m, 1H), 2.76 (s, 2H), 1.99 - 1.93 (m, 4H), 1.56 - 1.45 (m, 2H), 1.37 - 1.34 (m, 2H), 1.24 - 1.22 (m, 5H), 1.10 - 1.07 (m, 2H). HRMS calculated value: [C 18 H 25 F3N2+H] + 327.2042; found: 327.2036 (deviation 2.2 ppm).

[0384] Example

[19] - Ethyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate Step 1 Example [1], adapting the procedure used in Step 2, 0.15 g of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] was reacted to give ethyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [19.1] (0.14 g, 79% LCMS MH + = 463.2) as a colorless liquid.

[0385] Step 2 Example [2], adapting the procedure used in Step 4, 0.1 g of ethyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [19.1] was reacted to give ethyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

[19] (0.062 g, 72%, LCMS MH + = 363.2) as an off-white solid. 1 1H-NMR (400 MHz, DMSO-d6): δ 7.77 (bs, 3H), 7.63 - 7.58 (m, 1H), 7.54 - 7.45 (m, 2H), 4.13 - 4.08 (m, 2H), 3.55 (bs, 2H), 1.44 (s, 2H), 1.35 (bs, 2H), 2.00 - 1.50 (m, 6H), 1.50 - 1.10 (m, 3H). HRMS calculated value: [C 17 1 22 19F4N2O2+H] + 363.1690; found: 363.1686 (deviation 1.1 ppm).

[0386] Example

[20] - Methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate Step 1 Example [3], adapting the procedure used in Step 1, react 0.25 g of 1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropane-1-amine [9.1] and 0.19 g of tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate [2.1] to give the product (1-((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate tert-butyl [20.1] (0.26 g, 60%, LCMS MH + = 407.2).

[0387] Step 2 Example [1], adapting the procedure used in Step 2, react 0.26 g of (1-((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate tert-butyl [20.1] to give the product methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate [20.2] (0.18 g, 60%, LCMS MH + = 465.2).

[0388] Step 3 Example [2], adapting the procedure used in Step 4, react 0.18 g of methyl (2-((tert-butoxycarbonyl)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate [20.2] to give (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate methyl

[20] (0.1 g, 71%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): δ 7.68 (bs, 2H), 7.46 - 7.42 (m, 1H), 7.28 (bs, 2H), 3.62 (s, 3H), 3.50 (bs, 2H), 1.41 (bs, 2H), 1.25 (bs, 2H), 1.12 (s, 6H). HRMS calculated value: [C 16 H 20 F4N2O3 + H] + 365.1483; measured value: 365.1473 (deviation 2.6 ppm).

[0389] Example

[21] - N-(2-Amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide Step 1 Adapting the procedure used in Example [2], Step 4, 0.3 g of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] was reacted with 0.26 g of sulfuryl dichloride to give tert-butyl (1-(N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamide)-2-methylpropan-2-yl)carbamate [21.1] (0.12 g, 33%, LCMS MH + = 469.2).

[0390] Step 2 Adapting the procedure used in Example [2], Step 4, 0.12 g of tert-butyl (1-(N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamide)-2-methylpropan-2-yl)carbamate [21.1] was reacted to give N-(2-Amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide

[21] (0.048 g, 50%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): δ 7.77 (dd, J = 2.40, 6.40 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.48 - 7.40 (m, 1H), 3.16 (s, 2H), 3.11 (s, 3H), 1.75 - 1.68 (m, 2H), 1.55 (s, 2H), 1.36 (d, J = 1.20 Hz, 2H), 0.98 (s, 6H). HRMS calculated value: 15 H 20 F4N2O2S + H] + 369.1254; measured value: 369.1242 (deviation 3.2 ppm).

[0391] Example

[22] - (R)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid methyl Step 1 Adapting the procedure used in Step 1 of Example [2], 2 g of tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate was reacted to give tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate [22.1] (1.5 g (crude), 79%) as a pale yellow liquid.

[0392] Step 2 Adapting the procedure used in Step 2 of Example [2], 1.5 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] was reacted with tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate [22.1] to give tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate (1.3 g, 48%, LCMS MH + = 403.2) as a colorless liquid.

[0393] Step 3 Example [1], adapting the procedure used in Step 2, 0.25 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [22.2] and 0.09 g of methyl chloroformate were reacted to give tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [22.3] (0.13 g, 52%, LCMS MH + = 361.4 (Boc cleavage mass)) as a colorless gum.

[0394] Step 4 To a stirred solution of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [22.3] (0.12 g, 0.26 mmol) in DCM was added HCl gas in diethyl ether at 0 °C and the reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by trituration in diethyl ether to give methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

[22] (HCl salt) (0.1 g, 97%, LCMS MH + = 361.2). 1 1H-NMR (400 MHz, DMSO-d6): δ 9.30 - 9.00 (bs, 1H), 8.60 - 8.20 (bs, 1H), 7.54 - 7.38 (m, 3H), 3.76 - 0.75 (m, 1H), 3.62 - 3.50 (m, 4H), 3.30 - 3.18 (m, 1H), 3.12 - 3.00 (m, 1H), 2.04 - 1.94 (m, 1H), 1.90 - 1.82 (m, 2H), 1.57 - 1.50 (m, 2H), 1.40 - 1.30 (m, 2H). HRMS calculated value: [C 17 H 20 F4N2O2 + H] + 361.1534; found: 361.1521 (deviation 3.6 ppm).

[0395] Example

[23] - (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid methyl ester Step 1 Adapting the procedure used in Step 1 of Example [2], 3 g of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate was reacted to give tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate [23.1] (2 g (crude), 62%) as a pale yellow liquid.

[0396] Step 2 Adapting the procedure used in Step 2 of Example [2], 1 g of 1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropane-1-amine [1.1] was reacted with tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate [23.1] to give tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2] (1.2 g, 66%, LCMS MH + = 403.2).

[0397] Step 3 Adapting the procedure used in Step 2 of Example [1], 1 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2] and 0.21 g of methyl chloroformate were reacted to give tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate (0.25 g, 73%, LCMS MH + = 461.2).

[0398] Step 4 Example

[22] , adapting the procedure used in step 4, 0.12 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [23.3] was reacted to give (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid methyl

[23] (HCl salt) (0.09 g, 90%, LCMS MH + = 361.2) as an off-white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 9.60 - 9.40 (bs, 1H), 9.00 - 8.20 (bs, 1H), 7.49 - 7.38 (m, 3H), 3.73 - 3.60 (m, 6H), 3.23 - 3.07 (m, 2H), 1.98 - 1.85 (m, 3H), 1.70 - 1.40 (m, 3H), 1.36 - 1.29 (m, 2H). HRMS calculated value: [C 17 H 20 F4N2O2+H] + 361.1534; found: 361.1524 (deviation 2.6 ppm).

[0399] Example

[24] - Methyl (2-acetamido-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate Example [1], adapting the procedure used in step 2, 0.1 g of methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [2] and 0.022 g of acetyl chloride were reacted to give 0.034 g (30%) of methyl (2-acetamido-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

[24] as a colorless gum. 1 H-NMR (400 MHz, DMSO-d6): δ 7.53 - 7.38 (m, 2H), 7.30 (bs, 3H), 3.73 (s, 2H), 3.61 (s, 3H), 1.52 (s, 3H), 1.43 (bs, 2H), 1.30 (bs, 2H), 1.14 (s, 6H). HRMS calculated value: [C18 H 22 F4N2O3 + H] + 391.1639; Measured value: 391.1637 (deviation 0.7 ppm).

[0400] Example

[25] - N1-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-2-methylpropane-1,2-diamine Adapting the procedure used in Example [2], Step 4, 0.1 g of tert-butyl (1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-yl)carbamate [2.2] was reacted to give N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-2-methylpropane-1,2-diamine

[25] (0.05 g, 67%) as a colorless gum. 1 H-NMR (400 MHz, DMSO-d6): δ 7.74 (dd, J = 2.00, 7.00 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.43 - 7.36 (m, 1H), 2.59 (bs, 1H), 2.20 (s, 2H), 1.40 (bs, 2H), 1.00 - 0.98 (m, 2H), 0.93 (s, 6H). HRMS calculated value: [C 14 H 18 F4N2 + H] + 290.1479; Measured value: 291.1467 (deviation 4.1 ppm).

[0401] Example

[26] - Methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate Step 1 Example [1], adapting the procedure used in Step 2, react 0.45 g of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [14.2] to give, as a colorless gum, tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine-1-carboxylate [26.1] (0.125 g, 25%, LCMS MH + = 447.1).

[0402] Step 2 To a stirred solution of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine-1-carboxylate [26.1] (0.25 g, 0.56 mmol) in dichloromethane (6 mL) at 0 °C was added trifluoroacetic acid (4 mL, 52 mmol), and the reaction was stirred at room temperature for 12 h. The reaction was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give, as a white solid, methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

[26] trifluoroacetate (0.035 g, 19%, LCMS MH + = 347.1). 1 1H-NMR (400 MHz, DMSO-d6): δ 8.58 (bs, 1H), 7.60 - 7.45 (m, 2H), 7.38 (s, 1H), 4.43 (bs, 1H), 3.90 (bs, 1H), 3.85 - 3.75 (m, 2H), 3.66 - 3.63 (m, 3H), 3.63 - 3.60 (m, 1H), 2.35 - 2.10 (m, 2H), 1.50 - 1.25 (m, 4H). HRMS calculated value: [C 16 H 18 F4N2O2 + H] + 347.1377; found: 347.1374 (deviation 0.9 ppm).

[0403] Example

[27] - Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamate Following the procedure used in Example [2], Step 2, 0.08 g of methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

[23] was reacted to give 0.055 g (73%) of methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamate

[27] as a colorless gum. 1 H-NMR (400 MHz, DMSO-d6): δ 7.49 - 7.42 (m, 3H), 3.65 - 3.60 (m, 3H), 3.33 - 3.26 (m, 2H), 2.89 - 2.86 (m, 1H), 2.50 - 2.30 (m, 1H), 2.20 (s, 3H), 2.08 - 2.06 (m, 1H), 1.23 - 1.61 (m, 8H). HRMS calculated value: 18 H 22 [C + F4N2O2 + H]

[0404] Example

[28] - Methyl (S)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate Step 1 Following the procedure used in Example [3], Step 1, 0.3 g of 1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropan-1-amine [9.1] was reacted to give 0.3 g (54%, LCMS MH + = 419.2) of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [28.1] as a light brown gum.

[0405] Step 2 Example [1], adapting the procedure used in Step 2, 0.3 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [28.1] was reacted to give tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [28.2] (0.3 g, 85%, LCMS MH + = 477.1) as a colorless gum.

[0406] Step 3 Example [2], adapting the procedure used in Step 4, 0.15 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [28.2] was reacted to give methyl (S)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

[28] (0.65 g, 60%, LCMS MH + = 377.1) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 9.20 (bs, 1H), 8.45 (bs, 1H), 7.50 - 7.42 (m, 1H), 7.25 (bs, 2H), 3.69 (bs, 1H), 3.64 (s, 3H), 3.56 (s, 2H), 3.30 - 3.20 (m, 1H), 3.12 - 3.02 (m, 1H), 2.05 - 1.45 (m, 1H), 1.95 - 1.28 (m, 2H), 1.60 - 1.40 (m, 3H), 1.35 (bs, 1H), 1.25 (bs, 1H). HRMS calculated value: [C 17 H 20 F4N2O3 + H] + 377.1483; found: 377.1476 (deviation 1.8 ppm).

[0407] Example

[29] - (R)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate Step 1 Example [3]: Adapting the procedure used in Step 1, 0.4 g of 1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropane-1-amine [9.1] was reacted to give (R)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl [29.1] (0.35 g, 49%, LCMS MH + = 419.1) as a colorless liquid.

[0408] Step 2 Example [1]: Adapting the procedure used in Step 2, 0.35 g of (R)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl [29.1] was reacted to give (R)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl [29.2] (0.2 g, 50%, LCMS MH + = 477.2) as a light brown rubber.

[0409] Step 3 Example [2]: Adapting the procedure used in Step 4, 0.1 g of (R)-2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl [29.2] was reacted to give (R)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid methyl

[29] (HCl salt) (0.05 g, 58%, LCMS MH + = 377.2) as a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 9.15 (bs, 1H), 8.25 (bs, 1H), 7.27 - 7.22 (m, 1H), 7.13 (bs, 2H), 3.80 - 3.68 (m, 1H), 3.64 (s, 3H), 3.62 - 3.50 (m, 2H), 3.30 - 3.20 (m, 1H), 3.12 - 3.02 (m, 1H), 2.05 - 1.78 (m, 3H), 1.60 - 1.40 (m, 2H), 1.40 - 1.20 (m, 2H). HRMS calculated value: [C 17 H 20 F4N2O3 + H] + 377.1483; found: 377.1472 (deviation 2.9 ppm).

[0410] Example

[30] - Methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)carbamate Following the procedure used in Example [2], Step 2, 0.19 g of methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

[26] was reacted to give methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)carbamate

[30] (0.02 g, 10%, LCMS MH + = 361.1) as a colorless gum. 1 H-NMR (400 MHz, CDCl3): δ 7.28 - 7.20 (m, 1H), 7.15 - 7.10 (m, 1H), 7.06 - 7.03 (m, 1H), 3.69 (s, 3H), 3.45 - 3.25 (m, 3H), 2.64 (bs, 1H), 2.20 (bs, 3H), 1.95 - 1.73 (m, 2H), 1.63 (bs, 2H), 1.44 (bs, 1H), 1.30 - 1.18 (m, 2H). HRMS calculated value: [C 17 H 20 F4N2O2 + H] + 361.1534; found: 361.1528 (deviation 1.7 ppm).

[0411] Example

[31] - Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamate Adapting the procedure used in Example [2], Step 2, 0.02 g of methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

[22] was reacted to give 0.013 g (62%) of methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)carbamate

[31] as a colorless gum. 1 H-NMR (400 MHz, DMSO-d6): δ 7.60 - 7.30 (m, 3H), 3.59 (s, 3H), 3.35 - 3.25 (m, 2H), 2.91 - 2.80 (m, 1H), 2.38 (s, 1H), 2.19 (s, 3H), 2.11 - 2.00 (m, 1H), 1.70 - 1.50 (m, 4H), 1.50 - 1.20 (m, 4H). HRMS calculated value: 18 H 22 [C + F4N2O3 + H]

[0412] Example

[32] - Methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate Step 1 Adapting the procedure used in Example

[14] , Step 1, 0.6 g of 1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropan-1-amine [9.1] was reacted to give 0.6 g (56%, LCMS MH + = 419.2) of tert-butyl 2-((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamoyl)azetidine-1-carboxylate [32.1] as a colorless gum.

[0413] Step 2 To a stirred solution of tert-butyl 2-((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamoyl)azetidine-1-carboxylate [32.1] (0.6 g, 1.43 mmol) in anhydrous THF (3 mL), borane dimethyl sulfide complex (0.46 g, 5.74 mmol) was added dropwise under a N2 atmosphere. The resulting reaction mixture was gradually warmed to room temperature and then heated to 60 °C for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography using ethyl acetate / hexane as the eluent to give tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [32.2] (0.2 g, 34%, LCMS MH + = 405.1) as a colorless gum.

[0414] Step 3 Adapting the procedure used in Step 2 of Example [1], 0.2 g of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [32.2] was reacted to give tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine-1-carboxylate [32.3] (0.2 g, 87%, LCMS MH + = 463.2) as a colorless gum.

[0415] Step 4 Example

[26] , adapting the procedure used in Step 2, 0.2 g of tert-butyl 2-(((1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine-1-carboxylate [32.3] was reacted to give methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate

[32] (0.055 g, 35%, LCMS MH + = 463.2) as a colorless gum. 1 1H-NMR (400 MHz, DMSO-d6): δ 7.42 (t, J = 10.40 Hz, 1H), 7.30 - 7.05 (m, 2H), 3.91 (s, 1H), 3.57 (s, 3H), 3.50 - 3.40 (m, 2H), 3.05 (s, 1H), 2.08 - 1.80 (m, 3H), 1.50 - 1.28 (m, 2H), 1.23 (s, 2H). HRMS calculated value: 16 C 18 H + F4N2O3 + H]

[0416] Example

[33] - Methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(2-(hydroxyamino)-2-methylpropyl)carbamate Step 1 To a stirred solution of methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [2] (0.25 g, 0.717 mmol) in DMF (5 mL) were added benzoyl peroxide (0.26 g, 1.076 mmol) and potassium phosphate (0.146 g, 1.076 mmol) at 0 °C. The resulting reaction mixture was gradually warmed to room temperature and stirred at room temperature for 12 h. The reaction mixture was quenched with water, extracted with ethyl acetate (2 × 25 mL), the organic layers were combined, dried over sodium sulfate, concentrated to give a crude product, and purified by column chromatography using 15% ethyl acetate in hexane as the eluent to afford methyl (2-((benzyloxy)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [33.1] (0.18 g, 54%) as an off-white solid.

[0417] Step 2 To a stirred solution of methyl (2-((benzyloxy)amino)-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate [33.1] (0.16 g, 0.341 mmol) in methanol (5 mL) was added hydrazine monohydrate (3 mLg, 61.72 mmol) at 0 °C. The resulting reaction mixture was gradually warmed to room temperature and stirred at room temperature for 12 h. The reaction mixture was quenched with water, extracted with ethyl acetate (2 × 25 mL), the organic layers were combined, dried over sodium sulfate, concentrated to give a crude product, and purified by preparative HPLC to afford methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(2-(hydroxyamino)-2-methylpropyl)carbamate

[33] (15.7 mg, 13%) as an off-white solid. 11H-NMR (400 MHz, DMSO-d6): δ 7.50 (bs, 1H), 7.42 (t, J = 8.80 Hz, 2H), 6.87 (s, 1H), 5.05 (bs, 1H), 3.56 (s, 3H), 3.40 - 3.35 (m, 2H), 1.28 - 1.26 (m, 2H), 1.22 - 1.24 (m, 2H), 0.85 (d, J = 10.40 Hz, 6H). HRMS calculated value: [C 16 H 20 F4N2O3 + H] + 365.1483; found: 365.1478 (deviation 1.3 ppm).

[0418] Example

[34] - (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)ethyl carbamate Step 1 Adapting the procedure used in Example [1], Step 2, 0.25 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2] was reacted to give tert-butyl (S)-2-(((ethoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [34.1] (0.16 g, 55%, LCMS MH + = 375.2 (boc-cleavage mass)) as a colorless gum.

[0419] Step 2 Adapting the procedure used in Example [2], Step 4, 0.14 g of tert-butyl (S)-2-(((ethoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate was reacted to give ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

[34] (0.1 g, 83%) as a white solid. MS (M + 1) + = 375.2. 11H-NMR (400 MHz, DMSO-d6): δ 9.40 - 9.05 (broad singlet, 1H), 8.60 - 8.20 (broad singlet, 1H), 7.65 - 7.52 (multiplet, 1H), 7.49 (triplet, J = 9.20 Hz, 2H), 4.11 (quartet, J = 7.20 Hz, 2H), 3.70 - 3.65 (multiplet, 1H), 3.65 - 3.52 (multiplet, 2H), 3.30 - 3.18 (multiplet, 1H), 3.15 - 3.00 (multiplet, 1H), 2.05 - 1.60 (multiplet, 3H), 1.65 - 1.40 (multiplet, 3H), 1.40 - 1.10 (multiplet, 5H). HRMS calculated value: [C 18 H 22 F4N2O2 + H] + 375.1690; found: 375.1686 (deviation 1.2 ppm).

[0420] Example

[35] - (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)ethyl carbamate Following the procedure used in Example [2], Step 2, 0.1 g of (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)ethyl carbamate

[34] was reacted to give (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylpyrrolidin-2-yl)methyl)ethyl carbamate

[35] (0.075 g, 80%, LCMS MH + = 389.1) as a colorless gum. 1 1H-NMR (400 MHz, DMSO-d6): δ 7.52 (doublet, J = 5.20 Hz, 2H), 7.38 (triplet, J = 8.80 Hz, 1H), 4.08 (quartet, J = 7.20 Hz, 2H), 3.30 (doublet, J = 6.00 Hz, 2H), 2.90 (quartet, J = 4.80 Hz, 1H), 2.22 (singlet, 3H), 2.12 (quartet, J = 8.40 Hz, 2H), 1.70 - 1.50 (multiplet, 4H), 1.50 - 1.20 (multiplet, 4H), 1.16 (triplet, J = 6.80 Hz, 3H). HRMS calculated value: [C 19 H 24 F4N2O2 + H] + 389.1847; found: 389.1843 (deviation 1.0 ppm).

[0421] Example

[36] - (S) -N-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide Step 1 Adapting the procedure used in Example [1], Step 2, 0.8 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2] and 0.69 g of methanesulfonyl chloride were reacted to give 0.4 g (42%) of tert-butyl (S)-2-((N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamido)methyl)pyrrolidine-1-carboxylate [36.1] as a colorless gum.

[0422] Step 2 Adapting the procedure used in Example

[22] , Step 4, 0.4 g of tert-butyl (S)-2-((N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamido)methyl)pyrrolidine-1-carboxylate [36.1] was reacted to give 0.28 g (80%) of (S)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide

[36] as an off-white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 9.50 - 9.25 (s, 1H), 8.95 - 8.65 (s, 1H), 7.84 - 7.78 (m, 2H), 7.46 (t, J = 8.80 Hz, 1H), 3.80 - 3.55 (m, 3H), 3.35 - 3.00 (m, 2H), 2.92 (s, 3H), 2.10 - 1.65 (m, 3H), 1.65 - 1.50 (m, 3H), 1.35 - 1.26 (m, 2H). HRMS calculated value: [C 16 H 20 F4N2O2 + H] + 381.1254; found: 381.1250 (deviation 1.3 ppm).

[0423] Example

[37] - (S) -N-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-((1-methylpyrrolidin-2-yl)methyl)methanesulfonamide Adapting the procedure used in Step 2 of Example [2], 0.12 g of (S) -N-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide

[36] was reacted to give (S) -N-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-((1-methylpyrrolidin-2-yl)methyl)methanesulfonamide

[37] (0.08 g, 67%) as a colorless gum. 1 H-NMR (400 MHz, DMSO-d6): δ7.69 (dd, J = 2.12, 6.68 Hz, 1H), 7.61 - 7.60 (m, 1H), 7.47 (t, J = 9.04 Hz, 1H), 3.25 (dd, J = 40.00, Hz, 1H), 3.13 - 3.04 (m, 1H), 2.95 - 2.90 (m, 3H), 2.90 - 2.85 (m, 1H), 2.40 - 2.32 (m, 1H), 2.30 - 2.20 (m, 3H), 2.15 - 2.00 (m, 1H), 1.70 - 1.50 (m, 6H), 1.45 - 1.20 (m, 2H). HRMS calculated value: [C 17 H 22 F4N2O2 + H] + 395.1411; measured value: 395.1406 (deviation 1.3 ppm).

[0424] Example

[38] - (R)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)ethyl carbamate Step 1 Example [1], adapting the procedure used in Step 2, 0.25 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [22.2] and 0.07 g of ethyl chloroformate were reacted to give, as a colorless gum, tert-butyl (R)-2-(((ethoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [38.1] (0.14 g, 48%, LCMS MH + = 375.1 (Boc-cleavage mass)).

[0425] Step 2 Example

[22] , adapting the procedure used in Step 4, 0.13 g of tert-butyl (R)-2-(((ethoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate was reacted to give, as a white solid, ethyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

[38] (HCl salt) (0.115 g, 99%, LCMS MH + = 375.1). 1 1H-NMR (400 MHz, DMSO-d6): δ 9.30 - 9.10 (bs, 1H), 8.60 - 8.20 (bs, 1H), 7.58 - 7.46 (m, 3H), 4.13 - 4.08 (m, 2H), 3.80 - 3.50 (m, 3H), 3.30 - 3.18 (m, 1H), 3.15 - 3.00 (m, 1H), 2.10 - 1.70 (m, 3H), 1.59 - 1.49 (m, 3H), 1.35 - 1.07 (m, 5H). HRMS calculated value: [C 18 H 22 F4N2O2 + H] + 375.1690; found: 375.1688 (deviation 0.5 ppm).

[0426] Example

[39] - Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamate Project 1 To a solution of (S)-4-(tert-butoxycarbonyl)-morpholine-3-carboxylic acid (0.37 g, 1.642 mmol) in dichloromethane (10 mL) cooled in ice, triethylamine (0.76 mL, 5.474 mmol) was added, followed by a solution of propylphosphonic anhydride (2.61 g, 4.106 mmol) under a N2 atmosphere. The resulting reaction mixture was stirred at 0 °C for 20 minutes, then 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine [1.1] (0.3 g, 1.368 mmol) was added and the reaction was stirred at room temperature for 5 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2 × 80 mL). The combined organic layers were washed with 10% sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamoyl)morpholine-4-carboxylic acid tert-butyl [39.1] (0.55 g, 93%, LCMS MH + = 433.1) as a yellow liquid.

[0427] Project 2 To a solution of (S)-3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamoyl)morpholine-4-carboxylic acid tert-butyl [39.1] (0.55 g, 1.271 mmol) in anhydrous THF (5 mL) cooled, borane dimethylsulfide complex (9.6 mL, 2.543 mmol) was added dropwise under a N2 atmosphere. The resulting reaction mixture was gradually warmed to room temperature and stirred at room temperature for 16 hours. The reaction mixture was quenched with methanol, refluxed for 1 hour, and then concentrated under reduced pressure. The resulting residue was diluted with water and extracted with dichloromethane (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (3R)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)morpholine-4-carboxylic acid tert-butyl [39.2] (0.28 g, 52%, LCMS MH + = 419.2) as a colorless gum.

[0428] Step 3 Adapting the procedure used in Example [1], Step 2, 0.25 g of tert-butyl (3R)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)morpholine-4-carboxylate [39.2] was reacted to give the product tert-butyl (R)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)morpholine-4-carboxylate (0.2 g, 71%, LCMS MH + = 477.2) as a colorless gum.

[0429] Step 4 Adapting the procedure used in Example [1], Step 2, 0.2 g of tert-butyl (R)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)morpholine-4-carboxylate [39.3] was reacted to give methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamate

[39] (0.15 g, 88%, LCMS MH + = 377.2) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 9.11 (bs, 1H), 7.70 - 7.30 (m, 3H), 3.85 (d, J = 11.20 Hz, 2H), 3.75 - 3.68 (m, 1H), 3.63 (bs, 3H), 3.60 - 3.40 (m, 4H), 3.24 (d, J = 32.00 Hz, 1H), 3.10 - 3.00 (m, 1H), 1.53 (bs, 2H), 1.50 - 1.20 (m, 2H). HRMS calculated value: [C 17 H 20 F4N2O3 + H] + 377.1483; found: 377.1475 (deviation 2.1 ppm).

[0430] Example

[40] - Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamate Adapting the procedure used in Example [2], Step 2, 0.1 g of methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamate

[39] was reacted to give methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamate

[40] (0.08 g, 85%, LCMS MH + = 391.2) as a colorless gum. 1 H-NMR (400 MHz, DMSO-d6): δ 7.54 - 7.44 (m, 3H), 3.61 - 3.58 (m, 3H), 3.47 - 3.39 (m, 2H), 3.34 - 3.33 (m, 2H), 3.30 - 3.26 (m, 1H), 3.20 - 3.10 (m, 1H), 2.67 - 2.61 (m, 1H), 2.27 - 2.07 (m, 5H), 1.46 - 1.25 (m, 4H). HRMS calculated value: [C 18 H 22 F4N2O3 + H] + 391.1639; found: 391.1633 (deviation 1.7 ppm).

[0431] Example

[41] - (R)-N-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide Step 1 Adapting the procedure used in Example [1], Step 2, 0.25 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate and 0.11 g of methanesulfonyl chloride were reacted to give tert-butyl (R)-2-((N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamide)methyl)pyrrolidine-1-carboxylate [41.1] (0.16 g, 34%, LCMS MH+ gave = 381.1 (Boc-cleavage mass).

[0432] Step 2 Adapting the procedure used in Example

[22] , Step 4, 0.15 g of (R)-2-((N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl [41.1] was reacted to give (R)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide

[41] (HCl salt) (0.11 g, 84%, LCMS MH + = 381.1). 1 1H-NMR (400 MHz, DMSO-d6): δ 9.27 (bs, 1H), 8.67 (bs, 1H), 7.80 - 7.75 (m, 2H), 7.52 (t, J = 9.60 Hz, 2H), 3.65 - 3.56 (m, 3H), 3.22 - 3.12 (m, 2H), 2.90 (s, 3H), 2.00 - 1.75 (m, 3H), 1.70 - 1.50 (m, 3H), 1.30 (bs, 2H). HRMS calculated value: [C 16 H 20 F4N2O2S + H] + 381.1254; found: 381.1251 (deviation 0.7 ppm).

[0433] Example

[42] - (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamic acid methyl Step 1 Adapting the procedure used in Example [2], Step 2, 0.8 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] was reacted with (3R)-3-formylmorpholine-4-carboxylic acid tert-butyl to give (S)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)morpholine-4-carboxylic acid tert-butyl [42.1] (0.9 g, 59%, LCMS MH +gave ( = 419.2).

[0434] Step 2 In Example [1], adapting the procedure used in Step 2, 0.3 g of tert-butyl (S)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)morpholine-4-carboxylate [42.1] was reacted to give tert-butyl (S)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)morpholine-4-carboxylate [42.2] (0.17 g, 50%, LCMS MH + gave ( = 377.2).

[0435] Step 3 In Example [2], adapting the procedure used in Step 4, 0.17 g of tert-butyl (S)-3-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)morpholine-4-carboxylate [42.2] was reacted to give methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamate

[42] (0.135 g, 92%; LCMS MH + gave ( = 377.2). 1 1H-NMR (400 MHz, DMSO-d6): δ 9.15 (bs, 2H), 7.50 - 7.37 (m, 3H), 3.86 (d, J = 11.60 Hz, 2H), 3.75 - 3.40 (m, 8H), 3.25 (d, J = 40.00 Hz, 1H), 3.12 - 2.95 (m, 1H), 1.57 (bs, 2H), 1.31 - 1.23 (m, 2H). HRMS calculated value: [C 17 H 20 F4N2O3 + H] + 377.1483; measured value: 377.1476 (deviation 1.9 ppm).

[0436] Example

[43] - Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamate Adapting the procedure used in Example [2], Step 2, 0.1 g of methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamate

[42] was reacted to give 0.075 g (80%, LCMS MH + = 391.2) of methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamate

[43] as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 7.52 - 7.42 (m, 3H), 3.70 - 3.55 (m, 5H), 3.53 - 3.37 (m, 2H), 3.35 - 3.22 (m, 1H), 3.00 - 3.02 (m, 1H), 2.68 - 2.58 (m, 1H), 2.35 - 2.18 (m, 4H), 2.15 - 2.05 (m, 1H), 1.55 - 1.33 (m, 4H). HRMS calculated value: [C 18 H 22 F4N2O3 + H] + 391.1639; found: 391.1633 (deviation 1.7 ppm).

[0437] Example

[44] - Isopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate Step 1 Adapting the procedure used in Example

[45] , Step 1, 0.1 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylate [23.2] and 0.67 g of isopropyl chloroformate were reacted to give 0.1 g (83%) of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(isopropoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [44.1] as a colorless liquid.

[0438] Step 2 Example

[26] , adapting the procedure used in Step 2, 0.1 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(isopropoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate [44.1] was reacted to give 0.07 g (88%) of isopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate

[44] as a pale yellow liquid. 1 H-NMR (400 MHz, DMSO-d6): δ 8.45 (bs, 1H), 7.57 (d, J = 2.64 Hz, 1H), 7.48 (t, J = 8.24 Hz, 2H), 4.83 (t, J = 6.24 Hz, 1H), 3.70 - 3.48 (m, 3H), 3.28 - 3.18 (m, 1H), 3.12 - 3.02 (m, 1H), 1.99 (bs, 1H), 1.92 - 1.74 (m, 2H), 1.60 - 1.38 (m, 3H), 1.38 - 1.24 (m, 2H), 1.22 - 1.05 (m, 6H). HRMS calculated value: [C 19 H 24 F4N2O2+H] + 389.1847; found: 389.1838 (deviation 2.3 ppm).

[0439] Example

[45] - (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)cyclopropylcarbamate Step 1 (S)-2-(((1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl [23.2] (0.15 g, 0.37 mmol) in acetonitrile (4 mL) was added to a stirred solution of cesium carbonate (0.36 g, 1.12 mmol) and cyclopropanecarbonyl chloride (0.09 g, 0.75 mmol). The reaction was stirred at room temperature for 3 h, filtered and concentrated to give the crude product, which was purified by flash column chromatography using ethyl acetate in petroleum ether as the eluent to give (S)-2-(((cyclopropoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl [45.1] (0.16 g, 89%, LCMS MH + = 387.1 (boc cleavage mass)).

[0440] Step 2 Following the procedure used in Example

[26] , Step 2, 0.16 g of (S)-2-(((cyclopropoxycarbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl [45.1] was reacted to give (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamic acid cyclopropyl

[45] (0.1 g, 83%) as a yellow liquid. 1 H-NMR (400 MHz, DMSO-d6): δ 7.43 - 7.41 (m, 3H), 3.50 - 3.00 (m, 3H), 2.90 - 2.70 (m, 2H), 1.80 - 1.50 (m, 4H), 1.40 - 1.10 (m, 5H), 0.80 - 0.30 (m, 4H). HRMS calculated value: [C 19 H 22 F4N2O2 + H] + 387.1690; found: 387.1688 (deviation 0.5 ppm).

[0441] Example

[46] - Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamate Step 1 Adapting the procedure used in Example [2], Step 2, 0.7 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine [1.1] and tert-butyl (2R)-2-formyl-2-methylpyrrolidine-1-carboxylate were reacted to give, as a colorless liquid, tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)-2-methylpyrrolidine-1-carboxylate [46.1] (0.68 g, 51%, LCMS MH + = 417.2).

[0442] Step 2 Adapting the procedure used in Example [1], Step 2, 0.5 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)-2-methylpyrrolidine-1-carboxylate [46.1] was reacted to give, as a brown liquid, tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)-2-methylpyrrolidine-1-carboxylate [46.2] (0.13 g, 22%, LCMS MH + = 375.1 (boc-cleavage mass).

[0443] Step 3 Adapting the procedure used in Example

[22] , Step 4, 0.15 g of tert-butyl (R)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)-2-methylpyrrolidine-1-carboxylate [46.2] was reacted to give, as a colorless gum, methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamate

[46] (0.125 g, 96%, LCMS MH+ gave (m / z = 375.4). 1 1H-NMR (400 MHz, DMSO-d6): δ 8.64 (bs, 1H), 8.40 (bs, 1H), 7.59 - 7.48 (m, 3H), 3.84 (bs, 1H), 3.68 (bs, 3H), 3.60 (bs, 1H), 3.24 - 3.22 (m, 3H), 2.00 - 1.85 (m, 2H), 1.77 (bs, 2H), 1.95 (bs, 3H), 1.32 - 1.20 (m, 1H), 1.10 (bs, 2H). HRMS calculated value: 18 H 22 [C14H19F4N2O2 + H]+ + 375.1690; found: 375.1684 (deviation 1.8 ppm).

[0444] Example

[47] - N-((1-Aminocyclopropyl)methyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine Following the procedure used in Example [2], Step 4, 0.1 g of tert-butyl (1-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)cyclopropyl)carbamate [3.1] was reacted to give N-((1-aminocyclopropyl)methyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine

[47] (0.08 g, 96%, LCMS MH + = 288.1). 1 1H-NMR (400 MHz, DMSO-d6): δ 10.60 - 10.20 (m, 2H), 8.90 - 8.65 (m, 2H), 8.20 - 7.90 (m, 2H), 7.65 - 7.55 (m, 1H), 3.30 - 3.10 (m, 2H), 1.75 - 1.55 (m, 2H), 1.35 - 1.15 (m, 2H), 1.14 - 0.80 (m, 4H). HRMS calculated value: 14 H 16 [C14H18F4N2 + H]+ + 289.1322; found: 289.1310 (deviation 4.2 ppm).

[0445] Example

[48] - (S)-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)cyclopropylmethyl carbamate Step 1 Adapting the procedure used in Example

[45] , Step 1, 0.15 g of (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl [23.2] and 0.125 g of cyclopropylmethyl chloroformate were reacted to give 0.25 g (80%) of (S)-2-((((cyclopropylmethoxy)carbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl [48.1].

[0446] Step 2 Adapting the procedure used in Example

[26] , Step 2, 0.12 g of (S)-2-((((cyclopropylmethoxy)carbonyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl [48.1] was reacted to give 0.085 g (88%) of (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)cyclopropylmethyl carbamate

[48] as a yellow liquid. 1 H-NMR (400 MHz, DMSO-d6): δ 7.52 - 7.43 (m, 3H), 3.87 (d, J = 7.00 Hz, 2H), 3.55 - 3.45 (m, 3H), 3.00 - 2.53 (m, 2H), 4.80 - 1.55 (m, 4H), 1.45 - 1.20 (m, 4H), 1.00 (s, 1H), 0.45 (s, 2H), 0.20 (s, 2H). HRMS calculated value: [C 20 H 24 F4N2O2 + H] + 401.1847; found: 401.1845 (deviation 0.3 ppm).

[0447] Example

[49] - N-((1-Aminocyclopropyl)methyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide Step 1 Adapting the procedure used in Example [1], Step 2, 0.3 g of tert-butyl (1-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)cyclopropyl)carbamate [3.1] and 0.13 g of methanesulfonyl chloride were reacted to give, as a white solid, tert-butyl (1-((N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamido)methyl)cyclopropyl)carbamate [49.1] (0.3 g, 83%, LCMS MH + = 367.2).

[0448] Step 2 Adapting the procedure used in Example [2], Step 4, 0.1 g of tert-butyl (1-((N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methylsulfonamido)methyl)cyclopropyl)carbamate [49.1] was reacted to give, as a white solid, N-((1-aminocyclopropyl)methyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide

[49] (0.08 g, 93%, LCMS MH + = 367.2). 1 1H-NMR (400 MHz, DMSO-d6): δ 8.41 (bs, 3H), 7.76 (s, 1H), 7.66 (d, J = 4.96 Hz, 1H), 7.49 (t, J = 8.80 Hz, 1H), 3.53 (s, 2H), 3.01 (s, 3H), 1.67 (bs, 2H), 1.33 (s, 2H), 0.92 (d, J = 44.32 Hz, 4H). HRMS calculated value: [C 15 1 18 9H4F4N2O2S+H] + 367.1098; measured value: 367.1089 (deviation 2.5 ppm).

[0449] Example

[50] - Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamate Step 1 Adapting the procedure used in Example [2], Step 2, 0.5 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-amine [1.1] and tert-butyl (2S)-2-formyl-2-methylpyrrolidine-1-carboxylate were reacted to give (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl [50.1] (0.65 g, 68%, LCMS MH + = 417.2) as a colorless liquid.

[0450] Step 2 Adapting the procedure used in Example [1], Step 2, 0.4 g of (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl [50.1] was reacted to give (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl [50.2] (0.32 g, 70%, LCMS MH + = 375.1 (boc-cleavage mass)) as a brown liquid.

[0451] Step 3 Adapting the procedure used in Example

[22] , Step 4, 0.3 g of (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl [50.2] was reacted to give methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamate

[50] (0.25 g, 96%, LCMS MH+ gave (375.0). 1 1H-NMR (400 MHz, DMSO-d6): δ 8.70 (bs, 1H), 8.46 (bs, 1H), 7.52 (q, J = 9.68 Hz, 3H), 3.81 (t, J = 45.48 Hz, 4H), 3.22 (d, J = 6.84 Hz, 2H), 1.95 (d, J = 8.36 Hz, 2H), 1.92 (d, J = 5.52 Hz, 2H), 1.44 (s, 3H), 1.27 (bs, 2H), 1.10 (s, 3H). HRMS calculated value: 18 H 20 [C + H

[0452] Example

[51] - (1S,2S)-N1-(1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopentane-1,2-diamine Step 1 Adapting the procedure used in Example [2], Step 2, 0.8 g of 1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] and tert-butyl N-[(1S)-2-oxocyclopentyl]carbamate were reacted to give, as a yellow rubber, ((1S,2S)-2-((1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)cyclopentyl)carbamate tert-butyl [51.1] (0.43 g, 58%, LCMS MH + = 403.2) and, as a white solid, ((1S,2R)-2-((1-(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)cyclopentyl)carbamate tert-butyl [51.2] (0.31 g, 42%, LCMS MH + = 403.2).

[0453] Step 2 Example

[22] , adapting the procedure used in Step 4, 0.04 g of tert-butyl ((1S,2S)-2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)cyclopentyl)carbamate [51.1] was reacted to give (1S,2S)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopentane-1,2-diamine

[51] (0.012 g, 35%, LCMS MH + = 303.2) as a brown rubber. 1 1H-NMR (400 MHz, DMSO-d6): δ 7.93 (t, J = 22.80 Hz, 2H), 7.51 (t, J = 9.20 Hz, 1H), 3.54 (d, J = 1.60 Hz, 2H), 3.40 (d, J = 6.80 Hz, 2H), 3.15 (t, J = 1.20 Hz, 1H), 2.00 - 1.88 (m, 2H), 1.63 - 1.55 (m, 3H), 1.63 - 1.55 (m, 5H). HRMS calculated value: [C 15 H 18 F4N2 + H] + 303.1479; found: 303.1472 (deviation 2.3 ppm).

[0454] Example

[52] - (1R,2S)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-cyclopentane-1,2-diamine Step 1 Example

[22] , adapting the procedure used in Step 4, 0.15 g of tert-butyl ((1S,2R)-2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)cyclopentyl)carbamate [51.2] was reacted to give (1R,2S)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopentane-1,2-diamine

[52] (0.112 g, 88%, LCMS MH + = 303.2) as an off-white solid. 11H-NMR (400 MHz, DMSO-d6): δ 10.66 (bs, 1H), 8.80 - 8.30 (m, 1H), 8.30 - 7.60 (m, 3H), 7.70 - 7.45 (m, 1H), 7.39 - 7.14 (m, 1H), 4.50 - 3.80 (m, 2H), 3.80 - 3.55 (m, 1H), 2.00 - 1.50 (m, 6H), 1.50 - 1.05 (m, 5H). HRMS calculated value: 15 H 18 [C + H4F4N2+H]

[0455] Example [53-(S)-(azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methyl carbamate Step 1 Adapting the procedure used in Example

[39] , Step 1, 1.3 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1-amine [1.1] was reacted to give (S)-2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamoyl)azetidine-1-carboxylic acid tert-butyl [53.1] (2.2 g, 92%, LCMS MH + = 303.1 (boc-cleavage mass)) as a brown liquid.

[0456] Step 2 Adapting the procedure used in Example

[32] , Step 2, 2.2 g of (S)-2-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamoyl)azetidine-1-carboxylic acid tert-butyl [53.1] was reacted to give (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylic acid tert-butyl [53.2] (1.2 g, 57%, LCMS MH + = 389.2) as a colorless liquid.

[0457] Step 3 Example [1], adapting the procedure used in Step 2, 0.25 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)methyl)azetidine-1-carboxylate [53.2] was reacted to give, as a brown rubber, tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine-1-carboxylate [53.3] (0.26 g, 92%, LCMS MH + = 447.2).

[0458] Step 4 Example

[26] , adapting the procedure used in Step 2, 0.5 g of tert-butyl (S)-2-(((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)methyl)azetidine [53.3] was reacted to give, as a brown liquid, methyl (S)-(azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate

[53] (0.04 g, 11%, LCMS MH + = 347.0). 1 1H-NMR (400 MHz, DMSO-d6): δ 7.44 - 7.28 (m, 3H), 3.91 (s, 1H), 3.58 - 3.33 (m, 5H), 3.05 (s, 2H), 2.00 (t, J = 43.60 Hz, 1H), 1.76 (s, 2H), 1.39 (s, 2H), 1.24 (s, 2H). HRMS calculated value: [C 16 H 18 F4N2O2 + H] + 347.1377; measured value: 347.1369 (deviation 2.4 ppm).

[0459] Solubility of the Example

[54] - Compound The purpose of this experiment was to determine the solubility of the test compound in 50 mM phosphate buffer by using HPLC. Method

[0460]

Table 1

[0461] Preparation of phosphate buffer (pH 7.4): 2.79 g of K2HPO4 and 0.54 g of KH2PO4 were dissolved in 390 mL of Milli-Q water. The pH was adjusted to 7.4 using 1N HCl / 1N NaOH, and the final volume was made up to 400 mL with Milli-Q water.

[0462] Preparation and dilution of test compounds: An 80 mM master stock solution of the test compound was prepared in 100% DMSO. For compounds that did not dissolve / had low stoichiometry, a 40 / 20 / 10 mM stock solution was prepared and used in the experiment.

[0463] Assay procedure: · 245 μL of 50 mM phosphate buffer was added to each well of a 1.1 mL 96-well plate, followed by 5 μL of each test compound / standard (80 mM) at each position. · A DMSO control was prepared by adding 245 μL of 100% DMSO and then 5 μL of the test compound to each well of a 1.1 mL 96-well plate. · The plate was incubated at room temperature (about 23 °C) with mixing at 1600 RPM for 16 hours. · After incubation, the samples were filtered using a Millipore plate. · The filtrate was analyzed by HPLC-UV.

[0464] Calculation of solubility: The solubility was calculated using the following formula:

[0465]

Number

[0466] Results

[0467]

Table 2

[0468] conclusion The compounds tested have solubilities ranging from 400 to 1700 μM in pH 7.4 phosphate buffer, with NS6180 shown to have a solubility of 2.8 μM.

[0469] Example

[55] -K Ca 3.1 Inhibition red blood cell K Ca 3.1 Assay Human blood was collected from healthy human volunteers in standard heparinized blood collection vials (Vacutainer, Li / heparin, BD Biosciences, Plymouth, UK). Red blood cells were packed by centrifugation and plasma and buffy coat were removed by aspiration. Red blood cells were washed three times with laboratory salt solution and stored at 0°C until use. Blood samples from NMRI mice or Wistar rats were treated similarly. The principles of the methodology are outlined in Macey et al. (1978) and further described in Strobaek et al. (2013). Red blood cell K Ca 3.1 Channel activation is Ca 2+ This was obtained by the addition of the ionophore A23187, which caused a synchronous hyperpolarization and has been reported as a CCCP-mediated shift in the unbuffered extracellular pH of the red blood cell suspension. Standard procedure: 3 mL of unbuffered laboratory salt solution (in mM: 2 KCl, 154 NaCl, 0.05 CaCl2) was heated to 37 °C with stirring. Packed red blood cells were added (50 μL, final cytocrit 1.5%) and the extracellular pH (pH o ) followed by a glass / calomel (pHG200-8 / REF200, Radiometer, Denmark) electrode pair. CCCP (3 μL, final concentration 20 μM) was added, followed by various concentrations of test compounds (DMSO concentration constant). After stabilization of the pH at approximately 7.2, A23187 (3 μL, final concentration 0.33 μM) was added to start the experiment. After achieving peak hyperpolarization, the intracellular pH (pH during the experiment) was determined by hemolyzing the red blood cells through the addition of 100 μL of Triton-X100. i constant) was calculated.

[0470] Red blood cell membrane potential, Vm is calculated according to the following:

[0471] [Number]

[0472] to obtain the remaining Ca at the blocker concentration C 2+ Activation K + Ratio of conductance, fG K (C) was calculated from the following.

[0473] [Number]

[0474] where K + Equilibrium potential E K = -107 mV, Cl - Equilibrium potential E Cl = -12 mV and V m (0) and V m (C) are the peak hyperpolarizations in the presence of the control and the blocker at the concentration of C, respectively.

[0475] The IC 50 values of the compounds were calculated by fitting to the Hill equation using a custom program written in IGOR-Pro software (WaveMetrics, Lake Oswego, OR, USA) from the plot of fG K (C) vs C. All IC 50 values are reported in μM.

[0476] [Table 3]

[0477] Conclusion All compounds have been shown to inhibit K Ca 3.1.

[0478] References Macey et al., Biochim. Biophys. Acta 1978, 22, 512(2), 284-95 Strobaek et al., Br. J. Pharmacol. 2013, 168(2), 432-444 WO 2014 / 001363 [Clevexel Pharma; Aniona ApS; Saniona ApS] WO 2013 / 191984 [Boehringer Ingelheim] WO 2014 / 067861 [Hoffmann La Roche]

Claims

1. A compound of formula (XVI): 【Chemical 1】 wherein R １４ is selected from the group consisting of -C(O)-C １－８ alkyl; -C(O)-O-C １－８ alkyl; -C ３－８ alkyl; and -S(O) ２ -C １－８ alkyl; R ３ is H, C １－５ alkyl, or a bond; R ４ is H, C １－５ alkyl, or a bond; R ５ is H, a bond, or C where one methylene group may be replaced by -O- １－８ alkyl; R ６ is H, a bond, or C where one methylene group may be replaced by -O- １－８ alkyl; R ７ is H, a bond, —OH, or C in which one or more methylene groups may each be replaced by —O— and / or may be replaced by ═O; １－８ is alkyl; R ８ is H, a bond, —OH, or C in which one or more methylene groups may each be replaced by —O— and / or may be replaced by ═O; １－８ is alkyl; R ３ 、 R ４ 、 R ５ 、 R ６ 、 R ７ 、 and R ８ may be joined together to form a ring; A is phenyl or pyridinyl, where phenyl or pyridinyl is halogen, -CX ３ , -OCX ３ , -CHX ２ , -OCHX ２ , -CH ２ X, -OCH ２ X, -CH ２ CX ３ , -OCH ２ CX ３ , -C １－４ alkyl, -OC １－４ alkyl, -C ３－４ cycloalkyl, -OC ３－４ cycloalkyl, and -SF ５ is optionally substituted with one or more substituents R １３ selected individually from the group consisting of; X is halogen; the compound, or a pharmaceutically acceptable salt thereof.

2. A is a moiety of formula (IX): 【Chemical Formula 2】 wherein R ９ is -C(H)-, -N-, or -C(R １３ )-; R １３ is individually selected from the group consisting of halogen, -CX ３ , -OCX ３ , -CHX ２ , -OCHX ２ , -CH ２ X, -OCH ２ X, -CH ２ CX ３ , -OCH ２ CX ３ , -C １－４ alkyl, -OC １－４ alkyl, -C ３－４ cycloalkyl, -OC ３－４ cycloalkyl, and -SF ５ ; and is individually selected from the group n is an integer from 0 to 4; X is halogen, the compound according to claim 1.

3. A is a moiety of formula (X): [Chemical Formula 3] wherein R ９ is -C(H)-, -N-, or -C(R １３ )-; R １０ 、R １１ 、R １２ 、and R １３ are each independently selected from the group consisting of H, halogen, -CX ３ , -OCX ３ , -CHX ２ , -OCHX ２ , -CH ２ X, -OCH ２ X, -CH ２ CX ３ , -OCH ２ CX ３ , -C １－４ alkyl, -OC １－４ alkyl, -C ３－４ cycloalkyl, -OC ３－４ cycloalkyl, and -SF ５ ; X is halogen, the compound according to claim 1.

4. R ９ is -C(H)- or -N-; R １０ is H or halogen; R １１ is H or halogen; R １２ is -CX ３ , -OCX ３ , H or halogen; X is halogen, the compound according to claim 3.

5. The compound according to claim 3 or 4, wherein R12 is -CF3, -OCF3, or halogen.

6. The compound according to any one of claims 3 to 5, wherein R9 is -C(H)-, R10 is H, R11 is F, and R12 is -CF3.

7. R ３ and R ４ is -H, R ５ and R ６ is methyl, R ７ and R ８ is -H, the compound according to any one of claims 1 to 6.

8. A compound of formula (XVIII), formula (XIX), formula (XXI), formula (XXII) or formula (XX): 【Chemical Formula 4】 the compound according to any one of claims 1 to 6.

9. R １４ is -C(O)-O-C １－４ alkyl or C ３－４ alkyl, a compound according to any one of claims 1 to 8.

10. Methyl N-(2-(dimethylamino)ethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; Methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; Methyl ((1-aminocyclopropyl)methyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; Methyl 3-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(methoxycarbonyl)amino)azetidine-1-carboxylate; Methyl azetidin-3-yl(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; N-(cyclopropylmethyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)azetidin-3-amine; Methyl (2-aminoethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; N1-(cyclopropylmethyl)-N1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-2-methylpropane-1,2-diamine; N-(2-Amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)cyclopropanecarboxamide; N1-Cyclopropyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine; Methyl (2-amino-2-methylpropyl)(1-(3,5-dichlorophenyl)cyclopropyl)carbamate; Methyl (2-amino-2-methylpropyl)(1-(3-bromophenyl)cyclopropyl)carbamate; Methyl (2-amino-2-methylpropyl)(1-(3-chlorophenyl)cyclopropyl)carbamate; 1-((Azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)amino)-2-methylpropan-2-ol; Methyl (2-amino-2-methylpropyl)(1-(3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; 1-((1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((1-methylazetidin-2-yl)methyl)amino)-2-methylpropan-2-ol; Methyl (2-amino-2-methylpropyl)(1-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)cyclopropyl)carbamate; N1-Cyclobutyl-2-methyl-N1-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)propane-1,2-diamine; Ethyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; Methyl (2-amino-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate; N-(2-Amino-2-methylpropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide; Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate; Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate; Methyl (2-acetamido-2-methylpropyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; Methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate; Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(((1-methylpyrrolidin-2-yl)methyl)carbamate; Methyl (S)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate; Methyl (R)-(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate; Methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(((1-methylazetidin-2-yl)methyl)carbamate; Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(((1-methylpyrrolidin-2-yl)methyl)carbamate; Methyl (azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethoxy)phenyl)cyclopropyl)carbamate; Methyl (1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(2-(hydroxyamino)-2-methylpropyl)carbamate; Ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate; Ethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(((1-methylpyrrolidin-2-yl)methyl)carbamate; (S)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide; (S)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(((1-methylpyrrolidin-2-yl)methyl)methanesulfonamide; Ethyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate; Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamate; Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamate; (R)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-N-(pyrrolidin-2-ylmethyl)methanesulfonamide; Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(morpholin-3-ylmethyl)carbamate; Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((4-methylmorpholin-3-yl)methyl)carbamate; Isopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate; Cyclopropyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate; Methyl (R)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamate; Cyclopropylmethyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)(pyrrolidin-2-ylmethyl)carbamate; N-((1-aminocyclopropyl)methyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)methanesulfonamide; Methyl (S)-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)((2-methylpyrrolidin-2-yl)methyl)carbamate; and Methyl (S)-(azetidin-2-ylmethyl)(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)carbamate A compound according to any one of claims 1 to 9, selected from the group consisting of.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10.

12. A pharmaceutical composition for use in the treatment of inflammatory bowel disease (IBD) comprising a compound according to any one of claims 1 to 10.

13. The pharmaceutical composition according to claim 12, wherein the inflammatory bowel disease (IBD) is ulcerative colitis or Crohn's disease.

14. A pharmaceutical composition for use in the treatment of hereditary spherocytosis, comprising the compound according to any one of claims 1 to 10.

15. A pharmaceutical composition for use in the treatment of acute respiratory distress syndrome (ARDS), comprising the compound according to any one of claims 1 to 10.

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